• When route used to provide systemic effect, first-  pass effect is reduced.   • Some dosage forms used for topical  administration require particular patient advice  to ensure safe and appropriate drug  administration   • When systemic absorption is required, lipid  solubility of drugs is a required characteristic.   This is a system of drug delivery where drug mole-  cules are presented in a variety of sizes and shapes  that allow for absorption through the skin and into  the bloodstream at various rates.   • Effectiveness for a long period of time allowing  for retention of patch for a number of hours   Inhalers present the drug as an aerosol, usually as  liquid, sometimes as a powder formulation, and are  intended for topical application in the respiratory  tract (see also Chapter 25).   • Provide rapid onset of action and minimal side-  effects due to topical action.   Oxygen therapy is by inhalation and it is prescribed  by specifying the flow rate, concentration, method of  delivery and length of time of administration.   • Note that 100% oxygen may result in oxygen  toxicity, presenting with symptoms such as    alveolar collapse, intra-alveolar haemorrhage and  disturbance of the central nervous system   • Patients may require domiciliary use of oxygen  and therefore access to oxygen cylinders or  oxygen concentrators and patient information on  the safe handling of the equipment is required.   • Concentrators depend on electricity supply and  so back-up cylinders may need to be considered.   Preparation must be sterile and patient should be  advised that once opened product should be  discarded within 4 weeks. Good practice requires  that the opening date is documented on the pack to  ensure that products that have been opened more  than 4 weeks previously are not used.   Patients or their carers require knowledge of the  proper technique for application of the product to  avoid touching the container against the eye or  anything else to avoid contamination of the  containers (see also Chapter 55).   • Patient must remain on his or her side for about  5 minutes to allow formulation to reach inner  ear canal.   • Caution when using ear drops if patency of  eardrum is not ensured (see also Chapter 58).   • Nasal drops: preferred in infants due to better  spread as opposed to spray.    • Nasal spray: preferred since they are less likely to  be associated with postnasal drip of the drug  leading to an aftertaste.   • Bypasses the oral route and so is useful when  when patient is nauseated or vomiting, post-  operative and not able to take medicines orally.   • May be used for a local effect in the colon (e.g.  in constipation).   Suppositories are a solid dosage form; enemas are oily  or aqueous solutions. Patient should be advised to  lubricate suppository tip with a water-soluble lubri-  cant or to moisten the tip with cool water. Supposi-  tory should be inserted pointed end first until it is past  the muscular sphincter of the rectum. Where patient  needs to use half a suppository, the suppository  should be split in half longitudinally.   • Allows for administration of drugs intended for a  systemic effect that cannot be presented through  other routes because of erratic absorption or  first-pass effects    • Depending on the formulation used and the  dosage form, may be used to provide a fast onset  of action or a prolonged action   Injections are sterile solutions, suspensions or emul-  sions presented in a suitable aqueous or non-aqueous  vehicle intended for administration into the body  tissues. Intravenous injections should be aqueous and  should not contain particles. Whole blood and fat  emulsions are exceptions.   • Given just below the skin and the layer of fatty  tissue usually in the arm or thigh   • Administered into a large muscle usually in  buttocks or anterior lateral thigh   • Used for aqueous and oily suspensions with the  latter presenting a prolonged action   • Larger amount can be administered than  subcutaneous injection (up to 5 mL)   • Absorption more rapid than subcutaneous  injection but can be modified by the addition of  adrenaline or hyaluronidase   • Administered usually on internal flexure of  elbow, but other sites may be used.   • Volume varies from <1 mL to >3000 mL  where the fluid is administered as an  infusion.    • Used in emergency, when immediate effect is  required, when drug is not available in other  routes, or when large volumes of fluid are  required (infusion).   • Gauge (G) - diameter of lumen, 16-30G; the  larger the number, the smaller the diameter   • Device inserted surgically under the skin for  delivery of medication   • Medication is administered via pump to provide  continuous flow into the system.   • Pump is electronically programmed to deliver a  predetermined amount of drug over a  predetermined amount of time. Alarms should  not be overridden.   • Examples are opioid analgesia in postoperative  or palliative care, insulin therapy.   • When administering medicines, the choice of  product and route of drug administration  depends on a number of factors including patient  and drug characteristics.   • Pharmaceutical development of drugs is a time-  consuming process that requires a pre-  formulation phase which takes into consideration  drug characteristics required to establish the  formulation for the different dosage forms.   1 Explain the differences between the intravenous  route of drug administration and the  intramuscular route of drug administration.   2 What are the advantages of transdermal drug  delivery and give an example of a drug that is  presented in this way?   3 Name two advantages for using the rectal route  of drug administration.   4 What are the limitations to the use of eye drops?   1 The differences between the intravenous route  of drug administration and the intramuscular  route of drug administration are summarized in  Table 3.1.   2 Advantages: easy application, effective for a  long period of time, consistent blood drug level  of drug. Examples: glyceryl trinitrate  transdermal patches for angina.   3 Suppositories can be used in patients who are  unable to ingest medications orally (e.g.  confused or non-compliant patients such as  infants, children, old and comatose patients).  They may also be used in patients where the  oral route is not available, e.g. in nausea and  vomiting.    Table 3.1 Comparison of intravenous and intramuscular routes of drug administration   Administered into a large muscle, usually into buttocks  or anterior lateral thigh, needle is inserted at a   Aqueous solutions used. May be adopted in emergency  situations when an immediate effect is required, when  drug is not available in other routes or when large  volumes of fluid are required (IV infusion).    4 Eye drops must be discarded 4 weeks after  opening and there is risk of contamination  during use. Patients should be advised not to  touch the eye with the dropper during  administration. Another limitation is that  some patients may not be willing to use this  method of drug administration due to the  inconvenience.   American Society of Health-System Pharmacists (2004).  Medication Teaching Manual , 8th edn. Bethesda, MD:  Amercian Society of Health-System Pharmacists.  Podczeck F and Jones B E (2004). Pharmaceutical Capsules ,  2nd edn. London: Pharmaceutical Press.   Winfield A J and Richards R M E (2004). Pharmaceutical  Practice , 3rd edn. London: Churchill Livingstone.   • To appreciate steps undertaken in research and  development of new medicines and in the  development of new formulations to ensure drug  safety   • To introduce concepts of safe medicine use and  appreciate risks involved    • To identify pharmacists' actions in adverse drug  reaction monitoring and management   • To describe medication errors and practices to  minimise their occurrence.   • In an attempt to improve patient safety due to  different nomenclature of medicines, European  law 1 requires the use of the Recommended  International Non-proprietary Name (rINN),  which is coordinated by the World Health  Organization.   • For some medicines the British Approved Name  (BAN) differed from the rINN. For example,  benzhexol (former BAN) and trihexyphenidyl  (rINN), frusemide (former BAN) and furosemide  (rINN), dothiepin (former BAN) and dosulepin  (rINN).   • Former BANs have been modified to accord with  the rINN.   • Currently United States Adopted Names (USAN)  are more likely to be identical to the rINN.   • A few medicines still carry synonyms that are  more commonly used in some countries such as  the USA. Examples include paracetamol and  acetaminophen, aspirin and acetylsalicylic acid  (ASA).    • Adrenaline and noradrenaline are the terms used  in the European Pharmacopoeia but the names  epinephrine and norepinephrine are still used in  the United Kingdom.   A medical device is any instrument, apparatus,  material, software or any other device that is used  alone or in combination with accessories for the diag-  nosis, prophylaxis, monitoring and management of  disease, injury or handicap, or for the investigation,  replacement or modification of anatomy or of a  physiological process or for the control of concep-  tion . 2 Examples include sutures, dressings, contact  lens care products, incontinence devices (e.g.  catheters, stoma care devices, such as bags).   European Directives provide for mandatory CE  marking of all devices, declaring that the product  satisfies the requirements essential for it to be consid-  ered safe and fit for its intended purpose. This is  regarded as equivalent to a marketing authorisation.   The basic research and discovery stages for  compounds suitable for development are usually  carried out by the pharmaceutical industry. Identifica-  tion of a lead compound (a new chemical entity that  shows potential for development into a drug) which  demonstrates beneficial clinical effects with minimal  side-effects leads to further development into a poten-  tial medicine. High-throughput screening may be  adopted where libraries of compounds are screened  to identify products that are bioactive and potent.  Lead optimisation is undertaken to modify such  compounds to achieve improved chemical properties.   Laboratory (e.g. on cells) and animal testing is under-  taken to assess the safety of the new compound. The  tests estimate toxicity of the product when given  acutely or repeatedly, identify the organs and systems  involved, and evaluate carcinogenic potential and  reproductive toxicology. For animal testing, toxicolog-  ical studies in two species are required and results have  to be submitted to the regulatory authorities when  compiling an application for registration of a new  compound. Duration of pre-clinical testing is 2-4 years.   • Phase I: safety and dosage testing (tolerability,  bioavailability, pharmacokinetics) in healthy  volunteers. Results indicate dose, regimen and  duration of therapy to be adopted in phase II  study. Duration: 1—1.5 years.   • Phase II: safety and efficacy testing on patient  volunteers. Evidence of efficacy and safety of the  drug in patients is identified and optimal dose  and dosing regimen are identified. Duration: 2-3  years.   • Phase III: safety and efficacy testing on larger  numbers of patients. The trials aim at comparing    the new treatment with placebo or comparator  products in terms of safety, tolerability, efficacy,  patient acceptability, compliance and  pharmacoeconomic analysis. Duration:   • The benefit of administration of medicines  should be considered in relation to the risk  involved.   • Anticancer agents: increased life expectancy vs  gastrointestinal side-effects, hair loss.   • Some medicines available in the same dosage  form but in different strengths (e.g. co-amoxiclav  tablets 1 g, 625 mg or paracetamol suspension  120 mg/5 mL, 250 mg/5 mL).   • Sugar-free oral liquid preparations: do not  contain fructose, glucose or sucrose, suitable for  diabetics, preferred in children for maintenance  of oral health   • May include components that may be allergenic  (e.g. tartrazine, arachis (peanut) oil).   • This service does not cover the reconstitution of  dry powders with water or other diluents.   • A product should be prepared extemporaneously  when there is no product with a marketing  authorisation available   • Equipment in the pharmacy must be maintained  in good order   • Standard operating procedures should include  acquisition of raw material, labelling, expiration  date, environmental control and record keeping.   • Whenever a product that is likely to affect ability  to drive is dispensed, patients should be advised   • These effects are increased by consumption of  alcohol. Examples include hypnotics such as  benzodiazepines (e.g. lorazepam) or  antihistamines (e.g. chlorphenamine).   • To keep all medicines out of reach of children  (note use of child-resistant containers)   • Storage at conditions appropriate for the specific  medicine: storing in the refrigerator for products  required to be kept at 2-8°C (e.g. insulin and  vaccines), storing in a cool place for products  requiring storage temperature ranging between 8  and 15°C and storing at room temperature for  products requiring storage between 15 and 25°C   • Do not take indigestion remedies at the  same time of day as this medicine (e.g.  enteric-coated tablets).   • Do not take indigestion remedies or  medicines containing iron or zinc at the  same time of day as this medicine (e.g.  tetracyclines, quinolones).   • Take at regular intervals. Complete the  prescribed course unless otherwise  directed (e.g. antibacterial medications).   • . . . with or after food (e.g. non-steroidal  anti-inflammatory drugs).   • Swallow whole, do not chew (e.g. enteric-  coated and modified-release oral  formulations such as bisacodyl).   • To be spread thinly (e.g. corticosteroid  preparations for application on the skin).   • For external use only (e.g. for products to  be applied externally).   Practice guidelines are adopted in clinical scenarios  to provide information and reduce barriers to proper  use of medicines, ensure patient safety and reduce  risks. Practice guidelines are systematically developed  statements designed to assist clinician and patient  decisions in disease management. They may draw on  evidence-based practice, which is based on research  evidence, clinical expertise and patient values.   This entails conscientious, explicit and judicious use  of current best evidence in decision-making in  patient care. Evidence of effectiveness of therapy is  based on:   Use of medicines requires a collaborative approach  between different health professionals and the indi-  vidual patient so as to identify rational and safe drug  therapy that will achieve desired patient outcomes  with minimal clinical risk. This requires:   • patient monitoring for drug-related problems and  occurrence of adverse drug reactions    Examples where clinical risk led to changes in drug  use include:   • rofecoxib (Vioxx), a selective COX-2 inhibitor  that was approved in 1999 and withdrawn in  2004   • hormone replacement therapy, approved in 1985  for the management of menopausal symptoms. In  2003 studies indicated relationship with  increased cancer risk.   • Adopting an individual holistic approach  to patient management and monitoring of  patient characteristics which increase  clinical risk with medications (e.g.  patients at higher risk of presenting  extrapyramidal symptoms from  antipsychotic agents due to concomitant  drug therapy).   Table 4.1 summarises the factors to take into consid-  eration in identifying patient needs.   • Liver disease may alter the response to drugs  (e.g. due to impaired drug metabolism).   • Drug prescribing should be kept to a minimum  in all patients with severe liver disease and doses  need to be reviewed in patients with liver disease.   Need for treatment to be established on an individual basis (e.g. taking into account  patient's lifestyle)    • For example, the use of paracetamol in patients  with liver disease: dose-related toxicity may  occur, large doses should be avoided.   • The use of drugs in patients with reduced renal  function can give rise to problems such as failure  to excrete drug or its metabolites.   • Detection and recording of adverse drug  reactions (ADRs) are important.   Pharmacists in organised healthcare systems  (hospitals, day centres, institutions, outpatient  clinics and primary care practice) should  develop comprehensive, ongoing programmes  for monitoring and reporting adverse drug  reactions.   • Reporting of ADRs: reporting to national  regulatory authority (e.g. MFiRA in the UK).  The national regulatory authority undertakes  coordination and monitoring of suspected ADRs  on a local and an international level.   • Pharmacists should participate in mechanisms  that monitor the safety of drug use in high-risk  populations (e.g. older people, children, FIIV  patients).   • Pharmacists should lead education of health  professionals regarding potential ADRs.   • Participation in the development of policies and  procedures and description of responsibilities of   • Educating prescribers and other health  professionals on the implementation and running  of an ADR programme   • Administration of two or more drugs at the same  time may lead to an exertion of their effects  independently or may cause an interaction.   • The interaction may be potentiation or  antagonism of one drug by the other.   • Occurrence and impact of drug interactions  should be evaluated on the basis of clinical  significance and potential for hazardous  outcomes.   These may occur as a result of inappropriate drug  prescribing. For example, cisapride was withdrawn  from the market because the drug could not be used  safely due to its interaction with macrolides or due to  inappropriate patient monitoring.   • Dispensing error: medication dispensed is  inappropriate (e.g. due to incorrect interpretation  of the prescription).   • Omission error: dose skipped or medication is  not being administered.   • Deteriorated drug error: medication dispensed is  not of good quality.   - quantities less than 1 gram should be written  in milligrams   - quantities less than 1 milligram should be  written in micrograms   • Avoid use of abbreviations: micrograms and not  pg, nanograms and not ng   • Participation in procurement, distribution  and storage of drugs in pharmacy and at  ward level    other, use of containers and labels to  reduce risk of confusing medications  • Documentation systems to trace  medication dispensing.   Supportive care is undertaken and treatment is  aimed at managing symptoms (e.g.  hypertension). Vital functions should be  monitored.   The American Society of Health-System Pharmacists  refers to a classification of medication errors that  was initially described by Hartwig, Denger and  Schneider . 1 2 3 4 ’ 5 6 This classified medication errors into six  levels of severity, according to the following:   3 Change in vital signs but no ultimate patient  harm occurred   4 Need for treatment with another drug or  increased length of stay   • Only considered if a life-threatening amount of a  poison has been ingested within the preceding  hour.   • Charcoal binds to many poisons and reduces  their absorption. It is relatively safe and the  sooner it is given the more effective the  procedure will be.   • Paracetamol: acetylcysteine to protect the liver if  given within 10-12 hours of ingestion of the  excessive dose   • Opiate poisoning presents with sedation, cough  suppression and respiratory depression leading to  coma. The antidote, naloxone, is an opioid  receptor antagonist available as an IV injection.   • All patients who show features of poisoning  should generally be admitted to hospital.   • Poisoning may take place with immediate action  poisons (e.g. alcohol (ethanol)) or delayed action  poisons (e.g. paracetamol).   • It may be difficult to establish with certainty the  identity of the poisoning agent and the size of   • Poisoning with aspirin is associated with  stimulation of respiratory centre (hyperpnoea)  and abdominal pain, nausea, tinnitus, deafness,  vertigo.   • Rehydration and alkalinisation of urine to  enhance drug elimination will promote ionisation   • The development of medicines requires a  lengthy process, out of which only a few  lead drugs are successfully developed into  medicines.   • Regulatory aspects govern the practices involved  in development of medicines.   • Use of medicines is associated with risks that  include occurrence of side-effects, drug  interactions, medication errors and drug  misuse.   • Pharmacists may identify patient needs and  characteristics that may increase clinical risk.   • Safe medicine use requires patient education  about the use of medicines and requires health  professionals to review patient drug therapy and  ensure minimal risks for the individual patient.  Risks of drug therapy have to be weighed against  the benefits of therapy.   • Pharmacists are involved in developing and  maintaining an adverse drug reaction monitoring  and management programme.   • Pharmacists can develop guidelines and  participate in strategies to minimise medication  errors.   • Poisoning may occur inadvertently due to patient  misunderstanding of the use of a medicine or  may be deliberate. It may occur as a result of  ingestion of drugs or of other substances,  including household items.   2 Describe the phase I and phase II clinical  testing required in the development of  medicines.   3 Describe how liver disease may interfere with  use of drugs.   monitoring of adverse drug reactions (ADRs)  on a local and international level.   1 The CE marking in medical devices indicates  that the device satisfies the requirements  essential for it to be considered safe and fit for  its intended purpose. The CE marking is  regarded as equivalent to a marketing  authorisation. There are European Directives  that provide for mandatory CE marking of   2 Phase I is intended to assess safety and dosage  in healthy individuals, while phase II is intended  to assess safety and efficacy on a number of  patient volunteers.   3 Liver disease may alter the response to drugs,  for example due to impaired drug metabolism.  Use of drugs should be kept to a minimum in  all patients with severe liver disease.   4 Detection and recording of ADRs are of utmost  importance. Pharmacists are urged to contribute  by reporting suspected ADRs on the appropriate  documents (Yellow Card prepared by the  Commission on Human Medicines of the  Medicines and Healthcare products Regulatory  Agency in the UK) to the local medicines  regulatory authority. Such an authority  undertakes coordination and monitoring of  suspected ADRs on a local and international  level through its participation at the European  Medicines Agency.   American Society of Health-System Pharmacists (2000).  ASHP statement on reporting medical errors. Am J  Health-Syst Pharm 57: 1531-1532.   American Society of Health-System Pharmacists (2006/  2007). Best Practices for Hospital and Health-system  Pharmacy. Bethesda, MA: American Society of Health-  System Pharmacists   Fidelino R J (2007). In pursuit of distinction: The method  of the non-proprietary name. J Gen Med 5: 45-52.   Medical devices. London: Royal Pharmaceutical Society.  Troy D B and Beringer P (2005). Remington The Science  and Practice of Pharmacy. Philadelphia: Lippincott  Williams &c Wilkins.   1 Directive 2001/83/EC of the European Parliament and  of the Council of 6 November 2001 on the Community  Code relating to Medicinal Products for human use as   2 Directive 2007/47/EEC of the European Parliament and  of the Council of 5 September 2007 amending Council  Directives 90/385/EEC, 93/42/EEC and 98/8/EC.   3 American Society of Health-System Pharmacists. ASHP  guidelines on adverse drug reaction monitoring and  reporting. Am J Health -Sy st P harm 1995; 52: 417-419.   4 American Society of Health-System Pharmacists. ASHP  guidelines on preventing medication errors in hospitals.  Am J Hosp Pharm 1993; 50: 305-314.   5 Hartwig S C, Denger S D and Schneider P J. A severity  indexed, incident-report based medication-error  reporting program. Am J Hosp Pharm 1991; 48:  2611-2616.   • To identify actions of community pharmacists in the • To describe the legal and professional issues of  provision of patient-focused services community pharmacy practice.   • Storage of medicines in appropriate conditions  (temperature, humidity, cleanliness, stock  monitoring)   • Dispensing of medicines chosen by patient or as  pharmacist-recommended products or on  presentation of a prescription   • Patient medication review, advise patients on use  of medicines and participate in adverse drug  reaction reporting   • Ensuring rational and safe use of medicines by  patients, developing care plans and collaborating  with prescribers to establish a therapeutic plan,  implement it and monitor patient outcomes   • Monitoring of self-care, responding to symptoms  and identifying cases warranting referral   • Health promotion and promotion of healthy  lifestyles (nutrition, physical activity, smoking  cessation, sexual and reproductive health)   • Participating in national health service schemes  to provide social pharmacy services   • Other responsibilities: nutritional supplements,  special foods (e.g. gluten-free products, food for  diabetic people), colostomy care and urinary  incontinence devices, disability and mobility aids  (e.g. wheelchairs, walking aids), oxygen supplies  and ventilation equipment, veterinary medicines.   • Personnel present: managing pharmacist,  pharmacists, pharmacy technicians, pharmacy  assistants, sales personnel. Staff management  includes identifying training needs and providing  appropriate training, management to develop a  team approach, continuing professional  development of professional personnel   • Premises: areas available for dispensing, storage  of medicines, patient counselling, health  promotion   • Equipment: dispensing equipment, diagnostic  equipment for point-of-care testing (e.g. blood  pressure measurement, blood testing, urinalysis)    • Documentation and information: registers to be  kept at the pharmacy, IT-supported systems for  documentation of pharmacist actions and for  maintaining pharmacy patient profiles, drug  information sources (books and electronic  access).   • Area should be spacious and designed in such a  way as to promote communication between  pharmacist and patient.   • Space should be available for patient advice and  counselling in privacy.   • Consultation areas should provide for space to  carry out point-of-care testing.   • Adequate facilities for dispensing must be  provided - cleanable floor and surfaces, adequate  fixtures and fittings, clean refrigerator with  appropriate temperature monitoring and control,  clean sink, logical layout of stock and a natural  workflow.   • Sufficient storage space to store medicines in a  dry place   • Stock rotation, monitoring of expiry dates and  systems to ensure that medicines are not  damaged   • Pharmacists practising at the pharmacy are  registered with a registering body.   - category of medicines that may be sold from  other outlets (such as drugstores) not only  pharmacies (e.g. general sales list, in countries  where this is permitted)   - category of medicines that may be sold after  being recommended by pharmacists   - category of medicines that are controlled (e.g.  buprenorphine, diamorphine, fentanyl,  methadone).   • Pharmacy services must be available for 24  hours, 7 days a week. Rosters are issued for  night-time service and for service on Sundays and  public holidays.   • Clinical governance relates to a commitment to  continuously improve the quality of professional  services provided and maintain standards of  practice.   • It involves development of quality standards,  audit, training and development of personnel,  staff management and monitoring of clinical  effectiveness.   • Quality standards include the development of  standard operating procedures for processes that  are carried out in a community pharmacy and  the implementation of audit processes (see  Chapter 70).   • Repeat dispensing: pharmacists dispense  medicines as a repeat prescription as directed by  prescriber.   • Supplementary pharmacist prescribing:  pharmacist prescribes medicines according to an  agreed protocol with prescriber.   • Pharmacist prescribing: pharmacist may  prescribe medicines that are designated as    pharmacist prescription drugs as long as he or  she has the required competency to do so  (competency is based on pharmacist skills and  patient characteristics presented).   • Electronic transmission of prescriptions from  prescriber or secondary care interface to  community pharmacy.   • Electronic patient records: pharmacy keeps  patient records which are treated as confidential  and where access is limited to authorised staff.  Through these records the pharmacy has a  history of medicines that are taken by the patient  and other relevant data. These data may be  shared with prescribers and with secondary care  interfaces.   • Medicines management services: pharmacist  medication review, medicines use review, chronic  medication monitoring.   • Pharmacist consulting rooms: where patients can  discuss their health issues and drug therapy  issues with pharmacists in privacy.   • Provision of enhanced services (e.g. preparation  of extemporaneous preparations which require a  dedicated area that is run according to  established quality systems), dispensing of special  items (e.g. gluten-free food) and provision of  home deliveries.   • Community pharmacy practice requires  management skills and involves continuing  education and development of personnel.   • Setting up and maintaining a community  pharmacy requires consideration of physical  aspects of storage and handling of medicines as  well as quality aspects.   • Documentation of processes carried out in the  pharmacy is essential. Quality systems are  required to ensure good standards and to  promote the value of patient-focused services  offered from community pharmacies.   • The development of patient-focused pharmacy  services and the orientation of pharmacist actions  towards individual patient care enhance the  practice of pharmaceutical care in the  community.    • Community pharmacy practice should be  undertaken in collaboration with other health  professionals and with pharmacy institutions in  other settings to ensure seamless care as the  patient is transferred from one setting to another.   1 What parameter should be monitored for a  refrigerator that is used to store medicines in a  community pharmacy? Define the range  required.   2 Explain the following features of a dispensary:  patient consultation area and controlled drugs  cabinet.   3 Describe what is meant by an extemporaneous  preparation area in a community pharmacy.   1 The temperature must be monitored. Range is  2-8°C. A large refrigerator should be  temperature mapped in a loaded scenario.   2 Patient consultation area: space dedicated for  patient advice and counselling in relative  privacy. Consultation areas may be used to  provide patient monitoring and follow-up,  medication review and point-of-care testing.  Controlled drugs cabinet: cabinet where  medications that require limited access (e.g.  methadone) are stored.   3 The extemporaneous preparation area is the  part of the dispensary area dedicated to the  preparation of medications (e.g. dilution of  creams, mixing different creams).   Armstrong P (2006). Standard operating procedures betray  a staggering poverty of intellect. Pbarm J 276: 262.   Avery A J and Pringle M (2005). Extended prescribing by  UK nurses and pharmacists. BMJ 331: 1154-1155.   Blenkinsopp A, Celino G, Bond C and Inch J (2007). Medi-  cines use reviews: the first year of a new community  pharmacy service. Pbarm J 278: 218-223.   Buisson J (2005). How to make space for a consultation  room in your community pharmacy. Pbarm J 275: 689.    Dewsbury C (2002). Guide to clinical governance: What it  means for community pharmacy. Pharm J 268: 119.   Laaksonen R, Duggan C and Bates I (2009) Overcoming  barriers to engagement in continuing professional  development in community pharmacy: a longitudinal  study. Pharm J 282: 44-48.    Royal Pharmaceutical Society of Great Britain (2009).  Medicines, Ethics and Practice: A guide for pharmacists  and pharmacy technicians. London: Pharmaceutical  Press.   • To review the process of following a prescription • To outline pharmacist interventions in the   The patient walks into the pharmacy and presents the  prescription. At this stage, communication and inter-  action with the pharmacy staff take place. In the  modern age of electronic documents, e-prescribing is  already being practised in some countries and is  expected to develop even further. In electronic  prescribing, the prescription is transferred electroni-  cally and the pharmacist receives an electronic docu-  ment. Once the patient presents at the pharmacy and  provides the required details for retrieval of the  electronic prescription, the process of communication  and interaction with the patient commences.    Prescription is reviewed to see which medicines are  required and to note patient details. Pharmacy staff  should check:   This step may be carried out either manually, where  the pharmacy or pharmacy assistant picks up the  required product from the pharmacy storage section,  or mechanically, where the pharmacist requests the  product through a machine interface and the product  is selected from the magazine and delivered at the  dispensing bench.    During this step, pharmacist intervention to  decrease occurrence of dispensing errors includes:   • care in selecting appropriate medicine; there are  some medicines that have very similar names  (e.g. amlodipine and amiloride, Lescol and  Losec)   • care in selecting the appropriate strength; there  are medicines that are available in different  strengths (e.g. amoxicillin 250 and 500 mg  capsules, atenolol 25, 50 and 100 mg tablets)   • care in selecting the appropriate dosage form;  there are medicines that are available in different  dosage forms (e.g. diclofenac gel, tablets,  modified-release tablets, suppositories).   The label should be clear and legible to ensure that  the patient takes the medicine as prescribed. The  information presented has to be understood by the  patient.   To avoid confusion, where several containers of the  same medicine have to be dispensed, it should be  indicated on the label that there is more than one  container of the same medicine (e.g. 1 of 4, 2 of 4).   If, during the dispensing process, there is a require-  ment to repack the medicines, the appropriate  container should be chosen for the medication. This    includes taking into consideration stability of the  product and interaction of the product with the  material used for the container. Usually repacking  takes place in a controlled area under a quality  assurance system and pre-packs are produced to be  available for the pharmacist during the dispensing.   In the UK, original pack dispensing is required,  whereby the pharmacist can dispense branded or  generic products as packaged in the original form as  produced by the manufacturer.   Recheck that the prescription and the medicine  prepared are consistent and that the right medicine in  the right dosage form and strength has been identi-  fied, that the right label is attached and that the right  patient instructions are provided.   The pharmacist hands over the medicine and explains  to the patient when and how to take the medication.  Refer to Chapters 8 and 9 for discussion on  communication, patient counselling and compliance.   • The pharmacist should ensure that the dispensing  process implemented in the pharmacy implies the  correct attitude and transfer of knowledge from  reading the prescription to the handing over of  the medicine to the patient.   • The dispensing process includes communication  and interaction between the patient and the  pharmacist. The way that this interaction takes  place may influence the efficacy of the dispensing  process.   • The dispensing process employed could be  outlined in good dispensing procedures to ensure  standardisation of the dispensing process within  a pharmacy.   • Pharmacist intervention should ensure that the  process eliminates dispensing errors. Factors that    decrease dispensing errors include: dispensary  layout and workflow, systems of drug storage,  lighting, limitation of noise and use of electronic  equipment (e.g. scanners).   • Pharmacist intervention should ensure that the  patient understands the use of the medicine, its  correct application and information about any  side-effects expected and action that might need  to be taken in the case of missed doses.   • When the customer is not the patient but a  proxy, emphasis should be placed on the need for  correct onward transmission of the information  to the patient or carer.   1 For each of the following abbreviations, which  may be used on prescriptions, give a brief  explanation and an example of a product for  which this abbreviation is used, stating generic  name and dosage form(s): p.c., p.r.n.   2 For each of the following cautionary and  advisory labels, give one example of a drug  where the label should be used:   (b) Do not take milk, indigestion remedies and  medicines containing iron or zinc at the  same time of day as this medicine   (c) Take at regular intervals. Complete the  prescribed course unless otherwise directed.   3 Give two examples of products that should be  taken after food. Give reasons for your choice.   1 p.c. - after food, ibuprofen (tablets, suspension),  p.r.n. - when required, paracetamol (tablets,  soluble tablets, suspension, suppositories).   (b) Do not take milk, indigestion remedies and  medicines containing iron or zinc at the same  time of day as this medicine - ciprofloxacin.   (c) Take at regular intervals. Complete the  prescribed course unless otherwise directed -  co-amoxiclav.   3 (a) Diclofenac potassium tablets - should be  taken after food to minimise gastrointestinal  irritation, (b) Itraconazole capsules - should  be taken after food to ensure optimal  absorption.   Azzopardi L M (2000). Validation Instruments for  Community Pharmacy: Pharmaceutical care for the  third millennium. Binghamton, NY: Pharmaceutical  Products Press.   Royal Pharmaceutical Society of Great Britain (2007).  Developing and implementing standard operating  procedures for dispensing. Guidance documents.  http://www.rpsgb.org/pdfs/sops.pdf.   • To identify the intervention of the pharmacist in • To develop skills required to participate in health   • Health promotion: a process enabling people to  increase control over and to improve their health.   • Health education: giving information and  working towards improving individual attitude  and behaviour changes to sustain healthy living.   In health promotion, pharmacists provide informa-  tion and skills to individuals so that they can prevent  specific diseases and participate in services for early  detection and treatment of disease. The process  involves a behavioural change approach such as in  advising individuals on the importance of preventing  and managing obesity.   Health promotion activities from community  pharmacies include the organisation of theme-  oriented weeks where patrons are advised on the  theme, and written and other visual aids are available  in the pharmacy for further information and for shop  window dressing.    Sustainable development and public health  are closely related. Through health promotion  activities pharmacists can contribute towards  the reduction of carbon footprints and to  practices that tackle climate change. This can  be achieved by:   The information presented should be educational but  at the same time acceptable to busy patrons. An  entertaining presentation helps to make the informa-  tion attractive and prompts the individual to take  notice of the message being transmitted (Figure 7.1).   The impact of the information transmitted  depends on the methods used to convey the informa-  tion. The information presented has to be under-  standable by the individual. Pharmacists are in a  position of interpreting scientific information so as to  convey the message to the individuals in an under-  standable manner (Figure 7.2).   • Identify resources that can be used and are  already available    • Pharmacists are accessible health professionals  who can play a very proactive role in promoting  health.   • Pharmacists should actively promote healthy  lifestyles including discouraging smoking,  pointing out the importance of exercise and  highlighting the benefits of a healthy diet.   • Pharmacists in any practice setting should  encourage positive behavioural changes.   1 List five points helpful in counselling patients  on smoking cessation.   1 (a) Act as a role model by not smoking and not  allowing smoking on the premises (e.g.  putting up no smoking signs).   (b) Provide patient with information on the  risks associated with smoking (e.g. use  patient leaflets about smoking).    (c) Encourage abstinence by directly advising  the patient on how to quit and highlighting  benefits of stopping smoking (e.g. effects on  family members particularly patients with  cardiovascular disease and children).   (d) Refer patient to smoking cessation support  groups (e.g. programmes organised by the  local health promotion centre).   (e) Follow up on the use of smoking cessation  products and maintenance strategies (e.g.  schedule a follow-up visit).   Anderson C, Blenkinsopp A and Armstrong M  (2009). The contribution of community pharmacy to  improving the public’s health: Summary report of the  literature review 1990-2007. London: Pharmacy-  HealthLink.   McClelland C and Rees L (2000). A foundation for health  promotion in pharmacy practice. In: Gard P (ed.) A  Behavioural Approach to Pharmacy Practice. London:  Blackwell Science.   Root G (2008). Help the public and the planet by engaging  in sustainable development. Fharm J 281: 596-597.   • To identify good communication skills • To identify factors that should be considered when   • To appreciate pharmacist intervention in patient  counselling on health-related issues and the use of  medicines   For effective pharmacist actions in the promotion of  health, responding to symptoms and management of  disease states, it is necessary to use communication  skills that convey the correct information to the  patient and encourage discussion of health-related  problems.   • in providing advice on self-care: advice on  product selection and use, non-drug self-care,  referral and health assessment.   • Discussing patient health-related and social  problems that impact on health status    • Empowering individuals to be active in health  promotion and preservation.   • Through the communication process, anticipate  different perceptions according to the individual’s  needs (e.g. social problem associated with  occurrence of acne may impact differently on  individuals).   • Use effective questions by adopting open  questions to obtain information that is necessary.   • Structure the flow of questions to follow a  logical pattern.   • Use probing questions to follow up patient’s  response. Patients may not be aware that certain  information must be known by the pharmacist to  suggest appropriate line of action.   • Encourage patient participation by pausing both  after asking a question and after the initial  response.   • Place the most important points at the beginning  of the communication session.   • Limit the information to the essentials to prevent  cognitive overload.   • Environmental factors such as lack of privacy,  lack of space in the pharmacy   • Time available for pharmacist to dedicate to the  patient for listening   In addition to a sound knowledge of drugs and the  ability to adopt a comparative approach between  possibilities of treatment, the pharmacist also needs  the ability to:   • explain information clearly and in terms that are  understandable to patients of different backgrounds   • pose the right questions to patients without  putting them off   • Well-informed patients are more likely to  use their medications correctly.   • The intervention of the pharmacist in the  provision of advice on medicines  improves medicine safety.   • This should be an integral part during dispensing  of medicines.   • Pharmacists should be visible and accessible for  patients to request advice.   • To ensure that patients are adequately informed  about their medication   • To predict any problems which might cause loss  of efficacy of the drug or be detrimental to  health of patient   • Recognising the need for counselling: extent of  counselling required varies from one individual  to another.   • Assessing and prioritising the needs: what points  need to be emphasised?   • Checking assessment methods: to identify  outcomes and follow-up counselling process.   • Environment in pharmacy: must be conducive to  privacy and to induce patients to ask for  professional advice from the pharmacist.   • Professional appearance of pharmacist: to project  a professional appearance that enables  individuals, including those who feel that they  have a very sensitive issue to discuss, to address  the pharmacist with confidence.   • Is it a repeat medication I Patients who have  already taken the medication also require  counselling to ensure proper use of medicines. If  the patient is taking medication for the first time  more information is required.   • Polytherapy: patients who are taking more than  one medicine need more support to manage the  drug-handling process.   • Complex instructions: with medicines that have a  complex drug regimen or require an unusual  drug-taking pattern (e.g. bisphosphonates) the  pharmacist needs to provide counselling and  must ensure that the patient has understood the  drug regimen.   • Narrow therapeutic index drugs: the risk  associated with these medications (e.g. warfarin)  is higher if patient is not aware of how to take  medication, which side-effects should be reported  and the necessity of relevant routine checks.   • Patient characteristics: the pharmacist needs to  adapt the counselling session according to patient  characteristics and to individualise the session  (e.g. elderly, frail, psychiatric conditions).   Patient needs vary according to a number of factors.  The counselling process has to be developed  according to each individual patient’s needs. Patient  priorities in life (e.g. lifestyle) should be taken into  consideration during the counselling session if  maximum patient benefit is expected. Information  about patients that will help to prioritise the needs  includes:   During follow-up counselling sessions, which may  take place during dispensing of a repeat medication,  identification of the following factors should be  considered:    • patient problems with medication (side-effects,  complex drug regimen, drug therapy interfering  with lifestyle)   • Warning cards (e.g. used for lithium,  anticoagulant therapy, steroids, benzodiazepines)   When communicating with patients, establishing a  good rapport with the patient, active listening, rele-  vant questioning and appropriate body language  enhance the process. Pharmacist counselling pro-  grammes can be developed focusing on themes such  as:   - monitoring of body weight, lipid profile,  glucose levels and blood pressure   - counselling on nicotine replacement therapy  (transdermal nicotine patch, chewing gum,  inhalator) and smoking cessation psychological  behaviour   - giving information on condition, advising on  proper techniques for insulin storage and  administration   - identifying and providing guidance on actions  to monitor and compensate for aberrations in  glucose levels, dietary and exercise  management, and foot care   - identifying and providing guidance on actions  to compensate for aberrations in peak flow  meter readings and exercise management   - providing counselling on impacts of drug  therapy, lifestyle measures and requirement for  continuous monitoring.   1 List factors that could hinder communication  with patients in a community pharmacy.   Beardsley R S, Kimberlin C L and Tindall W N (2007).  Communication Skills in Pharmacy Practice , 5th edn.  Philadelphia: Lippincott, Williams & Wilkins.   Hargie O D W, Morrow N C and Woodman C (2000).  Pharmacists evaluation of key communication skills in  practice. Patient Educ Couns 39: 61-70.   Schnipper J L, Kirwin J L, Cotugno M C, Wahlstrom S A,  Brown B A, Tarvin E et al. (2006). Role of pharmacist    counseling in preventing adverse drug events after  hospitalization. Arch Intern Med 166: 565-571.   Waterfield J, Aspinall V and Hall S (2009). The use of  digital video media in the teaching of communication  skills. Pharm J 282: 135.   • To appreciate factors that increase risk of a patient's • To develop skills necessary for pharmacists' actions  inability to follow drug therapy and in promoting adherence,   This is a term that has been established to describe a  patient’s degree of conformity with the advice and  recommendations given by health professionals. The  term non-compliance was used to describe significant  failure to conform with the advice and recommenda-  tions to an extent that it interferes with achieving the  patient outcomes planned. Since this term has a nega-  tive nuance for the patient and overrides the concept  that the patient may have a problem with the medica-  tion or recommendations, the term non-compliance  is not very much supported today.   The concept of compliance seems to denote a  relationship in which the patient has a passive role  and is expected to follow the doctor’s orders. Since  the term does not emphasise patient participation,  there has been a shift towards the use of ‘adherence’  as a term instead.   As opposed to the concept of compliance, adherence  seems to denote a relationship in which the patient  has an active role and is expected to contribute to the    establishment of the treatment to be followed. In the  concept of adherence the patient is free to decide  whether or not to adhere to recommendations by  health professionals and failure to do so should not be  a reason to blame the patient. Health professionals  have a responsibility to facilitate adherence.   This term is used to denote the degree to which the  patient and the health practitioner agree about the  nature of the illness and the need for management,  and the relative risks and benefits of the proposed  line of treatment. In the concept of concordance, the  patient’s views are taken into account during the  prescribing phase in order to increase the likelihood  of better compliance.   • Secondary non-adherence: patient has access to  medicine but does not take it due to:    - accidental non-adherence: forgets to take  medication or is unable to take medication due  to lifestyle   It is still hard to quantify the consequences of poor  adherence to medication. There is no consensus as to  the quantification of partial adherence (number of  missed doses).   • Direct methods: observation of ingestion of the  drug or by detecting its presence in body fluids   • Indirect methods: assume ingestion based on  proxy evidence such as patient’s self-reporting,  number of dosages remaining, number of dosages  removed from a container through data recorded  in medication compliance aids. These include:   - electronic monitors: incorporation of  electronic devices into the medicine container  recording time and date of usage   - patient self-reporting on health status and how  the condition has improved.   • Therapy-related factors: type of dosage form (e.g.  large solid oral dosage forms, inability to use  metered dose inhalers), problems with handling  container (e.g. opening of child-resistant  containers, blister packs), polypharmacy (e.g.    patient has to handle a number of different  drugs), dosage frequency (e.g. multiple daily  dosing), occurrence of side-effects   • Condition-related factors: non-adherence  particularly noted in conditions where patient is  not seeing benefit from drug therapy (e.g.  hypertension), in conditions that are associated  with a social stigma (e.g. psychiatric disorders,  HIV), where patients may not be ready to accept  medications for the condition (denial of illness or  of need for medications)   • Fatient-related factors: patient’s knowledge,  beliefs about and attitudes towards medicine and  disease state   • Health-system factors: relationships with the  healthcare team, ability to get prescription and  medicines, inadequate patient education   • Social and economic factors: social factors such  as lack of patient support and income, problems  with living conditions and problems at home,  level of education and literacy.   One helpful final question that may be asked  to confirm likelihood of adherence would be:  How have we agreed that you are going to  take the medicines?   • Packaging: while taking into account stability of  the product, ensure patient accessibility and  acceptance of product appearance   • Compliance aids: use of devices that can be used  to remind patient to take medication, dispensing  medication in blister pack according to dosage  regimen, preparing medicine reminder charts,  administration devices (e.g. eye-drop applicators)   • Review patient prescriptions and medications: to  reduce dosing frequency and multiple drug  therapy where relevant   • In January 2009 in the UK, the National Institute  for Health and Clinical Excellence prepared a  guideline on medicines adherence. 1   • It can be difficult for patients to take medicines  and follow recommendations by health  professionals due to a number of factors.   • Factors that interfere with adherence should be  evaluated for each individual patient so as to  minimise occurrence of non-adherence.   • Pharmacist skills required to improve adherence  include communication techniques with the  patient and the prescribes availability and  accessibility.   • Pharmacist actions to improve adherence include  the initiation and facilitation of discussion with  patient on drug therapy, eliciting the patient’s  view and experience of treatment, undertaking  regular review of all medications taken,  providing information that meets patient’s needs,  liaising with other health professionals to ensure  continuity of care, acting as the navigator in the  healthcare system and collaborating with  prescribers to identify and/or improve treatment  protocols.   1 List three interventions that help to promote  adherence to therapy.   • To calculate concentrations in amount strength,  ratio strength, parts per million, percentage  concentration   • To calculate the amount of ingredients and doses,  including consideration of body weight and body  surface area   • To develop mathematical skills required in the  handling of drug therapy.    The metric system (or the SI) is the system most  commonly used for expression of quantities in phar-  macy. The metric system is a decimal system of  weights and measures.   The apothecaries’ system is the historic system  of weights and measures used in pharmacy.  Today, on a metrically written prescription,  the dram symbol 3 is used with reference to a  dose; it means a teaspoonful, which is today  considered to be equivalent to 5 mL.    • Concentration may be expressed as quantity per  volume, percentage concentrations, ratios and  parts.   • Quantity per volume gives the amount or weight  of drug (moles or grams) in a volume of solution.   • Ratio concentration is the number of parts of a  solvent in which one part of the drug is dissolved  or dispersed.   (a) 27 g in 40 mL. The weight per millilitre is  0.675 g/mL (27/40)   equivalent to 625 g, the weight per millilitre  is 1.25 g/mL (625/500).   3 Ten millilitres of distilled witch hazel are made  up to 70 mL of solution. Express the  concentration of the final solution as an amount  strength. In 1 mL there is 0.143 mL of distilled  witch hazel (1/70 X 10).   4 Fluocortolone is available as 0.25% w/w cream.  Express this as a ratio strength. The ratio  strength of this preparation is 1 in 400 (1/0.25 X  100 ).   5 Mometasone is available as 0.1% w/w cream.  Express this as a ratio strength. The ratio  strength of the cream is 1:1000 (100/0.1).   6 The carbon monoxide content in medical oxygen  should not exceed 5 ppm. Express this as a  percentage strength (v/v). The carbon monoxide  content should not exceed 5 mL in 1000 000 mL  of oxygen, therefore the percentage strength is  0.0005% v/v (5 X 100/1000 000).   7 A patient dissolves two 500 mg paracetamol  tablets in 250 mL of water. What is the  percentage strength of the solution? Two 500 mg  tablets are equal to 1 g. The percentage strength  is 0.4% w/v (100/250).   8 Ofloxacin is available at a concentration of  1.5 mg/0.5 mL. Express this in % w/v. Since  1.5 mg is equivalent to 0.0015 g, ofloxacin is  available at a concentration of 0.3% w/v (0.0015  X 100/0.5).   9 Xalacom eye drops contain 50 micrograms  latanoprost and 5 mg timolol per mL. Calculate  the percentage strength for latanoprost. Fifty  micrograms are equivalent to 0.00005 g and  the percentage strength for latanoprost is  0.005% w/v.    One millimole solution of sodium chloride  contains 1 mmol (equivalent to 0.058 g) of  the compound dissolved in 1 litre of solution.   • Dilution means to diminish the strength often by  adding a diluent.   • In a dilution, the weight of the active ingredient  will stay the same throughout: c 1 X iq = c 2 X v 2 .   • The strength of a pharmaceutical preparation is  based on the quantity of the primary ingredient  relative to the quantity of the whole preparation.  A dilution of the preparation means a  preparation of a lesser strength is prepared.   • Concentration is the opposite of dilution,  namely, to render a preparation to a greater  strength (e.g. by evaporation).   10 If 100 g of aqueous cream are added to 30 g of  cream containing azelaic acid 15% what is the  strength of the resulting cream expressed as a  percentage? 30 g of cream contains 4.5 g of  azelaic acid (30/100 X 15). The new  preparation contains 4.5 g in 130 g of cream  (100 + 30), therefore the percentage strength  w/w is 3.46% (3.5%).   11 A prescription is presented for Betnovate  ointment 2 parts with 3 parts aqueous cream.  Express the amount of aqueous cream required  if you start with 30 g Betnovate ointment.  Forty-five grams of aqueous cream need to   be mixed with 30 g of Betnovate ointmerit  (3 X 30/2).   1 2 What volume of chlorhexidine gluconate  solution 0.2% w/v is required to prepare 250  mL of a 0.1% w/v solution? A 250 mL volume  of a 0.1% w/v solution contains 0.25 g of  chlorhexidine gluconate (0.1 X 250/100).   This is present in 125 mL of the 0.2% solution  (100 X 0.25/0.2).    A stock solution is a relatively concentrated  solution of a substance used as the source of  that substance to prepare a solution of lesser  concentration. The strength of stock solution  is expressed in percentage strength or in ratio  strength.   • The density of a liquid is the weight per unit  volume expressed as grams per millilitre.   • Displacement volume is the quantity of solvent  that will be displaced by a specified quantity of a  solid during dissolution.   • Displacement value is used in calculations when  solids are incorporated into another solid.   • Displacement values are commonly used in  preparing extemporaneous preparations such as  suppositories. In the preparation of  suppositories, displacement values are used to  calculate the amount of suppository base  required when an amount of a drug has to be  incorporated in the base.   1 3 Calculate in kilograms the weight of 5 L of  glycerol. The density of glycerol is 1.25 g/mL.  Since 1 tnL weighs 1.25 g, 5000 mL weigh  6250 g, equivalent to 6.25 kg.   The density of a substance is required to  convert a volume of a product to its weight or  vice versa.   14 Calculate the volume of diluent required to be  added to 250 mg of drug when a concentration  of 400 mg/mL is required given that the  displacement value of the drug is 0.5 mL/350  mg. Since a concentration of 400 mg per 1 mL  is required, 250 mg should be present in 0.625  mL (250/400). With a displacement volume of    0.5 mL/350 mg, 250 mg occupies 0.357 mL  (0.5 X 250/350). Therefore 0.268 mL of  diluent should be added to 250 mg of drug  (0.625-0.357).   The displacement value is used to calculate  the volume that will be occupied by a known  amount of solid.   • A number of calculations in pharmacy involve  the need to know the molecular weight or the  molecular structure of the drug. Molecular  weights are given in a number of reference books  (e.g. Martindale: The Complete Drug Reference),  pharmacopoeias or may be calculated from the  atomic weights if the chemical formula is known.   • All the atoms in a molecule must be included in  the calculation of molecular weight.   • Associated water molecules (e.g. water of  crystallisation) must also be included in the  calculation of molecular weight.   • It is sometimes important when calculating a  specific dosage to express it in terms of the base  or in terms of the salt. This is especially relevant  when the indicated dosage was calculated from  clinical studies based on only one part of the  molecule since only that part is  pharmacologically active.   Molecular weight of a drug is the sum of all  the atomic weights of the individual atoms in  the molecule given in grams.   1 5 Calculate the milligrams of ferrous chloride  (FeCl 2 ) that will contain the same amount of  iron ion as 150 mg of ferrous sulphate (relative  molecule mass (rmm) chlorine = 35.452, iron  = 55.845, oxygen = 15.999, sulphur =    32.066). One mole of ferrous sulphate weighs  151.907 g (55.845 + 32.066 + 4(15.999)). In  150 mg of ferrous sulphate there is 55.144 mg  of iron (55.845 X 150/151.907). One mole of  ferrous chloride weighs 126.75 g (55.845 +  2(35.452)) and 55.144 mg of iron are present  in 125.15 mg of ferrous chloride (126.75 X  55.144/55.845).   16 A patient is receiving 2 L of potassium chloride  0.3% w/v and glucose 5% w/v intravenous  infusion. For each litre, 40 mmol of potassium  are delivered. How many grams of potassium is  the patient receiving every day? (rmm of  potassium = 39). For every 2 L of potassium  chloride, the patient is receiving 80 mmol of  potassium (40 X 2). One millimole of  potassium weighs 39 mg and 80 mmol of  potassium weigh 3120 mg (39 X 80),  equivalent to 3.12 g.    • Extemporaneous preparations should be  prepared only when commercial  preparations with a marketing  authorisation are not available.   • Uncoated tablets are preferred over  coated tablets to use for extemporaneous  preparations.   • Controlled-release dosage forms are to be  avoided in the preparation of  extemporaneous preparations.   • The use of fewer tablets or capsules is  preferred over the use of a larger number  (e.g. use two 100 mg atenolol tablets if  one requires 200 mg of atenolol for a  preparation rather than eight 25 mg  atenolol tablets).    It is often helpful when required to calculate  the molecular weight from a structural  formula first to form the empirical formula.  Figure 10.1 shows the calculation of the  molecular weight of aspirin, for example.   • Tablets and capsules are used to prepare liquid  dosage forms for children and adults who are  unable to swallow solid dosage forms (see  Chapters 49 and 50).   Figure 10.1 Calculating the molecular weight of aspirin  from its structural formula.    1 7 How many 25 mg amitriptyline tablets are  required to prepare 80 mL of a paediatric  preparation containing 10 mg amitriptyline per  millilitre? The paediatric preparation contains  800 mg of amitriptyline (10 X 80). Thirty-two  tablets are required to prepare the solution  (800/25).   1 8 Cetirizine is available as an oral solution  containing 5 mg/5 mL presented in 200 mL  containers. How many grams of cetirizine are  present in one container? One container contains  200 mg (5 X 200/5), equivalent to 0.2 g.   19 Calcipotriol cream contains 50 micrograms/g.  What is the amount of cream that contains 30  mg of calcipotriol? Fifty micrograms is  equivalent to 0.05 mg. Thirty milligrams are  present in 600 g of cream (30/0.05).   20 Gaviscon Advance contains 500 mg sodium  alginate and 100 mg potassium bicarbonate per  5 mL. What is the quantity of sodium alginate  in kilograms that is required to prepare 50  containers of 500 mL? The total amount to  prepare is 25 000 mL (50 X 500). The total  amount of sodium alginate is 2500 000 mg  (500 X 25 000/5), equivalent to 2.5 kg.   21 Calculate the amount of white soft paraffin  that is required to be added to 100 g of    Betnovate ointment to prepare an ointment  according to the following formula:   According to the formula, 75 g of white soft  paraffin should be added to 100 g of Betnovate  ointment (30 X 100/40).   22 A sugar-free suspending agent is prepared  according to the following formula:    What are the quantities required of each  ingredient when 30 mL of the suspending agent  solution is required? The quantities required for  each ingredient are 0.3 g of methylcellulose  (30/100), 0.09 g of saccharin sodium  (0.3 X 30/100) and 0.06 g of benzoic acid  (0.2 X 30/100).   23 Ten millilitres of an ophthalmic preparation  contain 0.2% w/v ciprofloxacin and 1% w/v  hydrocortisone. What weight in grams of  ciprofloxacin is required to increase the  concentration of ciprofloxacin to 0.3% w/v? In  order to obtain a concentration of 0.3% w/v,   0.03 g of ciprofloxacin are required in 10 mL of  solution (0.3 X 10/100). The 0.2% w/v solution  contains 0.02 g in 10 mL (0.2 X 10/100). The  amount of ciprofloxacin required to increase the  concentration is 0.01 g (0.03-0.02).   24 Tetramil eye drops contain 0.3% pheniramine  and 0.05% tetrazoline. Calculate the amounts  of active ingredients in 10 mL. Tetramil eye  drops contain 0.3 g of pheniramine in 100 mL  and 0.05 g of tetrazoline in 100 mL. In 10 mL,  0.03 g of pheniramine and 0.005 g of  tetrazoline are present.   25 Elidel cream consists of 1% w/w pimecrolimus  and is available in 15 g tubes. How many  milligrams of pimecrolimus are required to  manufacture 30 tubes? For a 1% whv cream,   1 g of pimecrolimus is present in 100 g of  cream. Thirty tubes contain 450 g of cream  (15 X 30), and 4.5 g of pimecrolimus are  required for 30 tubes (450/100). This is  equivalent to 4500 mg.   • Calculation of dosage may be carried out  according to body weight or body surface area.   • A dosage is often calculated to obtain a certain  drug concentration and to maintain this  concentration a dosage regimen is often  established.   • Drug concentrations achieved depend on the  maintenance dose, the dosage interval and the  elimination half-life (see Chapter 13).   • In order to calculate the correct dose for certain  drugs specific data on the drug or the patient  such as body weight, body surface area,  pharmacokinetic parameters or clinical  laboratory values (such as liver and renal  function tests) may be required.   26 A patient receives 20 micrograms of  ethinylestradiol daily for 28 days. How much  ethinylestradiol in milligrams does the patient  receive in 28 days? The patient receives 560  micrograms in 28 days (20 X 28). This is  equivalent to 0.56 mg.   27 A salbutamol inhaler presents 100 micrograms/  metered inhalation and each inhaler presents  200 doses. How many milligrams of  salbutamol are there in each inhaler? Each  salbutamol inhaler contains 20 mg (100 X  200 / 1000 ).   28 How many millilitres of 100 units/mL soluble  insulin should be administered to achieve a  dose of 40 units? One hundred units are  available in 1 mL. Forty units are available in  0.4 mL (40/100).   29 Nicotine patches are available as packs of seven  where each nicotine patch of 22 cm 2 delivers  21 mg over 24 hours. How much nicotine in  grams is delivered in 6 weeks? The amount of  nicotine delivered in 6 weeks is 882 mg (21 X 7  X 6), equivalent to 0.882 g.   30 A patient is prescribed 2.5 mL co-trimoxazole  suspension every 12 hours. Co-trimoxazole is  available as a suspension where 5 mL contain  40 mg trimethoprim and 200 mg  sulphamethoxazole. How many milligrams of  each ingredient is the patient receiving per dose?  The patient is receiving 2.5 mL per dose and this    contains 20 mg trimethoprim (40 X 2.5/5) and  100 mg sulphamethoxazole (200 X 2.5/5).   31 A patient is prescribed 75 micrograms per day  of levothyroxine. Levothyroxine is available as  50 microgram tablets and each pack contains  28 tablets. How many packets should be  dispensed for a 2-month supply? The patient  takes 1.5 tablets daily, which is equivalent to  90 tablets in 2 months (1.5 X 60). Therefore  four packs should be dispensed.   32 A patient receives one tablet Fosavance a week  which contains 70 micrograms of colecalciferol  and 70 mg of alendronic acid. How much  colecalciferol in milligrams does the patient  receive in 4 weeks? Seventy micrograms is  equivalent to 0.07 mg and the patient receives  0.28 mg in 4 weeks (0.07 X 4).   33 How many millilitres are required per dose if a  patient is prescribed gentamicin by intravenous  injection at a daily dose of 210 mg in three  divided doses? Gentamicin injection is available  as 40 mg/mL in 2 mL vials. Each individual  dose should cofitain 70 mg (210/3) and 70 mg  is available in 1.75 mL (70/40).   34 Doxorubicin is available as 25 mL vials at a  concentration of 2 mg/mL. The dose required is  200 mg. How many vials are required? Each  vial contains 50 mg of doxorubicin (25 X 2),  and 200 mg is present in four vials (200/50).   35 An obese child weighing 70 kg is prescribed  amprenavir at a dose of 20 mg/kg every 12  hours at a maximum daily dose of 2.4 g. How  many milligrams of amprenavir per day should  the patient receive? The child should receive  2800 mg daily but this exceeds the maximum  daily dose so the child should receive 2400 mg  daily, which is the maximum daily dose.   36 Vancomycin should be administered to children  at a dose of 5 mg/kg every 6 hours. What is  the daily dose administered to a child weighing  4.2 kg? The daily dose that should be  administered is 21 mg every 6 hours (5 X 4.2)  and 84 mg in 24 hours (21 X 4).   37 Filgrastim is available as 300 micrograms/mL  injection. A patient with a body weight of    95 kg is prescribed 5 micrograms/kg daily. How  many millilitres are required to present the  daily dose? The patient should receive 475  micrograms of filgrastim (95 X 5), which is  present in 1.58 mL (475/300).   38 How many millilitres of paclitaxel are required  to prepare a dose of 100 mg/m 2 for a patient  whose estimated body surface area is 1.68 m 2 ?  Paclitaxel is available as 6 mg/mL. The patient  should receive 168 mg (100 X 1.68). This is  available in 28 mL of solution (168/6).   • The dosage interval may depend on  whether the dosage form is a controlled  release or a normal release. Controlled-  release preparations often achieve a better  compliance but take longer to be  eliminated from the body, which is  especially relevant if an adverse reaction  such as allergic reaction occurs (see  Chapter 9).   • Calculating the dose using the body  surface area is preferred for patients  receiving cancer chemotherapy and for  paediatric patients.   • For intravenous solutions, the dosage  administered is often calculated through the rate  of flow of the solution.   • The rate of flow is usually determined by the use  of an administration pump or through measuring  number of drops per minute.   • The volume of intravenous solution that delivers  a particular amount of drug over a specific time  period may be calculated.   • Sometimes the administered solution is required  to be isotonic. (Calculations of isotonicity are  described in textbooks of pharmaceutics and  pharmaceutical calculations.)    39 If 60 mg disodium pamidronate are diluted to  250 mL in sodium chloride solution, how many  millilitres are required per minute to deliver   60 mg at a rate of not more than 1 mg/min  over not more than 100 minutes? One  milligram of disodium pamidronate is present  in 4.17 mL (250/60). To administer the  solution at a rate not exceeding 1 mg/min,  not more than 4.17 tnL/min should be  delivered. By delivering 4 mL/min, the  solution would be administered in 62 minutes,  resulting in an administration time of less than  100 minutes.   40 A patient is receiving 25 micrograms of a drug  per hour. The syringe driver has a volume of  2.5 mL and a length of 25 mm. It is set to  deliver 2 mm/h. What is the concentration of  the infusion solution in micrograms per  millilitre? Twenty-five micrograms of drug is  available in 2 mm and 312 micrograms are  therefore available in 25 mm (25 X 25/2). Since  312 micrograms are present in 2.5 mL, the  patient is receiving 125 micrograms/mL.   41 Pantoprazole injections are available as powder  for reconstitution in 40 mg strength. The dose  for infusion is 40 mg. Each vial is diluted with  100 mL sodium chloride 0.9%. If the time for  infusion is 1 hour, how much is the rate of  delivery in mg/min? Since 40 mg is delivered  over 60 minutes, the delivery rate is 0.67  mg/min (40/60).   42 Isosorbide mononitrate is available as 0.05%  w/v injections. How many millilitres of  isosorbide mononitrate injection should be  drawn into a syringe to deliver 5 mg? For a  0.05% w/v solution, 50 mg (0.05g) of  isosorbide mononitrate are present in 1 00 mL  and 5 mg are present in 10 mL (100 X 5/50).   43 A 300-mL infusion containing 100 mg  dacarbazine is to be administered over 150  minutes. A giving set which delivers 20 drops/  mL is used. What is the infusion rate in  drops/minute that should be used? The patient  should receive 2 mL every minute (300/150).  This is equivalent to 40 drops (20 X 2).  Therefore the infusion rate should be 40  drops/minute.    44 The infusion rate for intravenous insulin is  0.1 unit/kg per h until glucose level drops to  250 mg/dL. The insulin is prepared in 100 mL  0.9% saline at a concentration of 0.05 unit/  mL. What is the infusion rate in millilitres per  hour for a patient with a body weight of 85 kg?  The patient should receive 8.5 units/hour (0.1   X 85). Since the insulin solution is prepared at  a concentration of 0.05 units/mL, 8.5 units are  delivered ivith 170 mL (8.5/0.05). The infusion  rate should be set at 170 mL/h.   45 Disodium pamidronate 60 mg is diluted to  250 mL in sodium chloride solution. Calculate  the number of millilitres required per minute to  deliver 60 mg at a rate of not more than 1 mg/  min over 90 minutes. The disodium  pamidronate should be delivered at a rate of  2.78 mL/min (250/90). This will deliver   0.67 mg/min, which is less than 1 mg/min  (60 X 2.78/250).   When injecting a small amount of drug  directly into the vein it is often indicated to be  administered over a period of time. This is  best achieved through dilution in a suitable  solution such as physiological saline (0.9%  w/v sodium chloride in water).   Ansel H C and Prince S J (2004). Pharmaceutical Calcu-  lations: The pharmacist’s handbook. Philadelphia:  Lippincott Williams &c Wilkins.   Ansel H C and Stoklosa M J (2001). Pharmaceutical  Calculations , 11th edn. Philadelphia: Lippincott  Williams & Wilkins.   Coben D and Atere-Roberts E (2005). Calculations for  Nursing and Healthcare , 2nd edn. New York: Palgrave  Macmillan.   Bonner M C, Wright D J and George B (2000). Practical  Pharmaceutical Calculations. London: LibraPharm Ltd.   Rees J A, Smith I and Smith B (2005). Introduction to  Pharmaceutical Calculations. London: Pharmaceutical  Press.   • To become familiar with possibilities for point-of-  care testing in a community pharmacy or hospital  outpatient setting   • To give examples of tests that could be carried  out within a point-of-care service.   Point-of-care testing (POCT) is defined as any  analytical test performed for a patient by a health-  care professional outside a conventional laboratory  setting. It involves the use of kits to diagnose or  monitor a wide variety of conditions including  pregnancy, abnormal levels of cholesterol, glucose  and prostate-specific antigen, blood pressure, coag-  ulation, occurrence of Chlamydia and detection of  faecal blood. Equipment such as weighing scales is  available in pharmacies for weight management of  clients. For examples, see Table 11.1.   Pregnancy tests, glucose, red blood  cells, leukocytes, nitrites,  occurrence of menopause and  ovulation prediction   • increases pharmacist participation in rapid  response, chronic disease management and  patient follow-up.   • Non-invasive test: a test that does not  entail penetration of the skin or the body  with a needle or other device (e.g. blood  pressure monitoring, urinalysis,  monitoring of exhaled air).   • Invasive test: a test that requires  penetration of the skin or body to obtain  blood (e.g. blood glucose and cholesterol  testing).   Invasive tests require more preparation, such  as segregation, storage and disposal of clinical  waste, and dealing with spillage and accidental  needle-stick injuries.   • Sensitivity: ability of the test to identify true  positives. In a quantitative test, sensitivity also  refers to the range over which the quantitative  result is accurate.   • Specificity: ability of the test to identify true  negatives. In a quantitative test, specificity refers  to the degree to which results are not affected by  other factors (e.g. other substances in the  sample).   • Accuracy: extent to which the mean  measurement reflects the true value.   • May be carried out at a community pharmacy or  a hospital outpatients setting   • Is required to confirm suspected diagnosis (e.g.  urinary infection), to detect disease recurrence, to  monitor patient outcomes   • May be adopted as screening tests as part of a  health promotion activity (e.g. serum cholesterol,  blood glucose levels, blood pressure)   • Characteristics that are required for the test to be  practical include: fairly simple to carry out,  highly sensitive, easy to interpret results, not  expensive   • Quality assurance of the testing carried out and  the professional service provided should be in  place to ensure reliability and robustness of  service provided    • Record keeping should include date of testing,  strip-reagent used, batch number, result, operator  and patient identity.   • Reduces chances of analytical error due to  inappropriate storage of sample, inappropriate  labelling, mishandling of results.   • Quality assurance and quality control of test  performance and devices used    Make contact with an accredited local labora-  tory to get advice on:   In home testing patients are encouraged to partici-  pate in disease management. Examples of home  testing include blood glucose, blood pressure, preg-  nancy and body weight monitoring. Pharmacist  interventions in home testing include:    Up-to-date knowledge of tests and interpreta-  tion of results is required from pharmacists  providing the service. Provision of the service  should adopt a holistic approach whereby  individual patient management is implemented.  Risk factors should be identified and the  patient should be advised on behavioural  changes to follow a healthy lifestyle (e.g.  exercise, diet, smoking cessation).   The auscultatory method is the mainstay of blood  pressure measurement, involving the Korotkoff tech-  nique - measuring the appearance of clapping sounds  (phase I) as the systolic and the disappearance of the  sounds completely as the diastolic (phase V) pressure.  See also Chapter 20.   The patient should be seated and relaxed for  about 10 minutes before the blood pressure is  measured. When a high blood pressure  reading is obtained, the pharmacist should  recommend that the patient should have his or  her reading checked on two further occasions.   • Mercury sphygmomanometer: not used in some  places due to environmental impact   The monitoring of body weight in babies is used as  an indicator of development. In adults, monitoring of  body weight is used to evaluate occurrence of obesity  and overweight. The body mass index (BMI) is calcu-  lated after measuring the weight and height of an  individual. See Table 11.2 for classification of body  weight for adults.    • Mercury sphygmomanometers are the  gold standard for clinical measurement  and are used to test other  sphygmomanometers.   • Wrist manometers require further  evidence and are therefore not  recommended, although they may be  useful for obese patients. They should be  held at the level of the heart.   Error in blood pressure measurement is large when  the cuff is too small relative to the patient’s arm  circumference. The length of the cuff also plays a    part in the accuracy of blood pressure measurement.  See Table 11.3 for cuff size guidelines.   • The specimen collection and the test itself must  not be undertaken within the dispensary area.   • Apply simple protective measures designed to  avoid contamination of the person or clothing  and use good basic hygienic practices.   • Control surface contamination by blood and  body fluids by disinfection.   Blood glucose meters use the principle that the sample  reacts with glucose oxidase, generating electrons and  producing a current proportional to the glucose  content, which is measured electronically.   • Meter should be calibrated often (e.g. for every  new batch of test strips).   • Deliver a full blood drop on the test area or  touch the tip of the test strip with the drop of  blood depending on the type of meter being used.   • Blood samples for glucose may be taken from  alternative sites other than the fingertips.   • Variations may occur when sample is taken from  other sites (e.g. forearm, palm, abdomen or  thigh).   • The variation is more significant for alternative  sites when the measurement is taken when  levels are changing rapidly (e.g. post-  prandially, after insulin administration and  with exercise).    • When alcohol is used to clean puncture  site, dry thoroughly before puncturing.   - testing time is less than 2 hours after a  meal, after taking medication or  performing exercise   - participation in risky activities (e.g. car  driving and operating machinery) is  envisaged   - hypoglycaemia symptoms are not recog-  nised easily (hypoglycaemia unaware-  ness).    • The same meter may often be used to carry out  tests for creatinine and albumin levels. These are  indicators of kidney disease   Blood testing is carried out to analyse cholesterol and  triglyceride levels. This has been adopted as a  screening test, to monitor patients who have hyper-  lipidaemia and to assess cardiovascular risk.   Cholesterol is produced endogenously in the liver  and is also taken up from foods of animal origin. It  is used in the synthesis of steroid hormones, vitamins  and bile acids.   A common reaction used to measure the amount of  cholesterol is the Trinder reaction, in which the  cholesterol ester is hydrolysed by cholesterol esterase  to form cholesterol which is subsequently oxidised to  produce hydrogen peroxide by cholesterol oxidase.  Hydrogen peroxide reacts with a substrate (an indi-  cator) in the presence of cholesterol peroxidase to  give a coloured dye.    • When a fasting sample is required, it is  best to take the sample in the morning  (e.g. for a full lipid profile).   • Two or more cholesterol measurements  are required to diagnose high blood  cholesterol due to factors (e.g. day-to-day  and time) that may influence readings.   • Assess therapeutic efficacy of treatment  for hyperlipidaemia after 4 weeks of  initiation of therapy.    • The international normalised ratio (INR) range  for the patient is usually established in a  secondary care environment. Anticoagulant  therapy requires regular INR measurement. This  can be done in community pharmacies and in  outpatient settings.   • Pharmacists can monitor patients who are taking  anticoagulants to monitor therapy and to  monitor patient outcomes when treatment is  adjusted or new drugs included.    • In the interpretation and actions  following an INR test from a point-of-  care test the use of computer decision  support software (CDSS) may be used.  CDSS standardises dosage adjustments  carried out following INR testing.  Pharmacists still need to take into  consideration individual patient features  (e.g. change in diet due to travel,  introduction of a new drug therapy,  alcohol consumption, missed doses,  bruising or bleeding, patient general well-  being) when following the CDSS-  recommended dose adjustments.   • Dose of warfarin should be indicated to  patients both in milligrams and by colour  of tablets.   • Blood testing is carried out as a point-of-care test for in patients with gastric pain. See also  to measure prothrombin time. Chapter 16.    • H. pylori testing is considered cost-effective in  the initial management of patients with dyspepsia  in primary care, especially after failure of initial  acid suppression.   • It can be carried out as a follow-up test to  confirm eradication of H. pylori after eradication  therapy.   • Testing may be carried out by serology, urea  breath test and faecal antigen test.   • Sensitivity 90% and specificity 88%. Large  number of false positives and false negatives  possible.   • Test is based on diffusion of antibodies from a  drop of serum or whole blood obtained by finger  puncture through a membrane and an  immunogen reaction.   • Since antibodies remain after a few months of  eradication, the serology test is not indicated to  be used to test treatment outcomes after  eradication of therapy.   • Orange juice may be administered before test to  delay gastric emptying.   • Simple kits available to collect sample (exhaled  air) are easy to use.   • This is a non-invasive test based on monoclonal  antibody testing.   • It is the least frequently used test but  developments are expected to take place to  establish it for point-of-care testing.    • A number of positive serology tests could  be false positives.    • Positive serology tests can be confirmed  with a laboratory breath or stool test.   • Serology may not clearly distinguish  active infection from occurrence of  antibodies due to previous infection.   • Carry out test within 4 hours of specimen  collection to avoid:   - a bacterial reduction of glucose and the  formation or reduction of nitrite,   - an increase in pH due to ammonia produced  as a result of bacterial reduction of urea   • Notwithstanding the result of the test, the patient  should be strongly advised to consult her general  practitioner   • Patients planning a pregnancy should be advised  to take folic acid supplementation daily before  conception and on initiation of pregnancy. See  Chapter 51.   • May be adopted in the monitoring of therapy  (e.g. for urinary tract infection) and as a  screening in preventive medicine.   2 Wipe test strip along rim of vessel to remove  excess urine.   Glycosuria is the occurrence of glucose in urine. It is  no longer considered a reliable diagnostic test for  diabetes since there is great inter-individual variation  in the renal threshold above which glucose appears in  urine.   • Conditions that may present with urobilinogen in  urine include hepatitis, hepatic congestion and  myocardial infarction.   • Occurs in urine when there is jaundice which  reflects liver disorders or an underlying condition  that is precipitating jaundice.   • Point-of-care testing is a convenient way to  identify and monitor disease states.   • Test sensitivity, specificity and practical  implications should be considered when assessing  service development.   • A high-quality point-of-care testing service  requires close cooperation with other healthcare  providers.   • The interpretation of results and patient  counselling are essential to complement the service.   1 What devices are necessary to diagnose the  following conditions: hypertension, pyrexia,  haematuria?   3 List four conditions for which it is recommended  that a patient undergoes blood cholesterol testing.   4 List ten principles that need to be checked  before providing a diagnostic service.    2 The patient should be seated and relaxed for  about 10 minutes before the blood pressure is  measured. When a high blood pressure reading  is obtained the pharmacist should recommend  that the patient should have the reading checked  on two further occasions. Blood pressure can be  measured using a mercury sphygmomanometer,  a semi-automatic apparatus or an automatic  apparatus.   3 Family history or personal history of heart  disease, hypertension, diabetes, overweight.   4 Training of staff, proper environment, quality  control and assurance of the service, contact  with accredited laboratory, insurance, health  and safety rules especially regarding handling of  body fluids and sharps, guidelines on  requirement for patient consent, record keeping,  method of interpretation of results, quality and  maintenance of equipment.   Braden B, Teuber G, Dietrich C F, Caspary W F and  Lembeke B (2000). Comparison of new faecal antigen  test with C-urea breath test for detecting Helicobacter  pylori infection and monitoring eradication treatment:  prospective clinical evaluation. BMJ 320: 148.   Delaney B C, Qume M, Moayyedi P, Logan R F, Ford A C,  Elliott C, et al. (2008). Helicobacter pylori test and    treat versus proton pump inhibitor in initial manage-  ment of dyspepsia in primary care: multicentre random-  ized controlled trial. BMJ 236: 651-654.   Elwyn G, Taubert M, Davies S, Brown G, Allison M and  Phillips C (2007). Which test is best for Helicobacter  pylori ? A cost-effectiveness model using decision  analysis. Br J Gen Bract 57: 401-403.   Hobbs FDR, Fitzmaurice D A, Murray E T, Holder R,  Rose P E and Roper J (1999). Is the international  normalised ratio (INR) reliable? A trial of comparative  measurements in hospital laboratory and primary care  settings. J Clin Pathol 52: 494-497.   International Pharmaceutical Federation (2004). FIP state-  ment of policy: Point of care testing in pharmacies.  http://www.fip.nl/www/uploads/database_file.php?id=  161&table_id= (accessed June 2009).   Megraud F and Lehours P (2007). Helicobacter pylori  detection and antimicrobial susceptibility testing. Clin  Microbiol Rev 20: 280-322.   Pickering T, Hall J E, Appel L J, Falkner B E, Graves J, Hill  M N et al. (2005). Recommendations for blood pres-  sure measurement in humans and experimental animals  (Part 1). Hypertension 45: 142-161.   Royal Pharmaceutical Society of Great Britain (2009). Prac-  tice guidance: Diagnostic testing and screening services.  http://www.pharmacyplb.com/servicespracticeguidance.  aspx (accessed June 2009).   Rust G, Gailor M, Daniels E, McMillan-Persaud B,  Strothers H and Mayberry R (2008). Point of care  testing to improve glycemic control. Int J Health Care  Qual Assur 2: 325-335.   Urban R, Hirst L and Hildebrandt M (2009). Pharmacists  with a special interest in anticoagulation raise standards.  Clin Pharm 1: 145.   • To appreciate the practice of pharmaceutical care in • To identify steps required in the development and  the primary and secondary care settings handling of pharmaceutical care plans.   • Clinical pharmacy (CP) is the discipline  concerned with the use of medicines in patients.  It requires the application of pharmaceutical  science in order to solve drug therapy problems  in individual patients.   • Pharmaceutical care (PC) is the integration of  clinical pharmacy knowledge, skills and attitudes  into a system of multidisciplinary care which  aims to provide quality assurance of medicines in  use (Figure 12.1).   • Evidence base for use of a medicine or a  combination may be lacking   • Pharmaceutical care is a monitoring and enquiry  strategy to validate the treatment plan.   • Reasonable expectations of these relationships so  as to anticipate the effect of drugs   The preparation of a pharmaceutical care plan can be  divided into four stages:   • All actual or potential (e.g. due to co-  morbidities) healthcare problems   Ms XZ, a 55-year-old patient living on her  own, has hyperglycaemia. She has been diag-  nosed with type 2 diabetes for 2 years and is  receiving treatment. She is receiving human  insulin treatment but the patient states that  she does not take the medicine regularly  because sometimes it makes her dizzy.   Mr BW is a 60-year-old patient with prostate  cancer. He is complaining of severe pain that  is interfering with his daily activities. He takes  paracetamol with codeine, when needed, for  pain and has received treatment for prostate  cancer.   • oral antidiabetic agents: sulphonylureas  (e.g. gliclazide) or biguanides (e.g.  metformin)   • insulin - short acting (e.g. insulin aspart)  or intermediate acting (e.g. insulin zinc  suspension)   • insulin mixture or biphasic preparation  (e.g. biphasic insulin aspart - 30% insulin  aspart, 70% insulin aspart protamine)   • assessment of onset of side-effects due to  medications (e.g. nausea, hypoglycaemic  attacks).   • assessment of onset of side-effects due to  medications (e.g. nausea, constipation).    Once the patient’s healthcare needs are defined  and the pharmacotherapeutic goals established  (pharmaceutical care issues), healthcare providers  need to collaborate and go through a decision-  making process to identify a therapeutic regimen  which may include non-pharmacological approaches.  This therapeutic plan has to be verified and   • Patients with diabetes participate in monthly  consultations with community pharmacists.    • Pharmacist contributes to education of the  patient, clinical assessment and recommending  referrals as necessary.   • Pharmaceutical care requires integration of  clinical pharmacy knowledge which has a  pharmaceutical science baseline within a  multidisciplinary approach.   • Pharmaceutical care is practised in both primary  and secondary care settings.   • Documentation is required in the practice of  pharmaceutical care: patient profile, medication  profile, laboratory tests and the pharmaceutical  care plan.    • Checks and changes to the pharmaceutical care  plan are required to ensure quality assurance of  the care provided.   • Checks require patient monitoring using clinical  cues such as patient interviews, laboratory  markers, quantitative tools to establish disease  progression, and occurrence of signs and  symptoms.   • Changes take place when there is modification of  the original pharmaceutical care plan during plan  verification, treatment monitoring and patient  outcomes evaluation.   1 Outline the features to be considered in a  pharmaceutical care plan for a patient with  chronic hypertension.   (b) Establish the importance of non-  pharmacological measures (e.g. diet and  exercise).   (d) Identify the optimal treatment options for  the particular patient, taking into  consideration co-morbidities and individual  patient risks.   (f) Identify signs of comorbidities (e.g.  ischaemic heart disease, heart failure,  kidney disease, diabetes, impairment of  vision).    (g) Monitor blood pressure regularly and  encourage patient to take up self-monitoring.   (h) Monitor clinical parameters (e.g. blood  glucose levels, lipid profile, creatinine  clearance).   (i) Monitor for the occurrence of drug-related  problems (e.g. side-effects, patient safety).   (j) Verify compliance, assess outcomes and  confirm treatment or suggest changes.    (k) Refer patient back to prescriber or secondary  care interface as necessary.   Sexton J, Nickless G and Green C (2006). Pharmaceutical  Care Made Easy. London: Pharmaceutical Press.   • To understand how drugs work at the molecular • To identify mechanisms underlying inter-individual   - targeting macromolecules usually proteins:  receptors (e.g. adrenaline, histamine,  sympathomimetics) or enzymes (e.g. ACE  inhibitors such as enalapril)   - interfering with membrane ionic channels,  such as the movement of sodium, calcium and  potassium (e.g. calcium channel antagonists  such as amlodipine)   - cytotoxic actions, such as damage to DNA and  other macromolecules (e.g. antibacterial and  anticancer drugs).   • Receptors: specific molecules usually protein to  which endogenous substances (e.g.  neurotransmitters or hormones) or drugs bind.   • Agonists: elicit a physiological or biochemical  response that is similar to the response  achieved when the neurotransmitter attaches  to the receptor. The chemical structure of an  agonist is often similar to that of the  neurotransmitter.   • Antagonists: bind to receptors but do not elicit a  physiological response and prevent the  neurotransmitter from attaching to the receptor.  The chemical structure of an antagonist is similar  to that of the neurotransmitter so that it allows  the drug to attach to the receptor but the fit with  the receptor is very sluggish due to a bulky  structure.   Drugs act as agonists or antagonists on the various  receptors; some have an equal effect on all types of  the receptors while others have a more predominant  action on one type of receptor rather than on  others.   • Alphaj receptors: phenylephrine, an agonist  producing vasoconstriction, and prazosin, an  antagonist producing vasodilatation   Ephedrine is an agonist that acts on both alpha 3 and  alpha 2 receptors.   • Beta : receptors: dopamine, an agonist that  increases heart rate; atenolol, an antagonist that  decreases heart rate   • Beta 2 receptors: salbutamol, an agonist causing  bronchodilatation and uterine relaxation.   Propranolol is an antagonist acting on both beta 3  and beta 2 receptors causing a decrease in heart rate  and blood pressure and bronchoconstriction. See also  Chapter 20.   • Muscarinic receptors: bethanechol, an agonist  acting on gut and urinary motility; atropine, an  antagonist that increases heart rate and causes  mydriasis   • Nicotinic receptors: suxamethonium which  effects the contraction of striated muscle.   • H 2 receptors: ranitidine, an antagonist that  decreases gastric acid secretion.   This is also known as serotonin and is divided into  subgroups (e.g. 5HT 1A D , 5HT 3 , 5HT 4 ).    • 5HT 1A receptors: buspirone, an agonist with  anti-anxiety and antidepressant properties   • 5HT 4 receptors: cisapride, an agonist with effects  on the gastrointestinal tract which was  withdrawn (see also Chapter 1)   • Re-uptake inhibitors: may act by inhibiting the  re-uptake of transmitters (e.g. fluoxetine), which  selectively inhibits the re-uptake of serotonin  (SSRI).   • morphine and fentanyl, agonists acting on mu,  kappa and delta receptors with analgesic and  narcotic properties   • naloxone, an antagonist acting on mu, kappa  and delta receptors which reverses opioid-  induced respiratory depression   • buprenorphine, a partial agonist at the mu  receptors and an antagonist at the kappa  receptors; it is an adjunct in the management of  opioid dependence.    Some drugs act as antagonists for different  lengths of time. Those acting for a short time  are termed competitive (reversible). Those  acting for a longer time are termed non-  competitive (irreversible). In practice this    means that the action of a competitive antag-  onist can be stopped by an agonist. For  example, the action of the beta-antagonist  atenolol, can be stopped by the beta-agonist  isoprenaline.   These are mostly protein molecules and may be either  activated or inhibited. The action of some drugs is  explained by their inhibition of enzymes - for  example, aspirin inhibits cyclo-oxygenase, carbidopa  inhibits decarboxylase, allopurinol inhibits xanthine  oxidase, phenelzine inhibits monoamine oxidase.    The side-effects of vigabatrin, an antiepileptic  that acts as an irreversible inhibitor of the  enzyme gamma-aminobutyric acid amino-  transferase, may last for some time after the  drug has been stopped.   • Cytotoxic actions often result in death of cells  (e.g. bacteria, cancer cells).   • Cell death occurs through toxic action on  receptors or enzymes.   • Alkylation caused by drugs could damage DNA  and other cell structures.   • Antibacterial action could be either bactericidal  or bacteriostatic (see Chapter 34).   • Potency for a drug is the biological activity per  unit weight.   • Potencies are compared on the basis of doses that  produce the same effect.   • Efficacy is the intrinsic activity of the drug, the  magnitude of response.    • Efficacy is related to the tendency of the drug to  combine with the receptor (affinity) and the  number of receptors occupied.    The potency of a drug is relatively unimpor-  tant. Pharmacists often confuse potency and  efficacy. High potency is often overrated as an  advantage in pharmacotherapeutics. The fact  that a drug is more potent than another is  often irrelevant in clinical pharmacy practice.  It may influence pharmacoeconomic consid-  erations in establishing the cost of manufac-  ture and of the finished product. A drug with  greater efficacy may accomplish results that  are unattainable with one that is less effica-  cious (e.g. furosemide is more effective than  chlorthiazide).   Drug responses differ in different individuals as a  result of variation:   • in metabolism (e.g. drug metabolism, tissue  metabolism disorders such as glucose-6-  phosphate dehydrogenase (G6PD) deficiency)   • due to anatomical disorders (e.g. fatal reactions  by digitalis in hypertrophic subaortic stenosis).   Inter-individual differences may be due to genetic  factors. For example, people who are slow acetyl-  ators of isoniazid are more prone to develop periph-  eral neuropathy, while rapid acetylators respond  less favourably to isoniazid as a treatment for tuber-  culosis.    The acetylator phenotype may be determined  by administering sulfamethazine. Slow or rapid  acetylators are classified according to the  concentration ratio of acetylsulfamethazine to  sulfamethazine in plasma determined at  specific times.   • Identical doses of drugs can produce large  differences in pharmacological response.   • Body weight, body mass index, age, gender,  concomitant diseases and physical activity  influence drug action.   • For discussion of body weight and body mass  index (difference in children, elderly and adults)  see Chapters 49 and 50.    Amoxicillin is an example of a drug that has a  broad therapeutic index.   The relevance and quantification of drug action may  be enhanced through pharmacoepidemiological, bio-  statistics and pharmacoeconomic reviews by esti-  mating the probability of beneficial effects, adverse  reactions and drug use in populations.   • Biostatistics: study of the significance of the  results to identify drug action; it aids in  understanding risks of medicine use and reduces  errors in clinical practice (e.g. f-values, chi-  squared values, standard errors, probability (P  values), variation).   • Pharmacoeconomics: study of drug treatment in  terms of cost and effectiveness.    It is not always clinically relevant to make  dosage adjustments in adults according to the  individual patient’s body weight unless there  is a difference of more than 50% from the  average weight, taken to be 70 kg. In practice,  dosage adjustments for body weight are made  for children, unusually small or obese adults,  and for specific therapy such as anaesthesia  and cancer chemotherapy.   • Therapeutic equivalence: two similar drugs that  have comparable efficacy and safety are said to  have therapeutic equivalence.   • Therapeutic index: the ratio of toxic dose to  effective dose of a drug. With drugs that have a  narrow therapeutic index (e.g. warfarin) the  effective dose is very close to the toxic dose.   • Descriptive: describe disease, exposure  (epidemiology); calculate rates (e.g. incidence,  prevalence, drug utilisation (biostatistics)).   • Analytical: observational (case-control, cohort  studies) (e.g. randomised clinical trials, statistical  hypothesis testing studies (differences between  exposed group and control group)).   • Continuous monitoring for the occurrence of  unwanted effects and other safety-related aspects  of drug action.    Pharmacotherapy should identify the benefits against  the risks for individual patients. Risks and benefits  vary between drugs and from patient to patient.   It is useful to be able to deduce the action of a drug  and its expected side-effects from the pharmaco-  logical classification of the drug. In the autonomic  nervous system, drugs can be classified as fast or  slow acting.   • Adrenergic agonists (sympathomimetics): fright,  fight and flight reaction (e.g. adrenaline  (epinephrine)). Action: increase blood pressure,  heart rate, nervousness and glycosuria; reduce  bronchospasm.   • Cholinergic blockers (parasympatholytics,  anticholinergics, antagonist effect): drying,  dilatation and decreased motility (e.g. atropine;  antiemetic, antinausea, antispasmodic). Action:  increase heart rate, dilate pupils, dry mouth,  urinary retention, constipation, confusion.   • Monoamine oxidase inhibitors (MAOIs):  vasopressor action (hypertensive crisis) (e.g.  phenelzine, isocarboxazid; antidepressants).  Action: decrease depression, increase  accumulation of amine neurotransmitters (e.g.  clinically significant interaction with concomitant  administration of sympathomimetics found in   • Cholinergic agonists (parasympathomimetics):  resting mode and gastrointestinal motility (e.g.  betanechol, pilocarpine). Action: decrease  respiration, intraocular pressure, heart rate;  constrict pupil, increase secretions, peristalsis,  bladder contractions, muscle strength, nausea,  vomiting, diarrhoea, sweating.   • Beta-adrenergic blockers (sympatholytics):  decrease blood pressure and pulse rate (e.g.  propranolol). Action: decrease blood pressure,  pulse, blood glucose; increase fatigue, depression,  bronchoconstriction.   • Cholinesterase (acetylcholinesterase, AChE)  inhibitors: enhance neuromuscular transmission  in muscle, cognitive enhancement (e.g.  edrophonium, neostigmine, malathion  (insecticide)). Action: decrease heart rate, blood  pressure, intraocular pressure, pupil size; increase  acetylcholine neurotransmitters, cognition,  bronchoconstriction, bronchial secretions,  sweating, salivation, diarrhoea, lacrimation,  micturition.   1 What are the clinical implications for a drug  with a narrow therapeutic index?   1 Drugs with a narrow therapeutic index (i.e.  drugs with a little difference between toxic and  therapeutic doses) such as warfarin, lithium and  digoxin require extensive therapeutic drug  monitoring (TDM) both to achieve therapeutic  levels and to minimise toxicity. Drugs with a  broad therapeutic index such as amoxicillin are  safer as very high doses are required to result in  toxicity. Therapeutic index = toxic  dose/effective dose.   Durham T A and Turner J R (2008). Introduction to  Statistics in Pharmaceutical Clinical Trials. London:  Pharmaceutical Press.    Elliott R and Payne K (2005). Essentials of Economic  Evaluation in Healthcare. London: Pharmaceutical  Press.   Jekel J F, Katz D L and Elmore J G (2001). Epidemiology,  Biostatistics and Preventive Medicine , 2nd edn.  Philadelphia: Saunders.   • To understand the principles of pharmacokinetics • To describe inter-relationships of drug dose, drug   • To familiarise oneself with the clinical relevance of  pharmacokinetic parameters   • Pharmacokinetics is the study of drug movement  in the body over time.   See Figure 14.1 for movement of orally administered  drugs in the body.   Factors affecting rate and degree  of absorption (oral route of  administration)   The rate and degree of absorption of a drug may be  affected by various factors including the chemical  and physical properties of the drug, the surface area  of the absorbing surface, intestinal motility, blood  flow and pharmaceutical factors.   • Degree of ionisation is determined by the  surrounding pH and their pK a .   • The surface area of the small intestine from where  a number of drugs are absorbed may be reduced  by surgery and inflammatory bowel disease.   • A short transit time and a rapid gastric emptying  can decrease rate of absorption of drugs.   • The extent of blood perfusion affects the rate of  distribution of drugs.   • Dosage form: drug absorption increases in the  following order: tablets, capsules, suspensions,  solutions.   • Slow-release preparations: designed for  controlled dissolution and consequently  prolonged absorption.   • Bioavailibility is the extent of absorption  of a drug following its administration by   - absorption (e.g. low lipid and water  solubility), lack of mechanism  facilitating passage through membrane  (active transport), drug interaction (e.g.  antacids can reduce the absorption of  drugs such as quinolone antibacterials  by binding with them in the gut)   - first-pass effect: drug is metabolised in  the liver before reaching systemic  circulation (e.g. when glyceryl trinitrate  is administered orally).   • In plasma, most drugs are partly in solution and  partly bound to plasma proteins.   • Only the unbound fraction is able to transfer  across membranes and produce an effect.   • drug lipophilicity - increased lipophilicity  increases ability of the drug to cross  membranes, such as the blood-brain barrier  (e.g. anaesthetics)   Volume of distribution is the apparent volume into  which a drug distributes, based on the amount of drug  in the body and the measured concentration in the  plasma and serum. For example, volumes of distribu-  tion (L/kg): chloroquine 200, digoxin 7, propranolol  4, phenytoin 0.65, gentamicin 0.25, aspirin 0.14,  warfarin 0.10.   • For drugs that have a low lipid solubility, low  tissue binding or high plasma protein binding,  the volume of distribution is low.   • For drugs that have a high lipid solubility, high  tissue binding and low plasma protein binding,  the volume of distribution is high.    Knowledge of volume of distribution may be  used to determine the size of the loading dose  for a quick response when drug response takes  days to develop with a regular dose (e.g.  digoxin). Care has to be taken that the loading  dose does not produce adverse effects.   • It is based on enzymes such as cytochrome P450  enzymes and any drug that interferes with these  enzymes has a high potential for drug-drug  interactions.   Inter-individual variation in metabolism may occur  as a result of various factors:    Patient monitoring is required in individuals  who are prone to a variation in metabolism of  a drug due to disease states or concomitant  drug therapy. Patient monitoring includes  detection of occurrence of side-effects, moni-  toring of liver function and identifying clini-  cally significant potential drug interactions.   • Some drugs are mainly excreted without  metabolism from the kidney (e.g. atenolol).   • Excretion from the kidney depends on  glomerular filtration rate and tubular secretion.   • In renal disease, lower dosage is required so as to  avoid reaching toxic drug blood levels due to a  low excretion rate.   • Other routes of excretion include: bile, saliva,  sweat, tears and lungs.    Patient monitoring is required in patients who  could be prone to changes in excretion rate  due to disease states or concomitant drug  therapy. Renal function is assessed through  evaluating creatinine clearance.   Half-life is the time taken for drug concentration to  fall to half its original value. Unit: hours. Examples:  chlorpropamide 24-72, glipizide 6-12, nitrazepam  >20, diazepam 20-50, lorazepam 10-20, triazolam  1.5-5, amlodipine >40, nifedipine 4-6, irbesartan  15-17, valsartan 5-9.   Clearance is the measurement of drug elimination  from the body. Unit: volume/time (L/h).   • Knowledge of half-life or clearance  provides a quantitative measurement of  persistence of drug in the body.   • For drugs eliminated by first-order  kinetics it takes four half-lives after  intravenous administration for the  amount of drug in the body to be reduced  to one-tenth of the original amount.   • Half-life may sometimes be used to  estimate duration of effect and dosing  frequency.   • A drug with a shorter duration of action  is often preferred in the elderly and in  patients with renal or hepatic impairment  to reduce risks of drug therapy (e.g.  glipizide rather than chlorpropamide to  reduce risk of hypoglycaemia, lorazepam  rather than diazepam to reduce risk of  morning-after hangover effects).   • When administering a drug the interaction of the  drug with the biological system depends on the  physical and chemical properties of the drug,  the pharmacokinetic profile and the  pharmacodynamic effect.   • Bioavailability of a drug differs between one  route of administration and another, and may  differ from one preparation to another  preparation of the same dosage form due to the   • When identifying drug therapy for a patient,  consideration of the pharmacokinetic profile of  the drugs and patient characteristics is required  to obtain optimum therapeutic effect and  decrease risks from drug therapy.   • Biopharmaceutics describe the relationship of the  drug product’s physical and chemical properties  to its bioavailability, LADME activity, and  pharmacodynamic and toxic effects.   2 Which route of administration is associated  with the highest bioavailability rate and why?   1 Pharmacokinetics is the study of drug movement  in the body over time while pharmacodynamics  is the study of how drugs act.   2 Intravenous (IV) route - when a drug is given  intravenously 100% of the dose enters the  general circulation.   Allen L V, Popovich N G and Ansel H C (2005). Ansel’s  Pharmaceutical Dosage Forms and Drug Delivery  Systems , 8th edn. Baltimore: Lippincott Williams &C  Wilkins.   Dhillon S and Kostrzewski A (2006). Clinical Pharmaco-  kinetics. London: Pharmaceutical Press.   • To appreciate factors that may contribute to  constipation and diarrhoea    • To develop skills required to identify signs that  warrant referral   • Constipation: a change from the normal body  habits, where normal body habits vary from one  individual to another, ranging from several stools  a day to the passage of one stool every 2-3 days.   • Diarrhoea: an increased frequency of bowel  movements and the production of soft or watery  stools resulting in fluid and electrolyte loss.   Constipation and diarrhoea can be a  symptom of an underlying condition and  require investigation if occurrence persists. A  good history of normal body habits, change  in habits, introduction of new drugs and  underlying conditions is required.   - elderly patients: due to sedentary lifestyle and  poor mobility which diminishes colonic  activity, due to multiple disease states and  polypharmacy, and due to decreased food and  fluid intake   - pregnant women: due to fetal pressure and  increased progesterone levels, which cause a  decrease in peristaltic movements    • About 10-20% of individuals believe that they  suffer from constipation because their normal  bowel habits are not occurring on a daily basis.   • Inflammatory bowel disease is characterised  by day-to-day variability in gastrointestinal  motility.   • In the constipation-predominant variant,  frequent passage of hard stools occurs.   These may cause retention of fluid in colonic  contents. They act directly or indirectly on the  colonic mucosa to decrease net absorption of water  and electrolytes or increase intestinal motility,  causing less absorption of salts and water due to  reduced transit time. There are four main types:   • stimulant laxatives: e.g. senna (tablets), bisacodyl  (tablets, suppositories), sodium picosulphate  (liquid), glycerol (suppositories)   These are polysaccharide and cellulose derivatives  that are not digested. They exert an effect within  12-72 hours of administration and are useful in hard  stools.   - support growth of colonic bacteria thereby  increasing bulk, fibre digested by bacteria to  metabolites which have a laxative effect   • Contraindications: intestinal obstruction, faecal  impaction, colonic atony, difficulty in swallowing.    Note: methylcellulose may interfere with absorption  of drugs such as digoxin.   These stimulate intestinal motility, probably through  an effect on the myenteric nerve plexus, decrease  absorption of electrolytes and water, and increase  synthesis of prostaglandins which reduce transit  time.   They have a rapid onset of action which makes  them suitable for the management of a chronic  attack. An effect is expected within 6-12 hours after  oral administration and within 15-30 minutes when  administered rectally.   - senna: anthraquinone group, which may cause  discoloration of the urine, dose: adults: 15-30  mg, 2-4 tablets at night   - bisacodyl: diphenylmethane derivative  available as enteric-coated tablets which  should be swallowed whole not crushed, to  reduce occurrence of abdominal cramps, or as  suppositories. The oral formulation should not  be taken within 1 hour of ingesting antacids or  milk. Dose: adults: 5-10 mg at night   • Counselling: not for chronic use since prolonged  use may cause diarrhoea and cathartic colon   Glycerol (glycerin) is a rectal stimulant that is effective  where intestinal obstruction or impaction is suspected.  It is safe to use in paediatrics (see Chapter 50).   • Poorly absorbed, acts in the distal ileum and  colon where it is metabolised by the bacteria to  fructose and galactose which increase osmotic  strength    • Increases amount of water in the intestines by  osmosis. This increased volume results in  distension of the lumen which promotes  peristalsis   • Reduces proliferation of ammonia-producing  organisms and for this reason it is useful in  hepatic encephalopathy   • Cause a very rapid action, used where complete  evacuation is required (e.g. prior to diagnostic or  surgical procedure)   • Contraindications: gastrointestinal obstruction,  acute gastrointestinal conditions, perforated  bowel, congestive heart failure    Conditions that may present with constipation  that requires further investigation include:    Diarrhoea may be acute or chronic. There are three  main types:   • Osmotic diarrhoea: non-absorbable solute retains  water in the intestine lumen. Examples include  osmotic substances such as sorbitol (found in  sugar-free sweets) and drugs such as magnesium-   • Secretory diarrhoea: damage to intestinal wall  leading to increased secretion in contrast to  absorption of electrolytes (e.g. infectious  diarrhoea).   • Motility diarrhoea: decreased contact time of  faeces in intestine resulting in fluidy faeces  (e.g. inflammatory gastrointestinal disease,  drugs).   • To use oral rehydration salts to rehydrate and  replace lost electrolytes   Oral rehydration salts (ORSs) provide fluid and elec-  trolyte replacement. They are presented in the form  of powder for reconstitution, consisting of sodium,  potassium and glucose. The intestinal absorption of  sodium and water is enhanced by glucose.   Patients should be advised to reconstitute ORSs  with potable water and any unused reconstituted  solution should be discarded within 1 hour after  preparation unless stored in a refrigerator where it   Rehydration, orally or intravenously, is  extremely important to prevent circulatory  collapse in severe diarrhoea.    can be kept for up to 24 hours. Factors that affect  patient acceptance are palatability and flavouring.   These relieve symptoms by reducing peristalsis  through stimulation of the mu opioid receptors on  the intestinal wall. They are not recommended for  use in children.    Opioid antidiarrhoeal drugs should be  avoided in children. The use of oral rehydra-  tion salts in patients using antidiarrhoeal  agents should be emphasised.   • Dose for loperamide: adults 4 mg followed by  2 mg after each unformed stool.   • When constipation or diarrhoea occur, confirm  that symptom is not secondary to another  condition.   • Lifestyle changes in constipation and adequate  rehydration in diarrhoea are mainstay of  treatment.   • Bulk-forming laxatives, osmotic laxatives,  stimulant laxatives and saline laxatives differ in  the mode of action, time for onset of action and  side-effects to be expected.   2 Compare a bulk-forming laxative with a  stimulant laxative considering mode of action,  onset of action, dosage regimen and side-effects.   1 Inflammatory bowel syndrome is a chronic  condition that may present with a higher  frequency of occurrence of constipation as  opposed to symptoms of diarrhoea. In  constipation-predominant disease, patients are  advised to increase fluid and fibre intake, avoid  intake of fats and undertake regular exercise. In  addition, regular use of a bulk-forming laxative  such as ispaghula husk may be considered,  particularly in those patients whose diet lacks  fibre.   2 Bulk-forming laxatives and stimulant laxatives  are compared in Table 15.2.   Stimulate enteric nervous system to promote intestinal  motility in the small and large intestine   May take several days for full effectiveness: 12-24 hours  and up to 72 hours, are indicated for chronic  constipation   Act within 6-12 hours (tablets) or within 15-30 minutes  (suppositories), therefore much faster onset of action  when compared with bulk-forming laxatives and are  indicated for acute constipation   Bloated feeling, blockage and impaction - very  important to maintain adequate fluid intake   Elringham M and Yiannakou Y (2003). Constipation:  current approaches to treatment. Prescriber 19 April:  69-76.   McNair A and Henderson R (2003). Diarrhoea manage-  ment. Prescriber 19 September: 39-42.   1 Cash B D and Chey W D. The role of serotonergic  agents in the treatment of patients with primary chronic  constipation. Aliment Pharmacol Ther 2005; 22:  1047-1060.   • To recognise the role of Helicobacter pylori in  gastrointestinal ulceration   • To develop skills to manage patients presenting  with upper gastrointestinal disorders.   In the parietal cells acid secretion is activated by  stimulation of gastrin receptors, histamine type 2  receptors and muscarinic type 3 receptors. After  stimulation, there is a common pathway through the  H + /K + -dependent ATPase proton pump which  releases H + into the stomach lumen. Secretion is  decreased by the stimulation of prostaglandin E 2  (PGE 2 ) receptors. Synthesis of the prostaglandin  PGE 2 is mediated via pathways involving cyclo-  oxygenase type 1 (COX-1).   • Reflux into the oesophagus of the gastric or  intestinal contents occurs which causes  oesophagitis due to acidic contents coming into  contact with the oesophagus.    • Risk factors: pregnancy, obesity, foods with high  fat content, spices, citrus fruit, coffee.   • Occurrence increases at night when patient is in  supine position.   • Avoid foods that irritate gastric mucosa (spicy  foods, citrus, tomato extracts), lower  oesophageal sphincter pressure (chocolate,  alcohol, peppermint, fatty food) or stimulate  secretion (cola, beer).   This is described as persistent or recurrent abdominal  discomfort in the upper abdomen. Of patients  presenting with dyspepsia:   - negative result: empirical therapy: H 2 -receptor  antagonists, or proton pump inhibitors.   This is the occurrence of discontinuity in the entire  thickness of the gastric or duodenal mucosa that  persists and results from acid and pepsin in the  gastric juice.   • H. pylori infection: 95% of duodenal ulcers and  80-85% of gastric ulcers are due to the  occurrence of this microorganism in the  gastrointestinal tract.    Enteric-coated preparations of NSAIDs  prevent physical damage during drug dissolu-  tion but do not reduce ulcer risk since damage  is due to systemic action by reducing mucosal  prostaglandin production.   • Endoscopy: very sensitive and reliable test,  invasive and some patients refuse to undergo this  investigation   When patients are diagnosed with H. pylori infection,  the triple therapy eradication technique should be  adopted.   One week of triple therapy using a proton pump  inhibitor, 1 e.g. omeprazole 20 mg twice daily plus:   • amoxicillin 1 g twice daily and clarithromycin  500 mg twice daily   • amoxicillin 500 mg three times daily plus  metronidazole 400 mg three times daily   • metronidazole 400 mg twice daily plus  clarithromycin 250 mg twice daily.   In patients at risk of developing an ulcer such as  elderly patients, patients who are taking drugs that  may increase risk (e.g. SSRIs) or patients with a past  history of gastrointestinal haemorrhage, prophylaxis  may be considered using:   • Drugs that do not inhibit acid secretion, but have  a cytoprotective effect:   • These products are weak alkalis that bring about  neutralisation of the acidic pH in the stomach.   • They provide symptomatic relief in dyspepsia,  peptic ulceration and gastro-oesophageal reflux.   • Antacids may be used when symptoms occur and  provide relief generally within 5-15 minutes of  administration.   • They should be administered between meals  and at bedtime (relief duration ranges from 1  hour to 3 hours).   • After oral administration it is absorbed and may  cause alkalosis.   • It should be used with care in patients on salt-  restricted intake (e.g. patients with hypertension).   • These can induce rebound acid secretion and so  should not be used for prolonged periods.   These are antacids that are not absorbed. They include  aluminium salts, magnesium salts and aluminium-  magnesium compound preprations (mixture).   • Antiflatulents: simeticone (used also in infant  colic - see Chapter 50), activated charcoal    Antacids may be used in addition to H 2 -  receptor antagonists or proton pump inhibitors  to manage occurrence of symptoms.   These products are structural analogues of histamine.  They act as antagonists to the histamine type 2 recep-  tors which are predominantly found in the gastric  parietal cells. Examples include cimetidine, raniti-  dine, famotidine and nizatidine. All have similar  effectiveness and all have rapid absorption after oral  administration. Cimetidine and ranitidine (Figure  16.1) are primarily metabolised in the liver while  famotidine and nizatidine are primarily excreted  from the kidneys.   • Ranitidine, famotidine and nizatidine have other  heteroaromatic rings instead of the imidazole  ring.   • Rare: headache, liver dysfunction, blood  disorders, bradycardia, confusion, gynaecomastia  (cimetidine).   Cimetidine binds to the cytochrome P450 enzymes  and it may cause clinically significant drug interac-  tions particularly for drugs with a narrow therapeutic  index. Examples include:   Proton pump inhibitors act by irreversibly binding to  K + /H + ATPase. They have a prolonged duration of  action. Examples include omeprazole, esomperazole,  lansoprazole, pantoprazole and rabeprazole. They  are used in gastro-oesophageal reflux disease, H.  pylori triple therapy eradication programme and  acid-NSAID peptic ulcer disease.   They are rapidly absorbed after oral administra-  tion and are eliminated by hepatic metabolism. Side-  effects include diarrhoea, nausea and vomiting, and  headache. Dosage frequency: once daily.   • Antiepileptics - omeprazole and esomeprazole:  effects of phenytoin may be enhanced   • Stability of proton pump inhibitors: the  active ingredient is unstable   • Patients unable to take a solid dosage  form: proton pump inhibitors only  available as solid dosage forms for oral  administration   • In triple therapy for patients sensitive to  penicillin: use a regimen that contains  metronidazole, macrolide and a proton  pump inhibitor.   Synthetic prostaglandin analogues, such as miso-  prostol, exhibit antisecretory and protective proper-  ties. They promote healing of ulcers and are used to  prevent NSAID-associated ulcers.   Bedtime ranitidine is more effective than bedtime  omeprazole on residual nocturnal acid secretion. This  is clinically significant for patients taking a proton  pump inhibitor twice daily who remain symptomatic  during the night.   • Around 50% of cases of acute upper  gastrointestinal bleeding are due to peptic  ulceration.   • Stabilisation of blood pressure is required and  endoscopy should be planned.   • In vitro studies suggest that platelet aggregation  and blood coagulation are impaired when the pH  of gastric fluids is below 6.8.   • Therefore haemostasis may be promoted by  suppressing acid secretion using proton pump  inhibitors.   • Use of intravenous injection or tablets of  omeprazole reduces risk of continued bleeding or  re-bleeding.   Patient presents at the community pharmacy  with upper abdominal discomfort, retrosternal  pain, heartburn, with or without nausea and  vomiting.    Table 16.1 Comparison of H 2 -receptor antagonists and proton pump inhibitors (PPIs)   • Lifestyle advice: to decrease weight,  smoking and alcohol consumption, heavy  meals and consumption of fried and spicy  food   • Drugs used in hyperacidity include antacids that  are used to control the symptoms, H 2 -receptor  antagonists and proton pump inhibitors which  aim to reduce acid secretion and the triple  therapy used to eradicate H. pylori that is  associated with occurrence of gastric ulcers.   • Advise patients on use of ulcer-healing agents  prescribed, dose, duration of treatment and  response to therapy; advise on triple therapy  where appropriate.   • Monitor frequency of medicine requests to  identify worsening of the symptoms.   • Gastrointestinal investigations are based on H.  pylori tests and endoscopy.   • Abnormal biochemical and haematological test  results may occur in perforation or bleeding  ulceration.   1 Give an example of an antiflatulent and state  reasons for its use.    2 Comment on the following statement: Particular  care is required in using proton pump inhibitors  in those presenting with ‘alarm features’.   1 Simeticone added to an antacid as an  antifoaming agent is used to relieve flatulence. It  is also licensed for infant colic.   2 Proton pump inhibitors may mask symptoms  that indicate occurrence of conditions that  require referral and further investigation such as  carcinoma. The occurrence of gastro-oesophageal  reflux disease and gastric pain in patients who  are older than 55 years or patients who present  with alarm features such as weight loss, anaemia  (or signs of anaemia) and vomiting require  referral to check for other underlying conditions.   Dominici P, Bellentani S, Di Biase A R, Saccoccio G, Le  Rose A, Masutti F et al. (1999). Familial clustering of  Helicobacter pylori infection: population based study.  BMJ 319: 537-541.   Griffin S M and Raimes S A (1998). Proton pump inhibitors  may mask early gastric cancer. BMJ 317: 1606-1607.   Hatlebakk J G, Hyggen A, Madsen P H, Walle P O, Schulz  T, Mowinckel P et al. (1999). Heartburn treatment in  primary care: randomised, double blind study for 8  weeks. BMJ 319: 550-553.   Jafri N S, Hornung C A and Howden C W (2008). Meta-  analysis: Sequential therapy appears superior to stan-  dard therapy for H. pylori infection in patients naive to  treatment. Ann Intern Med 148: 923-931.   Peghini P L, Katz P O and Castell D O (1998). Ranitidine  controls nocturnal gastric acid breakthrough on  omeprazole: a controlled study in normal subjects.  Gastroenterology 115: 1335-1339.   1 Martin J, ed. British National Formulary, 57th edn.  London: Pharmaceutical Press, 2009, pp. 43-44.   • To identify characteristics of inflammatory bowel • To develop skills required for drug therapy   Inflammatory bowel disease represents disorders  occurring in the gastrointestinal tract which are  chronic and relapsing. Routine treatment involves  mainly steroids and aminosalicylates.   • Crohn’s disease: may affect any part of the  gastrointestinal tract, from the lips to the anal  margin but ileocolic disease is the most common.  In contrast to ulcerative colitis, inflammation  extends through the bowel wall. Drugs that exert  a topical effect are less effective in Crohn’s  disease than in ulcerative colitis.   • Ulcerative colitis: affects colon and rectal mucosa  and the terminology used to describe the area  affected is:    • Infective agents possibly related to infections by  anaerobic Gram-negative bacteria.   • Deficiency of calcium, magnesium, vitamins C,  K, B 12 , folate, iron.   • Clinical assessment: clinical index - assessment of  occurrence of symptoms; lab parameters (which  indicate an inflammatory condition, though not  specific to inflammatory bowel disease):  C-reactive protein, erythrocyte sedimentation  rate, platelet count.   • Treatment is aimed at treating acute attacks,  maintaining remission and assessing the risk of  colonic carcinoma.   Foods that may cause bolus obstruction if there is an  intestinal stricture should be avoided. Patients are  advised to avoid intake of:   Corticosteroids are the mainstay of treatment espe-  cially during the acute attack. Their use is limited by    the occurrence of side-effects. Prednisolone oral  therapy is usually the preferred treatment. It is  usually given for 4-8 weeks after which gradual dose  reduction should be started. However, some patients  require longer treatment with prednisolone to counter-  act the inflammatory disease. During a severe acute  attack, hydrocortisone or methylprednisolone as a  parenteral administration is usually used.   The use of enteric-coated preparations of oral  steroids reduces the risk of gastrointestinal  damage. The use of these preparations in  patients who have already undergone intestinal  surgery, leading to a smaller surface area for  absorption, may result in poor absorption of  the drug.   • Example: sulfasalazine, which is composed of  sulphapyridine that acts as a carrier  (sulphonamide) and 5-aminosalicylic acid; the  newer aminosalicylates (e.g. balsalazide,  mesalazine, olsalazine) do not contain the  sulphonamide carrier and are therefore free of  the side-effects associated with this component.   • Dosage forms with the newer aminosalicylates  have been developed to increase local delivery of  the aminosalicylate to the lower intestine and    decrease systemic absorption so as to minimise  side-effects. However, this localised effect  decreases efficacy in Crohn’s disease.   • Side-effects: diarrhoea, nausea, vomiting,  abdominal pain, headaches, dizziness, and  idiosyncratic reactions, namely occurrence of  skin rash, hepatic and pulmonary dysfunction,  aplastic anaemia.   • Risk of blood dyscrasias (agranulocytosis,  aplastic anaemia, leukopenia,  neutropenia, thrombocytopenia): patient  advised to report any unexplained  bleeding, sore throat or fever, and carry  out FBC (full blood count) routinely   • Concomitant therapy: avoid lactulose or  drugs which alkalinise the gastrointestinal  tract since this interferes with the  formation of 5-aminosalicylic acid   • Used in patients with severe disease who have  not responded to aminosalicylates and  corticosteroids or for patients who cannot be  weaned off corticosteroids to maintain remission.   Associated with a lower occurrence of side-effects but may be less effective than oral  prednisolone.    • Azathioprine, 6-mercaptopurine and  methotrexate have a long onset of effect while  ciclosporin has a more rapid onset of action.   • Used for the management of severe active  Crohn’s disease and moderate-to-severe  ulcerative colitis that has not responded to  corticosteroids and immunosuppressants   • Administered by intravenous infusion and a  rapid onset is expected.   • Used in severe active Crohn’s disease in patients  who have not responded to corticosteroids and  immunosuppressants   When there is an infective component during an  acute attack, metronidazole is considered. Metro-  nidazole is also associated with immunosuppressive  properties. Ciprofloxacin is considered an alternative  to metronidazole.   • Anti-diarrhoeals: used in patients where  diarrhoea is a problem (loperamide is the drug of  choice)    • Bulk-forming laxatives: fibre improves  constipation (e.g. ispaghula husk is a non-  fermenting soluble fibre and tends to cause less  bloating than other laxatives).   • Pouches of mucosa extrude through the muscular  wall through weakened areas near blood vessels  to form diverticula   • Management: increase fibre content in diet; anti-  infective agents (ciprofloxacin, metronidazole)  are used when the diverticula become infected.   • Inflammatory bowel diseases are chronic  conditions where the aims of treatment are to  achieve and maintain remission.   • Long-term management of ulcerative colitis and  Crohn’s disease includes use of aminosalicylates,  immunosuppressants, infliximab and  adalimumab.   1 Infliximab is normally recommended for the  treatment of severe active Crohn’s disease when  treatment with immunomodulating drugs and  corticosteroids has failed or is not tolerated,  and when surgery is inappropriate.   (b) Explain the use of corticosteroids and  immunomodulating drugs in Crohn’s  disease.   (c) Comment on the recommendations to use  infliximab in severe active disease.   1 (a) Active Crohn’s disease is the relapse of the  inflammatory gastrointestinal tract condition  which presents with symptoms of ill-health  and abdominal pain. Rectal bleeding,  anaemia and obstruction may occur.   (b) Corticosteroids are the mainstay of  treatment during the acute attack. If  treatment fails, then the use of immuno-  modulating drugs such as ciclosporin may  be considered. The drugs should be used for  the shortest period possible.   (c) Infliximab is an expensive treatment that  requires parenteral administration and  patient monitoring.   Feighery C (1999). Coeliac disease. BMJ 319: 236-239.  Mpofu C and Ireland A (2006). Inflammatory bowel  disease: The disease and its diagnosis. Hosp Pbarm 13:  153-158.   St Clair Jones A (2006). Inflammatory bowel disease: Drug  treatment and its implications. Hosp Pharm 13:  161-166.   • To appreciate pathophysiology of nausea and • To develop skills necessary for the use of   vomiting and how this reflects on choice of drug antiemetics in specific scenarios,   Emesis, also referred to as vomiting, is usually  preceded by nausea. Nausea and vomiting occur  usually as a result of a natural protective reflex against  toxins or as a result of stimuli from the olfactory,  visual, vestibular or psychogenic mechanisms. There  are a number of aetiological factors related to the  occurrence of nausea and vomiting:   • Sweating, pallor, tachycardia as a result of  response by the autonomic nervous system   • Metabolic consequences (dehydration) as a result  of loss of fluid.   The vomiting centre in the brain is the main area  for coordination of the occurrence of this reflex.  The vomiting centre depends on feedback from the  vestibular system, the chemoreceptor trigger zone  (CTZ), the vagus nerve and higher brain centres. The  CTZ is rich in receptors, namely receptors sensitive to  serotonin (5HT 3 ) and dopamine (D 2 ). It is not  protected by the blood-brain barrier and therefore it  is very sensitive to drugs. The vestibular system is rich  in cholinergic and histamine receptors while the vagus  nerve reproduces feedback from the gastrointestinal  tract.   Antiemetic treatment should be considered either for  prophylaxis or for treatment of nausea and vomiting    when the cause has been identified. Choice of drug Common side-effects of antiemetics are listed in  therapy depends on the aetiology of the condition. Table 18.2.   • Consider routes other than oral route (e.g. Postoperative nausea and vomiting   • D 2 antagonists: phenothiazines (e.g.  prochlorperazine), butyrophenones (e.g.  droperidol, haloperidol), benzimidazoles  (e.g. domperidone)    In motion sickness, the vomiting centre is  triggered by the vestibular system. Anti-  emetics that have an antihistamine or an anti-  cholinergic activity are effective. Serotonin  and dopamine antagonists are not effective  (see Chapter 61).    a Drug therapy should if possible be avoided. Domperidone is contraindicated in pregnancy. When  phenothiazines are administered during the third trimester, extra pyramidal effects in neonates have been  reported. See also Chapter 51 .    • Type of surgery: intra-abdominal, gynaecological  and interventions to the middle ear are  associated with increased risk   • Duration of surgery: the longer the duration, the  higher the risk.   The occurrence of nausea and vomiting with the  administration of cytotoxic therapy may limit drug  administration because of patient compliance and  due to the metabolic complications associated with  the occurrence of vomiting. In patients who are  receiving highly emetogenic cytotoxic chemotherapy  or in patients susceptible to develop this side-effect, a  combination of antiemetics may be used. In addition  to the conventional antiemetics, a cannabinoid  (nabilone) or a neurokinin receptor antagonist  (aprepitant) may be considered in patients who are  resistant to the other drugs (see also Chapter 42).    Some antiemetic drugs that are used in cyto-  toxic chemotherapy present with constipation  as a side-effect. The occurrence of this side-  effect may be further precipitated in patients  receiving opioid drugs. Consider use of a  laxative that can be administered long term  such as lactulose.   • Risk of occurrence of dystonic reactions (facial  and muscle spasm) due to metoclopramide is  higher in females, and young (less than 20 years)  and very old people.   • Compared with metoclopramide and the  phenothiazines, domperidone does not readily  cross the blood-brain barrier and therefore  causes fewer central effects (sedation, dystonic  reactions).   • Antihistamines and anticholinergics are the  antiemetics of choice in motion sickness.   2 Giving examples, discuss therapeutic options in  the management of chemotherapy-induced  nausea and vomiting.   1 Sedation and dystonic reactions occur  especially in females younger than 20 years old  and in older persons.   2 For the acute symptoms: oral metoclopramide,  domperidone and prochlorperazine are  preferred. During chemotherapy intravenous,    administration, of serotonin antagonists is used.  Dexamethasone may be used as an adjuvant  drug. For delayed symptoms, occurring a few  hours after chemotherapy administration,  domperidone is the most effective. For  anticipatory nausea metoclopramide with a  short-acting benzodiazepine, such as lorazepam,  is used.   causes and complications. Hosp Fharm 14: 185-188.  Husband A and Worsley A (2007). Nausea and vomiting:  pharmacological management. Hosp Fharm 14:  189-192.   Rahman M H and Beattie J (2004). Post-operative nausea  and vomiting. Fharm J 273: 786-788.    • To present clinical assessment and parameters  (signs, symptoms and laboratory markers) that are  monitored in cardiovascular disease management    • To describe pharmacist actions (treatment checks  and treatment changes) in cardiovascular disease  management and the use of pharmacotherapy.    Cardiovascular disorders are chronic conditions, the  most common of which are:    • Signs of impaired cardiac function such as  reduced cardiac output and/or valvular  dysfunction (from echocardiography), increase in  heart size (cardiomegaly seen on echocardiogram  or X-ray and indicated by auscultation),  impaired renal function   • Symptoms of fluid retention (such as  breathlessness, oedema, raised blood pressure)   • Symptoms of circulatory disorder and/or  impaired oxygenation (pallor, muscular weakness  and pain, paraesthesia and cyanosis)   • Examination of the entire patient: to assess for  signs of tiredness, depression, anxiety, diminished  mobility and evidence of loss of quality of life or  well-being.   • Blood pressure: to identify high blood pressure as  a risk factor of ischaemic heart disease and  stroke or a low blood pressure associated with  heart failure   • Symptoms presented: fainting spells, cough at  night, oedema of the ankle, chest pain, dyspnoea.  Description of the type of chest pain felt helps to  differentiate between chest pain due to  cardiovascular disorders and non-cardiac chest  pain. In angina and myocardial infarction the  pain is described as being compressive in nature,  with the patient describing tightness, ‘crushing’  and heavy pressure.   • Investigation: chest X-ray to detect enlarged  heart due to heart failure (left ventricular  dilatation due to high pre-load, that is  overstretching of the heart in decompensated  heart failure).   • Stress test (exercise test): to determine heart  response to the stress associated with exercise -  muscular activity.   • Cardiac enzymes: creatine kinase (CK) and its  isoenzyme fraction CK-MB, lactic dehydrogenase  and its isoenzymes LDHj and LDH 2 are enzymes  that are found in the cardiac muscle. Their level  in serum rises subsequent to cardiac muscle cell  damage and they are used as parameters to  identify myocardial infarction. CK-MB rises  within 3-5 hours after a myocardial infarction  while LDH increases within 12 hours after a  myocardial infarction.   • C-reactive protein: a biological marker for  systemic inflammation and is increased in  patients at risk of myocardial infarction, stroke  and peripheral arterial disease.   • Troponins: troponin I and T are complexes of  proteins that are specific to cardiac muscle  involved in the mediation of actin and myosin  interaction at the muscular level. Their levels  increase within a few hours of a myocardial  infarction.   ECG is recorded at rest and during a standard  protocol of gradually increasing levels of exercise.  This:   Patients taking beta-adrenoceptor blockers and  calcium channel blockers tend to have bradycardia  and therefore are not able to achieve their maximal  heart rates. These patients would be limited from  exercising to full capacity during a stress test. Rapid  withdrawal of beta-adrenoceptor blockers and  calcium channel blockers may cause exacerbation of  angina.   It may be undertaken as a screening test or to  monitor patient outcomes following a myocardial  infarction or to assess therapeutic management.   • Contraindications: unstable angina, physiological  limitations (e.g. mobility restrictions, severe  respiratory disease).   Carried out to assess heart valves, septum and  cardiac muscle walls. Size, shape and movement  during the cardiac cycle are assessed. In Doppler  echocardiography, cardiac blood flow patterns are  evaluated.   A catheter is threaded through the right and left side  of the heart to assess pressures in the heart chambers.  It is used to evaluate cardiac function.   • In angiography a contrast agent is injected into  the coronary arteries for visualisation purposes.  Used to assess the size of the artery and extent of  occlusion and to plan interventions. Interventions  that may be performed during angiography  include percutaneous transluminal coronary  angioplasty and stent placement.    • In angioplasty a balloon catheter is introduced  into coronary arteries to correct for narrowing of  the blood vessels.   • Conditions that predispose to a higher risk of  bleeding during or after the intervention:  cerebrovascular accident, severe anaemia,  uncontrolled hypertension, active gastrointestinal  bleeding, anticoagulation (warfarin)   • Act on supraventricular and ventricular  arrhythmias (e.g. amiodarone, beta blockers such  as carvedilol and sotalol, flecainide)   Anti-arrhythmic agents have a negative  inotropic effect and this tends to be additive if  multiple therapy is adopted. The occurrence of    hypokalaemia or hyperkalaemia increases the  risk of arrhythmias. In post-CABG patients  atrial fibrillations are common in the early  postoperative days. Unless contraindicated,  beta blockers are preferred since following  surgery there is a high sympathetic tone.  Amiodarone and verapamil may also be  considered.   • Used in supraventricular arrhythmias, causes  temporary complete sinoatrial and  atrioventricular block   • Short duration of action (10-20 seconds),  prolonged if patient taking dipyridamole   • Side-effects: unpleasant sensation in the chest,  transient facial flush, headache   • Used for supraventricular and ventricular  arrhythmias, slows heart rate and AV conduction   • Disadvantages: very long half-life (50 days), side-  effect profile, drug interactions   • Side-effects: corneal microdeposits (interfere with  night vision), phototoxicity (requires use of  sunscreen continued for a few months after  withdrawal), thyroid dysfunction, peripheral  neuropathy, pulmonary fibrosis, hepatotoxicity   • Patient monitoring: thyroid function, liver  function, ECG, eye examination since drug  should be stopped to prevent blindness if optic  neuritis or optic neuropathy occurs   • Drug interactions: increased risk of arrhythmias  (e.g. with moxifloxacin, co-trimoxazole,  antipsychotics, tricyclic antidepressants),  increased anticoagulant effect (e.g. with  warfarin), increased risk of myopathy (e.g. with   • Used for supraventricular and ventricular  arrhythmias especially management of acute  arrhythmias   • Caution: hypokalaemia reduces efficacy of  flecainide and increases risk of precipitating  serious arrhythmias   • Drug interactions: increased risk of bradycardia  (e.g. with beta-blockers), increased risk of  arrhythmias (e.g. with antipsychotics, tricyclic  antidepressants)   • Used in ventricular arrhythmias especially in  emergency use and after myocardial  infarction   • Side-effects: dizziness, paraesthesia or drowsiness  (reduced by administering intravenous injection  slowly)   • Administration: parenteral (injection or infusion).  With intravenous injection, duration of action is  short (about 15-20 minutes).   • Positive inotropic drugs to stimulate heart muscle  contraction and increase heart rate   • Ventricular fibrillations may cause cardiac arrest  and they can be detected from the ECG.  Electrolyte imbalance, hypoxia and acidosis may  predispose a patient to develop ventricular  fibrillations. Patient is defibrillated using a  defibrillator.   • AV blocks (heart blocks) may occur after heart  surgery or myocardial infarction or damage to  the AV node.   • In ventricular fibrillations, adrenaline is  administered through an intravenous line to  induce heart beats and increase blood flow.   • In AV blocks, atropine is used and the degree of  heart block is assessed to identify need for a  pacemaker.   depend on the extent of activity at the different recep-  tors within the sympathetic nervous system (alpha,   • Adrenaline is a potent stimulator of alpha and  beta receptors   - anaphylactic shock - administered by  intramuscular injection; pen device for patient  self-administration for management of severe  allergy   - cardiac arrest - intravenous administration  preferably through a central line; if injected  through a peripheral line, drug must be   • Compared with adrenaline, noradrenaline lacks  the methyl substitution in the amino group.  Noradrenaline is a potent agonist at alpha  receptors. Compared with adrenaline it has  equipotent activity at betaj receptors but little  action on beta., receptors.   • Dopamine is a precursor of noradrenaline and  adrenaline. It is a cardiac stimulant through its  interaction with the beta t receptors in the cardiac  muscle. It also causes the release of  norepinephrine from nerve terminals.    • When given at low doses, it increases systolic  blood pressure with minimal effect on peripheral  resistance.   Increased for systolic blood pressure, diastolic blood  pressure increased at higher doses   Increased due to activity on alpha receptors, results in  decreased blood flow to kidneys and liver   • Atropine is a tertiary amine antimuscarinic agent  which increases the heart rate.   • It inhibits parasympathetic system and results in  blockage or slowing down of the sinoatrial node.   • It is used in bradycardia and in occurrences of  bradyarrhythmias such as prevention and  management of bradyarrhythmias in anaesthesia  and in cardiac arrest.   • It is administered intravenously as a single dose  in cardiopulmonary resuscitation.   • Patients with a cardiovascular condition may  have other cardiac comorbidities which need to  be taken into consideration when identifying  drug therapy and planning patient monitoring.   • Drug therapy and lifestyle modifications are for  the long term. Patient needs to receive  information on the medication, and drug-related  problems should be identified so as to achieve  patient compliance.   • Parameters of cardiovascular function, physical  examination and laboratory tests could be used  routinely to assess patient condition and monitor  treatment outcomes.   1 Sympathomimetic agents such as adrenaline are  used in acute anaphylaxis. Adrenaline is a potent  beta 2 agonist which increases heart rate and force  of contraction. A common side-effect is  tachycardia. It stimulates alpha receptors at  higher concentrations. Onset of action is 3-5  minutes. Administered as an intramuscular  injection or as a pen device for patient self-  administration for management of severe allergy.   Chernecky C, Alichnie M C, Garrett K, George-Gay B,  Hodges R K and Terry C (2002). ECGs and the Heart.  Philadelphia: WB Saunders Co.   Longe R L, Calvert J C and Young L Y, eds (1996). Physical  Assessment: A guide for evaluating drug therapy.  Vancouver: Applied Therapeutics Inc.   Tietze K J (2004). Clinical Skills for Pharmacists: A patient-  focused approach , 2nd edn. St Louis: Mosby.   Bernard Coleiro, Consultant Physician, Department of  Medicine, Mater Dei Hospital, Malta.   • To understand regulation of blood pressure and  significance of hypertension   • To identify drugs used in hypertension and  appreciate their characteristics   • To appreciate use of drug therapy, patient  monitoring and follow-up required   Hypertension is a chronic condition characterised by  a sustained diastolic reading greater than or equal to  80 mmHg and a systolic reading greater than or  equal to 120 mmHg (120/80 mmHg). Occurrence can  damage blood vessels and increase probability of  development of atheromatous disease. Treatment is  aimed to decrease morbidity and mortality.   • Cardiac output (depends on heart rate,  contractility, filling pressure, blood volume)   • Cardiovascular: constriction of arterioles and  insufficient blood flow to coronary vasculature  leads to angina, myocardial infarction; left  ventricular hypertrophy may occur due to  increased cardiac output leading to heart  failure.   • Renal: arteriolar nephrosclerosis leads to  polyuria, nocturia, protein and red blood cells in  urine, elevated serum creatinine, renal  insufficiency.   • Cerebral: decreased blood flow and decreased  oxygen supply lead to transient ischaemic  attacks, cerebral thromboses, haemorrhage.   • Retinal: damage to arterioles of retina leads to  haemorrhage, visual disturbances.   • Patient should be relaxed, sitting down with arm  at about the level of the heart; check pressure in  both arms.   • Three consecutive elevated readings taken on  three separate occasions should be documented  before the diagnosis of ‘hypertension’ is applied  to a patient.   • Interpretation of results: systolic reading is more  important than diastolic reading; patient history  and family history are taken into consideration  when deciding on line of action.   • European Guidelines for the management of  hypertension were issued in June 2007 by the  European Society of Elypertension jointly with  the European Society of Cardiology. 1   • Overall goal to achieve blood pressure (BP) of  140/90 mmHg.   • Goal takes into consideration comorbidities  (e.g. in diabetes the goal is to achieve  130/80 mmHg).   • Pharmacotherapy should consider the five  important drug classes: ACE inhibitors,  angiotensin receptor antagonists,  beta-blockers, calcium channel blockers and  diuretics.   - comorbidities (e.g. diabetes mellitus - ACE  inhibitors or angiotensin receptor antagonists;  metabolic syndrome - angiotensin-converting  enzyme (ACE) inhibitors, angiotensin receptor  antagonists, calcium antagonists)   - history of clinical events (e.g. myocardial  infarction - beta-blockers, ACE inhibitors,  angiotensin receptor antagonists; angina  pectoris - beta-blockers, calcium channel  blockers (avoiding short-acting  dihydropyridines); heart failure - diuretics,  beta-blockers (particularly carvedilol),   - organ damage (e.g. renal dysfunction - ACE  inhibitors, angiotensin receptor antagonists;  left ventricular hypertrophy - ACE inhibitors,  angiotensin receptor antagonists, calcium  channel blockers).   • Regardless of which drug therapy is used,  monotherapy achieves blood pressure goal   in only a limited number of patients. Majority of  patients require multiple drug therapy.   • Lifestyle measures are relevant for all  patients: smoking cessation, weight reduction  and maintenance, reduction of excessive  alcohol intake, physical exercise, reduction  of salt intake, increased fruit and vegetable  intake, decreased saturated and total fat  intake.   • High blood pressure (more than  180/110 mmHg with signs of  papilloedema and/or retinal haemorrhage)   • Suspected phaeochromocytoma (signs  include labile or postural hypotension,  headache, palpitations, pallor and  diaphoresis)   • Unusual signs and symptoms or  symptoms that suggest a secondary cause  of high blood pressure.   • Blood tests: glucose, electrolytes, creatinine,  serum total cholesterol and high-density  lipoprotein (HDL) cholesterol    blood pressure. (Note use of ambulatory blood  pressure monitors to detect variation of blood  pressure control.)   • Presence of target organ damage, renal disease,  diabetes or cardiovascular disease   • Interactions with drugs used for other conditions  by the patient   • Change to different class of drugs if drug is not  producing effect on blood pressure levels or if  side-effects are a significant problem   • Use formulations that provide a 24-hour control:  better adherence and ensure control of blood  pressure in early morning when there is surge of   • Sympatholytics: reduce ability of sympathetic  system to raise blood pressure    c alculation of risk  Computer programs/algorithms,  e.g. Coronary Risk Prediction Charts  (British Hypertension Society) 3   • Create a negative sodium balance resulting in a  reduction of blood volume   • Loop diuretics (e.g. furosemide) are used mainly  in pulmonary oedema due to ventricular failure,  chronic heart failure (see also Chapter 22).   • Reduce sodium and water retention in the distal  convoluted tubule in the kidney resulting in a  reduction of the peripheral resistance   Bendroflumethiazide and indapamide are com-  pared in Table 20.1 and their chemical structures   • Retain potassium and therefore no need to  consider potassium supplementation   • Are weak diuretics and in fact may be found in  combination products with thiazides.    a To be administered in the morning to reduce nocturnal need for  urination.   Tachycardia, dizziness upon standing up,  thirst, postural hypotension, decreased skin  turgor   Feeling of fullness in arch of foot,  occasionally painful joint - development of  gout (usually big toe), high serum uric acid   For potassium-sparing diuretics, hyperkalaemia  rather than hypokalaemia may occur. Key moni-  toring parameters to identify occurrence of hyper-  kalaemia include gastrointestinal hyperactivity,  muscle weakness and cramps.   • Potassium-sparing diuretics: ACE inhibitors since  ACE inhibitors may cause hyperkalaemia   • Competively block beta receptors of the  sympathetic system resulting in slowing of the  heart, reduction in the force of contractions and  lengthening of diastole.   • Side-effects: bradycardia, heart failure,  hypotension, bronchospasm, peripheral  vasoconstriction, fatigue, depression, vivid  dreams.   • Cautions/contraindications: asthma, COPD,  peripheral vascular disease, Raynaud’s  phenomenon, heart block, diabetes mellitus  (they may mask symptoms of hypoglycaemic  attacks).   Various beta-blockers are compared in Table 20.3  (see also Chapter 21) and their chemical structures  are shown in Figure 20.5.   Propranolol has a high octanol/buffer partition  coefficient indicating a high lipophilicity. It enters the  central nervous system better than other beta-  blockers. Its primary clearance route is through the  liver while more hydrophilic agents such as atenolol  are cleared primarily through the kidneys. This  should be kept in mind when selecting a drug in  patients with renal or liver disease.   Beta-blockers act by stimulating beta receptors when  background sympathetic activity is low and blocking  them when activity is high.   ACE inhibitors decrease formation of angiotensin II,  resulting in decreased vasoconstriction and decrease  in aldosterone production, which in turn results in  decreased fluid retention.   • Cautions: patients receiving diuretics, peripheral  vascular disease, renovascular disease, severe or  symptomatic aortic stenosis, hypertrophic  cardiomyopathy   • Care in elderly patients since they are at risk of  renal side-effects   • Avoid concomitant NSAID use in patients at risk  of renal side-effects since concomitant use  increases risk and antagonises hypotensive effect  of ACE inhibitors.   that is required for ACE inhibitory effects. The pres-  ence of the sulphhydryl group is associated with a  higher incidence of skin rashes and taste disturbances.  Also the sulphhydryl component may form a disul-  phide which results in a short half-life for the product.   Enalapril, lisinopril, perindopril and ramipril (see  Figure 20.7) are dicarboxylate-containing ACE  inhibitors that do not feature a sulphhydryl group.  The presence of large hydrophobic heterocyclic rings  in the N-ring of perindopril, ramipril, moexipril,  quinapril and trandolapril result in increased potency  and longer half-life when compared with enalapril and  lisinopril. This feature also results in enalapril and  lisinopril lacking lipid solubility. Perindopril shows the  highest oral bioavailability, followed by trandolapril.   Patients are advised to start first dose at night  to avoid consequences of hypotension.   These are specific angiotensin II receptor antagonists,  which thus block the vasoconstrictor and aldosterone-  secreting effects of angiotensin II.   Usually occurs if concomitant use of potassium  supplement or potassium-sparing diuretic    • Do not inhibit breakdown of bradykinin, so less  likely to cause cough as a side-effect   • Interfere with the opening/closing of calcium  channels in cardiac, vascular and smooth muscle  cells   • The dihydropyridines (e.g. nifedipine,  amlodipine) cause peripheral vasodilatation and  have little direct effect on heart compared with  verapamil and diltiazem (which are other types  of calcium channel blockers)   • Sustained-release preparations or long-acting  drugs such as amlodipine are preferred to  decrease risk of myocardial infarction   This drug selectively binds to Ij-imidazoline receptors  in the brainstem. The receptors influence adrenergic  vasomotor tone involved in blood pressure regula-  tion. I j -imidazoline receptors are also available in the  kidneys.    Rilmenidine is an antihypertensive agent with a  central action on the brainstem and a peripheral  activity in the kidney. Its characteristic is that it is  selective for the Ij-imidazoline receptors rather than  also interacting with cerebral alpha 2 -adrenergic  receptors.   • Available as tablets 1 mg, dosage regimen: one  tablet per day   The contraindications and cautions to use of drug  therapy are summarised in Tables 20.9 and 20.10.   Some of the common drug interactions with anti-  hypertensive drugs are listed in Table 20.11.   • Potassium-containing preparations (e.g. salt  substitutes, potassium citrate indicated for  cystitis).   • To provide patient support with drug  therapy and lifestyle modifications    • To discuss symptoms and medication  (identify unwanted drug effects, any other  drugs taken by patient for other disease  states)   • To evaluate need for patient referral to  prescriber (based on laboratory test  results and/or the presence of other  symptoms)   • To consider use of other drugs that reduce  cardiovascular risk (aspirin and statin  therapy).   • Effect of ACE inhibitors may be decreased due to  lower renin levels.   Two conditions associated with hypertension in preg-  nancy are pre-eclampsia - pregnancy-induced hyper-    tension, 140/90 mmHg developing during pregnancy  in a woman whose blood pressure was previously  normal - and eclampsia - occurrence of convulsions  caused by hypertension.   • Calcium channel blockers (amlodipine and  nifedipine): manufacturer advises avoidance but  risk of uncontrolled maternal hypertension  should be balanced against risk of use of drug.   • ACE inhibitors and angiotensin II receptor  blockers cannot be used - they may damage the  fetus and cause problems in the neonate.   • Leads to uncontrolled and irregular secretion of  adrenaline and noradrenaline   This is a severe elevation in blood pressure with a  diastolic above 120-130 mmHg and the presence of  acute or on-going end-organ damage, with cerebral  infarction and pulmonary oedema being the most  common occurrences of end-organ damage.   • This may be a medical emergency and requires  prompt reduction of blood pressure within  minutes to 1 hour   • Conditions that predispose to hypertensive  emergency include phaeochomocytoma, renal  vascular disease, head injury, severe burns,  eclampsia   • Very rapid fall in blood pressure can cause  reduced cerebral perfusion leading to: cerebral  infarction, blindness, renal function  deterioration, myocardial ischaemia   • Oral antihypertensive drugs are used to decrease  blood pressure slowly   • Direct-acting arterial and venous vasodilator that  is available for parenteral administration   • Caution: hypothyroidism, hyponatraemia,  ischaemic heart disease, impaired cerebral  circulation, elderly, hypothermia    • Side-effects: hypotension, nausea and vomiting; if  treatment is for more than 24-28 hours,  thiocyanate toxicity (it reacts with sulphhydryl  groups in blood and tissue producing  thiocyanate).   • Produces a reduction in peripheral vascular  resistance, blood pressure and heart rate   • Advantage: available for parenteral and oral  administration and so allows easy conversion  from intravenous administration to oral  therapy   • Causes a vasodilator effect on the arterioles  resulting in decreased peripheral resistance. It  also inhibits the secretion of insulin by the beta  cells of the pancreas   • Onset of action within 2-5 minutes with a  preliminary rise in blood pressure immediately  after administration   • Patient monitoring: blood pressure, blood  glucose levels particularly in patients with  diabetes.   • The regulation of blood pressure depends on the  peripheral resistance and the cardiac output.  These factors are affected by the sympathetic  nervous system and the renin-angiotensin-  aldosterone system.    • Drugs that are used as antihypertensives aim to  reduce blood volume (diuretics), decrease  sympathetic activity (beta-adrenoceptor  blockers), reduce peripheral resistance (calcium  channel blockers) and affect the renin-  angiotensin-aldosterone system (ACE inhibitors,  angiotensin II antagonists).   • Antihypertensives may be used in monotherapy  or as combination therapy.   1 Compare atenolol and enalapril considering  indications, dosage regimen, side-effects and  contraindications.   2 Name two conditions when thiazide diuretics  should be used with caution or are  contraindicated.   3 What is the clinical implication when a patient  who is receiving a thiazide diuretic is also  started on naproxen?   4 Giving reasons for your answer, explain when  bendroflumethiazide is indicated.   5 Describe drug therapy that should be considered  as first line in a 58-year-old patient diagnosed  with hypertension who has a history of diabetes  mellitus. What other preventive drug therapy  could be considered?   3 Naproxen is a non-steroidal anti-inflammatory  drug that causes salt and fluid retention, thus  decreasing the hypotensive effect of thiazide  diuretics.   4 Bendroflumethiazide is a thiazide diuretic that  reduces sodium and water retention in the distal  convoluted tubule in the kidney, creating a  negative sodium balance, resulting in a reduced  blood volume and a reduced peripheral  resistance. It is indicated in hypertension and  oedema.   5 In a 58-year-old patient diagnosed with  hypertension and with a history of diabetes  mellitus an angiotensin-converting enzyme  (ACE) inhibitor is indicated as first-line  treatment. ACE inhibitors should be used with  caution in renovascular disease; however, in  diabetes they have a renoprotective effect.  Renal function should be checked prior to  initiating therapy and monitored during therapy.  ACE inhibitors may cause profound first-dose  hypotension, so first doses should be given at  night. Potassium levels must be monitored.   Cardioselective beta-blocker. Works by selectively  blocking the beta receptors in the sympathetic nervous   ACE inhibitor which decreases the production of  angiotensin II, a potent vasoconstrictor, and also  decreases aldosterone production and hence fluid  retention. These actions lower the blood pressure   Profound first-dose hypotension, persistent dry cough,  renal impairment, hyperkalaemia, skin rashes   Asthma and chronic obstructive pulmonary disease,  heart block, peripheral vascular disease, diabetes    Persistent cough may be a problematic side-  effect. Angiotensin II receptor antagonists do  not inhibit bradykinin, have fewer side-effects  than ACE inhibitors and are indicated when  patients are intolerant to ACE inhibitors due to  the cough side-effect. Other preventive drug  therapy that can be considered to reduce  cardiovascular risk includes low-dose aspirin  and statin therapy.    the British Hypertension Society, 2004-BHS IV. J Hum  Hypertens 18: 139-185.   1 Mancia G, de Backer G, Dominiczak A et al., guidelines  for the management of arterial hypertension. J Hyper-  tens 2007; 25: 1105-1187.   2 Joint Formulary Committee. British National Formulary ,  57th edn. London: British Medical Association and  Royal Pharmaceutical Society of Great Britain, 2009.    Williams B, Poulter N R, Brown M J, Davis M, Mclnnes Acknowledgements  G T, Potter J F et al. (2004). Guidelines for management   of hypertension: report of the fourth working party of Bernard Coleiro, Consultant Physician, Department of    • To develop skills to be able to assess effectiveness  of pharmacotherapy and monitor patient  progress.   Ischaemic heart disease is a condition characterised  by a reduced supply of oxygenated blood to cardiac  tissue. This occurs as a result of:   • oxygen demand exceeding supply when vascular  supply to the heart is impeded (e.g. atheroma,  thrombosis)   • oxygen demand is increased (e.g. severe  ventricular hypertrophy as a result of  hypertension, iron-deficiency anaemia).   • Reversible coronary artery ischaemia results in  angina pectoris, which may present as:   - chronic stable/exercise-induced angina -  patient presents with a reproducible pattern of  angina that is precipitated by a certain level of  emotional stress or physical activity   The first few hours after a myocardial infarction  are the most critical and ventricular fibrillation is  most likely to occur.   • Pain: gripping or tight in nature occurring in the  retrosternal region of the chest; pain may radiate  to neck, back, left shoulder with possible  involvement of jaw, teeth or epigastrum   Symptoms of ischaemic heart disease may be very  similar to chest pain that is related to other conditions  such as:   • ECG: ST-segment depression, T-wave inversion  indicating angina and ST-segment elevation  indicating myocardial infarction   • Blood tests: elevation of cardiac-specific troponin  I and T, creatine kinase.   Lifestyle modifications are very important in the  management of patients with ischaemic heart disease.  Table 21.1 presents an estimate of the percentage  lowering of the risk of myocardial infarction per  intervention. Combining multiple interventions will  have an additive effect.   • To increase length of pain-free survival  with a good quality of life.   • These are converted to nitric oxide, which in  turn combines with sulphhydryl groups to form  nitrosothiols. These activate production of cyclic  GMP which causes smooth muscle relaxation  and vasodilatation.   • Nitrate esters are volatile and explosive. These  characteristics create problems during production  of the dosage forms. They are labile to moisture  since moisture will lead to hydrolysis of the ester  bond in turn leading to a decreased therapeutic  effect.   • Nitrates cause vasodilatation and venodilatation,  leading to a decrease in preload and a reduction  in cardiac work and may also cause coronary  vasodilatation to improve coronary blood supply.   • A disadvantage is that tolerance may occur. For  this reason plan a nitrate-free period for 4-8  hours per day. This nitrate-free period should be  undertaken when there is least risk of infarction  (e.g. during the night). During the nitrate-free  period, angina protection is received from  concomitant therapy with beta-blockers or  calcium channel blockers.   • Side-effects: throbbing headache, flushing,  postural hypotension (prevented by sitting  down), dizziness, fainting. Care should be taken  to avoid falls due to postural hypotension.   • Sublingual tablets: cheap, deteriorate rapidly,  storage in dark container without cotton-wool  wadding required; administered sublingually  since drug is metabolised due to first-pass effect   • Sublingual sprays: more expensive than  sublingual tablets, sprayed under or on the tongue   • Parenteral preparations: used in patients with  chest pain due to myocardial infarction or severe    ischaemia (unstable angina) and in the treatment  of left ventricular failure.   Glyceryl trinitrate is used for symptomatic  relief of angina. Sublingual tablets and the  aerosol spray provide rapid (1-2 minutes)  symptomatic effect that lasts for about 20-30  minutes. If first dose does not relieve pain the  patient can repeat dose within 5 minutes. If  the use of nitrates for symptomatic relief is  required regularly, the patient should seek  professional advice.   • Administration requires divided daily doses  which may have a negative impact on  compliance.   These cause a decrease in heart rate, blood pressure  and force of ejection in systole. The use of beta-  blockers in chronic angina has been shown to decrease  incidence of angina attacks and lower morbidity  and mortality in patients with other cardiovascular  disorders.   Cardioselective agents and agents with low  lipophilicity are preferred. Cardioselective agents  include atenolol, bisoprolol, metoprolol and nebivolol.  Agents that are mostly water soluble are less likely to  enter the brain and cause sleep disturbances. Such  products include atenolol, nadolol and sotalol.   • Contraindications: asthma, COPD, peripheral  vascular disease, heart failure, bradycardia, heart  block   • Cautions: diabetes - may cause deterioration in  glucose control and interfere with signs of  hypoglycaemia    • Care: should not be stopped abruptly especially  in patients with ischaemic heart disease since  abrupt withdrawal may precipitate angina due to  rebound receptor hypersensitivity   These act as arterial vasodilators. The dihydropyri-  dine calcium channel blockers such as amlodipine,  felodipine, nicardipine and nifedipine have more  influence on the blood vessels and less on the  myocardium compared with verapamil.   Modified-release formulations of nifedipine are  preferred to avoid large fluctuations in blood pres-  sure and occurrence of tachycardia. Amlodipine and  felodipine have a longer duration of action and are  given once a day.   Verapamil has more influence on heart rate. It is  indicated when beta-blockers are contraindicated. A  characteristic side-effect is marked constipation. It  should not to be used with beta-blockers (additive  effect leading to bradycardia).   • Side-effects: flushing, headache, reflex  tachycardia (may warrant the use of beta-  blockers) and ankle swelling   • Contraindications: severe hypotension, severe  aortic stenosis, extreme bradycardia, moderate-  to-severe heart failure, cardiogenic shock   • Similar efficacy to other anti-anginal drugs in  the prevention and long-term use in the  management of angina. Used with other anti-  anginal drugs   • Selective inhibitor of the sinus node I f , resulting  in a decrease in heart rate   • Particularly indicated in patients who have a  contraindication or intolerance to beta-blockers.   This is a 3-ketoacyl-CoA thiolase (KAT) inhibitor  which results in decreased fatty acid oxidation in the  myocardium, thus decreasing metabolic damage due  to ischaemia. It can be used in combination therapy  with other anti-anginal drugs.   The HOPE (Heart Outcomes Prevention Evaluation)  study (2000) 1 demonstrated the benefits of ACE  inhibitors in patients aged 55 years or older at high  risk of cardiovascular complications, characterised  by a high prevalence of diabetes, hypertension, stroke  and obstructive peripheral vascular disease.   The EUROPA (European Trial on Reduction of  Cardiac Events with Perindopril in Stable Coronary  Artery Disease) study (2003 )* has demonstrated the  positive outcomes with the use of perindopril in  patients with stable coronary heart disease. Among  patients with stable coronary heart disease without  apparent heart failure, perindopril can significantly  improve the outcome. Treatment with perindopril  together with other preventive medications should be  considered.   Patients should be advised to avoid drugs  containing sympathomimetics such as systemic  use of cold preparations.   • Oxygen to counteract the occurrence of hypoxia,  pulmonary oedema or continuing myocardial  ischaemia   • Intravenous diamorphine, sublingual glyceryl  trinitrate or intraveneous glyceryl trinitrate or  isosorbide dinitrate against pain and distress   • Drugs used to limit infarct size: thrombolytics+  aspirin+heparin, beta-blockers, ACE  (angiotensin-converting enzyme) inhibitors or  angiotensin II receptor antagonists.   These activate plasminogen to form plasmin which  degrades fibrin and so breaks up thrombi. Studies have  confirmed that the use of streptokinase and alteplase  reduce mortality. Other thrombolytics are also avail-  able (e.g. reteplase, tenecteplase). They have to be  administered parenterally within 12 hours of symptom  onset. The earlier the treatment is started the better.   • Cautions: risk of bleeding (e.g. patient has  undergone invasive procedures), hypertension  (blood pressure should be reduced below 180/100  mmHg before initiating therapy), elderly, diabetic  nephropathy, and recent or concurrent use of  drugs that increase risk of bleeding   • Antibodies to streptokinase occur after 4 days  and therefore it should not be used again beyond  4 days of first administration    • Contraindications: conditions that increase risk  of bleeding (e.g. trauma, recent surgery,  aneurysm, recent symptoms of peptic ulceration,  heavy vaginal bleeding)   • Side-effects: nausea, vomiting, bleeding,  reperfusion arrhythmias and recurrent ischaemia  and angina, hypotension.   • Take into consideration other disease  states (e.g. diabetics need to achieve  optimum blood glucose level control).   • Verapamil: highly negative inotropic calcium  channel blocker which reduces cardiac output  and slows heart rate. May precipitate heart  failure, not to be used in conjunction with  beta-blockers   • Target total cholesterol level <5 mmol/L, low-  density lipoprotein (LDL) <3 mmol/L   Disease states that occur with ischaemic heart disease  and preventive treatments are summarised in Table  21.2.   1 Giving reasons for your answer, explain when  glyceryl trinitrate is indicated.   2 Describe drug therapy that should be considered  as first line in a 52-year-old patient diagnosed  with ischaemic heart disease who has a history  of hyperthyroidism. What other preventive  drug therapy could be considered?   1 Glyceryl trinitrate is used in the prophylaxis and  treatment of angina. It is converted to nitric  oxide which in turn combines with sulphhydryl  groups to form nitrosothiols. These activate the  production of cyclic GMP which causes smooth  muscle relaxation and vasodilatation.   2 Use a beta-blocker such as atenolol: it decreases  heart rate, blood pressure and force of ejection   in systole, and reduces morbidity and mortality in  ischaemic heart disease. It also has symptomatic  control of tachycardia and tremor associated  with hyperthyroidism. Many of the common  symptoms of hyperthyroidism such as  palpitations, trembling and anxiety are mediated  by increases in beta-adrenergic receptors on cell    surfaces. Beta-blockers reduce rapid pulse  associated with the sensation of palpitations and  decrease tremor and anxiety.   Briffa T, Hickling S, Knuiman M, Hobbs M, Hung J,  Sanfilippo F M et al. (2009). Long term survival after  evidence based treatment of acute myocardial infarction  and revascularisation: follow-up of population based  Perth MONICA cohort, 1984-2005. BMJ 338: b36.   Hippisley-Cox J and Coupland C (2005). Effect of combi-  nations of drugs on all cause mortality in patients with  ischaemic heart disease: nested case-control analysis.  BMJ 330: 1059-1063.   1 EUROPA (European Trial on Reduction of Cardiac  Events with Perindopril in Stable Coronary Artery  Disease) Investigators. Efficacy of perindopril in reduc-  tion of cardiovascular events among patients with  stable coronary artery disease: randomized, double-  blind placebo-controlled, multicentre trial (the  EUROPA study). Lancet 2003; 362: 782-788.   • To review characteristics of congestive heart failure • To identify pharmacist intervention in patient care   Congestive heart failure (CHF) occurs when the heart  fails to sustain an adequate delivery of blood to tissues.  It is a common condition progressing to early death  and affecting quality of life (fatigue, breathlessness,  oedema).   • Class I: no symptoms (dyspnoea, fatigue,  palpitations) associated with ordinary activity.  Physical activity not limited   • Class II: asymptomatic at rest, but symptoms  occur with ordinary activity. Physical activity  minimally limited   • Class III: asymptomatic at rest, but symptoms  occur with less than ordinary activity. Physical  activity markedly limited interfering with daily  lifestyle   • Sodium restriction - very critical in  treatment of heart failure   • Self-monitoring by patient of body weight  - to assess fluid retention.   • ACE (angiotensin-converting enzyme) inhibitors:  standard of care unless there is a  contraindication to their use   ACE inhibitors used in the treatment of heart failure  are listed in Table 22.1.   • Provide effective symptomatic control in patients  with oedema with little long-term impact on  prognosis   • If gradual diuresis is aimed at or symptoms are  mild a thiazide diuretic (e.g.  bendroflumethiazide) is preferred   • If there is persistent volume overload despite the  use of thiazides, severe volume overload, or  decreased renal function, a loop diuretic (e.g.  furosemide) is preferred   5 mg daily increased by 5 mg every 12-24 hours  according to response   a Profound diuresis may occur; preferred for short-term use during acute period.   • A potassium-sparing diuretic which potentiates  thiazide or loop diuretics by antagonising  aldosterone   • Used in patients with severe heart failure who are  receiving an ACE inhibitor and a diuretic with  insufficient response   • Drug interaction with digoxin: spironolactone  increases plasma concentration of digoxin.   • Carvedilol, bisoprolol and metoprolol have  shown positive effects on prognosis   • Used in combination with ACE inhibitors,  diuretics, and digoxin to reduce the morbidity of  heart failure   • Caution: may initially worsen heart failure -  titrate dose and monitor patient, avoid abrupt  withdrawal of beta-blockers   • Oral administration: give with food to slow  absorption and minimise risk of orthostatic  hypotension   • Monitor digoxin levels with concurrent use,  increased risk of atrioventricular (AV) block and  bradycardia when given with digoxin    • For carvedilol: initial dose - 3.125 mg twice  daily; maximum dose 25 mg twice daily in  patients with body weight less than 85 kg  and 50 mg twice daily in patients over   • A positive inotropic agent indicated in patients at  highest risk for clinical deterioration or patients  who cannot tolerate ACE inhibitors or remain  asymptomatic   • Nitrate-free period each day of about 10 hours:  in heart failure the nitrate-free period should  occur during the day when dyspnoea can be  managed with diuretics while nitrate is used at  night to manage paroxysmal nocturnal  dyspnoea   • Used in combination since nitrates produce  mainly venous dilatation and hydralazine  produces arterial vasodilatation.   • May be considered in patients who cannot  tolerate ACE inhibitors   • CHARM 1 (Candesartan in Heart Failure:  Assessment of Reduction in Mortality and  Morbidity) study (1999) showed that  candesartan reduced cardiovascular deaths and  hospital admissions for symptomatic heart  failure.   Studies have indicated that the negative inotropic  effects of calcium channel blockers may result in wors-  ening of heart failure. This is particularly relevant for  verapamil and diltiazem. There is a possibility that  amlodipine and felodipine have minimal negative  inotropic effects but their use is not implicated in  adverse effects on morbidity and mortality.   • Antacids with high sodium content,  NSAIDs: renal retention of sodium and  water   • Non-compliance with treatment  particularly the diuretic therapy (patients  receiving diuretics should be advised  about timing of administration to avoid  inconvenient micturition).   • Goals of treatment: relieve symptoms and signs,  decrease hospitalisation and prolong survival.   • A number of factors may precipitate the  condition. Patient should be monitored regularly  to identify factors that may have a negative  impact on the progress of the condition.   • Drug therapy management requires titrating  diuretic dose according to patient need and  considering preventive therapy for cardiovascular  disease (e.g. aspirin, statins).   • Patient should be monitored for signs of effective  control (e.g. improvement in exercise tolerance,  decreased oedema) and for signs of toxicity (e.g.  digoxin toxicity), and signs of chronic excess of  diuretics which may lead to dehydration, fatigue  or fainting.   1 What is the relevance of using a diuretic in  congestive heart failure?   2 Give two examples of diuretics that may be  used in heart failure. For each example state  dose and side-effects to be expected.   1 Congestive heart failure is a disorder in which  the heart loses its ability to pump blood    Table 22.3 Doses and side-effects of two diuretics that may be used in heart failure   1 mg in the morning repeated after 6-8 hours, severe  cases 5 mg daily, maximum dose 10 mg   Gastrointestinal disturbances, impotence, gynaecomastia,  menstrual irregularities, lethargy, headache, confusion,  rashes, hyperkalaemia    efficiently throughout the body. Heart failure  may affect the left, right or both sides of the  heart. If the left half of the heart fails (left  ventricular failure), fluid will build up in the  lungs due to congestion of the veins of the  lungs. If the right half of the heart fails (right  ventricular failure), general body vein pressure  will increase and fluid will accumulate in the  body, especially the tissues of the legs and  abdominal organs. Fluid may build up in the  lungs and legs. Diuretics are important as they  relieve symptoms quickly and control fluid  retention. Diuretics provide effective  symptomatic control in patients with oedema  with little long-term impact on prognosis.   2 Bumetanide and spironolactone doses and  side-effects are summarised in Table 22.3.   Ahmed A, Aronow W S and Fleg J L (2006). Higher New  York Heart Association classes and increased mortality  and hospitalization in patients with heart failure and  preserved left ventricular function. Am Heart J 151:  444-450.    Jessup M, Abraham W T, Casey D E, Feldman A M, Francis  G S, Ganiats T G et al. (2009). Focused update:  ACCF/AHA Guidelines for the diagnosis and manage-  ment of heart failure in adults. / Am Coll Cardiol 53:  1343-1382.   Lock J (2003). The benefit of adding a pharmacist to the  heart failure team. Hosp Pbarm 10: 81-83.   Micale Foody J, Farrell M H and Krumholz H M (2002).  (3-blocker therapy in heart failure. JAMA 287:  883-887.   Poole-Wilson P (2004). NICE guidance on heart failure:  a challenge for primary care. Prescribe r 5 January:  8-16.   1 Pfeffer M A, Swedberg K, Granger C B, Held P,  McMurray J J V, Michelson EL et al. for the CHARM  investigators and committees. Effects of candesartan on  mortality and morbidity in patients with chronic heart  failure: the CHARM-Overall programme. Lancet 2003;  362: 759-766.    • To develop skills to be able to participate in patient  monitoring and identify patients eligible for drug  therapy.   Levels of serum cholesterol or triglycerides or both  denote increased risk of coronary artery disease.  Cholesterol, triglycerides and phospholipids are  transported as lipoproteins:   Of these, VLDLs and LDLs are undesired lipopro-  teins and HDLs are desirable to maintain levels of  protective HDLs.   Optimal levels of lipoproteins are listed in Table  23.1. Ideally the LDL:HDL ratio should be less than  3. If the ratio is higher than 4 risk of atherogenesis is  high (see also Chapter 11).    In the management of hyperlipidaemia, the  primary outcome of therapy should be to  lower low-density lipoprotein-cholesterol.   A condition characterised by fasting plasma tri-  glycerides >2 mmol/L (hypertriglyceridaemia) and  low-density lipoprotein >3 mmol/L.    • Usually occurs as a result of metabolic disorders  (e.g. insulin resistance)   • Statins are more effective in lowering LDL-  cholesterol than fibrates and also exert a  reduction in serum triglycerides though the latter  effect occurs to a lesser extent when compared  with fibrates.   • Limited saturated fat intake: reduced intake of  red meats, milk   • Lifestyle modifications should be  considered as a primary prevention  approach adopted even when patient has  no previous coronary heart disease and  no atherosclerotic vascular disease.   • Screening of adults over 20 years of age  or older once every 5 years is indicated to  identify patients at risk and recommend  lifestyle modifications as appropriate.   This is a condition in which high cholesterol concen-  trations occur due to a genetic risk. The condition  may lead to early onset of coronary heart disease and  atherosclerosis. Patients at risk of developing familial  hypercholesterolaemia including children should be  monitored and use of high-dose lipid-regulating drugs  considered.   • patients at high risk of developing cardiac  disease because of multiple risk factors  (smoking, hypertension, diabetes, family  history)   These are 7-substituted-3,5-dihydroxyheptanoic acids  which can feature either a bicyclic ring structure  (natural products), such as in simvastatin (Figure   • Inhibit 5-hydroxy-3-methylglutaryl-CoA (HMG-  CoA) reductase which controls the rate-limiting  step in the synthesis of cholesterol in liver.   • Significantly reduce the incidence of myocardial  infarction and improve survival in patients with  hypercholesterolaemia with or without coronary  heart disease. Reduce myocardial infarction and  overall mortality. High doses of statins are  supported   • Drugs of choice, combined with dietary and  lifestyle measures, monitoring of blood pressure,  and aspirin where appropriate   • LDL-lowering activity is: rosuvastatin >  atorvastatin > simvastatin > pravastatin >  fluvastatin   • Dose administered in the evening because  cholesterol biosynthesis reaches a peak during  the night. This is not so relevant for rosuvastatin  and atorvastatin since they have longer half-lives   • Patient monitoring: liver function tests have to be  carried out routinely, creatine kinase levels   • Risk of rhabdomyolysis (fatal skeletal muscle  disease) which increases when statins are  combined with other lipid-regulating drugs   • Patient advice: to report immediately  unexplained muscle pain, tenderness or weakness  since these are signs of myalgia, myositis and  myopathy that warrant cessation of therapy.   Doses for some commonly used statins are  summarised in Table 23.2.   Reversible myositis is a rare but significant side-effect  of statins. Statins also cause headache, altered liver  function tests (rarely hepatitis), paraesthesia and  gastrointestinal effects including abdominal pain,  flatulence, diarrhoea, nausea and vomiting. Rash and  hypersensitivity reactions (including angioedema and  anaphylaxis) have been reported rarely.   The side-effect profiles of some statins are  compared in Table 23.3.   Myalgia, myositis and myopathy have been reported  with the statins. If myopathy is suspected, creatinine  kinase should be measured and if it is markedly  elevated (more than five times upper limit of normal),  treatment should be discontinued. In patients at high  risk of muscle effects, a statin should not be started if  creatine kinase is elevated. Rhabdomyolysis with  acute renal impairment secondary to myoglobinuria  has also been reported.   Fatigue, dizziness, sleep disturbances, abnormal urination, sexual dysfunction, visual disturbances, alopecia   • receiving other drugs, namely fibrates,  lipid-lowering doses of nicotinic acid and  immunosuppressants such as ciclosporin.   • Patient advice: bezafibrate, fenofibrate to be  taken with food, gemfibrozil to be taken half to  one hour before food   • Cautions: correct hypothyroidism, hepatic  impairment, renal impairment, combination with  statins increases risk of muscle effects especially  with gemfibrozil (avoid concomitant use with  statins)   • Contraindications: severe hepatic and renal  impairment, hypoalbuminaemia, primary biliary  cirrhosis, gallbladder disease, nephrotic  syndrome, pregnancy, breast-feeding   • May be used as an adjunct to statins and the  combination exhibits an additive effect but risk  of rhabdomyolysis is increased   • Bind to bile acids resulting in the prevention of  their reabsorption and hence in increased  clearance of LDL-cholesterol    • May cause a rise in triglyceride level especially in  patients with already high levels; this occurs to a  lesser extent with colesevelam   • Patient advice: to take other drugs at least 1 hour  before or 4-6 hours after bile acid sequestrants   • Side-effects: gastrointestinal (constipation,  diarrhoea, nausea, vomiting); colesevelam is  associated with a lower incidence of  gastrointestinal side-effects   • These drugs lower both cholesterol and  triglyceride concentrations by interfering with the  biosynthesis pathway. They increase HDL-  cholesterol   • Use of nicotinic acid limited by occurrence of  side-effects particularly vasodilatation. Acipimox  tends to be associated with a lower occurrence  of side-effects but may be less effective as a  lipid-lowering agent than nicotinic acid   • Side-effects: diarrhoea, nausea, vomiting,  abdominal pain, dyspepsia, flushing, pruritus,  rash.   • May be used to reduce triglycerides in  combination with statins in combined  hyperlipidaemia.   • Identify patients including elderly at high risk of  atherosclerosis. Commence drug therapy early.   • Pharmacists should participate in the screening of  patients at risk, in preparing a treatment plan  and in ensuring patient compliance with lipid-  regulating drugs which require chronic use.   • Consideration of side-effect profile:  hepatotoxicity, myopathy (dose related). Patients  should be advised to report immediately any  muscle pain.   • Lifestyle modifications and relevant parameters  (lipid profile, blood pressure, blood glucose level,  body weight) should be monitored regularly.   1 List four side-effects that could occur with the  use of statins.   2 What patient monitoring is required in patients  receiving statins? What advice should be given  to patients?   3 When is the risk of rhabdomyolysis associated  with statins increased?   2 Blood cholesterol and lipid levels, liver function  tests, creatine kinase and renal function should  all be monitored in patients receiving statins.  Due to the risk of myositis, myalgia and  myopathy, patients should be advised to report  immediately any unexplained muscle pain,  tenderness and weakness. Patients should be  advised to take statins at night.   3 Rhabdomyolysis is a rare fatal skeletal muscle  disease which increases when statins are  combined with other lipid-regulating drugs such  as fibrates. Risk is increased in patients with  renal impairment and possibly in those with  hypothyroidism. Concomitant treatment with  immunosuppressants such as ciclosporin may  increase plasma statin concentration and the  risk of muscle toxicity.   Briel M, Ferreira-Gonzalez I, You J J, Karanicolas P J, Akl  E A, Wu P et al. (2009). Association between change in  high density lipoprotein cholesterol and cardiovascular  disease morbidity and mortality: systematic review and  meta-regression analysis. BMJ 338: b92.   Lopez L M (2002). Managing hyperlipidemia: current and  future roles of HMG-CoA reductase inhibitors. Am J  Health -Sy st P harm 59: 1173-1182.   National Institute for Health and Clinical Excellence  (2008). Familial hypercholesterolaemia: identification  and management of familial hypercholesterolaemia.  http://www.nice.org.uk/CG71.   Paulsen T (2009). Pharmacy’s role in the treatment of  dyslipidaemias. Hosp Pharm Eur July/August: 78-79.    Thompson P D, Clarkson P and Karas R H (2003). Statin-  associated myopathy. JAMA 289: 1681-1690.   Ye X, Gross C R, Schommer J, Cline R, Xuan J and St  Peter W L (2007). Initiation of statins after hospitaliza-  tion for coronary heart disease. J Manag Care Pharm  13: 385-396.   Bernard Coleiro, Consultant Physician, Department of  Medicine, Mater Dei Hospital, Malta   • To appreciate prophylaxis of venous and arterial • To develop skills to monitor and handle chronic   • To understand use of pharmacological agents in the  prophylaxis and management of thrombosis   • Venous occlusion: may lead to deep venous  thrombosis, pulmonary embolism   • Embolus: part of a clot becomes dislodged and  travels to other areas.   • Increase in prevalence in patients over 50 years  of age   • Increased progestogen levels (e.g. pregnancy,  combined oral contraceptives, hormone  replacement therapy)   • Presentation: pain in calf, redness of skin,  warmth in area, swelling of calf.   • To prevent damage to the valves and reduce risk  of post-phlebitic limb.   2 Warfarin for 3-6 months after the incident when  there is a reversible cause or a precipitating  factor, otherwise lifelong therapy.   • When there is haemodynamic instability, removal  of obstruction using thrombolytic drugs (see  Chapter 21).   • Without thromboprophylaxis, overall frequency  of deep vein thrombosis after general surgery is  about 25%. After 7-14 days, without  thromboprophylaxis, frequency of deep vein  thrombosis in total hip replacement, total knee  surgery and hip fracture is about 50-60%.   • Low-dose heparin by subcutaneous injection is  administered as prophylaxis in patients  undergoing general surgery and major  orthopaedic surgery to prevent post-operative  deep vein thrombosis and pulmonary embolism.   • Started as an intravenous loading dose and then  continued as necessary with continuous  intravenous infusion. May be administered  subcutaneously; however, bioavailability  following this route of administration is  significantly decreased    time (APTT), which reports clotting time in  seconds. It reflects changes in the intrinsic  pathway of the coagulation cascade. APTT  prolongation may be due to heparin therapy,  warfarin therapy (prothrombin time affected  more and that is why prothrombin time is the  test used to monitor warfarin therapy), liver  dysfunction or vitamin K deficiency   These are derivatives of commercial heparin that  have a mean molecular weight of 4000-5000 Da in  contrast to the unfractionated heparin which has a  mean molecular weight of 12 000-16 000 Da. Each  is derived from natural heparins by various manufac-  turing methods. Examples are enoxaparin sodium,  dalteparin sodium and tinzaparin sodium.   • Once-daily subcutaneous administration. They  exhibit improved bioavailability after  subcutaneous injection compared with heparin.   • Easier to administer by patients at home;  increased patient compliance   • No need for monitoring of APTT - dose is  calculated according to patient’s body weight.   • Advantages of LMWH and comparable  effectiveness indicate that they should replace  unfractionated heparin in the prophylaxis of  venous thromboembolism.   • In orthopaedic practice LMWHs are more  effective than unfractionated heparin.   • May be used in the treatment of deep vein  thrombosis, pulmonary embolism and unstable  coronary artery disease (e.g. enoxaparin).   This is used in the prophylaxis of venous thrombo-  embolism in medical patients, patients undergoing  major orthopaedic surgery of the legs or abdominal  surgery, treatment of deep vein thrombosis and  pulmonary embolism, treatment of unstable angina  and myocardial infarction. It is available for once-  daily administration as a subcutaneous injection.   • It is immune-mediated and does not usually  develop until after 5-10 days.   • Platelet count measured before initiation of  therapy and monitored thereafter if treatment  exceeds 4 days.   • Alternative anticoagulants such as hirudins (e.g.  lepirudin, fondaparinux) may be considered.   - is associated with increased risk with longer  duration of therapy, in diabeties, chronic renal  failure and hyperkalaemia   Warfarin (Figure 24.1) is a vitamin K antagonist  which blocks the reduction of vitamin K epoxide that  is necessary for its action as a cofactor in the  synthesis of factors II, VII, IX and X in the coagula-  tion cascade. It takes 48-72 hours for an effect  because of the time needed for the degradation of  factors that have already been formed.   • Maintenance dose: 3-9 mg daily at the same time  of day   • Monitoring: international normalised ratio (INR)  reports time taken to clot formation. It reflects  changes in the extrinsic and common pathways   Figure 24.1 Warfarin, a water-insoluble lactone that is  weakly acidic due to hydroxy substitution, is a chiral  compound where the S-enantiomer is more potent than the  R-enantiomer.    of the coagulation cascade. Warfarin and heparin  especially in high doses cause a prolongation of  the prothrombin time (see also Chapter 11).   • Increased anticoagulant effect: inhibition of  warfarin metabolism (e.g. cimetidine,  erythromycin, mefenamic acid, metronidazole,  ketoconazole, ciprofloxacin, sulphonamides)   • Reduced anticoagulant effect - pharmacodynamic  effect (e.g. oral contraceptives, vitamin K).   • Haemorrhage: identify indicators of haemorrhage  such as haematuria, skin petechia, oral bleeding.  It may occur more commonly in trauma,  infection, diabetics and the elderly.   Aspirin is more appropriate in reducing risk  of transient ischaemic attacks than oral anti-  coagulants.   • Heparins are preferred because they do  not cross the placenta; warfarin is  associated with congenital malformations  and fetal and neonatal haemorrhage.  Warfarin should not be used during  pregnancy.   • LMWHs have a lower risk of  osteoporosis and of heparin-induced  thrombocytopenia.   • In cerebral infarction anticoagulant treatment  may increase risk of conversion of infarction of  brain substance to haemorrhage. Control of  hypertension is important.   • Use of antiplatelet drugs that inhibit thrombus  formation on arterial side is indicated.   • Blocks synthesis of thromboxane A 2 from  arachidonic acid in platelets by acetylating  and hence inhibiting enzyme cyclo-oxygenase.   • Prevents production of prostacyclin from  endothelial cells; inhibits platelet aggregation.   • Dose: 75 mg daily for long-term use; a dose of  300 mg as soon as possible after ischaemic event  is recommended.   • Gastrointestinal irritation and bleeding may  occur, use of enteric-coated preparations may  reduce damage due to direct contact in the  gastric mucosa but will not exclude occurrence  of this side-effect (see also Chapter 31).   • An adjunct to oral anticoagulation for  prophylaxis of thromboembolism associated with  prosthetic heart valves. Modified-release  formulations are used (usually in combination  with aspirin) for secondary prevention of  ischaemic stroke and transient ischaemic attacks   • 300-600 mg daily in three to four divided doses  30 minutes before food   • Side-effects: hypotension, nausea, headache,  diarrhoea in the first weeks of treatment.   • Used in the prevention of atherosclerotic events  in patients with a history of symptomatic   • Cautions: haemorrhage; avoid for first few days  after myocardial infarction and ischaemic stroke   • User-friendly coagulometers using a fingerprick  sample are available making it possible for  pharmacists to participate in point-of-care  prothrombin time monitoring in outpatient  clinics and community pharmacies.   • Pharmacists should participate in providing  patient counselling regarding drug therapy and  side-effects to be expected.   - INR maintained between 2 and 3.5 depending  on condition being treated   • Warfarin is an oral anticoagulant drug that is  prone to numerous interactions with other drugs.  Patients should be advised to avoid taking other  medicines unless recommended by a health  professional who is aware that they are on  warfarin therapy. Regular monitoring of the  prothrombin time should be undertaken.   1 What patient monitoring is required in patients  receiving warfarin? What advice should be  given to the patients?   1 Prothrombin time expressed as INR  (international normalised ratio) should be  monitored. Patients should be advised not to  stop taking medication or start any other  medication without pharmacist or doctor advice  and to report any unexplained bleeding.   2 Heparin-induced thrombocytopenia is immune  mediated and does not usually develop until  after 5-10 days. Platelet count is measured  before initiation of therapy and monitored  thereafter if treatment exceeds 4 days. Signs  include: 50% reduction of platelets, thrombosis,  skin allergy. Heparin therapy should be  withdrawn when condition occurs and  alternative anticoagulants such as hirudins may  be used. Parameters that should be monitored:  platelet count, occurrence of bleeding.   Anon (2008). Community pharmacy plays its part in  making anticoagulation therapy safer. Pharm / 280: 78.   Coleman B, Patterson D, Long M and Farrell J (2003).  Setting quality standards for a community pharmacist-  led anticoagulant clinic. Pharm J 270: 308-311.   Rahman M H and Beattie J (2004). Drugs used to prevent  surgical VTE. Pharm J 273: 717-719.   Sellier E, Labarere J, Bosson J L, Auvray M, Barrelier M T,  Le Hello C et al. (2006). Effectiveness of a guideline for  venous thromboembolism prophylaxis in elderly post-  acute care patients. Arch Intern Med 166: 2065-2071.   • To develop skills to identify appropriate use of drug  therapy in allergic rhinitis    • To identify properties and characteristics of drugs  used in asthma and chronic obstructive pulmonary  disease.   Cough is a common symptom which may indicate  occurrence of infective conditions or allergy-  related, chronic conditions. Histamine is a protein  that is associated with the occurrence of allergic  reactions.    Histamine is an endocrine mediator that is found in  many tissues and upon release its effects are mostly  local. It is involved in allergic reactions and in the  regulation of secretion of gastric acid.   The histamine contents of human tissues are shown  in Table 25.1.    • Hj-receptor antagonists are useful in the  management of allergic reactions (hay fever,  rhinitis, urticaria, food allergy). Reduce  rhinorrhoea and sneezing, less effective against  nasal congestion.   • May also exhibit effects at other receptors  (cholinergic, dopaminergic and serotoninergic).   • Maximum effect occurs several hours after peak  serum concentration has been obtained.   • Amphoteric in nature, low penetration across  blood-brain barrier resulting in a lower potential  for sedation and psychomotor impairment.    Chlorphenamine is used by slow intravenous  administration as an adjunct to adrenaline in  emergency treatment of anaphylaxis and  angioedema.   The antihistamines generally consist of two aromatic  groups that are linked on the short chain to a tertiary  aliphatic amine. The chemical classification of antihis-  tamines is shown in Figure 25.1 and the characteristics  of the five groups in Table 25.3.   The sedative effects of selected first-generation  antihistamine drugs are compared in Table 25.4.   Very effective at low dosages, long duration of action, practical for daytime use due to low incidence of central sedative   High incidence of drowsiness and anticholinergic side-effects but a low occurrence of gastrointestinal side-effects,  relatively short half-life   High incidence of drowsiness, suppress cough reflux, pronounced antiemetic and antimuscarinic effects, prolonged action   Moderate sedation, significant antiemetic effect leading to some products having a primary use in the treatment of  motion sickness, vertigo, nausea and vomiting   Table 25.4 Comparison of sedative effects of  selected first-generation antihistamine drugs   • Loratadine and fexofenadine have been  shown to be associated with a lower  incidence of sedation than acrivastine and  cetirizine.   • Patients should still be advised to be  careful when driving or operating  machinery even when non-sedating  antihistamines are used.   • Advise patient that consumption of  alcohol with antihistamines increases risk  of sedation.   • Neonates and children (particularly  phenothiazines) due to higher susceptibility to  antimuscarinic effects   • Hazardous ventricular arrhythmias reported with  non-sedating antihistamine products (astemizole  and terfenadine).   • Mepyramine: topical skin preparations;  disadvantages: hypersensitivity and  photosensitivity (see Chapter 47).   • Migraine: doxylamine is used in compound  analgesic preparations for migraine for its  sedating properties and antiemetic effect    • Appetite stimulation: cyproheptadine, which is  an antihistamine and serotonin antagonist, is  used as an appetite stimulant, especially in  anorexia nervosa. Side-effects include sedation  and weight gain.   • Non-sedating antihistamines vs sedating  antihistamines: in patients with intermittent  symptoms or mild symptoms of allergic rhinitis,  antihistamines are recommended. The non-  sedating antihistamines are preferred since they  do not impact negatively on the patient’s daily  functioning.   • Steroid-containing nasally administered products  (e.g. beclometasone, budesonide, fluticasone):  used for persistent symptoms with nasal  congestion.   • Depot preparations are not recommended; they  may cause local fat atrophy and local abscess  formation.   • Decongestant-containing systemically  administered products: these alleviate the  symptoms of rhinorrhoea and nasal congestion.   • Montelukast and zafirlukast block the effects of  cysteinyl leukotrienes in the airways. May be  used in patients with concomitant asthma   • Products such as ipratropium bromide which  have an anticholinergic effect may be  administered topically to reduce watery, nasal  secretions. However, their use is not clinically  studied so much to date.    • Antihistamines should be used with  caution in older patients and in paediatric  patients   • In patients with allergy and a stuffy nose,  combination products containing an  antihistamine and a decongestant  administered systemically may cause less  drowsiness because the decongestant  product which is a sympathomimetic  agent will counteract the drowsiness  brought about by the antihistamine.   • Patients using intranasal corticosteroids  should be advised on proper admini-  stration technique so that the product is  sprayed towards the nostril lining rather  than on the septum. Repeated spraying of  the corticosteroid on to the nasal septum  may lead to damage.   A progressive and irreversible condition characterised  by diminished inspiratory and expiratory capacity of  the lungs causing dyspnoea and chronic cough.    • Patients should be advised to stop  smoking and to avoid smoking areas.   • Acute severe asthma attacks and  deterioration of COPD may be  exacerbated by upper respiratory tract  infections.   • Hospitalisation may have to be  considered in acute exacerbations of  COPD and in acute severe asthma  attacks.   • Beta 2 agonists (e.g. salbutamol and terbutaline,  which are short acting, and salmeterol,  formoterol, which are long acting and should not  be used for the management of an acute asthma  attack) should be used with caution in  hyperthyroidism, cardiovascular disease and  hypertension   • Antimuscarinics (e.g. ipratropium, which is short  acting, and tiotropium, which is long acting)  should be used with caution in glaucoma  (especially when administered by nebulisation),  prostatic hyperplasia and bladder outflow  obstruction.   Asthma is a condition in which inflammation of small  bronchi results in recurrent, reversible episodes of  airway obstruction, causing dyspnoea, wheezing and  cough.    • Salbutamol and terbutaline may be used  for the relief of an asthma attack since  they have a rapid onset of activity.   • Hypokalaemia may occur as a result of  beta 2 -agonist therapy, particularly when  high doses are used or when administered    systemically. Care should be taken in  patients receiving diuretics and  corticosteroids.   These reduce bronchial inflammation. In asthma they  are useful for the prevention of attacks and in COPD  they reduce exacerbations.   • Administered on a regular basis to achieve the  prophylactic effect   • May be used in combination with  bronchodilators. Combination inhalers that  present a corticosteroid and a long-acting beta,  agonist are available.   Beclometasone and fluticasone are halogenated  corticosteroids whereas budesonide is a non-  halogenated corticosteroid (Figure 25.2). They are  equally effective. The three of them exhibit a high  relative lipophilicity. This characteristic may improve  receptor affinity and increase retention of the drug in  the nasal or lung tissues. This increased lipophilicity  compared with oral steroids such as prednisolone and  hydrocortisone (which are less effective if adopted for  inhalation) results in a low oral bioavailability if  administered orally.    • In acute severe asthma attacks, the  administration of high-flow oxygen  therapy (see Chapter 3) and a short-acting  beta, agonist are first line of management.   • In COPD, mucolytics (Chapter 54) may  be considered for the management of  chronic productive cough.   In asthma and COPD, drugs are preferably adminis-  tered by inhalation since this route of administration  delivers the drug directly to the respiratory system,  minimising side-effects due to reduced systemic action.   • Pressurised metered-dose inhalers: require  coordination between the act of actuation and  inhaling for effective drug delivery   • Spacer device: used to improve drug delivery in  patients who have difficulty in achieving the  required coordination when using pressurised  metered-dose inhalers (e.g. paediatric patients  and the elderly) and to decrease local side-effects  from inhaled corticosteroids   • Solutions for nebulisation: used in the  management of severe asthma; require a  nebuliser that is usually driven by oxygen.    • In severe cases or during severe acute  attacks, oral or parenteral therapy with  bronchodilators and corticosteroids may  be required.   • When both bronchodilators and  corticosteroids inhalers are prescribed,  patients should be advised to first use the  short-acting beta 2 -agonist inhaler and  then to use the corticosteroid inhaler.   • Beta 2 agonists: fine tremor, headache,  palpitations, muscle cramps, nervous tension   • Corticosteroids: oral candidiasis; advise patient  to rinse mouth after administration; the use of a  spacer reduces incidence. After long-term  inhalation of high doses, osteoporosis, glaucoma  and in children growth retardation may occur.   • In allergic rhinitis, antihistamines are preferred in  intermittent symptoms and mild symptoms.  Cromoglicate is not as effective as intranasal  corticosteroids and no more effective than  antihistamines. Intranasal corticosteroids are  more effective than antihistamines and are  preferred in moderate-to-severe disease.   • In asthma and COPD, bronchodilators and  corticosteroids are the mainstay of therapy.  Combination therapy may be adopted.   • Inhalation therapy is the preferred route of drug  administration. Patients need to receive advice on  proper technique for drug administration.   2 Giving reasons for your answer, explain when  bronchodilators are indicated.   3 What is a spacer device and when is it used?   1 Both are first-generation or sedating  antihistamines. Chlorphenamine is an  alkylamine. It is very effective at low dosages,  has a long duration of action and is practical  for daytime use due to low incidence of central  sedative effects. Indications include  symptomatic relief of an allergy such as hay  fever, urticaria and emergency treatment of  anaphylactic reactions. Hydroxyzine is a  piperazine. It is associated with moderate  sedation. Indications include pruritus and  anxiety (short term). Chlorphenamine is  recommended for children aged over 1 year and  hydroxyzine for children over 6 months.  Cautions, contraindications and side-effects are  the same: elderly and paediatric patients,  cardiovascular disorders, benign prostatic  hypertrophy, glaucoma, hepatic and renal  disease, epilepsy. Side-effects: sedation, dizziness,  drying of secretions, dry mouth, urinary  retention, constipation, blurred vision.   2 Bronchodilators are useful in acute attacks and  maintenance therapy in asthma and COPD.   They dilate the bronchi and the bronchioles,  resulting in an increasing airflow.   3 A spacer is a device used by an asthmatic  person to increase the effectiveness of an  asthma inhaler. Spacers are specially designed  plastic or metal tubes that fit an inhaler on  one end, while the patient breathes normally  on the other end. Their use eliminates the  requirement to coordinate the actions of  actuation and inhalation which is required  with metered-dose inhalers.   Mason P (2003). Management of hay fever in the pharmacy.  Pharm J 270: 443-445.   Salib R and Howarth P (2002). Treating intermittent and  persistent allergic rhinitis. Prescriber 5 May: 47-66.   • To identify clinical issues associated with  maintenance treatment for schizophrenia    • To develop skills to be able to participate in patient  support and monitoring in the management of  schizophrenia.   Onset of schizophrenia commonly occurs in late  adolescence or early adulthood. Increasing evidence  supports a hypothesis that dopamine receptor defects  exist in schizophrenia. This does not exclude other  systems involving serotonin and noradrenaline.  Clinical presentation can be extremely varied and the  condition carries a high risk of suicide.   Schizophrenia is a chronic disorder of thought and  affect, with the individual having a significant distur-  bance in interpersonal relationships and the ability to  function in society on a daily basis.   • Positive  symptoms: hallucinations (visual or  auditory), agitation, delusions (persecution, guilt)   • Negative  symptoms: loss of interest, loss of  capabilities, lack of emotion, decreased initiation  of goal-directed behaviour   A At least two of the following each present for a  significant portion of time during a 1 -month  period:   B Function in areas of work, social relations and  self-care is low   C Continuous signs of illness for at least 6 months  of which at least 1 month of symptoms from  criterion A    Assess occurrence of coexisting conditions,  including other psychiatric disorders particu-  larly depression and anxiety.   • Direct expenses of treatment and care including  hospitalisation, professional services and clinic  visits   • Lost production for patient and carer including  economic burden to families and loss of  productivity caused by illness and need for  patient support.   • To reduce disruption of patient’s and carers’ lives  as a consequence of inappropriate behaviour,  anxiety, delusional thinking and hallucinations   • To reduce relapse: schizophrenia is associated  with a relatively poor outcome with many  patients experiencing exacerbation of symptoms  that may require hospitalisation and suicide  attempts.   A comprehensive management package that incor-  porates both pharmacotherapy as well as non-  pharmacological interventions should be adopted.  Non-pharmacological interventions include:   Antipyschotics block dopamine receptors. First-  generation (typical) antipsychotics have a high  affinity towards dopamine D 2 receptors. The atypical  antipsychotics (second and third generation) have a  lower affinity for dopamine D 2 receptors but have  significant affinity towards other receptors including  serotonin and noradrenaline receptors. This differ-  ence in affinity to receptors is thought to be the cause  of differences in the occurrence of side-effects.   The classification of neuroleptics based on  potency is summarised in Table 26.1 and anti-  psychotic drugs are compared in Table 26.2.    The atypical antipsychotics pose a lower risk of  extrapyramidal symptoms (EPS) but are asso-  ciated with hypotension, weight gain and an  increased risk of diabetes and hyperlipidaemia.    The occurrence of hyperprolactinaemia may  lead to galactorrhoea, gynaecomastia, amenor-  rhoea, anovulation, decreased libido and  decreased sexual arousal.   Phenothiazines are tricyclic antipsychotic agents  which consist of two benzene rings fused via a  sulphur and a nitrogen atom. They are further classi-  fied according to the nature of the nitrogen-  containing substituent on position 10 into aliphatics,  piperazines and piperidines. An electronegative  moiety at position 2 increases the antipsychotic  activity as witnessed in chlorpromazine when  compared with promazine (which effectively has the  same chemical structure but lacks the chlorine moiety  at position 2) (Figure 26.1).   Thioxanthenes (e.g. flupentixol; see Figure 26.2) are  chemically related to phenothiazines. They consist of  two benzene rings linked by a sulphur and a carbon  atom.   Butyrophenones (e.g. haloperidol; see Figure  26.3) are heterocyclic compounds with a prolonged  action. The presence of a tertiary amino group  attached to the fourth carbon of the butyrophenone  structure is required for neuroleptic activity. The  presence of halogen atoms in haloperidol explains  the relatively high potency of the drug.   The side-effects of antipsychotic drugs other than  phenothiazines are compared in Table 26.4.    Common anticholinergic side-effects include  dry mouth and throat (which could cause  dental caries), constipation, urinary retention  and dry eyes.   Blood dyscrasias may occur with antipsychotic drugs.  The use of clozapine (Figure 26.4) may lead to agran-  ulocytosis in some patients. For this reason the use of  clozapine is limited.    Regular white blood counts should be carried  out in patients receiving clozapine to reduce  risk of agranuloctyosis. Patients should be  advised to report immediately occurrence of  fever, malaise or respiratory infections.   • A lower dose should be used in older patients  and in patients with renal insufficiency.   • Better response in the long term is expected when  treatment is started early.   • Regular review of medicines by health  professionals should be undertaken to identify  drug-related problems and patient non-  compliance.   • Continued treatment (maintenance therapy) is  required in a number of cases and, to achieve  this, the establishment of a therapeutic alliance  with the patient and the carers is necessary.   The great majority of patients show substantial  improvement with antipsychotic medicines. However,  in some patients poor response may occur. In these  patients, check compliance, assess dosing, monitor  unacceptable stress levels and consider addition of  mood stabilisers (see Chapter 27).   • At start-up: check for personal or family history  of diabetes, dyslipidaemia, hypertension,  cardiovascular disease, epilepsy.   • Patient advice: diet, exercise, weight control and  information on how to take medication.   - at baseline - blood glucose, lipid profile, blood  pressure, ECG    Special considerations in elderly patients (e.g.  higher risk of occurrence of postural hypoten-  sion especially with blockers of alpha ; recep-  tors such as risperidone and olanzapine).  Consider occurrence of comorbidities and use  of other drugs.   • Hepatic and renal impairment, cardiovascular  disease, Parkinson’s disease, epilepsy, depression,  myasthenia gravis, prostatic hypertrophy,  glaucoma, the elderly   • For the atypical: concomitant use with drugs that  prolong QT interval, cardiovascular disease,  epilepsy, the elderly.   • Increased risk of stroke reported with olanzapine  and risperidone in older people   • Risk factors for cerebrovascular disease and past  history of stroke and transient ischaemic attacks  increase risk.   • Withdrawal of treatment requires close  monitoring since it may result in a    disastrous relapse. Occurrence of relapse  may be delayed after cessation of  treatment.   • Compliance: high rates of termination of  antipsychotic treatment. Lieberman et al r  report that 74% of patients studied  discontinued treatment before  18 months.   • In acute attacks, antipsychotics may be used to  control agitation and disturbed behaviour.   • They may be given by the intramuscular route  (e.g. chlorpromazine, olanzapine).   • There is no first-pass effect with intramuscular  route and so a lower dose can be used than for  the oral route.   • Weight gain for atypical antipsychotics (check  cardiovascular risk factor - could impact on  patient adherence to treatment and in the long  term on increased mortality): olanzapine >  clozapine > risperidone > quetiapine >  sertindole > zotepine.    • Atypicals are associated with occurrence of  sedation: clozapine > olanzapine > quetiapine.   • Care should be taken when using antipsychotics  in patients with cardiovascular disorders.   • Clozapine should be introduced at the earliest  opportunity in patients with treatment-resistant  schizophrenia.   1 All are first-generation neuroleptics indicated in  schizophrenia. They are effective only for the  positive symptoms of schizophrenia  (hallucinations, agitation, delusions). The three  preparations have a different chemical  classification and potency resulting in differing  side-effect profiles.   • Haloperidol is a butyrophenone (not a  phenothiazine) which has a very strong  potency.   Chlorpromazine causes anticholinergic side-  effects, sedation and hypotension to a greater  extent compared with trifluoperazine and    haloperidol (haloperidol less than  trifluoperazine). On the other hand,  chlorpromazine poses the least risk for the  occurrence of extrapyramidal symptoms (EPSs)  whilst trifluoperazine and haloperidol cause  EPSs to a greater extent. The extent of EPSs is  related to potency. All may cause prolactin  elevation.   Guthrie S K (2002). Clinical issues associated with mainte-  nance treatment of patients with schizophrenia. Am J  Health-Syst Pharm 59(suppl 5): S19-S24.   Maguire G A (2002). Comprehensive understanding of  schizophrenia and its treatment. Am J Healtb-Syst Pbarm  59(suppl 5): S4-S11.   National Institute for Health and Clinical Excellence  (2009). Schizophrenia: core interventions in the treat-  ment and management of schizophrenia in primary  and secondary care (update), http://www.nice.org.uk/  guidance/index, j sp ? action = bylD&o =11786.   1 American Psychiatric Association (2000). Diagnostic  and Statistical Manual of Mental Disorders , 4th edn.  Washington: American Psychiatric Association.   2 Lieberman J A, Stroup T S, McEvoy J P, Swartz M S,  Rosenheck R A, Perkins DA et al. Effectiveness of anti-  psychotic drugs in patients with chronic schizophrenia.  N Engl J Med 2005; 353: 1209-1223.   • To develop skills to be able to assess the impact of  psychotropic medications.   • Depression: a medical condition that is  characterised by a low mood and sleep  disturbances that occur persistently.   • Mania: a medical condition that is characterised  by an elevated, expansive or irritable mood that  occurs persistently.   • Bipolar disorder: formerly known as manic  depressive disease, refers to patients who present  with mixed episodes of both mania and  depression.   • Aetiology: genetic predisposition, environmental  factors (e.g. stressful events), biochemical factors,  medication, other illness.   • Cardiovascular agents: beta-adrenoceptor  blockers, calcium channel blockers, clonidine,  digoxin, methyldopa   Patient assessment tools may be used by the clinical  team to be able to identify mood disorders and assess  patient progress. Examples include:   • rating scales such as Beck Depression Inventory  (BDI), Elamilton Rating Scale for Depression  (HAM-D) and Inventory for Depressive  Symptoms (IDS). The BDI and IDS are brief  scales that can be used in primary care settings to  assess patient progress.   The American Psychiatric Association has described  criteria for diagnosing depressive disorders. 1   • Five or more of the following symptoms have  been present during the same 2-week period and  represent a change from the patient’s previous  functioning:   • Symptoms cause clinically significant distress or  impairment in social and occupational areas.   • Three or more of the following symptoms have  been present to a significant degree for at least 1  week:   • Mood disturbance is sufficiently severe to cause  marked impairment in occupational functioning  or in social activities.   • Symptoms are not due to the direct physiological  effects of a substance or a general medical  condition.   Choices for the acute treatment of a major depressive  disorder are summarised in Table 27.1.    Table 27.1 Choices in the acute treatment of a major depressive disorder   • Severity of illness: patients presenting with a  major depressive disorder are more likely to  experience multiple episodes in life.   • Social factors: peer pressure, environment,  support from family and carers.   • Pharmaceutical issues: treatment terminated, low  dose, occurrence of side-effects, non-compliance,  failure to appreciate need to continue treatment.   Antidepressant drugs act by increasing the activity of  monamines particularly dopamine, noradrenaline  and serotonin.   These drugs have a three-ring structure in which  two benzene rings are linked by a seven-membered  central ring (Figure 27.1).   • Cautions: cardiac disease, history of epilepsy, the  elderly, hepatic impairment, thyroid disease,  history of mania, psychoses, glaucoma, history of  urinary retention.   Maprotiline is structurally related to the tricyclic  antidepressants. It consists of an additional ethylene  bridge across the central six-carbon ring (Figure 27.2).   Within the class of SSRIs, different drugs have  differing chemical structure (Figure 27.3) but a  similar side-effect profile. Their advantages over  TCAs include a lower side-effect burden, safety in  overdosage and once-daily administration.  Pharmacoeconomic analyses have shown that despite  the higher cost of SSRIs they are more cost-effective  due to higher rates of medication adherence and  decreased relapse (see also Chapter 28).   Fluoxetine: has a long half-life and an active  metabolite that has a long half-life; this  should be kept in mind when switching drugs.   • Cautions: epilepsy, history of mania, cardiac  disease, diabetes, glaucoma, history of bleeding  disorders, hepatic/renal disease, pregnancy and  breast-feeding.   • Suicidal tendencies: use in patients under  18 years is not recommended.   • Gastrointestinal bleeding: SSRIs inhibit  uptake and therefore storage of serotonin  of platelets. This is significant because   Figure 27.3 Chemical structures of some selective  serotonin re-uptake inhibitors (SSRIs).   - relative risk of gastrointestinal bleeding  similar to use of NSAIDs   - avoid in elderly and in patients who are  concurrently using NSAIDs   - consider use of a proton pump  inhibitor in high-risk patients.   Venlafaxine (Figure 27.4) is a serotonin-  noradrenaline re-uptake inhibitor (SNRI). Side-  effects are very similar to those found with SSRIs. It  also may present with side-effects due to increased  noradrenaline activity such as hypertension. A risk of  suicidal tendencies in children reported.   • Contraindications: heart disease, electrolyte  imbalance, hypertension, severe renal and hepatic  disease   • Cautions: ECG before treatment, monitor blood  pressure, history of epilepsy and bleeding  disorders, angle-closure glaucoma.   This is a reversible inhibitor of monoamine oxidase  type A enzyme (RIMA). It is referred to as an  monoamine oxidase inhibitor (MAOI) with RIMA  activity. MAOIs interact with other drugs and tyra-  mine-containing food (e.g. aged cheese, red wine,  yeast extracts) leading to a potentiated pressor effect  of tyramine and amine drugs. This may cause a  dangerous rise in blood pressure. Moclobemide poses  a lower risk for this interaction since it inhibits only  the type A monoamine oxidase. However, patients  should still be advised to avoid consuming large  amounts of tyramine-rich food.   • Reboxetine: a selective inhibitor of noradrenaline  re-uptake. May cause insomnia and postural  hypotension   • Tryptophan: as a precursor of serotonin, it may  be used as adjunctive therapy in patients who are  refractory to treatment. Has been associated with  eosinophilia-myalgia syndrome (EMS).   TCAs are preferred where sedation is desired.  However, they should be used with care or  avoided in patients with cardiovascular  disease.   • TCAs: recent myocardial infarction, arrhythmias,  severe liver disease, manic phase    SNRI, serotonin-noradrenaline re-uptake inhibitor; SSRIs, selective  serotonin re-uptake inhibitors; TCAs, tricyclic antidepressants.   Discontinuation syndrome is an adverse reaction that  occurs following withdrawal of antidepressants.  SSRIs are associated with a higher risk of discontinu-  ation syndrome than TCAs.   • Occurrence may be mistaken for recurrence of an  acute depressive effect.    CNS, central nervous system; NSAIDs, non-steroidal anti-inflammatory drugs; SSRIs, selective serotonin  re-uptake inhibitors; TCAs, tricyclic antidepressants.    • Its occurrence may indicate that the patient has  stopped treatment or is not taking the drug  regularly, leading to the onset of discontinuation  syndrome.   • When drug is being discontinued consider  tapering off drug therapy or for SSRIs switching  to fluoxetine which is less likely to cause this  effect due to a long half-life.    Since fluoxetine has a long half-life and is meta-  bolised into an active metabolite, it appears to  be much less likely to be associated with discon-  tinuation symptoms reported with other SSRIs  (e.g. paroxetine, citalopram, sertraline).   This association occurs especially in elderly patients  due to inappropriate secretion of antidiuretic hormone.  It is more frequently reported with SSRIs.   • Risk factors: older age, female, diuretic therapy,  low body weight, low baseline serum sodium  concentration.   St John’s wort is a herbal preparation that is used in    • Hyponatraemia and dehydration (which may be  due to diuretics) lead to increased renal  reabsorption which may result in lithium toxicity   • May worsen severe cardiac disease, induce  hypothyroidism and weight gain, and complicate  the presentation of diabetes mellitus   • Baseline lithium work-up: creatinine and  electrolytes, thyroid function tests, urinalysis,  ECG.   • Serum lithium concentrations: every 3-6 months  for six months; every 6-12 months thereafter   • Thyroid function tests: every 3-6 months; every  6-12 months thereafter    Patients who are started on SSRIs should be  advised against the concomitant use of St  John’s wort.   In the acute management of mania, mood stabilisers  such as lithium and anticonvulsant therapy such as  valproate and carbamazepine are recommended as  monotherapy. The use of atypical antipsychotic drugs  (aripiprazole, olanzapine, quetiapine, risperidone,  ziprasidone) (see Chapter 26) as monotherapy or in  combination with lithium or anticonvulsants may be  considered. The atypical antipsychotics are used to  manage acute agitation and aggression. Benzodia-  zepines (see Chapter 28) may be used as adjunctive  treatment to treat agitation and hyperactivity and to  produce sedation and reduce anxiety.    Since bioavailability varies from one prepara-  tion to another, care should be taken if  changing preparation.   Antidepressants including TCAs, the heterocyclics,  MAOIs and SSRIs pose the risk of switching a  depressed patient to a manic phase within a few weeks  after initiation of therapy. SSRIs and venlafaxine seem  to be less likely to induce this switch. For this reason it  is recommended that, for maintenance therapy in  bipolar disorder, mood stabilisers including anti-  psychotics (see Chapter 26), lithium or anticonvul-  sants are considered as first line of therapy.  Antidepressants, preferably SSRIs or venlafaxine, may  be considered as adjunct therapy.   • Efficacy of antidepressants is similar; choice  depends on side-effects to be avoided.   Reduce dose, give once daily at bedtime, use slow-release preparations, add propranolol   Reduce dose, give once daily at bedtime, use slow-release preparations, add amiloride   Take with food, reduce dose, give once daily at bedtime, use slow-release preparations   Give once daily at bedtime, use slow-release preparations, switch to valproic acid or carbamazepine    • Outcome can be improved by applying non-  pharmacological factors in addition to  pharmacotherapy.   • Preference of SSRIs as first-line therapy due to  better patient acceptability.   • Lag period of 1-4 weeks which may be longer in  elderly patients before positive outcomes of  therapy are experienced.   • Compliance is a problem in patients with mood  disorders, resulting from ambivalence to take  antidepressants or mood stablisers due to social  stigma, side-effects, periodic lack of insight into  need for medication (non-compliance range  10-60% reported in most studies).   1 Describe the discontinuation syndrome associated  with selective serotonin re-uptake inhibitors.   1 Gastrointestinal disturbances, headache, anxiety,  dizziness, paraesthesia, sleep disturbances,  fatigue, influenza-like symptoms and sweating  are the most common features which result if  an SSRI is stopped abruptly after regular  administration for 8 weeks or more or a marked  reduction of the dose. The dose should  preferably be reduced gradually over a period of  about 4 weeks, or longer if withdrawal  symptoms emerge (6 months in patients who  have been on long-term maintenance treatment).    Fluoxetine has a long half-life and is  metabolised into an active metabolite. It  appears to be much less likely associated with  discontinuation symptoms reported with other  SSRIs. Patient may be switched to fluoxetine  and weaned off slowly.   Akerblad A, Bengtsson F, Ekselius L and Knorring V L  (2003). Effects of an educational compliance enhance-  ment programme and therapeutic drug monitoring on  treatment adherence in depressed patients managed by  general practitioners. Int Clin Psychopharmacol 18:  347-354.   Bleakley S (2009). The management of depression. Pharm J  282: 285-288.   Jacob S and Spinier Sa A (2006). Hyponatraemia associated  with selective serotonin-re-uptake inhibitors in older  adults Ann Pharmacother 40: 1618-1622.   National Institute for Health and Clinical Excellence  (2006). Bipolar disorder: the management of bipolar  disorder in adults, children and adoloscents in primary  and secondary care. http://guidance.nice.org.uk/CG38.   National Institute for Health and Clinical Excellence  (2004). Depression: management of depression in  primary and secondary care, http://www.nice.org.uk/  CG023.   Spigset O and Martensson B (1999). Drug treatment of  depression. BMJ 318: 1188-1191.   Vieta E, Fresno D and Amann B (2006). Atypical anti-  psychotics in bipolar disorders. Hosp Pharm Eur  May/June: 53-56.   1 American Psychiatric Association (2000). Diagnostic and  Statistical Manual of Mental Disorders , 4th edn revised.  Washington DC: American Psychiatric Association.   • To differentiate between the characteristics of the • To appreciate the use of antidepressants and   Although anxiety is a universal feeling, anxiety dis-  orders are among the most frequently diagnosed  psychiatric disorders. Patients with anxiety disorders  tend to be high users of healthcare facilities for non-  psychiatric reasons.   • Disproportionate response to fear triggers such  as flying or to social situations   • Pathology: disrupted serotoninergic, glutamatergic,  GABA-ergic, noradrenergic systems and  involvement of the corticotrophin-releasing factor.   • Somatic symptoms: palpitations, chest pain,  shortness of breath, dizziness, dysphagia,  gastrointestinal disturbance, headache and  tremor.    A Phobic disorders: social phobia, simple phobia  B Panic disorder: with or without agoraphobia  C Agoraphobia without a history of panic disorder  D Generalised anxiety disorder (GAD)   Some drugs used in the treatment of anxiety are listed  in Table 28.1.   This is a persistent condition characterised by exces-  sive anxiety and worry about two or more life  circumstances without panic or phobic symptoms. It  is not usually due to situation-specific triggers. The  patient feels on edge, has difficulty in concentrating,  feels muscle tension and is irritable.   Benzodiazepines are the drugs of choice in an  acute attack and, for long-term management, SSRIs  or TCAs are preferred.    GAD, generalised anxiety disorder; OCD, obsessive-compulsive disorder; SSRIs, selective serotonin re-uptake inhibitors; TCAs, tricyclic  antidepressants.   • Potent anxiolytic effect exerted at lower doses  than those required for a hypnotic effect (see also  Chapter 29)   • Rapid onset of effect makes them useful in acute  attacks   • Side-effects: tolerance (develops to a lesser extent  for anxiolytic effect than psychomotor effects),  psychomotor impairment (memory loss),  affective reactions (aggravate depression, suicidal  tendencies), dependence   • Effectiveness is similar for different  benzodiazepines; choice is influenced by  pharmacokinetic parameters and incidence of  side-effects.   • Probably acts as a serotonin partial agonist,  enhances dopaminergic neurotransmission and  facilitates noradrenergic activity   • Used in patients with prominent cardiovascular  symptoms of anxiety such as palpitations and  tremors   • Little evidence to support effectiveness but  sedative properties may be useful   • Due to side-effect profile and safety profile in  overdosage, SSRIs and SNRIs are preferred to  TCAs.   Time required after initiating antidepressants  for patients with anxiety disorders to experi-  ence positive outcomes with therapy may be  longer than time required when antidepres-  sants are used in the management of depres-  sion. Risk of withdrawal syndrome has to be  kept in mind when withdrawing therapy.   This disorder is characterised by recurrent and  unexpected panic attacks. The patient may show  hyperventilation prior to attack. Symptoms may be  misinterpreted as being caused by physical illness,  commonly heart disease.   An attack involves an intense period of fear with  four or more of the following symptoms developing  abruptly and reaching a peak within 10 minutes:   • Recurrent and persistent ideas, thoughts or  images that are experienced as intrusive and  senseless   • Person attempts to ignore or suppress such  thoughts or to neutralise them   • Person recognises that the obsessions are the  product of his or her mind.   • Repetitive, purposeful and intentional behaviours  that are performed in response to an obsession.   • Behaviour is designed to neutralise or to prevent  discomfort or some dreaded event or situation.   • Drugs that inhibit re-uptake of serotonin (e.g.  clomipramine, fluoxetine, fluvoxamine,  sertraline)   • Treatment should be continued for several  months (12) in patients who respond to therapy    • Consider use of an antipsychotic as an adjunct in  patients who do not respond to therapy.   This is a reaction to a traumatic event which carries  the threat of death or serious injury to the patient or  significant others. It involves continued experience in  dreams and flashbacks.   Symptoms that were not present prior to event  and, occur with a duration of at least 1 month  include:   • TCAs (e.g. amitriptyline); SNRIs may be  considered as second-line therapy   • The use of antispychotics could be considered  where paranoia or flashbacks are prominent.   - SSRIs: chronic symptoms of more than 4  weeks or underlying depression   - lag time of 2-4 weeks: in panic disorders and  OCD symptoms may persist up to 4-10 weeks  after treatment is started   - antidepressants (e.g. SSRIs and venlafaxine)  are associated with initial worsening of panic  symptoms; consider co-prescribing  benzodiazepines in the short term.   - have a tranquillising effect without impairing  consciousness and without causing paradoxical  excitement   1 Benzodiazepines can be effective in alleviating  anxiety states and are indicated for the short-  term relief of severe anxiety. Diazepam,  alprazolam and chlordiazepoxide have a  sustained action. Shorter-acting compounds such  as lorazepam may be preferred in patients with  hepatic impairment and the elderly, but they  carry a greater risk of withdrawal symptoms.  Unwanted effects include: tolerance which would  require higher doses to achieve same desired  effect, aggravation of depression, and increased    suicidal tendencies and dependence. Occurrence  of dependence and risk of withdrawal syndrome  limit use in chronic conditions. Effectiveness is  similar for different benzodiazepines and choice  is influenced by pharmacokinetic parameters  and incidence of side-effects.   Bleakley S (2008). An overview of anxiety disorders. Pharm  J 281: 511-514.   National Institute for Health and Clinical Excellence  (2004). Anxiety: management of anxiety (panic  disorder with or without agoraphobia, and generalised  anxiety disorder) in adults in primary, secondary and  community care. http://www.nice.org.uk/CG22.   • To understand normal sleep physiology • To appreciate conditions that may disturb sleep   • Difficulty maintaining sleep - waking up for  more than 30 minutes and having a sleep  efficiency ratio of less than 85%   • Transient: lasts for 2-3 days and is due to  external factors such as jet lag, noise. Occurs in  individuals who normally do not complain of  insomnia.   • Short-term: lasts up to 3 weeks and is  usually associated with physical or emotional  trauma.    • Chronic: insomnia on most nights lasting for 3  weeks or more. Psychiatric disorders and alcohol  consumption are common factors leading to  chronic insomnia. Treatment should address the  underlying condition selecting drug therapy that  also alleviates insomnia.   • Consists of two states: rapid eye movement  (REM) cycles alternating with cycles of non-  rapid eye movement (NREM)   • Quality of sleep depends on the ratio between  the REM and NREM cycles   • Sleep may be studied through the use of  electroencephalogram to monitor electrical brain  activity   • Disturbance could occur as wakefulness, early  waking, difficulty in falling asleep.   • During NREM sleep, repair of bodily tissues  takes place. This phase is further subdivided into   • REM sleep is associated with the restoration of  memory function, along with repair of brain  tissue and laying down of memories. During this  phase the eyes may move with the eyelids closed.  Blood pressure, heart rate and breathing rate  may vary. Dreams are associated with this phase.  Catecholamines are involved.   • If the ratio between NREM and REM sleep is  disrupted, the sleep efficiency ratio is very low,  meaning that the patient will report a feeling of  tiredness despite having slept an appropriate  amount of hours. In adults NREM sleep  constitutes 75-80% and REM sleep 20-25% of  the sleep duration.   • What is a ‘good night’s sleep’? Nocturnal sleep  requirements decrease with age and there is great  inter-individual variation. So when a patient  complains of insomnia the patient’s perspective  of a good night’s sleep has to be established.   • Understanding sleeplessness: is the patient  experiencing difficulty falling asleep, early  morning wakefulness or difficulty maintaining  sleep?   • Combat sleeplessness naturally: use herbal teas  (e.g. chamomille and valerian)   • Ask the patient to complete a sleep diary to  understand sleep patterns, patient’s lifestyle and  symptoms.    Factors affecting the ability to relax and sleep are  summarised in Table 29.2.   There is not, as yet, an ideal hypnotic available. The  effectiveness of currently available hypnotics in stim-  ulating deep and satisfying sleep is limited. The sleep  efficiency ratio achieved is low indicating, that the    hypnotics induce sleep but do not achieve a physio-  logically normal sleep cycle.   The main hypnotic drugs available are benzodi-  azepines (e.g. nitrazepam, diazepam, lorazepam), non-  benzodiazepines (e.g. zaleplon, zolpidem, zopiclone),  sedative antihistamines (e.g. promethazine) and  chlomethiazole (used for elderly patients, also used in  alcohol withdrawal symptoms).   Benzodiazepines are relatively safe when compared  with phenobarbital and morphine since the lethal  dose is over 1000 times greater than the typical ther-  apeutic dose. They enhance the binding of gamma-  aminobutyric acid (GABA) to the receptor. This  results in a greater entry of chloride ions, which  hyperpolarises the cell making it difficult to depo-  larise, and therefore reduces its neural excitability.  This action leads to a lower output of excitatory  neurotransmitters such as noradrenaline, serotonin  and dopamine.    Benzodiazepines increase total sleep. However,  they cause a mild suppression of REM sleep.   • Flurazepam: 2-4 hours (produces active  metabolite with a very long half-life)   The structure of benzodiazepines (Figure 29.1) is  based on 5-phenyl-l,4-benzodiazepine-2-one. Halogen  substitution on ring A at position 7 increases func-  tional hypnotic and anxiolytic effects. A 3-hydroxy  moiety on ring B as in lorazepam increases excretion  rate. Annelation of the 1,2-bond on ring B with S-  triazole, as in triazolam, maintains clinical effective-  ness since it promotes ligand binding.   • Benzodiazepines should not be used in patients  with sleep apnoea, respiratory depression and  conditions that predispose to respiratory  weakness including myasthenia gravis and acute  pulmonary insufficiency.   • Benzodiazepines should be used with caution in  patients with a history of respiratory disease,  muscle weakness or myasthenia gravis, in  patients with a history of drug or alcohol  dependence, in pregnancy and breast-feeding,  and in hepatic and renal impairment.   • Dependence (physical and psychological):  treatment with benzodiazepines should be short  term (2-4 weeks)   • Hangover effects: drowsiness and light-  headedness the day after drug administration,  confusion and ataxia, less common with short-  acting benzodiazepines    Benzodiazepines, particularly triazolam and  lorazepam, are associated with memory  impairment. This is a dose-dependent effect  and, if it is reported by patient, dose should  be lowered.   Due to the occurrence of dependence, abrupt with-  drawal of a benzodiazepine may lead to anxiety,  headaches, increased pulse rate, increased blood  pressure, increased body temperature, tremor,  rebound insomnia, confusion, toxic psychosis and  convulsions. The withdrawal syndrome may occur  immediately upon stopping the drug (for short-  acting products) or take up to 3 weeks to develop.   Drugs that are more potent and rapidly elimi-  nated (e.g. lorazepam, triazolam) have more frequent  and severe withdrawal problems. Gradual with-  drawal should be effected. The prescriber may  consider changing to a long-acting benzodiazepine  such as diazepam before considering withdrawal.   Less potent and more slowly eliminated drugs  (e.g. flurazepam) continue to improve sleep even  after discontinuation, and are therefore associated  with less severe withdrawal problems.   These drugs act at the benzodiazepine receptor and  have a rapid onset of action and a short duration of  action. They are useful in patients who have diffi-  culty in falling asleep. They are associated with  dependence to a lesser extent when compared with  benzodiazepines. Cautions and contraindications to  the use of these drugs are similar to those noted for  benzodiazepines.   Antihistamines such as promethazine are useful for  their sedative effect. The sedative effect of antihista-  mines may decrease rapidly with continued treatment.  See also Chapter 25.   • Hypnotics increase sleeping time but may  produce a hangover effect in the morning.   • Hypnotics produce a reduction in the  occurrence and duration of REM sleep,  resulting in patients feeling irritable and  unrested the day after.   • Patients who have used benzodiazepine  hypnotics for long periods can be  gradually weaned using non-  benzodiazepine hypnotics as doses of the  benzodiazepine are gradully lowered.   • Hypnotics should be considered only  when the insomnia is severe and  disabling.   • In older patients hypnotics are potentially  hazardous and should be avoided.   • A reduction in urinary clearance and  accumulation of drug in adipose tissue may    result in a prolonged half-life, leading to  confusion and ataxia that increase risk of falls  and injury.   • Clomethiazole may be considered for short-term  use in severe insomnia in older patients or in  restlessness and agitation because of its lower  risk of hangover effects. However it may cause  dependence and common side-effects include  nasal congestion and irritation, conjunctival  irritation and headache.   • Children are more susceptible to the central  nervous system depressant effects of  benzodiazepines. Hypnotics are not  recommended for children. Sedating  antihistamines are preferred.   This is produced by the pineal gland when exposed  to darkness; bright light and physical activity result  in decreased secretion. It regulates sleep by affecting  the circadian rhythm and increases total sleep time  and causes a faster onset of sleep. It is useful in  patients suffering from jet lag and in patients suffering  from insomnia due to night shift work.   Snoring occurs when air does not flow smoothly  through the nasal and throat pathways. Predisposing  factors are obesity, alcohol intake, drugs (hypnotics,  antidepressants, antipsychotics), age, gender and  sleep apnoea.   • nasal strips - when snoring is due to small or  collapsing nostrils   This is a neurological disorder characterised by repet-  itive periods during sleep with breathing cessation for  at least 10 seconds. It results in impacting negatively  on quality of sleep.   Obstructive sleep apnoea is the most common  type. During sleep the throat is closed and breathing  stops temporarily, resulting in patient gasping for air  and falling back to sleep. Snoring is a presenting  complaint.   Sleep apnoea is associated with obesity, smoking  and alcohol. There is increased risk in patients with  hypertension, coronary artery disease and cere-  brovascular disease, and a relationship with meta-  bolic syndrome is being examined. Patients with  sleep apnoea tend to be high users of healthcare  services due to increased risk of cardiovascular  morbidity and use of psychoactive medicines,  especially if obstructive sleep apnoea is undiagnosed.    In obstructive sleep apnoea, anatomic devices such  as a mandibular splint are used. In central sleep  apnoea a continuous positive airway pressure machine  (CPAP) is indicated. The CPAP machine provides a  constant flow of air through a mask that is worn by  the patient during sleep, thus preventing breathing  cessation. CPAP is a symptomatic management since  once it is stopped apnoea episodes re-occur.   The use of hypnotics in sleep apnoea is not indi-  cated since they may interfere with the stimulation of  breathing once this has stopped.   This is a neurological condition characterised by  uncomfortable sensations in the legs that demand  movement when at rest and at night. The condition  contributes to insomnia and patients complain of  impaired daytime functioning due to disturbed sleep.   The condition is common in: geriatric patients,  Parkinson’s disease, hypothyroidism, kidney disorders,  rheumatoid arthritis, neuropathy, chronic venous  insufficiency and iron-deficiency anaemia.   Investigation to assess whether restless leg  syndrome occurs as a secondary condition should be  undertaken. Most commonly it may present as a sign  of undiagnosed anaemia. The underlying condition  should be treated.   Non-pharmacological management includes sleep  hygiene, reducing caffeine and alcohol intake, regular  exercise, smoking cessation.   Choice depends on severity of symptoms and  concomitant disease states. Dopamine agonists (see  Chapter 33) such as pramipexole and ropinirole are  used, but they may induce insomnia. The use of  opioids may be considered to induce an analgesic  effect, but their use is limited due to side-effect  profile and dependence. Anticonvulsants such as  carbamazepine and gabapentin and magnesium  supplementation may be considered. For patients  with iron-deficiency anaemia, iron supplementation  is required.   • In the management of insomnia, behavioural  interventions should be considered since these are  free from any side-effects and have a sustained  effect.   • Duration of use of hypnotics should be minimal  and preferably of less than 4 weeks’ duration.   • When hypnotics are used, exit strategies should  be planned when treatment is started, and  patient information on the duration of treatment  and advice on the effects of the drugs explained  (e.g. care when driving or operating machinery).   • Snoring could be a sign of sleep apnoea.  Occurrence of sleep apnoea may go undiagnosed  but may impact on daytime activities,  cardiovascular morbidity and overuse of  psychoactive medications.   • The occurrence of restless leg syndrome requires  investigations to identify the possible occurrence  of underlying pathology.   1 Give an example of a benzodiazepine that has a  short duration of activity. Explain the clinical  implications of this characteristic.   1 Benzodiazepines with a short half-life include  lorazepam and triazolam. The duration of    action is implicated in the frequency of rebound  insomnia resulting from discontinuation of  benzodiazepine therapy. The drugs that are  more potent and rapidly eliminated have more  frequent and severe withdrawal problems, and a  higher risk of rebound insomnia when  compared with the more slowly eliminated  drugs such as diazepam. Rebound insomnia  results in a worsening presentation of the  original symptoms of difficulty in falling asleep  or in maintaining sleep.   Allen S (2005). Insomnia and its management. Pbarm J 274:  243-246.   Allen S (2005). Sleep and sleeping disorders. Fbarm J 274:  187-190.   Holmes J, Millard J, Greer D and Silcock J (2003). Trends  in psychotropic drug use in older patients in general  hospitals. Pbarm J 271: 584-586.   Lam J and Ip M (2007). An update on obstructive sleep  apnea and the metabolic syndrome. Curr Opin Pulm  Med 13: 484-489.   Morin A K, Jarvis C I and Lynch A M (2007). Therapeutic  options for sleep-maintenance and sleep-onset  insomnia. Pbarmacotberapy 27: 89-110.   Nathan A (2005). Snoring and the evidence behind the  various treatments available. Pbarm J 274: 309-312.   Reese J P, Stiasny-Kolster K, Oertel W H and Dodel R C  (2007). Health-related quality of life and economic  burden in patients with restless legs syndrome. Exp Rev  Pbarmacoeconomics Outcomes Res 7: 503-521.   Tarasiuk A, Greenberg-Dotan S, Simon-Tuval T, Oksenberg  A and Reuveni H (2008). The effect of obstructive sleep  apnoea on morbidity and health care utilization of  middle-aged and older adults. J Am Geriatr Soc 56:  247-254.    • To develop skills to be able to promote lifestyle  changes to address obesity and eating disorders.   The term ‘eating disorders’ generally refers to  anorexia nervosa and bulimia nervosa which are two  conditions that commonly coexist with other psychi-  atric conditions including depression and anxiety  (obsessive-compulsive disorder, post-traumatic stress  disorder) and with substance abuse. In this chapter  the term ‘eating disorders’ is applied in a broader  sense to include obesity and lack of appetite.   In palliative care, corticosteroids (e.g. pred-  nisolone and dexamethasone) are used to improve  appetite and maintain a state of well-being.   This term is used to describe chronic fatigue due to  sleep disorders, stress or chronic disease.   • Symptoms: headache, malaise, anorexia,  xerostomia, diaphoresis, pallor, heartburn,  abdominal pain, flatulence.   • Treatment is sulbutiamine: precursor to thiamine  (vitamin Bj), improves memory and intellectual  tiredness, and reduces fatigue.   Obesity is a disorder that is becoming increasingly  predominant among Western societies. It occurs as a  result of an abnormal energy balance, usually  resulting from excessive caloric intake and inadequate  caloric loss. This reflects excess energy being stored as  body fat.   • Physiological factors: disturbances in the hunger  and satiety centres in the hypothalamus, effects  on neurotransmitters, neuropeptides and  hormones that regulate food intake   • Genetic factors: genetic predisposition together  with environmental factors tend to result in  occurrence of obesity   • Metabolic abnormalities: hypothyroidism,  diabetes, psychiatric disorders, pregnancy,  congestive heart failure   Obesity in children has been rising. Obesity that starts  during critical periods in life appears to increase risk  of persistent obesity and of related complications.  Critical periods include gestation and early infancy,  age between 5 and 7 years, and adolescence.   Childhood obesity should be given priority and  management should emphasise behavioural changes  necessary to achieve a reduction in weight gain.   • Diagnosis: body mass index (BMI) - obesity  >30 kg/m 2 , overweight 25-29.9 kg/m 2 ; waist  circumference men >102 cm, women >88 cm   • Investigations: blood pressure, blood tests (blood  glucose, lipid profile, thyroid function tests).  Hypothyroidism is a potential cause for weight  gain   • Reduction of caloric intake: a weight  reduction programme should include  educating the patient on evaluation of  caloric content of food items. Patients  should receive information on reducing  fat and how to avoid rapid reduction in  body weight. Crash diets and starvation  diets are to be avoided since they result in  a rapid weight reduction. However,  patients do not learn to modify and  adjust food intake patterns, so weight  regain will occur once dieting is stopped.    • Behavioural modification: patients should  learn how to limit eating in between  meals and snacking on high-fat food  items. Keeping a diary of food intake  patterns could help individuals to  recognise over-indulgence in food.  Individuals may find encouragement and  support from attending weight reduction  groups.   • Chitosan: derived from polysaccharide chitin, it  attaches to lipids or fats in the stomach to  prevent their absorption.   • a plateau is reached after initial success with  dieting alone   An anti-obesity drug should be considered only  for those with a body mass index of 30 kg/m 1 or  greater in whom at least 3 months of managed  care involving supervised diet, exercise and  behaviour modification fails to achieve a realistic  reduction in weight.    In the presence of risk factors ( such as  diabetes, coronary heart disease, hypertension  and obstructive sleep apnoea) it may be  appropriate to prescribe a drug to individuals  with a BMI of 27 kg/m 2 or greater, provided that  such use is permitted by the drug’s marketing  authorisation. Drugs should never be used as the  sole element of treatment. 1   Pharmacotherapy available today includes drugs  that act on the gastrointestinal tract (orlistat) or  centrally acting appetite suppressants (sibutramine).   In the 1950s and 1960s the effect of amphetamines  as appetite suppressants led to amphetamines being  used in the management of obesity. However, they  have addictive and euphoric properties. Later, other  appetite suppressants that had a centrally acting  effect such as phentermine and diethylpropion were  developed. Compared with the amphetamines these  had a lower occurrence of addiction and unwanted  effects. Their use is still restricted in many countries.   In the 1990s fenfluramine and dexfenfluramine  provided an alternative to amphetamines and sym-  pathomimetic products. Fenfluramine and dexfen-  fluramine stimulate serotonin release. They resulted  in a lower occurrence of addiction and a few cardiac  and CNS side-effects. They were withdrawn from the  market in the mid-1990s, however, because of an  association with valvular heart disease and primary  pulmonary hypertension.   Orlistat is a reversible inhibitor of lipases, which  interferes with hydrolysis of dietary fat. It has a  topical action resulting in decreased absorption of  ingested fat and is suitable for patients who have a  high intake of fat in their diet.   • Capsules are taken with meals or up to 1 hour  after and should be omitted if meals contain no  fat.   • If patient takes a multivitamin preparation, this  should be taken 2 hours after the orlistat dose.   • Side-effects: interference with absorption of fat-  soluble vitamins, oily spotting in faeces, flatus  and faecal urgency.   • Low-dose orlistat has been granted centralised  over-the-counter status by the European  Medicines Agency.   • Used for patients aged between 18 and 75  years who have lost at least 2.5 kg body  weight by lifestyle modifications   • Treatment should continue beyond 3  months if weight loss is greater than 5%,  beyond 6 months if loss is greater than  10 %   • Treatment should not usually continue  beyond 1 year and never beyond 2 years.   This drug inhibits re-uptake of serotonin and nora-  drenaline. It acts centrally, resulting in increased  adrenergic and serotonin activity leading to down-  regulation of alpha- and beta- adrenergic receptors and  serotonin receptors. This causes a sensation of satiety.   • May be used as an adjunctive management of  obesity in patients with other risk factors such as  type 2 diabetes and dyslipidaemia   • Patient advice: dose to be taken in the morning,  check before using other medications  concurrently (e.g. avoid nasal decongestants due  to sympathomimetic effect, antidepressants and  antipsychotics due to increased risk of CNS  toxicity)   • Contraindications: psychiatric illness, history of  cardiovascular disease, uncontrolled  hypertension, hyperthyroidism, prostatic  hypertrophy   • Cautions: epilepsy, glaucoma, predisposition to  bleeding, family history of motor or vocal tics,  history of depression, ocular hypertension    • Side-effects: headache, dizziness, depression,  anxiety, insomnia, hypertension, constipation,  dry mouth, nausea.   • Treatment should not be continued for  more than 1 year   • Treatment should be discontinued if  weight loss after 3 months is less than  5%, when weight loss stabilises at less  than 5% and in individuals who regain  3 kg or more after previous weight loss.   This is a syndrome characterised by self-starvation,  extreme weight loss, body image disturbance and  an intense fear of becoming obese. A BMI index  <17.5 kg/m 2 is used to describe anorexia nervosa.  Weight loss, refusal to maintain normal BMI, irra-  tional fear of becoming overweight and amenorrhoea  are classic symptoms.   This is a condition characterised by binge eating  usually followed by some form of purging. Individuals  experience a sense of lack of control over volume of  food intake or food intake within short time frames  which is followed by inappropriate behaviour to  prevent weight gain such as self-induced vomiting,  misuse of laxatives and diuretics, or excessive exercise.   This is a newly delineated disorder characterised by  bingeing not followed by purging. It results in exces-  sive caloric eating and occurs commonly in obese  individuals and in the older age group. It is related to  negative emotional stress.   • Girls in early to late teens who exhibit  weight loss (anorexia) or significant  weight fluctuations (bulimia)   • Young men and boys may also present  with eating disorders.   • Personality: low self-esteem, fear of becoming  fat, sensitivity to rejection, perfectionism   • Biochemistry: serotonin and noradrenaline  activity lower in patients with eating disorders.   SSRIs are more effective in bulimia nervosa and in  binge eating disorder than in anorexia nervosa, prob-  ably because in anorexia nervosa there is reduced  dietary tryptophan.   SSRIs may be considered in anorexia nervosa in  patients with prominent depressive or obsessive-  compulsive symptoms which continue after normal  body weight has been achieved. They reduce binge  eating and vomiting in patients with binge eating  disorder and in bulimia nervosa. Duration of treat-    continue beyond 1 year and never beyond 2  years. Sibutramine inhibits re-uptake of  serotonin and noradrenaline. It acts centrally  and causes a sensation of satiety. Patients should  be advised to take the dose in the morning and  not to use other drugs before seeking advice  from a health professional. Blood pressure and  pulse rate should be monitored. Sibutramine is  contraindicated in psychiatric illness, glaucoma,  history of cardiovascular disease and side-effects  include dry mouth, headache and constipation.    ment for at least 6 months is recommended for a  better long-term outcome compared with shorter  duration of therapy.   • Ideal body weight is commonly assessed  according to the body mass index (weight in  kilograms/square of height in metres).   • A comprehensive management approach is  required in the management of eating disorders  which includes behavioural modification, patient  support and education on food patterns.   • In obesity, pharmacotherapy should be  considered as an adjunct to exercise, diet and  behavioural modification in patients without risk  factors with a BMI index of 30 kg/m 2 or greater  or in patients with an obesity-related risk factor  and a BMI index of 27 kg/m 2 or greater.   1 Orlistat is a reversible inhibitor of lipases  interfering with hydrolysation of dietary fat. It  has a topical action. Side-effects include  interference with absorption of fat-soluble  vitamins, oily spotting, flatus and faecal urgency.  Orlistat can be used by patients aged between  18 and 75 years. Treatment with orlistat should  continue beyond 3 months if weight loss is  greater than 5%, beyond 6 months if loss is  greater than 10%. Treatment should not usually   Ali O (2002). Getting to grips with obesity: incidence and  associated risks. Pharm J 268: 616-618.   Ali O (2002). Getting to grips with obesity: non-drug  strategies. Pharm J 268: 652-654.   Ali O (2002). Getting to grips with obesity: pharmaco-  therapy. Pharm J 268: 687-689.   Ali O (2002). Getting to grips with obesity: how pharma-  cists can contribute to obesity management. Pharm J  268: 720-722.   Anon (2006). Sibutramine - four years experience. Aust  Adverse Drug React Bull 25: 11.   Eissa MAH and Gunner K B (2004). Evaluation and  management of obesity in children and adolescents.  J Pediatr Heatlh Care 18: 35-38.   Riedl A, Becker J, Rauchfuss M and Klapp B R (2008).  Psychopharmacotherapy in eating disorders: a system-  atic analysis. Psychopharmacol Bull 41: 1-22.   Sonnenberg G E, Matfin G and Reinhardt R R (2007). Drug  treatment for obesity: where are we heading and how  do we get there? Br J Diabetes Vase Dis 7: 111-118.   1 Martin J (ed.). British National Formulary , 57th edn.  London: Pharmaceutical Press, 2009, p. 218.   • To recognise sources of pain, categories of pain and  therapeutic response required   • To identify properties and characteristics of opioid  and non-opioid drugs   • To develop skills required in the use of opioid  analgesics and patient monitoring required   Pain is an uncomfortable experience that occurs as a  result of tissue damage and which has an emotional  dimension in addition to the physical damage. The  extent to which the same level of pain interferes with  the emotional dimension and with a patient’s lifestyle  varies from one individual to another due to variation  in the pain threshold.   • Neuropathic pain: arising from nervous system  (e.g. trigeminal neuralgia, shingles)   Endogenous peptide agonists, such as enkephalins  and endomorphins, act on opioid receptors which  present as:    • (i receptor: agonist effect causes analgesia at  supraspinal level, euphoria, respiratory  depression, dependence   • Psychosocial assessment: impact of pain on  psychological well-being and social activities   • Factors that influence pain: activities that  increase or decrease occurrence of pain   • Qualitative analysis using visual analogue:  patient can describe quantitatively the impact of  pain   • Measurement instruments: to evaluate impact of  pain on patient’s physical and psychological well-  being   • Diaries: to identify activities that may relate to  the occurrence or deterioration of the condition.   • Dosage forms: tablets (500 mg), soluble tablets  (500 mg), oral suspension (125 mg/5 mL,   • Dosage: adults: 0.5-1 g every 4-6 hours to a  maximum of 4 g daily; children: every 4-6 hours  up to a maximum of 4 doses in 24 hours:   • Overdosage: hepatotoxicity. Paracetamol is  metabolised to a quinone imine which is extremely  toxic. This metabolite is normally eliminated in  the liver by a reaction with gluthatione. In  overdosage, the quinone reacts with cellular  proteins and nucleic acid in the liver.   These contain a non-opioid drug with an opioid  component (e.g. co-codamol is paracetamol and  codeine).    A number of cold preparations contain para-  cetamol. Advise patients using cold prepara-  tions that contain paracetamol against the  concomitant use of paracetamol to avoid  overdosage.   Aspirin (Figure 31.4) has analgesic, antipyretic and  anti-inflammatory actions; the anti-inflammatory  action is experienced at high doses when side-effects  are more common. It inhibits cyclo-oxygenase,  resulting in decreased release of prostaglandins, and  has an antiplatelet effect, irreversibly inhibiting cyclo-  oxygenase in platelets and preventing formation of  thromboxane A 2 (platelet aggregation agent).   • Dosage forms: tablets, dispersible tablets  (300 mg), low-dose aspirin tablets (75 mg)   • Indications: headache, transient musculoskeletal  pain, dysmenorrhoea, pyrexia; low-dose:  prophylaxis of cerebrovascular disease and  myocardial infarction   • Dosage regimen: maximum adult daily dose 4 g  daily (300-900 mg every 4-6 hours)   • Side-effects: gastrointestinal disturbances  (irritation, blood loss, peptic ulceration),  increased bleeding time, bronchospasm   • Cautionary labels: take after food, use enteric-  coated tablets to decrease physical damage  during drug administration   • Contraindications: children (occurrence of Reye’s  syndrome - fatty liver degeneration accompanied  by encephalopathy), haemophilia and bleeding  disorders, acute or history of peptic ulcers   • Cautions: asthma, allergic disease, the elderly,  hepatic and renal impairment, pregnancy   • Pregnancy: during the third trimester use of  aspirin may present potential bleeding disorders  in mother and fetus, delayed onset and increased  duration of labour with increased blood loss   • Indicated for symptomatic relief in osteoarthritis  and rheumatoid arthritis in patients at high risk  of developing a gastroduodenal ulcer   • Administration of high doses of NSAIDs  or more than one NS AID   • Morphine (Figure 31.6): the standard drug  against which other opioids are compared   • Codeine (Figure 31.7): higher bioavailability than  morphine but less potent   • An event that occurs in response to a  disease state or pathogen   • Non-steroidal anti-inflammatory drugs  (e.g. aspirin, ibuprofen, diclofenac,  mefenamic acid, celecoxib, meloxicam).    Opioids can cause respiratory depression.  They should be avoided in patients with acute  respiratory insufficiency, sputum retention,  bronchiectasis and chronic bronchitis.   • Used in chronic, severe pain in advanced cancer  and in post-operative pain   • Has a central analgesic action, produces euphoria  and a sense of detachment, all of which could be  useful in advanced cancer and in palliative care    - normal release morphine elixir: effect within  20 minutes, peak 60 minutes   - injections: considered when patient presents  with persistent nausea and vomiting, difficulty  in swallowing and when patient is not  cooperative.   • More soluble than morphine allowing effective  doses to be injected in smaller volumes   • May cause less nausea and hypotension than  morphine. This characteristic is particularly  useful in patients in cardiac and emergency units.   • Has a rapid onset of action and a short duration  of action (2 hours)   • Metabolised to norpethidine which can cause  seizures in renal impairment due to  accumulation.   • Used for intra-operative analgesia but is not  suitable for post-operative analgesia since the  duration of action is short   • Remifentanil: has a rapid onset of action  (2 minutes) and a short duration of action.    In patients receiving opioid analgesics,  prophylaxis for nausea and vomiting should  be considered using antiemetics and when  opioid is being used long term consider a  laxative such as lactulose due to incidence of  constipation as a side-effect. Opioids can  cause confusion, especially in older patients.   • Neuropathic pain: include use of adjuvant  analgesics such as anticonvulsants (e.g.  carbamezepine), antidepressants (e.g.  imipramine) and others (e.g. baclofen)   • Unknown cause: opioids with adjuvant  analgesics such as anticonvulsants,  antidepressants.   Table 31.4 shows adjuvant drugs used in the treat-  ment of pain.   This involves the injection of local anaesthetic close  to the sensory area where the pain is occurring so as  to block conduction of pain impulses. The use of  adrenaline in combination with the local anaesthetic  is considered to increase duration of action of the  anaesthetic due to the vasoconstriction that occurs.   An opioid drug is delivered in a pump system which  delivers a pre-set dose on activation. A safety feature  (lock-out time) ensures that the patient does not re-  activate and get release of drug immediately after an  activation. The pump delivers the drug by subcut-  aneous injection. It gives the patient a feeling of control  over pain management and results in individual  dosing.   The durations of action of some common local  anaesthetics are compared in Table 31.5.   Concomitant administration of a vasoconstrictor  (e.g. adrenaline) to increase duration of action may  be considered. Such practice is contraindicated if the  anaesthetic is being used near extremities, due to  ensuing vasoconstriction.    Reasons for analgesic treatment failure include  inadequate management (dose, frequency, drug  selection), occurrence of side-effects, fear of  addiction and patient misunderstanding.   • Presentation: localised to the periorbital area or  forehead; blowing the nose intensifies pain   • Presentation: bilateral, diffuse pain often over the  top of the head   • Possible cause: distension or dilatation of  intracranial arteries or traction or displacement  of large intracranial veins   • Duration: aura 30 minutes before onset of  attack; several days   • Caution: pre-existing cardiac disease (angina,  hypertension, transient ischaemic attacks, stroke)  since they cause vasoconstriction, hepatic  impairment   Triptans should be started as soon as symptoms  of migraine occur.   • Dietary factors: cheese, alcohol, caffeine  withdrawal or excessive caffeine intake   • Acute treatment: analgesics or 5HTj  agonist ± metoclopramide (if  accompanied by nausea)   • Prophylaxis: beta-blockers (e.g.  propranolol), calcium channel blockers,  tricyclic antidepressants (e.g.  amitriptyline), pizotifen, anticonvulsants  (e.g. valproate, topiramate).   • Occurs commonly: by age 7 years 40% of  children experienced headaches and by age 15  years 75% of individuals would have  experienced headaches    • Before adoloscence headache is mainly migraine  and with adoloscence pattern changes to muscle  contraction headache.   • Rebound patterns of headache from repeated use  of symptomatic headache medications  (analgesics, ergot alkaloids, triptans)   • Most frequent secondary cause of chronic daily  headache (headache for >4 hours on >15 days/  month)   • High occurrence with combination analgesics  containing caffeine and with triptans.   • Dysmenorrhoea: use of oral contraceptive agents  when menstrual cycle disorders are associated  with clinical dysmenorrhoea (see Chapter 40)   • Trigeminal neuralgia: characterised by abrupt,  intense bursts of pain along one side of the face.  Carbamazepine and phenytoin may be  considered during the acute phase   • Herpetic and postherpetic neuralgia: post-  herpetic neuralgia may persist for a number of  months. Antiviral agents are used during the  herpetic phase and amitriptyline and gabapentin  may be considered in the postherpetic phase   • Consists of a small, battery-operated instrument  that delivers rapid pulses of a small electric  current to electrodes applied to the skin   • Provides relief and is indicated within a pain  management programme.   Pyrexia or fever occurs when the body temperature is  higher than the normal core temperature of 37°C.  Body temperature is controlled in the hypothalamic  heat-regulating centre. Fever occurs when interleukin  1 generates prostaglandins which disturb the heat-  regulating centre. Complications of fever include  febrile convulsions and status epilepticus.   The advantages and disadvantages of mercury-in-  glass and electronic thermometers are summarised in  Table 31.6.   • Act on hypothalamic heat-regulating centre in  the central nervous system   • Febrile convulsions should be avoided. If they,  occur patient is treated with intravenous or rectal  administration in solution of diazepam.   • The three principal compounds - aspirin,  ibuprofen and paracetamol - are all effective for  mild-to-moderate pain; the first two are indicated  more where pain is due to inflammation such as  musculoskeletal, dental and dysmenorrhoea.   • Aspirin and ibuprofen have similar indications  but ibuprofen appears to be more effective with a  lower profile of adverse effects.   • Paracetamol is preferred in children under 16  years, and patients with a history of asthma or  gastrointestinal problems.   • Soluble preparations have a faster onset of action  and for NSAIDs produce less gastric irritation.   • Review treatment regularly; if one type of  analgesic fails, move up the ladder.   • Avoid recurrence of pain; drugs with a short  duration of action are not suitable in the  management of sustained severe pain.   • Consider adjuvant drugs, social and  psychological support in addition to analgesics.   • In chronic pain adopt patient self-report measures  which assess occurrence of pain, for example at  rest, during movement or during sleep.   2 Describe the mode of action of ibuprofen and  list indications for use.   3 List common adverse reactions that could be  expected with NSAIDs.   4 What are the distinguishing characteristics  between indoleacetic acid NSAIDs and  propionic acid NSAIDs?   5 What is pyrexia and what devices can be used  to monitor the condition?   2 Mode of action: ibuprofen inhibits the cyclo-  oxygenase 1 (COX-1) enzyme, resulting in a    decrease in inflammatory mediators such as  prostaglandins and leukotrienes. It, however,  also inhibits the COX-2 enzyme which results  in a decrease in the protective prostaglandins  in the stomach and the kidney, hence causing  side-effects such as gastrointestinal irritation  and renal impairment. Indications: headache,  transient musculoskeletal pain, dysmenorrhoea,  pyrexia.   3 Gastrointestinal disturbances (irritation, blood  loss, peptic ulceration), increased bleeding time,  bronchospasm.   4 Indoleacetic acids (e.g. indometacin) are very  potent with many side-effects including  gastrointestinal disturbances, headaches and  dizziness. Propionic acid derivatives (e.g.  ibuprofen, naproxen and diclofenac) are less  potent with fewer side-effects. This distinction  is attributed to a difference in structure.   5 Pyrexia is body temperature that is higher than  the normal core temperature of 37°C. Body  temperature is controlled in the hypothalamic  heat-regulating centre. Fever occurs when  interleukin 1 (IL-1) -generated prostaglandins  disturb the heat-regulating centre. Medical  devices used to measure pyrexia include  mercury-in-glass and electronic thermometers.   6 In adjuvant analgesia, products with a primary  indication other than for pain are used in  combination with analgesics, for example  tricyclic antidepressants such as amitriptyline  which is used in neuropathic pain.   Aronoff G (2006). The use of opioids in chronic pain  management. Hosp Pharm Eur January/February:  67-71.   Dickman A (2007). Opioid analgesics in palliative care.  Pharm J 278: 745-748.   Hankin C S, Schein J, Clark J A and Panchal S (2007).  Adverse events involving intravenous patient-controlled  analgesia. Am J Health-Syst Pharm 64: 1492-1499.  Helme R D (2006). Drug treatment of neuropathic pain.  Aust Prescrib 29: 72—75.   Pizzuto M, Wirth F, Azzopardi L M, Zarb-Adami M and  Serracino-Inglott A (2009). Palliative care in cancer  patients. Hosp Pharm Eur 42: 66-69.   • To appreciate the use of pharmacotherapy in • To identify use of adjunctive therapy in the   • To develop skills to support patient and caregivers  to cope with condition and benefit from drug  therapy prescribed   Dementia is a syndrome of acquired abnormality in  cognitive functions (including memory, language,  judgement), behaviour and participation in social life.  Dementia leads to a deterioration in emotional control  (patients may at times become aggressive), a change in  social behaviour patterns and motivation.   Alzheimer’s disease is a common example of  dementia. Alzheimer’s disease is a systemic neuro-  degenerative disease that causes slow and gradual  progressive dementia.   • Deficiency of neurotransmitters, particularly  acetylcholine, due to decreased occurrence of  acetyltransferase   • May be as a result of various pathophysiological  pathways and may depend on multiple factors   • Possibility that NSAIDs, oestrogen therapy,  antioxidants (vitamin E) and higher education  decrease likelihood of disease.   • Average age of onset is 75 years (range  52-89 years)   • Short-term memory lapse developing into  deterioration of cognitive function, urinary  incontinence, depression and hallucinations   • Scales such as the Global Deterioration Scale  may be used to describe the extent of cognitive  decline, which ranges from very mild decline  (forgetfulness) to very severe decline (loss of  psychomotor and verbal skills and incontinence).  Cognitive decline impacts negatively on work  and social life and leads to agitation and  aggression.   • Establishment of dementia by clinical  examination and using scales such as the Mini-  Mental State Examination (MMSE)   • Occurrence of deficits in two or more areas of  cognition: language, memory, perception    • Progressive worsening of memory and other  cognitive functions, impairment in daily living  and altered behavioural patterns   • Absence of other systemic disorder or brain  disease that may account for deficits in memory  and cognition   • Review drug therapy to identify use of  medications that may have a negative impact on  cognitive function (e.g. benzodiazepines).   • To induce patient to keep active and take up  exercise and suggest participation in patient  support groups   • To avoid polypharmacy to reduce tablet-taking  burden on patient and carers   • To monitor use of medications that may have an  effect on the central nervous system.   • Acetylcholinesterase inhibitors (e.g. donepezil,  galantamine, rivastigmine, which is also licensed  for dementia associated with Parkinson’s disease)  are used in mild-to-moderate disease.   • NMDA (N-methyl-D-aspartate) antagonists (e.g.  memantine) are used in moderate-to-severe  disease.   Pharmacotherapy alleviates the symptoms but  the condition will gradually deteriorate to an    extent where the patient becomes unable to  communicate and to cope independently.   These slow the rate of cognitive and non-cognitive  deterioration. In addition to activity on acetyl-  cholinesterase, galantamine stimulates nicotinic  receptors and rivastigmine inhibits butyryl-  cholinesterase activity, which is another pathway for  acetylcholine metabolism. They are associated with a  lag time of 3 months.   • Efficacy is judged on assessment of cognition,  behaviour and daily activities.   • Cautions: cardiac disease, asthma, COPD,  pregnancy, breast-feeding, and hepatic and renal  impairment.    Acetylcholinesterase inhibitors are better  tolerated if taken with or after food.   These have a neuroprotective effect since in  Alzheimer’s disease there is probably an age-related  change in NMDA receptors. They are indicated for  moderate-to-severe disease and may be used in  patients who cannot tolerate cholinesterase inhibitors.   • Side-effect profile is low: constipation,  hypertension, headache, dizziness and drowsiness   Other possible therapies that are currently being  evaluated include: MAOIs, antioxidants and Gingko  biloba.   • Use of cholinesterase inhibitors in mild-  to-moderate disease may allow patients to  stay longer at home rather than being  institutionalised   • Treatment postpones disease onset but  decision has to be taken when treatment  should be withdrawn (end-point of  treatment) if patients are not responding  or tolerating the drugs   • Assessment of outcome of therapy using  quality-of-life scores; functional and  behavioural assessment should be carried  out within 3 months of initiating therapy.   Drugs that can cause confusion as a side-effect should  be used with caution in patients with dementia or  Alzheimer’s disease:   • Reassure and counsel to avoid guilty feelings as a  result of reactions by patients.   Achieving compliance in patients with  dementia is very difficult. Pharmacists should  establish contact with carers to explain use of  medication, to offer patient and carer support  and to provide signposting services.   Behavioural and psychological symptoms present in  patients with dementia and Alzheimer’s disease. The  following suggested therapies are available:   Antipsychotic therapy should be considered  for non-cognitive symptoms that are inter-  fering with patient’s lifestyle and where carers  report negative aspects of patient’s behaviour.   The use of atypical antipsychotic drugs is uncer-  tain since concerns about the safety have emerged.  The disadvantages of the atypical antipsychotics  include weight gain, diabetes mellitus, cardiac  conduction abnormalities, cerebrovascular events  and extrapyramidal symptoms. Patients with  dementia may be at a higher risk of developing stroke  associated with use of antipsychotics (see also  Chapter 26).   Before starting an atypical antipsychotic in  patients with dementia, who are in most cases    elderly, baseline assessment of cardiac func-  tion and occurrence of extrapyramidal symp-  toms should be undertaken and concurrent  medication reviewed.   benzodiazepines should be avoided due to their nega-  tive effect on cognitive function.   • Compliance may be an issue - treatment is not  effective with intermittent administration, patient  may have cognitive impairment which will  impact negatively on compliance, and family  supervision needs to be recruited.   • Titration of dose: start at low dose and titrate  up.   1 When is memantine used in Alzheimer’s disease?  List common side-effects that may occur with  its use.   1 Memantine is an N-methyl-D-aspartate (NMDA)  antagonist with a neuroprotective effect    indicated for moderate-to-severe Alzheimer’s  disease. The rationale for its use is that in  Alzheimer’s disease there is probably an age-  related change in NMDA receptors. Memantine  may be used in patients who cannot tolerate  cholinesterase inhibitors. The side-effect profile  includes constipation, hypertension, headache,  dizziness and drowsiness, and less commonly  vomiting, thrombosis, confusion, fatigue,  hallucinations and abnormal gait. Very rarely  seizures, pancreatitis, psychosis, depression and  suicidal ideation may occur.   Bullock R (2003). Guide to identifying and treating  dementia. Prescriber 19 October: 34-44.   Douglas I J and Smeeth L (2008). Exposure to ant-  ipsychotics and risk of stroke: self-controlled case series  study. BMJ 337: al227.   Herrmann N and Lanctot K L (2006). Atypical anti-  psychotics for neuropsychiatric symptosm of dementia:  malignant or maligned? Drug Safety 29: 833-843.   Husband A and Worsley A (2006). Different types of  dementia. Pbarm J 277 : 579-582.   National Institute for Health and Clinical Excellence  (2006). Dementia: Supporting people with dementia  and their carers in health and social care, http://  www.nice.org.uk/guidance/cg42 (updated September  2007).   Schneider L S, Tariot P N, Dagerman K S, Davis S, Hsiao J K,  Ismail S et al. (2006). Effectiveness of atypical anti-  psychotic drugs in patients with Alzheimer’s disease. N  Engl J Med 355: 1525-1538.   Thompson F C, Fraser K, Kelly J, Martin M and Lyons D  (2001). Drug treatment of dementia. Hosp Pbarm 8:  41-49.   Yaari R and Corey-Bloom J (2007). Alzheimer’s disease.  Semin Neurol 27: 32-41.    • To develop skills to identify concerns of the patient  with anti-parkinsonian drugs and develop an  individualised drug therapy programme.   This condition was described in 1817 by Dr James  Parkinson as ‘the shaky palsy’. It is a progressive neuro-  logical disorder characterised by impaired voluntary  movements.   Symptoms may disappear with treatment with-  drawal or may persist after discontinuation of treat-   • Reduced concentration of dopaminergic neurons  in corpus striatum and substantia nigra   • Signs: shuffling gait, blank facial expression,  speech impairment, inability to perform skilled  tasks    Depression is a common condition related to  parkinsonism. Signs need to be taken into  account when reviewing patient. Antidepres-  sant drug therapy, when required, should be  identified after considering current drug  therapy and disease state.   • Stage III: bilateral involvement, first sign of  impaired righting reflexes   • Drugs that inhibit dopamine metabolism:  monoamine oxidase-type inhibitor, catechol-O-  methyltransferase inhibitors    Patients and their carers should be advised  about the drug therapy and expected side-  effects and limitations of current pharma-  cotherapy in parkinsonism. Therapy with more  than one product may be required to control  the symptoms while avoiding as much as  possible the occurrence of side-effects. Patients  should be advised against abrupt withdrawal  of anti-parkinsonian drugs since this may  induce neuroleptic malignant syndrome.   Levodopa is a precursor of dopamine and is the  mainstay treatment. It is given in combination (co-  careldopa) with carbidopa, a dopa-decarboxylase  inhibitor, to reduce the peripheral conversion of  levodopa to dopamine, allowing for administration  of lower doses of levodopa and resulting in decreased  occurrence of side-effects.   • Cautions: pre-existing cardiovascular disease  since it may cause arrhythmias, peptic ulceration,  pulmonary disease, history of convulsions and  skin melanoma, psychiatric illness or dementia,  endocrine disease such as diabetes,  hyperthyroidism, osteomalacia,  phaeochromocytoma, hepatic or renal  impairment, glaucoma.   • Side-effects: nausea and vomiting, dry mouth,  anorexia, postural hypotension, cardiac  arrhythmias, involuntary movements,  behavioural changes including depression,  anxiety, psychoses and dementia (higher risk in  the elderly, and patients with dementia or  psychiatric illness) and drowsiness.   • Disadvantages: involuntary movements that may  occur as side-effects of treatment due to motor  complications, and end-of-dose deterioration  which leads to decreased benefit with time with  same amount of drug administration. This is due  to dopaminergic neuron loss with time.   • Drug interactions: phenothiazines,  butyrophenones, tricyclic antidepressants,  phenytoin, metoclopramide, benzodiazepines,  anticholinergics since they decrease effect of  levodopa.   • The modified-release oral formulations are used  to decrease fluctuations in blood levels of  levodopa and decrease occurrence of response  fluctuations. Also, the number of doses per day  are reduced, ensuring better patient acceptability  and compliance. A disadvantage to modified-  release oral formulations is that they may present  with a delayed onset of action in the morning to  counteract immobility when the patient needs to  get out of bed. In such cases either the modified-  release formulation is administered about 1 hour  before rising or else immediate-release  formulation is used in the morning.   • Drug holidays: this describes the practice of  withdrawal of levodopa therapy for a brief  period. This may improve therapeutic outcome  when therapy is re-instated possibly because  levodopa causes downregulation of dopamine  receptors. Disadvantages of drug holidays are    that patient may experience immobility which  will impact negatively on the physical and  psychological well-being of the patient. Patient  needs to be monitored closely.   These are bromocriptine and the newer dopamine  agonists cabergoline, pergolide, pramipexole, ropini-  role and rotigotine. They have a levodopa-sparing  effect since they are used early in treatment, delaying  the use of levodopa to later stages of the disease. May  be used in combination with levodopa.   • Less effective than levodopa in improving overall  motor performance. An advantage over levodopa  is that they have a longer half-life and therefore  require less frequent dosing.   • Caution in cardiovascular disease since they may  cause arrhythmias, in psychiatric disease or in  dementia.   • Side-effects: nausea, constipation, drowsiness,  postural hypotension, confusion especially in the  elderly, involuntary movements, behavioural  changes.   This has an effect on prolactin release from the pitu-  itary gland. It is used in hyperprolactinaemia.   • May cause fibrotic reactions (pulmonary,  retroperitoneal, pericardial). This requires  measurement of renal function, ESR and serum  creatinine, and a chest X-ray before initiating  therapy and on a yearly basis thereafter.   • Patient monitoring for occurrence of signs of  fibrotic reactions namely dyspnoea, persistent  cough, chest pain, cardiac failure, abdominal  pain and tenderness.    • Co-careldopa and dopamine receptor  agonists may cause excessive daytime  sleepiness or sudden onset of sleep.  Patients should be advised about this in  order to be careful when driving and  operating machinery especially during  initiation of therapy until occurrence of  side-effects is understood.   • Domperidone may be used as an  antiemetic to counteract the nausea  caused by levodopa or dopamine agonists  or both when used in combination.  Patient is advised to take  antiparkinsonian agents with meals.   Catechol-O-methyltransferase (COMT) inhibitors such  as entacapone and tolcapone increase the elimination  half-life of levodopa, thus prolonging the activity of  levodopa in the brain. Lower doses of levodopa may  be used and there is an increased amount of time  when levodopa therapy has a positive impact on the  disease. They do not have antiparkinsonian activity  and are used as an adjunct to co-careldopa.   • Side-effects: nausea, diarrhoea or constipation,  abdominal pain, urine discoloration, dry mouth   • Tolcapone may cause hepatotoxicity. Patients  should be advised to report any signs of liver  disease such as anorexia, fatigue, abdominal  pain, dark urine or pruritus. Liver function tests  should be carried out regularly.   Inhibitors of monoamine oxidase type B, such as  rasagiline and selegiline, enhance central dopamine  effects and delay the need for and allow for reduction  in doses of levodopa.   This is a synthetic antiviral agent. It improves  bradykinesia, tremor and rigidity, and probably  potentiates dopamine activity by causing release of  dopamine from storage vesicles in neurons.   • Administered in early disease so as to delay use  of levodopa   Examples include benztropine, orphenadrine, pro-  cyclidine and trihexyphenidyl. They are used when  tremor is a characteristic symptom and in drug-  induced parkinsonism.   • Cautions: cardiovascular disease, hypertension,  psychotic disorders, prostatic hypertrophy,  pyrexia, the elderly, glaucoma   • Side-effects: blurred vision, dry mouth,  constipation, urinary retention, mental  confusions, delusions, hallucinations, impaired  memory.   • Constipation: high fibre, increase fluid intake,  stool softeners, osmotic laxatives   • Haloperidol: used in motor tics and symptoms of  Gilles de la Tourette’s syndrome and related  choreas   • Propranolol or other beta-blockers: to treat  tremor including postural tremor in  parkinsonism which is not controlled by  antiparkinsonian agents   • Primidone: an antiepileptic drug which may be  used in tremor   • Piracetam: used as an adjunct treatment in  myoclonus of cortical origin.   • Treatment is symptomatic and there is treatment  failure after some years due to end-of-dose  deterioration; patients may suffer from on-off  effects where they abruptly experience treatment  failure lasting for a few minutes to hours.   • There is controversy over when to commence  therapy since current treatment reaches end-of-  dose effect.   • Quality-of-life assessment using tools to measure  mobility or potential for falls and assessment of  occurrence of complicating factors (e.g.  neuropsychiatric disease, autonomic dysfunction,  falls and sleep disorders).   • Coordinate with other health professionals,  namely psychotherapists, physiotherapists and  speech and language therapists, and provide  emotional support and address social needs.   • Ensure patient compliance with treatment since  treatment failure may be attributed to loss of  activity of drug therapy when patient is in actual  fact not compliant with treatment.   1 Mention the unwanted effects of levodopa.  Mention four conditions when levodopa should  be used with caution.   2 Giving examples, discuss therapeutic  alternatives to levodopa in the management of  parkinsonism.   1 Common unwanted effects of levodopa include  nausea and vomiting, sedation, hypotension,  cardiac arrhythmias and involuntary  movements. Levodopa should be used with  caution in pre-existing cardiovascular disease,   pergolide, pramipexole, ropinirole, rotigotine as  well as amantadine and monoamine oxidase B  inhibitors may be considered in the initial stages  of the disease. They are less effective than  levodopa but they have a levodopa-sparing  effect and levodopa may be used at a later stage  in the disease. Anticholinergic drugs such as  benztropine, orphenadrine, procyclidine and  trihexyphenidyl are more effective in drug-  induced parkinsonism.   Lim S-Y and Fox S H (2008). An update on the manage-  ment of parkinson’s disease. Geriatrics Aging 11:  215-222.   National Institute for Health and Clinical Excellence  (2006). Parkinson’s disease: Diagnosis and management  in primary and secondary care, http://www.nice.  org.uk/CG035.   1 Hoehn M and Yahr M. Parkinsonism: onset, progres-  sion and mortality 1967. Neurology 2001; 57(10 suppl  13): Sll-26.   • To appreciate principles of drug selection in anti-  infective therapy    • To develop skills required to manage clinical use of  anti-infective agents   • Anti-infective agents: products used in the  management or prophylaxis of infective  conditions caused by bacteria, mycobacteria,  fungi, protozoa or viruses   • Antibacterial agents: used in the management or  prophylaxis of infections caused by bacteria   • Generations of drugs: within the same class of  anti-infective agents the products can be  classified according to characteristics in their  structural development leading to different  generations within a class of drugs.   • Spectrum of activity: antibacterials such as  aminopenicillins have the potential to affect a  wide range of bacterial species; these are referred  to as broad-spectrum antibacterials. Other  products, such as clindamycin, affect only a few   • Antimicrobial prophylaxis: examples include  contacts of patients with meningococcal  meningitis, and use of antibacterials before and  after dental procedures in patients at risk of  endocarditis.   • Nosocomial infections: infection caused by  exposure to treatment in a hospital or a  healthcare institution.   • Exogenous infection: infection caused from  organisms that the body is exposed to.   • Endogenous infection: infection caused from  organisms that were within the body.   • Acute sepsis: infection that leads to the  formation of pus or to the multiplication of  bacteria in the blood.   Antibacterials that cause killing of bacteria at clinical  doses are referred to as bactericidal. Drugs that inter-  fere with bacterial multiplication at clinical doses are  referred to as bacteriostatic. Some bactericidal and  bacteriostatic drugs are listed in Table 34.1.   - cross-sensitivity: e.g. penicillins with  cephalosporins, about 10% of patients who  are penicillin sensitive are also sensitive to  cephalosporins   • Superinfections: especially with broad-spectrum  antibiotics, risk of superinfections with Candida  albicans causing oral or vaginal thrush.   • Some patients demand antibacterials every time  that there is illness.   • Overuse of antibacterial agents may result in the  suppression or destruction of weak organisms,  leaving the very virulent pathogens in the clinical  scenario.   • Overuse of antibacterial agents may lead to the  development of resistance of microorganisms  against anti-infective agents.   • Economic considerations: the use of anti-infective  agents without clinical evidence for the need of  treatment or prophylaxis using an anti-infective  agents is going to increase cost of treatment  without a valid rationale.    Table 34.1 Bactericidal (killing of the bacteria) vs  bacteriostatic (growth retardation)   • Assess severity of infection and withhold  systemic drugs in trivial infections   • Obtain specimens for culture before starting  anti-infective treatment so as to identify  organisms before any bacteriostatic or    bactericidal effect has kicked in (e.g. urine  sample for urinary tract infections).   • Site of infection: drug should attain adequate  concentrations at the location of infection  (e.g. otitis media, toenail infection)   • Single or combination therapy (e.g. use  of combination therapy in bacterial  meningitis)   • Drug interactions with medications that the  patient is already taking or medications that are  required (e.g. antihistamines and  macrolides)   • Age: e.g. tetracyclines are avoided in children due  to risk of teeth staining and dental hypoplasia in  growing teeth   • Comorbidities: e.g. renal disease - dose reduction  for cefaclor, ciprofloxacin, macrolides; liver  disease - dose reduction for ofloxacin,  erythromycin   • Pregnancy: avoid aminoglycosides (risk of  auditory or vestibular nerve damage),  tetracyclines (risk of dental discoloration in  neonate, maternal hepatotoxicity with large  parenteral doses).   • Degree of antibacterial activity: e.g. cloxacillin  (narrow spectrum) vs amoxicillin (broad  spectrum)   • Convenience of administration: e.g.  clarithromycin (lower dosage frequency) vs  erythromycin    The antibacterial drug used should reach the  site of infection in an effective concentration,  and should cause no toxicity and no clinically  significant interactions with other drugs being  taken by the patient.   • Intravenous administration of anti-  infective agents is considered in the event  of a serious infection, when the drug has  poor oral bioavailability and when  patient is unable to take drugs orally  (peri-operative, unconscious).   • Combination anti-infective therapy is  considered when a broad spectrum of  activity is required, in mixed infections,  for a synergistic effect and to decrease  drug resistance.   Conditions in which certain antibacterial drugs are  best avoided are summarised in Table 34.2.   Some examples of drug interactions with antibac-  terials are listed in Table 34.3.   • Clinical signs of infection (e.g. pyrexia, pulse and  respiratory rate, occurrence of urinary urgency  when urinary tract infection is suspected)   • Occurrence of side-effects (e.g. gastrointestinal  effects or signs of sensitivity reactions).   Penicillins are beta-lactam antibacterial agents in  which a cyclic amide ring consisting of four atoms is  fused to a substituted five-membered thiazolidine    ring. Due to this configuration the beta-lactam is  sensitive to hydrolysis.   Benzylpenicillin or Penicillin G (Figure 34.2) is acid  labile and requires parenteral administration. It is  beta-lactamase sensitive, with a narrow spectrum of  activity, mainly against Gram-positive cocci.   In phenoxymethylpenicillin or penicillin V (Figure  34.3) the addition of a phenoxymethyl moiety on the  amide side chain inhibits hydrolysis of the beta-  lactam ring and provides the product with acid  stability. The drug can be administered orally. It has  a spectrum similar to benzylpenicillin.   In ampicillin and amoxicillin (Figure 34.4) the addi-  tion of a primary amino group on the side chain    results in aminopenicillins where acid stability is  retained but the spectrum is shifted to include  Gram-negative bacteria. These products are there-  fore described as broad-spectrum antibacterials. The  addition of a hydroxyl group in amoxicillin leads to  better absorption profiles compared with ampicillin.  The products are penicillinase labile.   The addition of clavulanic acid (co-amoxiclav  contains amoxicillin with the beta-lactamase  inhibitor clavulanic acid) counteracts the tendency  of the penicillinases to destroy the antibacterial  agent. Clavulanic acid has minimal antibacterial  effects.   The beta-lactamase enzymes (penicillinases) destroy  the antibacterial agents. By having steric hindrance  near the side-chain amide bond, penicillinase-  resistant agents such as flucloxacillin (Figure 34.5)  are resistant to them. They are acid stable and are   In the antipseudomonal penicillins ticarcillin and  piperacillin (Figure 34.6) the amino group in the side  chain has been converted to a variety of ureas. These  are broad-spectrum products but have greater activity  than the aminopenicillins against Gram-negative  bacteria; some are active against Pseudomonas species.  They are available for parenteral administration and  are penicillinase sensitive.   • Have good penetration to most tissues but poor  entry to cerebrospinal fluid since they are poorly  lipid soluble. Meningeal inflammation increases  cerebrospinal fluid penetration and in fact may  be used in meningitis.   • May be used in combination with  aminoglycosides; there is a synergistic effect.   Cephalosporins feature a beta-lactam ring that is  annealed to a six-membered dihyrothiazine ring. The  cephalosporins are described in three generations:   • First generation: e.g. cefalexin, cefadroxil,  cefradine (Figure 34.7). Active against Gram-  positive cocci. Cefalexin and cefadroxil reflect  ampicillin and amoxicillin structures respectively.   • Second generation: e.g. cefuroxime, cefaclor  (Figure 34.8). Active against Gram-positive cocci  and some activity against Gram-negative  bacteria. The addition of a chlorine atom in  cefaclor gives it greater activity against Gram-  negative bacteria than cefuroxime.   • Third generation: e.g. cefotaxime, ceftriaxone,  ceftazidime (Figure 34.9). Active against  Gram-negative bacteria; less active against  Gram-positive cocci.   These are broad-spectrum drugs, active against  Gram-positive bacteria (including some penicillinase-  producing strains), Haemophilus influenzae (activity  greater for azithromycin), Chlamydia, Mycoplasma  and Legionella species. Examples are erythromycin  (Figure 34.10), clarithromycin and azithromycin  (long half-life).   • Side-effects: gastric pain, nausea and vomiting  which are less prominent with clarithromycin  and azithromycin   • Cautions: hepatic and renal impairment,  predisposition to QT interval prolongation   Macrolides have a large lactone (cyclic ester) ring.  The structure for erythromycin is shown in Figure  34.10. Clarithromycin (Figure 34.11) has enhanced  lipophilicity and a methyl ether introduced on the  C-6 hydroxyl group,   In azithromycin, an azalide antibiotic, an N-  methyl group is included and the carbonyl moiety is  removed.   The chemical amendments of clarithromycin and  azithromycin result in inhibition of the formation of  the cyclic internal ketal responsible for the gastro-  intestinal cramps that are associated with  erythromycin.   This is a ketolide, a derivative of erythromycin. It has  a spectrum similar to that of macrolides. It should be  used only to treat beta-haemolytic streptococcal  pharyngitis and tonsillitis, sinusitis and community-  acquired pneumonia when conventional treatment is  contraindicated.    • Disadvantages: may precipitate hepatic disorders,  visual disturbances or transient loss of  consciousness.   These include tetracycline (Figure 34.12), doxycycline  (long half-life) and minocycline (has a broader spec-  trum and is active against Neisseria meningitidis).  They are broad-spectrum antibiotics that are active  also against Chlamydia, Rickettsia, Mycoplasma and  Brucella species.   • Absorption affected by concomitant use of  antacids and milk (except for minocycline)   • Contraindications in children, pregnancy: they  bind to calcium in bones and teeth causing  impaired bone growth and dental discoloration  during active mineralisation   Nalidixic acid (Figure 34.13) was the first quinolone  developed. It is used for uncomplicated urinary tract  infection. Fluoroquinolones are broad-spectrum  products that are active against Gram-positive and  Gram-negative bacteria, particularly against Gram-  negative bacteria such as Pseudomonas, Neisseria and  Shigella species. Examples are ciprofloxacin (Figure  34.14), levofloxacin and moxifloxacin (have greater  activity against pneumococci than ciprofloxacin).   • Caution in children, pregnancy: arthropathy in  weight-bearing joints; epilepsy, myasthenia  gravis, renal and hepatic impairment   • Care: photosensitivity may occur, convulsions  may be a side-effect and risk is greater in patients  taking NSAIDs, risk of crystalluria (ensure  adequate fluid intake), risk of tendon damage  (including rupture) increased in elderly patients  or those receiving corticosteroids   • Side-effects: nausea, vomiting, dyspepsia,  abdominal pain, diarrhoea, headache, dizziness,  sleep disorders, rash and pruritus.   • Use decreased due to side-effects: blood  dyscrasias (bone marrow suppression and  agranulocytosis), erythema multiforme (including  Stevens-Johnson syndrome), renal failure due to  sulphonamide   • Cautions: hepatic and renal impairment, may  cause crystalluria (adequate fluid intake  recommended), existing haematological  conditions, elderly patients    • Pregnancy: trimethoprim may be teratogenic,  sulphonamides may cause neonatal haemolysis   • Drug interactions: warfarin (enhanced  anticoagulant effect), methotrexate (increased  risk of haematological toxicity), clozapine  (increased risk of agranulocytosis)   Aminoglycosides such as gentamicin, neomycin and  tobramycin are active against Gram-negative organ-  isms, including Pseudomonas spp., with some  activity against staphylococci. Tobramycin is two to  four times more active against Pseudomonas spp.,  than gentamicin.   • They are not absorbed from gut and parenteral  administration is required for systemic effect;  available for topical administration (eye/ear  drops, creams/ointment)   • Major side-effects that are concentration related  are ototoxicity and nephrotoxicity due to tubular  destruction   • Narrow therapeutic index. Serum drug  concentration monitoring recommended in  paediatrics, older persons and patients with renal  disease   • Pregnancy: they cross the placenta and may  damage the fetus.   • Side-effects when administered systemically:  blood disorders, peripheral neuritis, optic neuritis.    • Used for acne, and staphylococcal joint and bone  infections such as osteomyelitis.   • Serious side-effect that may occur:  pseudomembranous colitis (antibiotic-associated  colitis) especially in middle-aged and elderly  women; patient should be advised to discontinue  treatment if diarrhoea occurs.   • Effective for skin infections, particularly those  due to Gram-positive bacteria   Glycopeptide antibiotics such as vancomycin and  teicoplanin have bactericidal activity against aerobic  and anaerobic Gram-positive bacteria, especially  meticillin-resistant Staphylococcus aureus (MRSA).   • Vancomycin: administered intravenously, caution  since a rapid intravenous administration may  cause histamine release resulting in red man  syndrome (fever, chills, rash and hypotension)   • Excreted by the kidney, may cause  nephrotoxicity, monitoring of serum drug  concentration required in patients with renal  disease.   These include rifampicin, isoniazid, streptomycin,  pyrazinamide and ethambutol. Treatment of tubercu-  losis should be undertaken within a specialised team  due to occurrence of resistance and the involvement  of other organs outside the respiratory system.    The occurrence of infection caused by resistant  strains of Mycobacterium tuberculosis is quite  common in immunocompromised patients such as  HIV-positive patients. Culture to establish the type of  strain involved and drug sensitivity tests is required.   The azole antifungals (imidazole and triazole anti-  fungal drugs) inhibit fungal cytochrome P450 enzymes  responsible for synthesis of ergosterols that are essen-  tial for fungal cell membrane. Due to the interaction  with the cytochrome P450 enzyme they are associated  with possible drug interactions. Other antifungals are  the polyene antifungals and terbinafine.   The imidazole antifungals clotrimazole, ketoconazole  and miconazole are used for local treatment of  vaginal candidiasis and for dermatophyte infections.  Miconazole is available as an oral gel for treatment  of oral candidiasis. Ketoconazole (Figure 34.15) is  absorbed when administered orally.   • Monitor: signs of liver disorder (anorexia,  nausea, vomiting, fatigue, abdominal pain,  jaundice or dark urine)   • Chemical structure: consist of a five-membered  aromatic ring (azole characteristic) that contains  two nitrogens, which is attached to a side-chain  that contains at least one aromatic ring.   Examples include fluconazole, itraconazole, posi-  conazole and voriconazole. They are absorbed after  oral administration. Fluconazole and itraconazole  are used for the management of systemic mycoses  (e.g. tinea pedis, tinea corporis, pityriasis versicolor,  mucosal and vaginal candidiasis). Posiconazole and  voriconazole are used in life-threatening infections.   • Itraconazole (Figure 34.16): caution when used  in patients at high risk of heart failure, monitor  for liver toxicity; to be taken with food.   • Chemical structure: consist of a five-membered  aromatic ring (azole characteristic) that contains  three nitrogens, which is attached to a side chain  that contains at least one aromatic ring.   • Not absorbed when given by mouth but produce  a topical effect in the gastrointestinal tract.   • Used for dermatophyte infections of the nail,  tinea pedis and tinea corporis   Aciclovir and famciclovir are effective against the  virus but do not eradicate it. They interfere with viral    nucleic acid replication. Aciclovir (Figure 34.17) is a  synthetic analogue of deoxyguanosine. Famciclovir  (Figure 34.18) is a synthetic purine nucleoside  analogue related to guanine and has a longer half-life  than aciclovir.   • Used for generalised or systemic infection, skin  and mucous membrane infections.   • Adverse reaction with alcohol may occur -  advise patient to refrain from alcohol  consumption during treatment.   • Available for oral administration but a topical  effect in the gastrointestinal tract is achieved   • Risk factors for infection: type of surgery (e.g.  abdominal surgery increases risk), occurrence of  bacterial contamination during surgery, post-  operative wound exposure, patient characteristics  - age, obesity, cigarette smoking, malnutrition,  comorbidities (e.g. diabetes), concomitant drug  therapy (e.g. immunosuppressive therapy).   • Anti-infectives are started before surgery since it  is important to have antibacterial drug blood  levels at the time of wound incision. Depending  on the duration of the surgery and the  antibacterial agent used, administration of the  antibacterial during the intervention may need to  be considered to maintain adequate antibacterial  drug concentrations. Doses are continued for a  few days after the intervention.   • Route of administration: parenteral  administration in the preoperative stage is  preferred to ensure required drug blood levels;  oral administration may be considered in the  post-operative phase once the patient is in a  position to take drugs orally.   • Monitoring for signs of infection at incision site  should be carried out   Clean surgical procedures such as cardiac  interventions, vascular, orthopaedic and neuro-  surgery are associated with a lower risk of  surgical wound infection than interventions  such as gastrointestinal surgery, caesarean  section, hysterectomy.   • Factors to be considered in the choice of anti-  infective agents include spectrum of activity,  possibility of adverse events and pharmaceutical  dosage forms.   • Healthcare professionals should collaborate to  establish treatment protocols for the use of anti-  infective agents   • The possibility of drug interactions with azole  antifungals should be assessed when other drugs  are being used concomitantly.   1 What side-effects could be expected when an  antibacterial drug is administered?   2 What type of antibacterial agent is gentamicin?  What is a disadvantage in the administration of  gentamicin when used for a systemic effect?  What side-effects could occur with the use of  gentamicin?   3 Explain the term beta-lactam-containing  antibiotics. What are the clinical implications  of occurrence of beta-lactamases?   2 Gentamicin is classified as an aminoglycoside.  The main disadvantage of gentamicin when  used for a systemic effect is that it is not  absorbed from the gastrointestinal tract and  therefore cannot be given orally so the  parenteral route is required. Side-effects of  gentamicin include ototoxicity and  nephrotoxicity.    3 Beta-lactam antibacterials (penicillins and  cephalosporins) contain the beta-lactam ring as  the basis of their structure. Bacteria that  produce beta-lactamases will disrupt the beta-  lactam ring and render the antibacterial inactive.  For antibacterials to be effective they need to be  resistant to beta-lactamase-producing strains of  bacteria (e.g. the clavulanic acid component in  co-amoxiclav).   4 The macrolide antibacterials have an  antibacterial spectrum that is similar but not    identical to that of penicillins. They are active  against Gram-positive bacteria (including some  penicillinase-producing strains), Chlamydia and  Mycoplasma spp.   Schwartzberg E (2006). Cost-effective use of antibiotics in  hospitals. Hosp Pbarm Eur May/June: 13-15.   • To appreciate the impact of antiretroviral agents in • To identify risks associated with antiretroviral   • To develop skills to prepare individualised patient  therapy and to monitor patients receiving treatment   • achieve maximal and durable suppression of  HIV replication by reducing viral load to  <50 copies/ mL   • reduce the progression from HIV infection  to AIDS and death.   • Assess capability of patient to cope with tablet  burden and dosing frequency especially if patient  is also receiving other drug therapy   • Patient condition: if patient is asymptomatic, to  achieve better patient compliance, the least  complex regimen is preferred. Consider  concomitant disease (e.g. protease inhibitors  should be avoided in patients with cardiovascular  disease or hepatitis B or C)   • Identify viral sensitivity, prevent the development  of resistance and preserve future treatment options.   The factors to be considered in choosing HIV treat-  ment are outlined in Figure 35.1.   • Treatment to be started in all symptomatic  patients and in asymptomatic patients depending  on CD4 lymphocyte cell count, so that therapy is  started before the immune system is irreversibly  damaged. (Decline in CD4 lymphocyte count  leads to the development of AIDS)   • In 2006: four-drug regimen - has not shown  significant different plasma HIV levels.    ‘The message now is that if you want to start  treatment, then two drugs are better than one.  We still do not know when it is best to start  treatment but our data show that if a patient  already has AIDS it is not too late to treat.’   Dr Tim Peto, Consultant in Infectious  Diseases, Oxford (Pbarm J 1995; 255: 411)   Two nucleoside reverse transcriptase inhibitors +  one non-nucleoside reverse transcriptase inhibitor   Therapy should be changed with treatment failure or  due to intolerance or toxicity.   Nucleoside reverse transcriptase inhibitors such as  abacavir, didanosine, emtricitabine, lamivudine,  stavudine, tenofovir and zidovudine should be used  with caution in patients with chronic hepatitis B or C  due to increased risk of hepatic side-effects. This is  very relevant since patients with HIV may present  with concomitant hepatitis B or C.   • Caution: hepatic impairment, particularly obese  women with hepatomegaly, patients with alcohol  abuse, renal impairment, pregnancy   • Side-effects: gastrointestinal disturbances,  anorexia as well as peripheral neuropathy,  pancreatitis, lactic acidosis or lactic steatosis.  Lactic acidosis is due to mitochondrial toxicity  and is presented with gastrointestinal symptoms  and dyspnoea; if it occurs, treatment should be  withdrawn.   Examples include amprenavir, atazanavir, indinavir,  lopinavir, ritonavir, saquinavir and tipranavir.  Ritonavir is used in low doses to boost the plasma  concentrations of other protease inhibitors.   • Caution: hyperglycaemia and diabetes due to  lipodystrophy syndrome, haemophilia due to  increased risk of bleeding, hepatic impairment  and patients with chronic hepatitis B or C,  pregnancy    • Renal impairment: atazanavir, darunavir,  fosamprenavir and tipranavir do not require dose  adjustments as required with other protease  inhibitors   • Side-effects: gastrointestinal disturbances,  anorexia, hepatic dysfunction, pancreatitis,  lipodystrophy syndrome and metabolic effects   • Patient monitoring: since these drugs affect  glucose metabolism, lipid profile and blood  glucose monitoring are required in patients with  diabetes and hyperlipidaemia   • Patient advice: patient should be advised on  necessary dietary modifications. Risk of  myocardial infarction increases by 26% for each  year of exposure   • Statin therapy should be considered in patients  receiving protease inhibitors.   Non-nucleoside reverse transcriptase inhibitors such  as efavirenz and nevirapine show better patient accept-  ability than the nucleoside reverse transcriptase  inhibitors and protease inhibitors.   • Side-effect that is common to both drugs is skin  rash   • Hepatoxicity with nevirapine which may be fatal  may occur. This warrants monitoring of liver  function in patients receiving nevirapine  especially since they are likely also to be  receiving a nucleoside reverse transcriptase  inhibitor   • Neuropsychological effects and increased plasma  cholesterol concentration may occur with  efavirenz.   • Lipodystrophy syndrome is used to  describe side-effects associated with  antiretroviral therapy which include fat  redistribution, insulin resistance and  dyslipidaemia. Fat redistribution presents  with development of a buffalo hump and    breast enlargement and is associated with  protease inhibitors and nucleoside reverse  transcriptase inhibitors. Stavudine and  zidovudine are associated with a higher  risk.   • Dyslipidaemia, insulin resistance and  hyperglycaemia are associated particularly  with protease inhibitors. Before initiating  therapy with protease inhibitors baseline  levels of plasma lipids and blood glucose  should be carried out and monitored  thereafter.   • Not too early: to avoid patient getting side-  effects and to decrease occurrence of drug  resistance   • Drug resistance can occur with treatment when  viral suppression is not optimal.   • Viral genotyping and phenotyping may be  carried out to evaluate mutations in the  virus and the ability of the virus to grow  in the presence of antiretroviral agents  respectively.   • Patient may present with a resistant strain prior  to initiation of treatment and therefore it is  recommended to identify viral sensitivity before  starting therapy.   • Occurrence of viral resistance should be  considered when starting or changing therapy.  When changing treatment due to therapy failure,  the new regimen should contain antiretroviral  agents that were not used previously in the  patient.   • Patient may be asymptomatic and feel that drug  therapy is not necessary.   • Multiple therapy makes drug regimen complex  and difficult for the patient to follow   • Lack of information on drugs and how to take  them   • Packaging: while maintaining stability, prepare  drugs in compliance aids to help patient  recognise when to take drug therapy   • Pharmacist intervention during dispensing:  provide patient knowledge and education, use  pictograms during dispensing (e.g. to identify  drugs that need to be taken with food, such as  atazanavir)   • Treatment is considered to minimise viral load  and disease progression in the mother and to  prevent transmission of infection to the neonate   • However, teratogenic potential is unknown and  usually institutions select drug therapy on the  basis of previous shared experience.   • Avoidance of breast-feeding is recommended  when breast milk substitutes are feasible and  affordable to the mother.    Patients with HIV are at an increased risk of  developing other conditions, particularly  infective conditions caused by bacteria, fungi  and mycobacteria. These conditions can  prove difficult to treat and fatal. Also, they  are susceptible to neoplastic disease such as  lymphoma and Kaposi’s sarcoma.   • Monitor for occurrence of toxicity of  medications: gastrointestinal side-effects are  common to all classes of antiretroviral drugs and  their occurrence may impact negatively on  patient’s quality of life and on patient  compliance.   • Patients with HIV should receive advice on the  use of barrier methods of contraception to  reduce risk of transmission of HIV. Women  should be informed of the interactions with oral  contraceptives (e.g. contraceptive effect reduced  with efavirenz, metabolism of oestrogens  accelerated by ritonavir).   1 Stavudine is a nucleoside reverse transcriptase  inhibitor indicated in HIV infection in  combination with other antiretroviral drugs.  Atazanavir is a protease inhibitor used in HIV  infection in combination with other    antiretroviral drugs. Side-effects of stavudine  include peripheral neuropathy, pancreatitis,  lactic acidosis or lactic steatosis. If lactic acidosis  presents with gastrointestinal symptoms and  dyspnoea, treatment should be withdrawn.  Atazanavir causes gastrointestinal disturbances  as the main side-effect. It also affects glucose  metabolism and lipid profile and therefore  monitoring is required in patients with diabetes  and hyperlipidaemia.    Cohen C J (2006). Successful HIV treatment: lessons  learned. J Manag Care Pharm 12(7): S6-S11.   Gellaitry G, Cooper V, Davis C, Fisher M, Leake Date H  and Horne R (2005). Patients’ perception of informa-  tion about HAART: impact on treatment decisions.  AIDS Care 17: 367-376.   Hammer S M, Saag M S, Schechter M, Montaner J S G,  Schooley R T, Jacobsen D M et al. (2006). Treatment  for adult HIV infection: 2006 recommendations of the  International AIDS Society - USA Panel. JAMA 296:  827-843.   Zabinski R A (2006). Evidence-based health benefits  management: Strategies to optimize antiretroviral  medication adherence and outcomes in HIV/AIDS.  J Manag Care Pharm 12(7): S12-S16.    Beck E J (2003). HIV costs: individual and population  perspectives. Hosp Pharm Eur April/May: 48-50.   • To identify characteristics of different hepatitis • To review management of chronic hepatitis,   • Hepatitis A-E affect the liver and may lead to  liver damage including hepatocellular necrosis.   • Mode of transmission is primarily by the  faecal-oral route (including food borne) for  hepatitis A and E and is blood borne for  hepatitis B, C and D.   • Prophylaxis is available for hepatitis A and B (see  Chapter 61).   • Hepatitis may occur as an acute condition where  jaundice or increased serum aminotransferase  concentrations occur and the condition is limited  to a few months not exceeding 6 months.   • Chronic hepatitis involves hepatocellular necrosis  for 6 months or more after the onset of acute  illness. Chronic hepatitis is mostly associated  with hepatitis B and C.   contaminated water or food (e.g. shellfish). Its occur-  rence in different countries is highly related to the   • Prophylaxis: hepatitis A vaccination presents an  active form of immunisation. It should be  considered for travellers to high-risk countries,  homosexuals, intravenous drug users, people at  occupational risk, people with clotting disorders  and patients with chronic liver disease.   • Characteristic symptoms include malaise, fatigue,  anorexia, abdominal pain, nausea and vomiting.  Sometimes patients present with fever, headache,  arthralgias, myalgias and diarrhoea.   • About 66% of patients develop jaundice during  the acute attack.   • Diagnosis is based on serological detection of the  viral antigen and antibody as well as elevated  liver enzymes.   • Use drugs that are hepatically eliminated with  caution; try to switch drug therapy or where not  possible use lowest recommended dose.   This condition is transmitted via contaminated blood  or blood products and sexual contact. Persons at risk  of developing the condition are those who engage in  different heterosexual contacts, homosexuals,  injecting drug abusers, those who undergo acu-  puncture and tattooing, and people who have an  occupational risk.   Education on sexual behaviour, needle handling  and use of blood products is a key factor in prophy-  laxis. Vaccination should be recommended to individ-  uals at high risk of contamination, namely healthcare  workers, staff at nursing institutions, recipients of  blood products, haemodialysis patients, drug abusers,  homosexuals and inmates of long-term correctional  facilities. In addition most countries currently require  vaccination for all infants.   In acute infection symptoms are very similar to  hepatitis A infection and include fatigue, anorexia,  nausea and vomiting. Acute liver failure may occur  and this presents with hepatic encephalopathy,  lethargy, confusion and cerebral oedema, and may  ultimately lead to coma.   Chronic infection occurs in 5-10% of patients  and leads to cirrhosis and liver failure. Hepatocellular  carcinoma may develop.   Diagnosis is based on serological detection of  antigen and antibody. In chronic disease, monitoring  of liver function tests and liver biopsy are indicated.   • During the acute phase, supportive therapy and  patient monitoring for the development of  complications are recommended.   • Liver transplantation may need to be considered  in patients with chronic disease.    • Treatment in chronic hepatitis is discussed as a  separate section.   In hepatitis A and B supportive therapy is the  mainstay of treatment during the acute phase.   Hepatitis C has greater infectivity than the HIV virus.  It is commonly transmitted due to intravenous drug  abuse and sharing of needles as well as due to sexual  activity.   • Chronic infection occurs in about 85% and  patients present with fatigue, nausea, anorexia,  abdominal pain and depression.   • Patients with the chronic condition may develop  intractable ascites, gastrointestinal or  oesophageal bleeding, and encephalopathy. In  addition, extrahepatic symptoms such as corneal  ulcers, idiopathic pulmonary fibrosis and  rheumatoid arthritis may occur.   • Between 20% and 30% of patients progress to  end-stage liver disease and a smaller percentage  develop hepatocellular carcinoma.   • The genotype of the infecting hepatitis C virus  should be determined since treatment outcome  depends on genotype.   • Diagnosis is based on detection of antibodies and  a liver biopsy may be undertaken to estimate the  extent of liver injury. In chronic disease,  monitoring of liver function tests and viral load  is required.   In chronic hepatitis B, patients may be asymptomatic  and present with minor elevations in liver enzymes.  In this scenario treatment is not started and the  patient is monitored every 3-6 months. Once  patients are symptomatic, treatment should be initi-    ated to decrease viral replication, limit hepatocellular  damage and decrease the risk of long-term negative  impact on liver function.   In chronic hepatitis C patients, the aims of treat-  ment are to eradicate the virus, decrease morbidity by  improving clinical symptoms, decrease mortality, and  prevent progression to cirrhosis, hepatocellular carci-  noma and end-stage liver disease. A combination of  interferon and ribavirin is usually recommended.  Ribavirin as monotherapy is not effective.    In some chronic hepatitis patients there is  limited response to treatment and relapse  after treatment withdrawal is frequent. Phar-  macoeconomic implications of chronic  hepatitis are the high cost of therapy and the  costs incurred in managing the long-term  sequelae in addition to lost patient years.   • Peginterferon alfa, with the addition of a  polyethylene glycol molecule, is preferred over  interferon alfa because it has a longer half-life  and thus requires a lower weekly dosing  frequency. A disadvantage of pegylated  interferons is that the occurrence of cytopenias  and injection site reactions is higher than with  interferon.   • Sustained action reduces the incidence of viral  replication and leads to prolonged virological  response.   • Side-effects commonly include anorexia, nausea,  influenza-like symptoms (fever, chills, myalgias,  fatigue), lethargy. These tend to decrease in  occurrence with repeated drug administration.   • Patient monitoring is required to monitor for  the development of late-onset side-effects,  namely bone marrow suppression, alopecia,  thyroid disorders, hyperglycaemia and  hypertriglyceridaemia.   • telbivudine (should not be used in patients who  present with resistance to lamivudine due to  possibility of cross-resistance)   • tenofovir* (used as part of HAART in  patients who require treatment for HIV and  hepatitis).   In treating chronic hepatitis C the aim is to achieve  clearance of virus sustained for at least 6 months  after treatment is stopped. Peginterferon is used in  combination with ribavirin (antiviral agent).   • Education on prophylaxis of hepatitis is  necessary to prevent spread of infection.   • There are concerns about the development of  chronic hepatitis with hepatitis B and C due to  long-term sequelae.   • In the treatment of chronic hepatitis due to  hepatitis B and C, interferon plays an important  role. Interferon may cause worsening of liver  function.   1 What is the relevance of the genotype of the  hepatitis C virus in clinical practice?   2 What is the standard measurement of  effectiveness of treatment in the management  of hepatitis C?   1 Before starting treatment, the genotype of the  infecting hepatitis C virus should be determined  and the viral load measured as this may affect  the choice and duration of treatment.   2 The viral load is the standard measurement of  effectiveness of treatment in the management of  hepatitis C. The aim of hepatitis C treatment is  to achieve clearance of virus, sustained for at  least 6 months after treatment is stopped.   Knighton S (2008). Hepatitis C infection: clinical features  and diagnosis. Hosp Pharm 15: 411-412.   Knighton S (2008). Hepatitis C infection: current and future  treatment. Hosp Pharm 15: 413-419.   Nickless G (2008). An overview of hepatitis: Part 1. Pharm  J 280: 411-414.   Nickless G (2008). An overview of hepatitis: Part 2. Pharm  J 280: 477-480.   Spooner L M (2009). The critical need of pharmacist  involvement in the management of patients with  hepatitis C. J Manag Care Pharm 15: 151-153.   • To appreciate presentation of hypothyroid and • To develop skills for management of patients with   Thyroid gland synthesises, stores and secretes  thyroxine (T 4 ) and triiodothyronine (T 3 ). Hormone  secretion is controlled by thyroid-stimulating  hormone (TSH) or thyrotrophin which is released by  the anterior pituitary gland, which in turn is triggered  by thyroid-releasing hormone (TRH) secreted from  the hypothalamus. The process is controlled by nega-  tive and positive feedback.   Thyroid hormones probably activate mRNA  transcription processes and promote protein  synthesis or protein catabolism. Their function  relates to:   • Associated with the production and secretion of  excessive amounts of thyroid hormones   • Increased metabolism of all body systems due to  excess thyroid hormones   Skin problems associated with increased  sweat production and heat intolerance  Thinning or loss of hair   • Large goitre causing obstruction; in this case  surgery is preferred   • Pregnancy and neonates where riskrbenefit ratio  of the use of antithyroid drugs has to be considered   • Previous iodine exposure may limit repeat of  radioactive iodine therapy    Poor compliance with oral antithyroid drugs  might necessitate consideration of surgery or  radioactive iodine   Age (e.g. elderly patients where due to comorbid  conditions some of the lines of therapy might not  be appropriate).   • Inhibits synthesis of hormones. A disadvantage is  the low incidence of remission after  discontinuation of therapy   • Patient advice: to report symptoms and signs  suggestive of infection especially sore throat   • Monitoring: thyroid function tests, white blood  cell count (to be performed if there is evidence of  infection), assess improvement in clinical  symptoms   • Caution: should be stopped promptly if there is  clinical or laboratory evidence of neutropenia   • It crosses the placenta and may cause neonatal  hypothyroidism. Decision to use in pregnancy  depends on risk:benefit ratio for mother and  baby.   • T 4 checked every 4 weeks until a  maintenance dose between 5 and 15 mg  daily is reached    • Once maintenance therapy is achieved,  measure T 4 and TSH every 3 months   • Duration of treatment is usually 6-24  months; however some patients require  longer periods of treatment, especially  those who are not eligible for other  treatment modalities.   • Indicated for short-term use since they do not  control underlying condition   • Used prior to surgery or radioactive iodine  therapy to reduce heart rate and decrease risk of  thyroid storm.   • Emphasise importance to report skin rashes, sore  throat and mouth ulcers   • Preferred when obstructive symptoms due to  large goitre are present or where malignancy is  suspected.   • Use of beta-blockers and antithyroid drugs prior  to surgery to render patient euthyroid.  Propranolol is used to achieve pulse of 80 bpm.  This approach adopted so as to avoid thyroid  storm.   - hypoparathyroidism: occurrence may be  delayed up to 3 months postoperatively;  monitor serum calcium levels to identify its  occurrence; intravenous calcium gluconate is  used to correct it.   • Used in patients where antithyroid drugs cannot  be used (e.g. cardiac disease, elderly patients) or  where compliance is a problem and in patients  who were on carbimazole therapy and suffered a  relapse   • Eye complications: grittiness, early morning  soreness due to protrusion of the eyeball   • Propranolol 5 mg intravenously four times daily  or 80 mg orally twice daily   • Worsening of angina, occurrence of myocardial  infarction in patients with a history of angina   • Accelerated rate of bone loss, caution in  postmenopausal women; consider use of  prophylaxis for osteoporosis.   radioactive iodine therapy or surgery for hyper-  thyroidism. Other causes include congenital disease,   • Skin and appendages: dry, cool, flaking skin,  faint yellow colour, coarse, brittle hair   • Gastrointestinal: weight gain with decreased  appetite, abdominal distension, constipation, loss  of taste and smell   • Monitor cardiac function, thyroid function tests,  occurrence of clinical symptoms   • Side-effects: too rapid increase in metabolism  leading to diarrhoea, vomiting, angina pain,  arrhythmias, palpitation, tachycardia, tremor,  restlessness, excitability, insomnia.   Hypothyroidism may cause changes in the  ECG that mimic cardiac ischaemia. Before   • Increase in dosage may be required since thyroid  hormone requirements are increased.   • In diabetic patients, dose adjustment (increase) of  antidiabetic agent may be necessary with  initiation of thyroxine.   • Hypothyroidism is a common endocrine disease  in the elderly which can easily go undiagnosed.   • Non-specific symptoms occur such as stumbling,  incontinence and falls, which may lead to  misdiagnosis such as being mistaken for  parkinsonism.   • Correction of hypothyroid state may lead to  improvement in lipid profile and a subsequent  reduction in cardiac risks. Hypothyroidism may  predispose to an adverse lipid profile.   • Use of thyroxine sodium at a starting dose of 25  micrograms and increasing every 3-4 weeks by  25 micrograms.   • Caution: care in compromised coronary artery  circulation; thyroxine may unmask underlying  cardiac disease.   • Contains iodine and may cause thyroid disorders  (hypothyroidism or hyperthyroidism)   • It inhibits secretion of T 4 and T 3 and may cause  hypothyroidism    Patients receiving amiodarone or lithium  should have thyroid function tests performed  prior to initiation of treatment and every six  months.   • Patients with thyroid disorders should be  monitored regularly to assess their thyroid state.   • Patients require education on relevance of drug  therapy and side-effects to be expected.   • Patients with thyroid disorders who are also  receiving warfarin require careful monitoring of  their international normalised ratio (INR) since  response to warfarin therapy may vary according  to thyroid status.   1 Describe a pharmaceutical care plan for a  patient newly diagnosed with hyperthyroidism  who is started on carbimazole therapy.   1 (a Identification of patient needs: to educate  patient on condition, to advise patient on  carbimazole treatment (dosing and tapering  of dose, advice to report any signs of  infection).   measured include thyroid function tests and  liver function tests; identify any signs of  infection and carry out white blood cell  count when appropriate.   Demirkan K, Stephens M A, Newman K P and Self T H  (2000). Response to warfarin and other oral anticoagu-  lants: effects of disease states. South Med J 93:  448-455.   Rehman S U, Cope D W, Senseney A D and Brzezinski W  (2005). Thyroid disorders in elderly patients. South  Med J 98: 543-549.   Weetman A P (2007). Radioiodine treatment for benign  thyroid diseases. Clin Endocrinol 66: 757-764.   • To develop skills to be able to manage drug  therapy, provide patient education on drug therapy  and manage drug therapy failures   Diabetes is a heterogeneous group of disorders char-  acterised by varying degrees of insulin hyposecretion  and/or insulin insensitivity. It leads to hyper-  glycaemia.   • insulin-dependent diabetes mellitus Type 1 or  diabetes: occurs as a result of insulin  hyposecretion due to autoimmune destruction of  beta cells in the pancreas.   • non-insulin-dependent diabetes mellitus Type 2  or diabetes: is further subdivided into forms in  non-obese and obese patients. It occurs as a  result of decreased insulin secretion or due to  insulin insensitivity. Despite the nomenclature,  some patients may require insulin therapy in due  course.   • Polyuria and polydipsia as a consequence of  osmotic diuresis secondary to sustained  hyperglycaemia   • Blurred vision due to change in refraction as a  result of hyperosmolar state   • Genetic features are important but do not  explain fully the development of the disease.    • A strong immunological component is suspected  as a final event which precipitates onset of  clinical diabetes (e.g. an infection).   • The condition is characterised by acute onset of  signs and symptoms.   • If diagnosis is not made when common  manifestations of hyperglycaemia occur, diabetic  ketoacidosis may occur   • Obesity associated with hyperinsulinaemia and  marked insulin insensitivity and a decrease in  number of insulin receptors   • Patients, especially obese patients, may have few  or none of the classic symptoms   • Commonly presents with chronic skin infections,  general pruritus and vaginitis in females.   6.7 mmol/L or a random value of more than  10 mmol/L   • Glucose tolerance test: in clinical practice used  only in patients who have borderline results   • Urine testing not suitable due to the wide inter-  individual variation in renal threshold   This is a cluster of metabolic abnormalities including  insulin resistance, hyperglycaemia, hypertension,  reduced high-density lipoprotein-cholesterol levels  and increased triglyceride levels.   • Prevent the development or slow the progression  of the long-term complications namely:   1 Carbohydrate and total calorie restriction,  increased fibre intake, decreased fat intake and  increased physical activity to cause weight loss  and produce normoglycaemia.   In patients with type 2 diabetes oral  hypoglycaemic agents may be required. Some  patients with type 2 diabetes will eventually  require insulin therapy.   In obese type 2 diabetic patients, where  achieving weight reduction through diet and  physical exercise is not successful, the use of  weight-reducing products such as orlistat and  sibutramine may be considered.   • They may be used in combination therapy with  other antidiabetic agents.   • Glibenclamide has a shorter elimination half-life  than first-generation drugs (e.g. chlorpropamide)  but shows a prolonged biological effect possibly  due to slower distribution. Consequently  glibenclamide is associated with occurrence of  hypoglycaemia more than the shorter-acting  drugs such as gliclazide, which are preferred  especially in the older patients.   • Caution: obese patients since they encourage  weight gain, the elderly, hepatic and renal  impairment.   • Gliclazide modified-release tablets taken at  breakfast, between one and four tablets a day.  Modified-release tablets 30 mg should achieve  better glucose control than conventional  formulation.   - hypoglycaemia: most common, may be severe;  risk factors include reduced food intake,  weight loss   - gastrointestinal: affects 2%; may induce  nausea and vomiting; advise patient to take  medication with or after food   - dermatological: affects 1-3%; usually occurs  within first 2-6 weeks of therapy and includes  photosensitivity and pruritus.   There is little or no difference in clinical efficacy  between the different agents. The choice usually lies  on three factors:   • It is used when strict dieting and sulphonylurea  treatment have failed to control diabetes. May be  used in combination with other antidiabetic  agents.   • Compared with sulphonylureas, it is associated  with a lower incidence of weight gain and  therefore is the drug of choice in obese type 2  diabetic patients.   • Side-effects: gastrointestinal (anorexia, nausea,  vomiting, diarrhoea, abdominal pain), metallic  taste.   • Doses (up to three times daily) to be taken with  food to minimise gastrointestinal side-effects.   - suspend 2 days before surgery and restart  when renal function is normalised   - stop when iodine-containing X-ray contrast  media are used and restart after normal renal  function   • Acarbose is an alpha-glucosidase inhibitor. These  enzymes are present in enterocytes of the small  intestine and are responsible for breaking down  carbohydrates. Inhibition of the enzymes results  in delayed carbohydrate digestion and  absorption.    • It is usually used in combination with other  antidiabetic agents.   • Tablets are taken at the start of each main  meal.   • Side-effects: gastrointestinal disturbances  particularly flatulence, soft stools, abdominal  distension, diarrhoea (incidence of side-effects  is increased if tablets are not taken with  food).   • They may be used in combination with oral  antidiabetic agents; when combined with insulin  therapy risk of heart failure is increased.   • Cautions: cardiovascular disease, increased  risk of bone fractures in females, monitor liver  function.   • Contraindications: hepatic impairment,  history of heart failure, pregnancy and breast-  feeding.   • Monitor for signs of heart failure, occurrence of  liver dysfunction and bone density in women.   • These drugs stimulate release of insulin from  beta cells in pancreas.   • They have a rapid onset of action and short  duration of action; to be taken up to 30 minutes  before meals and dose should be skipped if meal  is not taken.   • Cautions: the elderly, debilititated patients,  moderate hepatic impairment for nateglinide,  moderate renal impairment for repaglinide.   • Inhibitor of dipeptidylpeptidase-4 which results  in increased insulin secretion and decreased  glucagon level   • It does not affect weight and does not induce  hypoglycaemia   • Side-effects: gastrointestinal disturbances,  peripheral oedema, respiratory tract infections,  pain, osteoarthritis.   • An incretin mimetic which results in increased  insulin secretion, suppression of glucagon  secretion and slowing of gastric emptying   • Side-effects: gastrointestinal disturbances,  headache, dizziness, asthenia, hypoglycaemia,  increased sweating, injection-site reaction.   • Insulin is a polypeptide hormone which will be  destroyed if administered orally.   • It is given by subcutaneous injection. Patient is  advised to use a different site for each injection  to minimise fat hypertrophy at injection sites.   • Dose may need to be reviewed in relation to  change in diet or increased exercise.   • Side-effects: local reactions and fat hypertrophy  at injection site, increase in body weight,  hypoglycaemia.   • Human insulin analogues are preferred to the  insulin extracted from pork pancreas.   • Short-acting insulin (e.g. insulin aspart and  insulin lispro) has a rapid onset of action.    • Intermediate- and long-acting insulin (e.g.  isophane insulin, which is a suspension of insulin  in protamine, or insulin zinc suspension, which  includes addition of a suitable zinc salt) has a  slower onset of action but action is of longer  duration.   • Mixtures of short-acting and intermediate-acting  insulin (e.g. in the proportion of 30% to 70%,  which is administered twice daily) may be used.   A short-acting insulin may be required before  meals to avoid excessive post-prandial  hyperglycaemia.   • Injection devices (‘pens’) are convenient to use;  preferred to the conventional administration  especially for patients with impaired vision,  limited manual dexterity and children. The insulin  is supplied in cartridges for the re-usable pens   This is a method of administering continuous insulin  release and bolus doses for example at mealtimes. It  is appropriate for patients who suffer recurrent or  unpredictable hypoglycaemic attacks or high blood  glucose levels in the morning despite appropriate  drug therapy. The patient needs to receive training on  handling the device and on the requirement to  monitor blood glucose concentration.   Diabetic patients receiving treatment, espe-  cially insulin, should be advised to keep a  supply of sugar (e.g. dextrose tablets or sweets)  so that if symptoms of hypoglycaemia occur  they can take some sugar which is rapidly  absorbed and corrects the hypoglycaemic state.   The occurrence of nocturnal hypoglycaemia  should be addressed with care since, if patient  does not recognise signs, the condition may  progress to coma. Symptoms at night include  nightmares, restless sleep, profuse sweating,  morning headache and morning hangover.   Patient should be advised to consume a rapidly  absorbed carbohydrate (e.g. dextrose tablets or non-  sugar-free sweets or soft drinks) immediately until  symptoms subside. If patient is unconscious then  patient requires administration of glucagon and  glucose.    Warning signs of hypoglycaemia may be  minimised in patients who are taking beta-  blockers and those who are experiencing  increased frequency of hypoglycaemic attacks.    Blood pressure control in diabetics is impor-  tant to reduce cardiovascular risk and decrease  occurrence of nephropathy and retinopathy.  Blood pressure should be maintained at  120/80 mmHg.   • Surgery: patients receiving oral antidiabetic  agents who undergo elective surgery are switched  to insulin from the day before the intervention  and continued on insulin until they start to eat  and drink.   • Accumulation of sorbitol which cannot be  metabolised by cells in the retina takes place and  this leads to oedema   • Damage to existing vessels and formation of new  unstable vessels   • Characterised by paresthesia and pain in the  lower extremities, and decreased sensation which  may contribute to foot injuries   • Management: pain - paracetamol or NSAIDs are  first line of treatment. Tricyclic antidepressants  particularly amitriptyline and imipramine are  used in patients where analgesics alone are not  sufficient. Carbamazepine and gabapentin may  also be considered. Other antiepileptic drugs,  namely lamotrigine and topiramate, have been  shown to be effective.   In diabetic ketoacidosis patients present with  moderate-to-high blood glucose levels together with  water and electrolyte depletion. This is because,  when hyperglycaemia occurs and is sustained, osmotic  diuresis occurs resulting in water and electrolyte  excretion.   • Signs and symptoms: hyperglycaemia  (consistently elevated blood glucose), thirst,  excessive urination, fatigue, blurred vision, fruity  breath odour, deep and difficult breathing,  dehydration (dry mouth, dry skin), nausea,  vomiting, stomach pains and loss of appetite.   - insulin: continuous intravenous infusion of  insulin and monitor blood glucose level   - electrolytes: potassium supplementation is  started once elevated potassium levels begin to  drop and good urine outflow is achieved. In  acidosis, serum potassium level may be high  initially.   • HbAlc (glycated haemoglobin) 6. 5-7.5%:  provides an indication of glycaemic control over  the previous 3 months   Peaks and troughs in blood glucose should be  avoided. Peaks, especially when they are  sustained, are associated with long-term  complications while troughs are associated  with occurrence of hypoglycaemia. Contin-  uous blood glucose monitoring may be under-  taken to establish blood glucose control,  especially during the night, and review  medication accordingly.   Drugs that should be considered in diabetics to  reduce cardiovascular risk include:   Points to consider in patient education are listed in  Table 38.1.    • Patient self-monitoring: to maintain blood  glucose level between 4 and 7 mmol/L before  meals and less than 9 mmol/L after meals.   • Monitoring for eye disease (yearly ophthalmic  check-ups), vascular complications (care with  injuries especially injuries in the feet), kidney  disorders (routine check of kidney function tests).   • Skin and infections: to refer immediately to  health professional; anti-infective therapy is  considered.   • Exercise: test blood glucose level before, during  and after exercise. Occurrence of hypoglycaemia  is more likely in patients taking insulin than  those taking sulphonylureas.   • Travelling: patients should be advised to take  enough drug therapy and blood testing supplies  for the journey. Meal regularity and lifestyle  measures should be maintained (e.g. requesting  meals for diabetics on flights). If travelling across  time zones blood glucose should be tested more  frequently.   - foods for diabetics: limited intake; may  contain sorbitol which may cause diarrhoea   2 Which classes of drugs are used to manage  diabetic nephropathy?   1 Factors that indicate diabetic nephropathy  include albuminuria, proteinuria and decreased  creatinine clearance which may be identified  through renal function tests. Hypertension and  oedema occur.   2 Angiotensin-converting enzyme inhibitors such  as perindopril and calcium channel blockers    such as amlodipine are used in diabetic patients  with nephropathy who usually also require  strict blood pressure control.   Azzopardi L M, Serracino Inglott A, Zarb Adami M and  Zerafa N (2006). Patient education in diabetes. Clin  Pbarm Eur 2: 45-46.   Eugenio K R and Eugenio Clark L M (2004). Community  pharmacists’ counselling about metformin-associated  lactic acidosis. J Am Pbarm Assoc 44: 629-632.   Hogan E G, Leal S, Slack M and Apgar D (2006). Diabetes  drug management: pharmacists vs physicians. Hosp  Pbarm Eur July/August: 16-17.   Peel E, Douglas M and Lawton J (2007). Self monitoring of  blood glucose in type 2 diabetes: longitudinal qualitati-  tive study of patients’ perspectives. BMJ 335: 493.   • To appreciate characteristics of the menopause • To appreciate patient monitoring required with the   • To develop skills so as to estimate risks and benefits   Menopause is signalled by the last menstrual  period. This can be diagnosed retrospectively and is  usually confirmed following 12 months of blood-  free interval. Cessation of menstruation is caused by  a loss of ovarian follicular activity resulting from  decrease in the female steroid hormone oestrogen.   Menopause is characterised by vasomotor symp-  toms, localised atrophy of the genitalia, psycholog-  ical symptoms and osteoporosis. Table 39.1 shows  ovarian hormone secretion after the onset of a  normal menstrual cycle.   ‘With the recent publication of data from  trials designed to assess the long-term risks  and benefits of HRT, and which considered  the associated risks of cardiovascular disease  and breast cancer in particular, pharmacists  will be approached by women with questions  about the use of HRT.’ 1   • the duration of therapy should be at least 5 years   • the patient should be informed of increased  incidence of cardiovascular disease and breast  cancer shown in studies   • the benefits of treatment over risks should be  re-assessed every year   • other options of pharmacotherapy for  osteoporosis should be considered (see  Chapter 46).    and estriol, are rapidly inactivated by the liver and so  cannot be administered orally. The attachment of an  ethinyl group to the 17a position of estradiol leads to  ethinylestradiol (Figure 39.1) which undergoes  slower metabolism in the liver, allowing for oral  administration. In addition to oral administration  there are other routes of administration.   • Patches present estradiol either alone or in  combination with a progestogen   • Patch should be applied to non-hairy skin of the  lower body and should be placed away from  breast tissue   • Provides a constant level of oestrogen for up to 6  months   • Convenient for the patient. However, once  inserted it cannot be readily removed and levels  take at least a month to fall following removal.  This may present a problem when drug therapy  needs to be withdrawn either due to side-effects  or, for example, due to surgery.   • Preferred when symptoms are limited to vaginal  area such as atrophic vaginitis.    • Dose: 1-4 puffs into each nostril daily at the  same time of day continuously or for 21-28 days   • Oestrogen therapy alone is suitable for long-term  continuous therapy in a woman without a  uterus.   • A woman with a uterus requires oestrogen with  cyclical progestogen for the last 10-13 days of  the cycle to limit risk of endometrial hyperplasia  and endometrial carcinoma.   • Progestogen used for the last 10-13 days of the  28 days   • Regular withdrawal bleeding occurs upon  cessation of the progestogen intake   • Patient pack either presents two different types  of tablets (one containing oestrogen only and  another containing the combination of oestrogen  and progestogen) or consists of a calendar pack  that presents two tablets to be taken during the  last days of cycle.   • Combination of oestrogen and progestogen is  taken throughout 28 days (continuous)   • Indicated for postmenopausal women since it  avoids occurrence of withdrawal bleeding.   It is essential to advise patient to follow  calendar pack when available since the tablets    may vary or there may be a requirement for  varied tablet-taking pattern.   The risks associated with HRT may exceed the bene-  fits in women who have predisposing factors to venous  thrombosis, such as a personal or family history of  deep vein thrombosis or pulmonary embolism, severe  varicose veins, obesity, surgery, trauma or prolonged  bed rest.   Risk of deep vein thrombosis especially in flights  longer than 5 hours’ duration should be considered.  Patient should be advised to use elastic hosiery and  where appropriate use aspirin prophylaxis. In  patients undergoing major surgery, orthopaedic and  vascular leg surgery, HRT should be stopped 4-6  weeks before surgery and should be started after full  patient mobilisation.   The increased risk of breast cancer is related to the  duration of HRT use and this excess risk disappears  within about 5 years of drug withdrawal.   Some studies have indicated that during HRT the  risk of ovarian cancer is increased. 2   Tibolone (Figure 39.2) is a synthetic steroid with  oestrogenic, progestogenic and androgenic effects.   • Protective against osteoporosis and suitable for  the treatment of vasomotor symptoms   • Long-term cardioprotective effect, which is  experienced with oestrogen-based HRT, is  questionable   • Increases risk of breast cancer to a lesser extent  than combined HRT. Associated with a risk of  stroke.   The Women’s Health Initiative Study was  stopped because of safety concerns about  HRT with oestrogen and progestogen. There  was an increase in breast cancer, but this was  not greater than the increase reported in  observational studies. Although there was an  increase in vascular events, many of the  women in the study had pre-existing risk  factors for cardiovascular disease. No long-  term trials of combined HRT are continuing,  so the balance between benefit and harm will  remain uncertain. 3 These findings emphasise  the importance for the need for continued use  to be reviewed annually for each individual  patient.   • HRT is associated with an increased risk of  endometrial cancer (reduced by progestogen)  and, after some years of use, possibly an  increased risk of breast cancer.   • It is appropriate for women whose lives are  inconvenienced by vasomotor instability and in  patients with early natural or surgical menopause    (before 45 years) since these patients are at high  risk of osteoporosis. In these patients HRT is  continued for 5-10 years.   • In menopausal women with a uterus the risks may  outweigh benefits if used for longer than 5 years.    • Before initiating therapy, a physical  examination should be carried out.   • Assessment of bone mineral density needs  to be undertaken regularly.   • Baseline and monitoring of serum  electrolytes and liver function tests are  necessary.   • Patient should be advised to undertake  routine cervical smear test and  mammography.   • Initially, patient is reviewed after 3  months of therapy, then reviewed  periodically every 6-12 months.   • Phyto-oestrogens: plant-based products that exert  mild oestrogenic effects such as isoflavones in  soy products   • Herbal preparations such as valerian, kava:  effective to counteract psychological effects of  menopause.   • HRT is used to control menopausal symptoms  and improve quality of life.   • Patients should be advised about the mixed risks  and benefits of HRT.   • Women with a uterus should not receive  oestrogen alone; a progestogen component needs  to be included either as a continuous therapy  (with each tablet) or a cyclical therapy (during  the last 10-13 days of the 28-day cycle).    • HRT is not advocated for treatment or  prevention of cardiovascular disease, the risk of  which is higher in postmenopausal women than  in premenopausal women.   • HRT therapy should be reviewed yearly to  determine benefit and time for cessation of  treatment.   • After 4-5 years of therapy it is appropriate to  opt for a trial period off HRT and to identify  whether vasomotor, genital and psychological  symptoms still interfere with the patient’s quality  of life.    and osteoporosis prophylaxis in women at risk  of fractures (second line). It is given  continuously and is not suitable for women  within 1 year of menopause.   Azzopardi L M, Serracino-Inglott A, Zarb Adami M and  Galea F (2003). HRT in practice: helping women make  the right choice. Nurs Pract May/June: 67-68.   Bath P M W and Gray L J (2005). Association between  hormone replacement therapy and subsequent stroke: a  meta-analysis. BMJ 330: 342-345.   Mcintosh J and Blalock S J (2005). Effects of media  coverage of women’s health initiative study on attitudes  and behaviour of women receiving hormone replace-  ment therapy. Am J Healtb-Syst Pharm 62: 69-74.   Tanna N (2003). Hormone replacement therapy: risks and  benefits. Pharm J 271: 646-648.   1 Tibolone is a synthetic steroid with oestrogenic,  progestogenic and androgenic effects. It is  indicated for the short-term treatment of  vasomotor symptoms of oestrogen deficiency  (including women being treated with  gonadotrophin-releasing hormone analogues)   1 Tanna N. Hormone replacement therapy: an overview.  Pharm J 2003; 271: 615-617.   2 Beral V, Million Women Study Collaborators. Ovarian  cancer and hormone replacement therapy in the Million  Women Study. Lancet 2007; 369: 1703-1710.   3 MacLennan A H. Hormone replacement therapy:  where to now? Aust Pres 2003; 26: 8-10.   • To review characteristics of premenstrual  syndrome, dysmenorrhoea, menorrhagia,  endometriosis and polycystic ovary  syndrome    • To appreciate pharmacotherapy in the  management of menstrual cycle disorders   • To review use of oral contraceptives and identify  patient monitoring required.   • Symptoms occur a day before menstruation  begins and disappear at the onset or shortly after  menstruation begins. Symptoms are cyclical and  may not be present with each cycle.   • Aetiology: physiological changes in hormone  levels. Condition may be exacerbated by other  factors (e.g. stress).   • Psychological and behavioural symptoms:  depression, tiredness, fatigue, lethargy, tension,  irritability, sleep disorders, aggression, food  cravings.   • Physical symptoms: breast tenderness, swollen,  bloated feeling, weight gain, headache, appetite   • Manage fluid retention that is associated with  PMS by advising patient to reduce salt intake,  increase intake of potassium salts (e.g. banana,  nuts, tomatoes) and increase intake of food with  diuretic effect (e.g. prunes, figs, celery, cucumber,  parsley).   • Advise patient to keep a diary to help identify  trigger factors or activities that exacerbate the  condition.   • Dosage regimen requires either daily dosing  throughout the month or higher doses that  are used 3 days before onset of menstruation  and continued for 2 days after start of  menstruation   • Synthetic steroid with antioestrogenic and  antiprogestogenic activity combined with weak  androgenic activity   • Occurrence of side-effects (e.g. nausea, weight  gain, acne, muscular pain, photosensitivity,  nervousness, mood changes and anxiety) limits  its use.   • Take 250 mg three times daily 12 days before  menstruation or 500 mg three times daily 9 days  before menstruation   • Helps in counteracting general aches and pain,  headache, tension, irritability and depression.   • Use of selective serotonin re-uptake inhibitors  (SSRIs) and other antidepressants may be  considered when depression is clinically significant.   • Presents with lower abdominal pain that radiates  to back and thighs, nausea, vomiting, diarrhoea,  headache    • Probably higher concentration of prostaglandins  occurs which in turn favours increased  myometrial contractility.   • Occurs in women 30-40 years old as a  consequence of other pelvic pathology (e.g.  endometriosis)   • Pain starts before menstruation and continues for  the duration of menses   • Characteristic symptoms are abdominal bloating,  backache and feeling of heaviness.   • Antispasmodics: however, these are thought to  have a negligible effect on the uterus.   In secondary dysmenorrhoea the underlying  pathology should be identified. If the under-  lying cause includes endometriosis this may  impact negatively on fertility, which may be  an issue in this age group.   where there is blood loss in excess of 80 mL. This is   The occurrence of menorrhagia should be investi-  gated and, once secondary conditions are eliminated,   • tranexamic acid: an antifibrinolytic drug  which is contraindicated in thromboembolic  disease   • surgery: undertaken when patient is in her peri-  menopausal state and where this is not going to  interfere with family planning.    Gonadorelin analogues inhibit production of  androgen and oestrogen. They are used in  patients with infertility and endometriosis.  Treatment should not exceed six months.  Side-effects: menopausal-like symptoms (hot  flushes, increased sweating, vaginal dryness),  decrease in bone mineral density, headache  and hypersensitivity reactions.   This is a condition characterised by the occurrence of  endometrial tissue outside the uterus (e.g. in the  cervix, ovaries, peritoneum, small intestine, genito-  urinary tract). Symptoms include:   Endometriotic tissue is oestrogen-dependent and  therefore drug therapy is aimed at opposing effects of  oestrogens:   • Low-dose combined oral contraceptives,  particularly those containing drospirenone as the  progestogen component   • Metformin: in patients experiencing insulin  resistance, use of insulin sensitisers lowers  testosterone blood levels and increases ovulation   Clomifene is an anti-oestrogen and it induces  gonadotrophin release by occupying oestrogen  receptors in the hypothalamus. Cautions to  its use include risk of ovarian cancer (recom-  mendation that therapy should be limited to  six cycles); cysts may enlarge during therapy  and multiple births. Side-effects: hot flushes,  abdominal pain. Withdraw therapy if visual  disturbances or ovarian hyperstimulation  occur. It is used in polycystic ovary syndrome  (PCOS) particularly where infertility is an  issue. It is also used in the treatment of  infertility.   Progestogens can be classified into two: progesterone  analogues and testosterone analogues.   These are less androgenic than the testosterone  analogues. Examples include dydrogesterone and  medroxyprogesterone .    Progestogen-only (POP) oral contraceptives are  also available. They are used when oestrogens are  contraindicated (e.g. due to a history or predisposi-  tion to venous thrombosis) and when breast-feeding  since they do not affect lactation.    • Dydrogesterone (Figure 40.1): used in infertility,  recurrent miscarriage, menstrual cycle disorders  (PMS, dysmenorrhoea, endometriosis,  amenorrhoea)   • Medroxyprogesterone (Figure 40.2): used in  malignant disease, menstrual cycle disorders  (amenorrhoea, endometriosis).   Testosterone analogues include norethisterone,  which is used in the postponement of menstruation  and in menstrual cycle disorders (PMS, dysmenor-  rhoea, endometriosis), and other progestogens (e.g.  norgestrel, levonorgestrel (Figure 40.3), desogestrel,  gestodene, norgestimate) which are included in  combination products with oestrogens for hormone  replacement therapy and combined oral contra-  ceptives.   Oral contraceptives may contain an oestrogen  together with a progestogen component and these  are referred to as the combined oral contraceptives  (COCs). COCs are usually taken for 21 days  followed by a 7-day pill-free period or inactive  tablet taking during which withdrawal bleeding  occurs. When COCs are used for the treatment of a  pathological condition, treatment may be given  continuously.   • Avoidance of dysmenorrhoea and menorrhagia  (lower occurrence of iron-deficiency anaemia)   The starting routine for COCs to achieve a  contraceptive effect is shown in Table 40.2.   The different preparations may be classified according  to the strength of the oestrogen component. For each  patient the lowest strength oestrogen product that  gives the desired clinical outcome should be used to  keep occurrence of side-effects to a minimum.   The progestogens included in COCs are testosterone  analogues which can be divided into second-  generation progestogens (e.g. norethisterone and  levonorgestrel) and third-generation progestogens  (e.g. desogestrel, gestodene, norgestimate and dros-  pirenone).   COCs containing desogestrel and gestodene  should be used only by women who are intolerant of  other COCs since they are associated with an  increased risk of venous thromboembolism.    Drospirenone is a derivative of spirono-  lactone and hence has anti-androgenic  activity together with anti-mineralcorticoid  activity. For this reason, COCs containing  drospirenone may be preferred in the  management of PCOS. It may cause an  increase in serum potassium.   COCs may present varying amounts of oestrogens  and progestogens depending on the stage of the cycle.  Such preparations are termed biphasic (two different  types of tablets) or triphasic (three different types of  tablets). Patient adherence to the calendar pack is  important so that the different tablets are taken  according to the stage of the cycle. Preparations that  contain the same amount of oestrogen and progesto-  gens are termed monophasic and do not require  special patient advice to ensure a specific pattern in  taking the tablets.    Patient compliance with COCs is essential to  ensure contraceptive effect. Patients should be  advised on factors that may occur during the  cycle which may interfere with the contracep-  tive effect. They should also be advised to  take the tablets at the same time of the day  each day.   When patients forget to take the tablet, this could  lead to loss of contraceptive effect for the cycle. The  risk is increased if the missed tablet occurs at the  beginning or end of a cycle.   Patients should be advised that if they forget a  dose they should take it as soon as possible and the  next one at the normal time. If tablet taking is  delayed by more than 24 hours and occurs for two or  more pills in a cycle, then contraceptive effectiveness  may be lost. The patient should continue normal pill  taking but will not be protected for the next 7 days.  If these 7 days run beyond the end of the packet, the  patient should start the next packet at once, skipping  the 7-day pill-free period or the seven inactive tablets.    • Nausea and vomiting, diarrhoea: when the  conditions last for more than 24 hours,  additional contraceptive protection is required.   • Antibiotics, namely ampicillin, amoxicillin and  related penicillins, tetracyclines and  cephalosporins disturb normal gut flora which  split oestrogen metabolites, entering the bowel,  and reduce reabsorption of re-activated  oestrogen. If patient is taking such antibacterial  agents, she should be advised that the  contraceptive effect of COCs may be lost.   The effectiveness of COCs and POP is reduced when  they are taken together with drugs that act as hepatic  enzyme inducers such as carbamazepine, phenytoin,  griseofulvin, rifampicin and St John’s wort. Hence a  high-dose oestrogen COC preparation is preferred or  else alternative methods of contraception should be  considered.   Occurrence of bleeding during tablet taking (break-  through bleeding) should be investigated since it may  occur as a result of changes in tablet-taking patterns  or may indicate pathological conditions. Minimal  amount of bleeding is referred to as spotting. If  breakthrough bleeding occurs with initiation of treat-  ment, this may resolve on its own. Breakthrough  bleeding in patients who have been taking the  medication for a while should be investigated.   In oral administration, factors that interfere with the  absorption of oestrogen and progestogen from the  gastrointestinal tract may lead to loss of the contra-  ceptive effect.    When no underlying pathology is detected with  breakthrough bleeding, strategies that may be  considered include:    • increasing progestogen dose: if bleeding is  occurring in late cycle   Tricycling is when the patient takes three or four  packets of monophasic preparations without the 7-  day pill-free period in between. It is adopted when:   • there is a predisposition to reduced efficacy (e.g.  missed tablets at end of cycle)   • the woman requests it to avoid withdrawal  bleeding during a holiday or an activity   New formulations of COCs that are termed extended  cycle or continuous cycle have been developed lately.  They provide a means of changing a woman’s with-  drawal bleeding associated with COCs. An example  of such a formulation consists of ethinylestradiol and  drospirenone which provides 24 days of therapy and  4 days of placebo and is associated with a lighter-  flow which is of shorter duration when compared  with a traditional formulation. Other formulations  where treatment is given over 84 days leading to four  withdrawal bleedings per year are available.  Currently these formulations are associated with a  higher risk of breakthrough bleeding and spotting.  They are useful for patients where withdrawal  bleeding is causing distress (e.g. menstrual migraine).   • Patients at risk of developing venous  thromboembolism, arterial disease and migraine   • History of severe depression, undiagnosed breast  mass and inflammatory bowel disease including  Crohn’s disease.    COCs should not be considered for patients  where the risks associated with therapy are  greater than the expected benefits. Before  starting use of these products, individual  assessment should consider the personal  history of venous or arterial thrombosis,  heart disease associated with pulmonary  hypertension or risk of embolus, history of  transient ischaemic attacks, liver disease,  systemic lupus erythematosus, pregnancy and  breast-feeding, among others. They should  not be used in patients who have been diag-  nosed with breast cancer and within 5 years  of evidence of disease.   • Increased risk of cardiovascular disease: blood  clots, heart attacks and stroke   - patients with hypertension, history of arterial  or venous thrombosis, ischaemic heart  disease   - patients undergoing surgery: COCs should be  discontinued 4 weeks before major elective  surgery and all surgery to the legs; it is  recommended to start therapy 2 weeks after  full mobilisation   - patients undertaking travel, particularly travel  over 5 hours: patient should receive advice on  prophylaxis of travel-related deep vein  thrombosis (see also Chapter 61).   • COCs are used in the management of  menstrual cycle disorders where fertility is  not an issue.   • Patients taking COCs should be advised to  take the tablet at the same time each day, adhere  to the schedule to visit the prescriber and to  report immediately any of the following  symptoms:   1 Metformin is used in polycystic ovary  syndrome in patients experiencing insulin  resistance. Use of insulin sensitisers lowers  testosterone levels and increases ovulation.  Clomifene is an anti-oestrogen. It induces  gonadotrophin release by occupying oestrogen  receptors in the hypothalamus. Cautions: risk  of ovarian cancer (recommendation that  therapy should be limited to six cycles), cysts  may enlarge during therapy, multiple births.  Side-effects include: hot flushes, abdominal  pain. Withdraw therapy if visual disturbances  or ovarian hyperstimulation occur. It is used  in patients who are considering a pregnancy.   Hendelmalm K and Samuelsson E (2005). Fatal venous  thromboembolism associated with different combined  oral contraceptives. Drug Safety 28: 907-916.   Shrader S P and Dickerson L M (2008). Extended- and  continuous-cycle oral contraceptives. Pharmacotherapy  28: 1033-1040.   Upadhya K and Trent M (2007). Effects of polycystic ovary  syndrome on health-related quality of life. Exp Rev  Pharmacoecon Outcomes Res 7: 597-603.   1 Compare the use of metformin and clomifene  in polycystic ovary syndrome.    • To appreciate characteristics of benign prostatic  hyperplasia and urinary frequency and  incontinence    • To understand principles of drug therapy in benign  prostatic hyperplasia and urinary frequency and  incontinence   • Enlarged prostate compresses urethra and  produces lower urinary tract symptoms and  symptoms of bladder obstruction.   • Symptoms: weak urinary flow, sense of  incomplete bladder emptying, delay in starting  urination, need to urinate frequently, urgency,  nocturia, urge incontinence and urinary leakage.   • Occasionally may result in acute retention of  urine, warranting catheterisation.   • The occurrence of chronic urinary retention  increases the risk of urinary tract infection which  is otherwise very rare in males.   • Measurement of flow rate: uroflow which records  peak flow (25 mL/s) and average flow (12 mL/s)    • Digital rectal examination to assess size and  presence of a tumour   • Measurement of prostate-specific antigen (PSA):  PSA is a glycoprotein which is normally detected  in minimum levels in all males. PSA levels  greater than 10 ng/mL indicate a high  probability of prostate cancer and require  further assessment   • Scoring systems can be used to assess degree of  hypertrophy in benign prostatic hypertrophy.  Factors that are considered include occurrence of  nocturia, daytime frequency, hesitancy,  intermittency, terminal dribbling, urgency,  impairment of size and force of urinary stream,  dysuria and sensation of incomplete voiding.   • Surgery: transurethral resection of the prostate is  one method that could be adopted. Surgery is  preferred when the hypertrophy is large or in the  presence of a tumour. Immediate complications  associated with surgery include failure to void,  haemorrhage and urinary tract infections. Long-  term complications include erectile dysfunction,  urinary incontinence and bladder neck  contractures.   • Produce an increase in urinary flow rate and an  improvement in obstructive symptoms   • Produce a rapid onset of action with clinical  effects noticeable within weeks of initiation of  therapy   • Side-effects: dizziness, hypotension (first-dose  phenomenon), headache, asthenia, dry mouth,  gastrointestinal disturbances.   • Dutasteride and finasteride inhibit 5a-reductase  which is responsible for metabolising  testosterone into dihydrotestosterone   • Result in improvement in urinary flow and in  obstructive symptoms; delay in positive outcome  of about 6 months   • Finasteride in low doses is also used in male  pattern baldness (see Chapter 47)   • Caution: decrease serum concentration of PSA  (may interfere with PSA test result); not to be  handled by women of childbearing potential;  excreted in semen   • Side-effects: impotence, decreased libido, reduced  ejaculatory volume, breast tenderness and  enlargement.   • Alpha-blockers produce symptomatic  relief within weeks and have an impact  on symptoms of chronic urinary retention  due to benign prostatic hyperplasia.   • Anti-androgens reduce prostate volume,  are less effective for symptomatic  improvement than alpha-blockers and  have a lag time to produce the expected  effect of a few months.   • Urgency: sudden compelling need to pass urine  which is difficult to defer   • Frequency: need to pass urine eight or more  times in a 24-hour period   • Nocturia: awakening at night two or more times  to pass urine.   • Negative impact on quality of life - interference  with physical, sexual, occupational and social  activities, psychological impact   • Indirect costs - cost of reduced productivity of  patient, cost of health professionals’ time.   • Acetylcholine stimulates muscarinic receptors  (M 2 and M 3 ) on the detrusor muscle   • Involuntary contractions of the detrusor muscle  result as the bladder fills.   • Female gender: the decline in oestrogen levels  during the postmenopausal stage can precipitate  symptoms of urinary incontinence   • Urge incontinence: involuntary leakage due to  urgent need to pass urine. Conditions that may  lead to its occurrence include cystitis, urethritis,  outflow obstruction and neurological disorders  such as stroke, dementia, parkinsonism and  spinal cord injury.   • Stress incontinence: bladder leakage during  exercise, coughing, sneezing, laughing or body  movements which put pressure on bladder; most  common in elderly women.   • Pharmacotherapy: antimuscarinic agents and  inhibitors of serotonin and noradrenaline  re-uptake for stress incontinence.   • Bladder contraction is mediated by muscarinic  receptors in the bladder wall.   • Contraindications: myasthenia gravis, significant  bladder outflow obstruction or urinary retention,  severe ulcerative colitis, toxic megacolon and in  gastrointestinal obstruction or intestinal atony.   • Side-effects: dry mouth, constipation, blurring of  vision, difficulty in micturition, sedation.   • Oxybutynin relaxes urinary smooth muscle  through a direct antispasmodic action on smooth  muscle of the bladder.    • Flavoxate has a direct smooth muscle relaxation  effect with very weak antimuscarinic activity,  fewer side-effects but is less effective than  oxybutynin.   • Tolterodine (Figure 41.1) offers functional  uroselectivity and efficacy and side-effects are  similar to those of modified-release oxybutynin.  Side-effects may also include dyspepsia, fatigue,  flatulence, chest pain, dry eyes, peripheral  oedema.   • Darifenacin, propiverine, solifenacin and  trospium (Figure 41.2) are newer products.  Darifenacin and solifenacin have specific activity  at the M 3 receptors. Propiverine also exhibits  calcium channel-blocking effects.   • Oxybutynin and tolterodine are tertiary amines  while trospium is a quaternary amine.  Compounds with a quaternary ammonium  structure present with unreliable absorption after  oral administration. In fact trospium should be  administered before food.   • Flavoxate is less used. Tolterodine and  trospium are preferred; both drugs  require a twice daily dose administration.   • Newer products (e.g. solifenacin and  darifenacin) that are selective M 3  antimuscarinics have a lower probability  of side-effects. They have a long half-life  and are administered once daily.   • Antidepressants (e.g. imipramine) are used for  nocturnal enuresis. They reduce bladder  contractility and have a sedative effect.   • Oestrogen therapy including topical vaginal  preparations may improve symptoms in  postmenopausal women.   • Caution: cardiac disease, hypertension, history of  mania/seizures, glaucoma, increased risk of  bleeding   • Side-effects: nausea, vomiting, dyspepsia,  constipation or diarrhoea, dry mouth, hot  flushes, insomnia or drowsiness, anxiety,  headache, dizziness, tremor, anorexia. Rarely  urinary retention may occur.   • Review medication history, problem could be  originating from drug therapy.   1 Compare the use of oxybutynin and solifenacin  in urinary incontinence.   1 Involuntary detrusor contractions cause urgency  and urge incontinence, usually with frequency  and nocturia. Antimuscarinic drugs reduce these  contractions and increase bladder capacity.  Oxybutynin has a direct relaxant effect on  urinary smooth muscle. Side-effects limit the use  of oxybutynin but they may be reduced by  starting at a lower dose. A modified-release  preparation of oxybutynin is effective and has  fewer side-effects; a transdermal patch is also  available. Solifenacin is a newer antimuscarinic  drug selective to the M 3 receptor and is licensed  for urinary frequency, urgency and incontinence.  Since both oxybutynin and solifenacin are  antimuscarinic drugs, cautions, contraindications  and side-effects are similar. Cautions: the elderly,  autonomic neuropathy, glaucoma, hiatus hernia,  reflux oesophagitis, hepatic and renal  impairment, cardiovascular disease,  hyperthyroidism and prostatic hypertrophy.  Contraindications: myasthenia gravis, significant  bladder outflow obstruction or urinary retention,  severe ulcerative colitis, toxic megacolon,  gastrointestinal obstruction or intestinal atony.  Side-effects: dry mouth, constipation, blurred  vision, difficulty in micturition, sedation. Dosage  regimen: oxybutynin is administered two to three  times daily unless the modified-release  preparation is used, while solifenacin is  administered once daily.   Lee M and Weberski J (2005). Options for treatment of  overactive bladder. In: Pharmacy Today: Topics in-  patient care. Washington DC: American Pharmacists  Association.   National Institute for Health and Clinical Excellence  (2006). Urinary incontinence: the management of   Thor K B and Viktrup K L (2007). Serotonin and nor-  adrenaline involvement in urinary incontinence, depres-  sion and pain: scientific basis for overlapping clinical  efficacy from a single drug, duloxetine. Int J Clin Tract  61: 1349-1355.   • To appreciate side-effects of cytotoxic • To develop skills for patient advice and monitoring,   Cancer represents a group of diseases including  leukaemias, lymphomas and solid tumours. Treatment  options include:   These malignant tumours of lymph nodes or other  lympathic tissue are classified into Hodgkin’s disease  and non-Hodgkin’s disease.   • Clinical features: painless enlargement of lymph  nodes especially in the neck, fever and weight  loss.   Haematological malignancy classified according to  cell morphology (e.g. chronic lymphoid leukaemias).   • Ten commonest causes of solid tumour death:  lung, breast (females), colon, prostate (males),  stomach, oesophagus, pancreas, rectum, bladder,  ovary (females)   • Clinical features: non-specific complaints (weight  loss, bleeding, malaise, pain), presence of a  painless lump   • Average number of tumour cells in terminal  stages of disease: 10 12 .   • To provide symptom relief: treatment has no  antitumour effects (e.g. analgesics).    Complications due to the malignant state  include malnutrition, mechanical obstruction,  pain, increased risk of venous thrombo-  embolism and anaemia.   These are physical rating scales applied before treat-  ment to help in the prognosis and to indicate the  patient’s ability to withstand aggressive chemotherapy  (e.g. Karnofsky’s Performance Index and W1TO  Performance Scale).   • To cure: achieve remission, patient is completely  disease free and has a normal life expectancy   • To provide palliation: bring disease under  control with the hope of relieving disease   For example, in breast  cancer use of TNM system,  in colon cancer use of  Dukes' classification   In the 1950s it was demonstrated that chemotherapy  was more effective when two or more drugs were  used in combination regimens to achieve additive or  synergistic effects (e.g. CMF - cyclophosphamide,  methotrexate, fluorouracil combination for breast  cancer). In combination chemotherapy, drugs included  should have different mechanisms of action and  minimal overlapping toxicities.   In the 1990s studies were started with regard to  in vivo administration of high-dose chemotherapy  with haematopoietic growth factors (e.g. epoietin)  which counteract the bone marrow depression, a  dose-limiting side-effect of cytotoxic drugs (see also  Chapter 43).   This follows definitive treatment of primary disease  (e.g. surgery) and is adopted when the risk of sub-  clinical metastatic disease is known to be high.   This is given before local therapy to reduce the  primary tumour size, thereby rendering local therapy  less destructive, more effective and easier.    Most cytotoxic drugs are teratogenic and all  may cause life-threatening toxicity.   • Reconstitution should be carried out in  designated areas where a biological safety cabinet  is available.   • Dose of cytotoxic drugs is calculated for the  individual patient based on body surface area.   • Some drugs have a maximum cumulative dose  (e.g. doxorubicin: if total dose administered  throughout the treatment is higher than   • Treatment is given in cycles (e.g. up to six cycles  with a 3- to 4-week interval between each cycle).   • Most drugs are administered parenterally and  extravasation may be a problem.   • Extravasation: severe local tissue necrosis if  leakage into the extravascular compartment  occurs. If pain occurs during administration,  administration is stopped and canula resited  somewhere in another vein. Products that are  associated with a risk of pain on extravasation  include doxorubicin and the vinca alkaloids, such  as vincristine and vinblastine.   • Prevention of chemotherapy toxicity:  managing nausea and vomiting,  monitoring for bone marrow suppression   • Symptom management: advice on how to  counteract symptoms, use of supportive  therapy such as paracetamol and lifestyle  modifications (e.g. good oral hygiene to  decrease stomatitis)   • Provide appropriate verbal advice specific  to the individual patient and provide  written information about treatment.   • Chemotherapy agents are not specific to tumour  cells and hence cause toxicity to host tissues and  organs where renewal of cell population is high  (e.g. lymphoid tissue, bone marrow and  epithelium of the gastrointestinal tract and  skin).   • Chemotherapy may increase risk of venous  thrombosis, especially in patients who have  restricted mobility.   • Hypersensitivity reactions to cytotoxic  chemotherapy agents (e.g. bleomycin, cisplatin,  daunorubicin, paclitaxel, rituximab,  trastuzumab) may occur. For drugs at high risk  of hypersensitivity reactions, corticosteroids are  administered intravenously simultaneously with  drug administration.   Type of cancer, patient characteristics, other  disease states and concomitant drug therapy  may impact on the side-effect profile  presented by individual patients.    The occurrence of side-effects in chemotherapy is  summarised in Table 42.1.   Nausea and vomiting as a consequence of  chemotherapy may be classified as:    • anticipatory - occurring prior to subsequent  dose, very much related to occurrence of  anxiety.   Occurrence varies depending on patient suscepti-  bility; the risk is higher in women, patients under 50  years and anxious patients. It is also related to the  emetic potential of drugs (Table 42.2).   • Intravenous administration during treatment  with 5HT 3 serotonin antagonists (e.g.  ondansetron) ± dexamethasone   • Oral metoclopramide is usually preferred with or  without dexamethasone or prochlorperazine.  Serotonin antagonists are less effective for  delayed symptoms.   • Lorazepam (orally or intravenously) is helpful  because it has a sedative, anxiolytic and amnesic  effect.   • Good control of acute and delayed symptoms of  nausea and vomiting decreases occurrence of  anticipatory nausea.   • Granisetron is more effective than  ondansetron in combination with  dexamethasone in preventing acute and  delayed vomiting with highly emetogenic  chemotherapy. This is of particular  significance in offering better control on  day 2 when patient is most likely to suffer  from nausea and vomiting and is usually  at home.   • Occurs 7-10 days after treatment when white  blood cell count is at nadir (lowest level), then  recovery occurs after 20 days and this explains  why treatment is given in cycles of 3-4 weeks.   • Before each treatment cycle, blood count is  checked and if it is too low treatment has to be  delayed.   • Patients should be advised to report immediately  occurrence of fever and, if patient is neutropenic,  antibacterial treatment is required.   • A urinary metabolite of cyclophosphamide,  acrolein, may cause haemorrhagic cystitis and  so advise patient to increase fluid intake for  24-48 hours after administration.   • It has a folate-antagonist action and folinic acid  (calcium folinate) is used to counteract this  action and speed recovery from methotrexate-  induced mucositis    • Calcium folinate is given 24 hours after  methotrexate, every 6 hours for two to eight  doses, depending on dose of methotrexate used.   • Metabolised to fluorouracil, an antimetabolite  drug that is administered by intravenous  injection since oral administration of fluorouracil  is associated with unpredictable absorption   • Monotherapy for metastatic colorectal cancer  and breast cancer, and can also be used in  combination therapy.   • Pemetrexed is used in lung cancer while  ralitrexed is used in colorectal carcinoma   • Vincristine and to a lesser extent vinblastine and  vinorelbine cause neurological toxicity:  peripheral or autonomic neuropathy that is  manifested as a tingling sensation and with  constipation    • Vinorelbine is available for parenteral and  oral administration. Vincristine and  vinblastine are available only for parenteral  administration.   • May cause hyperpigmentation and progressive  pulmonary fibrosis, which is manifested as  breathlessness   • May cause cardiomyopathy; monitor for  occurrence of breathlessness, tiredness and  malaise.   • Long-circulating pegylated liposomal  formulation which is comparable in efficacy to  doxorubicin   • Reduction in incidence of cardiotoxicity and  lower potential for local necrosis   • Occurrence of hand-foot syndrome (painful,  macular, reddening skin eruptions) after two to  three treatment cycles. May be dose limiting.  Prevention: cooling of hands and feet, avoid  tight-fitting footwear for 4-7 days after  treatment.   • Nephrotoxicity may occur: to avoid ensure pre-  treatment hydration and prolonged hydration  with intravenous fluids, monitor kidney function   • Used for ovarian cancer and secondary treatment  for breast cancer   • Hypersensitivity reactions can occur, peripheral  neuropathy, cardiac conduction defects with  arrhythmias, muscle pain, alopecia, oedema.   • Used for colorectal cancer and ovarian cancer  respectively as a secondary line of treatment   • Gastrointestinal side-effects, particularly  diarrhoea, and asthenia, alopecia and anorexia  may occur.   • A tyrosine kinase inhibitor that is available for  oral administration; licensed for the treatment of  pancreatic and lung cancer.   • For metastatic breast cancer with tumours  overexpressing the human epidermal growth  factor receptor 2 (HER-2)   • Caution: cardiotoxicity may occur, special care  when used in combination with anthracyclines  (e.g. doxorubicin).   • developing standard dosage systems (e.g.  CMF in breast cancer), which leads to  efficient utilisation of pharmacy staff time   • collating evidence for specific treatment  regimens in different types of cancers   • developing treatment protocols on  evidence-based care (e.g. all women with  early breast cancer should receive 3-6  months of adjuvant polychemotherapy)   • estimating costings and identifying  priorities of funding within a National  Health Service scheme.   • Care of patients where disease is not responsive  to curative treatment   • Attention to physical, emotional and spiritual  needs of the patient and close carers   • Drug treatment: minimise number of drugs,  adjust dose and pharmaceutical dosage form,  ensure accessibility to medication.   • A tyrosine kinase inhibitor that is available for  oral administration; licensed for the treatment of  renal cell carcinoma.   • An inhibitor of multiple kinases which is licensed  for renal cell and hepatocellular carcinoma.   • Analgesics are more effective in preventing pain  than in the relief of established pain. The aims  are to prevent occurrence of pain using  analgesics.    • Initiation of opioid analgesics should not be  delayed by concerns of dependence.   • Consider managing side-effects of opioid drugs  particularly nausea and constipation by using  antiemetic agents and laxatives when opioid  analgesia is started.   • In the management of cancer, education and  support of patient and carers are essential to  ensure good quality of life of patients.   • Monitoring of occurrence of side-effects: nausea  and vomiting, bone marrow suppression, liver  function (e.g. doxorubicin to reduce dose;  methotrexate and paclitaxel to avoid in severe  hepatic impairment), renal failure (e.g. cisplatin  and ifosfamide to avoid; methotrexate and  cyclophosphamide to reduce dose).   • Pharmacogenetic implications in the selection of  drug therapy (e.g. trastuzumab).   • Future considerations: chronotherapy leading to  appropriate timing of administration of  antineoplastic agents may improve efficacy and  diminish toxicity due to variation in enzyme  levels in circadian rhythm (e.g. irinotecan and  capecitabine are prodrugs), bioactivation depends  on enzyme activity (carboxyesterases). Consider  use of programmable automatic drug delivery  systems.   • In palliative care, patient access to medications  that encompass different systems (e.g. opioid  analgesics, antidepressants, laxatives, antiemetics,  adjuvant analgesics) should be ensured.   1 Explain the rationale of using liposomal  formulations of doxorubucin. Describe side-  effects that may occur with the administration  of this product.   2 Explain the rationale of applying  pharmacogenetic principles when considering  trastuzumab therapy in metastatic breast cancer.  What cautions are required when administering  trastuzumab?    3 Giving reasons for your answer, explain when  opioids are used in palliative care. List factors  that should be considered in pain management  in palliative care.   4 What are the disadvantages associated with the  use of morphine sulphate solution in patients  with terminal cancer?   1 Liposomal formulations of doxorubicin have  comparable efficacy with doxorubicin. However,  they have a decreased risk of cardiotoxicity and  local necrosis. Side-effects that may occur with  the administration of doxorubicin (including the  liposomal formulations) include nausea and  vomiting, alopecia and bone marrow suppression.   2 Trastuzumab is effective in patients who  respond positively to a test to identify tumours  that overexpress human epidermal growth factor  receptor 2 (HER-2). When administering  trastuzumab cardiotoxicity may occur and risk  is increased if administered with anthracyclines  (e.g. doxorubicin). Concomitant use with  anthracyclines should be avoided.   3 Palliative care is the care of patients where  disease is not responsive to curative treatment  and where attention is given to the physical,  emotional and spiritual needs of the patient and  close carers. In palliative care both non-opioid  and opioid analgesics are used and the initiation  of opioids should not be delayed by concerns of  dependence. Analgesics are more effective in  preventing pain than in the relief of established  pain and therefore it is imperative that analgesia  is provided to prevent the occurrence of pain.  When considering drug treatment in palliative  care it is important to assess the symptoms and  needs of the patient and to minimise the number  of drugs used, adjust doses and pharmaceutical  dosage forms and ensure accessibility to  medication. Common side-effects of opioid  analgesics are nausea and constipation. These  side-effects should be managed, for example  nausea with metoclopramide and constipation  with an osmotic laxative such as lactulose or a  stimulant laxative such as senna.    4 Side-effects of opioids include nausea and  vomiting and constipation. The occurrence of  these side-effects requires the use of antiemetics  such as metoclopramide and laxatives such as  lactulose. The unwanted effect of dependence is  not an issue that should limit use of morphine in  terminally ill patients. However, occurrence of  tolerance requires dose adjustments so as to  maintain the patient pain free.   Mader R M and Schwarz U (2004). Safety concerns in  oncology pharmacy - an evidence based approach. Eur  J Hosp Pharm 6: 28.   Wiela-Hojenska A and Orzechowska-Juzwenko K (2004).  Optimisation and individualization of anticancer  chemotherapy. Eur J Hosp Pharm 6: 24-25.   • To review presentation and management of iron- • To identify drugs that cause blood dyscrasias  deficiency anaemia and megalobastic anaemia   • a decrease in haemoglobin synthesis which may  be due to lack of nutrient or bone marrow  failure OR   • an increase in haemoglobin loss due to  haemorrhage or haemolysis.   • Male 4. 7-6.1 X 10 6 /mm 3 , female  4.2-5 .4 X 10 6 /mm 3    • Level is decreased: anaemia, haemorrhage,  bone marrow failure, renal disease,  pregnancy   • Level is increased: dehydration, chronic  obstructive pulmonary disease (COPD),  congenital heart disease.   • Male 14-18 g/dL, female 12-16 g/dL (reduced in  the elderly)   • Patient acceptability: side-effects, frequency of  administration (modified-release formulations are  available but these may be associated with poor  absorption)   • excessive adverse effects from oral iron or with  poor patient compliance   cause of anaemia that warrants further inves- This is a complex of iron and dextrans administered   • Caution: patients with inflammatory bowel  disease may present with an exacerbation of  diarrhoea, diverticular disease   • Patient advice: may discolour stools, absorption  is better if taken on an empty stomach, take  after meals if gastrointestinal side-effects  occur   • Also available in combination with folic acid as  an oral dosage form, intended for use during  pregnancy.   This is a complex of iron and sucrose that may be  administered as slow intravenous injection or by  intravenous infusion.   This is indicated in patients at high risk of  iron deficiency, such as those with gastro-  intestinal conditions leading to malabsorp-  tion (previous gastrointestinal surgery),  menorrhagia, pregnancy, haemodialysis or  poor diet.   • Vitamin B 12 deficiency: malabsorption,  pernicious anaemia - lack of gastric intrinsic  factor   Vitamin B 12 prophylaxis should be considered  in patients who have undergone partial or  total gastrectomy or total ileal resection.    • In deficiency, folic acid replacement therapy of  5-15 mg a day for about 4-6 months replenishes  depleted stores.   • In pregnancy daily supplementation reduces the  occurrence of neural tube defects. Women at low  risk of neural tube defects should take 400  micrograms daily pre-conception and during  pregnancy.   • Women at high risk of neural tube defects should  take 5 mg daily pre-conception and during  pregnancy. Risk is increased when either partner  has a neural tube defect or a family history of  neural tube defects, coeliac disease, diabetes or  sickle cell anaemia, or are taking antiepileptic  medicines.   • Triggered by certain drugs (e.g. quinolones,  nalidixic acid, sulphonamides, aspirin).   Treatment of vitamin B 12 deficiency:  hyd roxyco ba I a m i n   • Large doses of folic acid can reverse the  megaloblastic anaemia caused by vitamin B 12  deficiency but do not reverse the neurological  damage of vitamin B 12 deficiency. It is important  that in patients with vitamin B p deficiency folic  acid monotherapy is not adopted.   • Fiydroxycobalamin is retained in the body for  longer than cyanocobalamin and treatment can  be given every 3 months.   • Initial dose: 1 mg every 2-3 days for five  times.   Anaemia occurs due to reduced renal erythropoietin  production and the accumulation of toxic  metabolites which lead to reduced red blood cell  lifespan.   • Erythropoiesis-stimulating factor darbepoetin  alfa has a longer half-life therefore less frequent  administration than epoetin is required.   • Methoxy polyethylene glycol-epoetin beta  (pegzerepoetin alfa) - a continuous  erythropoietin receptor activator - has a longer  duration of action than epoetin.    • Caution: overcorrection of haemoglobin  concentration; such a situation may increase the  risk of thrombosis.   • Side-effects: peripheral oedema, hypertension,  arrhythmias, flu-like symptoms, nausea and  vomiting.   • Note: pure red cell aplasia may occur due to  formation of neutralising anti-erythropoietin  antibodies (severe anaemia resistant to epoetin  which may develop after 3-67 months of  treatment). Patients who develop pure red cell  aplasia should not be switched to other  erythropoietins.   • Cytokine release from neoplastic cells or injured  cells results in reduced production of red blood  cells   • Activation of macrophages which results in  reduced lifespan of red blood cells   • Consider use of erythropoietins in patients  presenting with anaemia in malignancy who are  receiving chemotherapy.   • Recombinant human granulocyte colony-  stimulating factor (rhG-CSF): filgrastim,  lenograstim, pegfilgrastim (pegylated derivative  of filgrastim which presents a longer duration of  action)   • Used in specialist scenario in congenital  neutropenia, chemotherapy-induced neutropenia,  bone marrow transplantation   • Side-effects: gastrointestinal disturbances,  headache, asthenia, fever, musculoskeletal and  bone pain, rash, alopecia and leukocytosis   • Do not use 24 hours before or after cytotoxic  agents.   • Occurrence of anaemia is a sign of an underlying  condition which should be assessed.    should be advised to take preparation before  food to increase absorption.   • Use of erythropoietins and recombinant human  granulocyte colony-stimulating factors require  patient monitoring.   • Erythropoietins may be used to shorten the  period of symptomatic anaemia in patients  receiving cytotoxic chemotherapy but should not  be used in patients with anaemia associated with  cancer since data indicate that there is a risk of  increased mortality and tumour progression.   1 Name two factors that could lead to iron-  deficiency anaemia.   2 Describe side-effects that could occur with  administration of filgrastim and outline patient  monitoring required.   2 Side-effects include gastrointestinal  disturbances, headache, asthenia, fever,  musculoskeletal and bone pain, rash, alopecia  and leukocytosis. Patient monitoring: full blood  count, body temperature, blood pressure and  pulse rate.   Ardevol M, Fontsere N, Casals M, Bonal J, Garcia L,  Gabas J et al. (2006). A feasibility cost-analysis study of  recombinant human erythropoietin and darbepoetin  alfa in ambulatory haemodialysis patients during  current clinical practice. Eur J Hosp Pharm Sci 12:  47-51.   Macdougall I C (2006). The treatment of anaemia in renal  disease. Eur J Hosp Pharm Pract 12: 46-48.   Mughal T I (2006). The use of erythropoietin in cancer  patients. Hosp Pharm Eur March/ April: 52-53.   • To characterise presentation of rheumatoid arthritis • To develop skills required to ensure patient safety   • To appreciate the use of disease-modifying  antirheumatic drugs and biologic agents in the  management of rheumatoid arthritis   Rheumatoid arthritis is a chronic systemic inflamma-  tory disease characterised by joint involvement as  well as extra-articular manifestations. Chronic  inflammation of synovial tissue lining of joints  (pannus) causes proliferation and erodes the bone  surface and cartilage.   The extra-articular features of rheumatoid arthritis  are listed in Table 44.1.   • Two per cent of males and 5% of females over  the age of 55 years have rheumatoid arthritis   • Age of onset reaches its peak in the fourth decade.   • Haematologic tests: anaemia, thrombocytosis,  increased erythrocyte sedimentation rate (ESR),  increased C-reactive protein, rheumatoid factor  positive.   • Arthritis of three or more joint areas (e.g. wrists,  elbows, shoulders, knees)   DMARDs are used to interfere with the progression  of the disease. A full therapeutic response may not be  obtained before 2-6 months of therapy. Hence, drug  therapy changes should not be undertaken within a  few weeks of initiation of therapy.    The DMARDS used to treat rheumatoid arthritis  are summarised in Table 44.2.    Since joint destruction develops  within the first 2 years of  disease early treatment with  disease-modifying anti-rheumatic  drugs (DMARDs) is recommended   Combination therapy with  different DMARDs and consideration  of the use of biologic agents    In rheumatoid arthritis, patients may present  with chronic joint pain and inflammation.  This may lead to decreased activity which can  result in loss in range of motion, atrophy and  weakness of affected limb or joint. Non-  pharmacotherapeutic recommendations such  as appropriate physical therapy and the use of  prosthetic devices may help to maintain  mobility.    Sulfasalazine and methotrexate are usually  the preferred first-line DMARDs because they  are better tolerated than penicillamine and  gold. A combination of two or more  DMARDs may be considered in patients  where monotherapy is not leading to the  therapeutic objective.   Initially 500 mg once daily  increasing to 1 g three times daily   If stable for 1 year every 6 months,  renal function tests and electrolytes  every 6 months   4 weeks after last dose increase,  thereafter every 6 months; renal  function tests and electrolytes every   10 mg IM test dose then 50 mg  weekly until signs of remission and  then reduce to monthly dose   FBC, urinalysis prior to each dose  since it may cause proteinuria,  annually chest X-ray   Initially 400 mg in divided doses,  maintenance of 200-400 mg daily   Every 1 5 days for 2-3 months: FBC,  U&Es, LFTs and then 1-2 monthly    BP, blood pressure; FBC, full blood count; LFTs, liver function tests; U&Es, urea and electrolytes.    Single weekly oral dose is the most common  dosage regimen. May be administered  subcutaneously or intramuscularly  Avoid alcohol intake to reduce risk of hepatic  fibrosis and liver toxicity   Nausea and stomatitis can be managed by  addition of folic acid dose once every week, a day  after the administration of the methotrexate dose  Patient education on dosage regimen and  symptoms to be reported to health professionals  is required. Patients should be advised to seek  advice if dyspnoea or cough (symptoms of  pulmonary toxicity), if easy bruising or bleeding  (symptoms of thrombocytopenia), if sore throat  or fever (symptoms of neutrophilia) develop. The    rationale for using methotrexate, which patients  may associate with the treatment of cancer, needs  to be explained since otherwise patients may be  hesitant to take the drug as it is an anticancer  agent   • Patients should not take aspirin or other NSAIDs  on same day of administration of methotrexate,  since concomitant administration reduces  methotrexate elimination from the body, leading  to increased toxicity   • As effective as methotrexate and sulfasalazine,  and may present better quality of life to patients    who cannot achieve stabilisation in their  condition with these two agents   • Presented as oral therapy but is more expensive  than methotrexate and sulfasalazine   • Side-effects: gastrointestinal disturbances,  headache, hypertension, alopecia, rash, bone  marrow toxicity, rarely potentially life-  threatening hepatoxicity, increased risk of  malignancy   • Patient monitoring: liver function tests, full blood  count, blood pressure, monitor for signs of  thrombocytopenia (easy bruising, bleeding) and  neutropenia (sore throat, fever)   • Leflunomide has an active metabolite that has a  long half-life and therefore this has to be taken  into consideration with the occurrence of adverse  effects, stopping the treatment, and when  switching to other DMARDs   • Teratogenic: in patients planning to conceive,  leflunomide treatment has to be withdrawn for 2  years in women and 3 months in males before  conception.   • These products are more expensive than other  DMARDs. They are used in patients resistant to  conventional DMARDs.    In rheumatoid arthritis, patients are reviewed  periodically and adjustments to drug therapy  are required according to clinical presenta-  tion. Effectiveness of the conventional  DMARDs may diminish as the disease  progresses or due to unacceptability of the  treatment regimen. Patient monitoring relies  on identifying occurrence of side-effects,  monitoring clinical parameters that may be  affected by the drug, measuring patient’s  quality of life and discussing specific issues  such as family planning.    • Adalimumab, etanercept and infliximab inhibit  the activity of tumour necrosis factor alpha  (TNFa). TNFa is believed to mediate  inflammation in rheumatoid arthritis.   • They are used in combination with methotrexate  or leflunomide except in patients where  methotrexate is contraindicated or cannot be  tolerated.   • Caution: administration has been associated with  occurrence of infections, including tuberculosis,  septicaemia and hepatitis B reactivation.  Therefore before starting treatment, screen for  infections including tuberculosis (chest X-ray,  tuberculin skin test) and hepatitis B. Before  planning a pregnancy, women should consult  with health professionals when taking these  drugs or immediately after stopping the drugs.   • Side-effects: predisposition to infections, nausea,  abdominal pain, worsening of heart failure,  hypersensitivity reactions, fever, headache,  depression, antibody formation, pruritus,  injection site reaction, blood disorders.   • Patient monitoring: monitor for infections,  symptoms of heart failure and hypersensitivity  reactions.    • Patient monitoring: full blood count should be  done routinely to monitor for neutropenia; assess    occurrence of symptoms suggestive of  neutropenia such as fever, sore throat and  infection.   • Is used in combination with methotrexate but  should not be used in patients receiving TNF  inhibitors   • Similar to the other biologies, it increases  predisposition to infection and may cause blood  dyscrasias   • Side-effects: abdominal pain, diarrhoea,  dyspepsia, nausea, flushing, hypertension, cough,  dizziness, fatigue, headache, infection, rhinitis,  rash.    Patients receiving DMARDs and biologic  agents should be advised to report immedi-  ately signs of bone marrow suppression such  as easy bruising or bleeding (in thrombo-  cytopenia) and sore throat or fever (in neutro-  philia). With biologic agents risk of serious  infections is higher and patients should be  monitored for occurrence of these signs and  educated to contact immediately a health  professional should signs of an infection  develop.    • Corticosteroids in rheumatoid arthritis provide a  rapid anti-inflammatory response in contrast to  the slow response given by DMARDs.   • Side-effects associated with long-term high doses  limit their place in therapy. If long-term therapy  is required, monitor bone mineral density and  consider using calcium supplementation and  prophylactic therapy for osteoporosis (see  Chapter 46).   • Usually oral prednisolone is used for temporary  relief during a flare-up or as a bridge therapy    until DMARD therapy becomes effective and  then the corticosteroid dose is tapered off slowly.   • Administration of oral dose may be carried out  in divided doses rather than as a single dose in  the morning. The advantage of administering  corticosteroids orally as a single morning dose is  that it mimics early morning physiological  secretion of cortisol, reducing  hypothalamic-pituitary-adrenal axis suppression.  On the other hand, in rheumatoid arthritis a  once-daily morning dose may lead to a reduced  anti-inflammatory effect during the night,  resulting in early morning stiffness when the  patient wakes up and is still due for the next  dose.   The use of NSAIDs should be to supplement  DMARDs and maintain the patient as symptom free  as possible. Their use should be reviewed periodically  so as to use them for the shortest time possible (see  also Chapter 31).   • Cyclo-oxygenase-2-selective inhibitors are  indicated for patients who are at high risk of  developing gastroduodenal ulceration or  bleeding. Such patients include the elderly,  patients on concomitant medication which  increases risk such as on SSRIs and patients with  a past medical history of gastroduodenal  ulceration or bleeding.   • They are not to be used for routine management  and should not be used in combination with  low-dose aspirin, which reduces the benefit of  COX-2.   • Pulmonary sensitivity to aspirin involves the  COX-1 enzyme and therefore use of COX-2  inhibitors can be undertaken with caution in  patients who are aspirin sensitive.   • Selective NSAIDs are associated more with  increased risk of thrombotic events, namely    myocardial infarction and stroke, compared with  the non-selective NSAIDs. However, non-  selective NSAIDs may also be associated with  this risk.   • Lipid solubility: more lipid soluble, therefore  greater anti-inflammatory activity, analgesia and  CNS toxicity (e.g. indometacin)   • Prodrug: may be less nephrotoxic (e.g. sulindac)  and produce fewer gastrointestinal side-effects  (e.g. nabumetone).   • To be used with caution in patients with renal  impairment since they may cause acute renal  failure and in patients with cardiac disease or  hepatic impairment since they may cause fluid  retention which will impact negatively on the  cardiac or hepatic disease.   • For selective NSAID cautions: history of heart  failure, left ventricular dysfunction, hypertension,  oedema, patients at risk of heart disease.   • For selective NSAIDs contraindications:  ischaemic heart disease, cerebrovascular disease,  peripheral arterial disease, moderate-to-severe  heart failure.   When NSAID use is started in patients receiving  antihypertensives, the hypotensive effect may be  antagonised. This may be witnessed during blood  pressure monitoring upon introduction of NSAID  therapy.   • It is important to check that the patient is taking  the correct medicine at the correct dose.   • This is particularly relevant for patients on  methotrexate, which is a weekly dose.   • It may be difficult for patients to access medicine  (e.g. problems with managing blister packs due  to impaired manual dexterity).   • Quantitative tools should be used to assess the  effect of condition on patients’ activities and  joint involvement.   • Regular patient monitoring and follow-up are  required and drug therapy should be adjusted  accordingly.   1 Name three side-effects that are associated with  systemic oral use of methotrexate and discuss  pharmaceutical care issues in patients receiving  methotrexate.   1 Side-effects: gastrointestinal (nausea and  vomiting, dyspepsia), bone marrow suppression,  pulmonary fibrosis. Pharmaceutical care issues:  patient education on the inflammatory condition    and on the treatment. Patient should be advised  to report any signs and symptoms of infection  and any symptoms indicating precipitation of  the condition. Patient should be advised on drug  administration since normally dose is taken once  weekly, followed the day after by a dose of folic  acid (to prevent oral mucositis). Patient should  be advised of the importance of attending  scheduled appointments including appointments  for blood tests. Patient monitoring required  includes evaluation of disease management,  identification of drug-related problems and  monitoring of renal and liver function and a  full blood count. For women of child-bearing  age, pregnancy and family planning must be  discussed since treatment review may  be required if patient is planning a pregnancy.   Breedveld F C and Huizinga T W J (2005). Rheumatoid  arthritis: what’s around the corner? Eur J Hosp Pbarm  3: 58-59.   Bayraktar A, Hudson S, Watson A and Fraser S (2000).  Arthritis. Pharm J 264: 57-68.   Doan Q V, Chiou C and Dubois R W (2006). Review of  eight pharmacoeconomic studies of the value of  biologic DMARDs in the management of rheumatoid  arthritis. Eur J Hosp Pharm 12: 555-559.   National Institute for Health and Clinical Excellence  (2009). Rheumatoid arthritis: the management of  rheumatoid arthritis in adults, http://guidance.nice.  org.uk/CG79.   Seed M (2009). Development of disease-modifying treat-  ments for rheumatoid arthritis. Pharm J 2009; 282:  191-192.   • To understand rationale for drug therapy and • To develop skills required to provide patient   identify characteristics of the drugs used in the support in the management of osteoarthritis and   In osteoarthritis there is breakdown of articular carti-  lage that lines the joint surface in weight-bearing  areas. Dense bone formation at the base of cartilage  lesion occurs.   • Avoiding excessive load on the joint involved  through use of walking support devices or  appropriate shoes.   • Paracetamol is now accepted as a first-line  therapy, taken on a regular basis (up to 4 g per  day) or on an as-required basis. It is not  associated with side-effects and is as effective as  NSAIDs for the symptomatic pain relief of  osteoarthritis.    • Compound analgesics: products containing an  opioid analgesic and a non-opioid analgesic.  However, the content of opioids may be at  somewhat subtherapeutic doses. These products  may present with constipation as a side-effect.   • Used to reduce pain and relieve synovitis  associated with acute attacks   • Injection is not carried out more frequently than  every 3 months since repeated injections in the  same joint may lead to joint damage such as  joint capsule calcification and microcrystalline  deposits of corticosteroid in the synovial fluid   • Dose differs according to joint (e.g. dose for  administration of methylprednisolone acetate to  the knee is 20-80 mg).   • When used chronically they result in  improvement in pain and function in patients  with osteoarthritis. Further studies are required  to understand mechanism of action.   • For glucosamine it should be used with caution  in patients with impaired glucose tolerance and  in patients with a predisposition to  cardiovascular disease.   • Hypercholesterolaemia may occur as a side-  effect. Common side-effects include nausea,  abdominal pain, indigestion, diarrhoea,  constipation, headache and fatigue.   • Hyaluronan naturally occurs in synovial fluid  and is intended to create a viscous medium  which will cushion joints and maintain normal  function of the joint    analgesics and corticosteroids has failed and in  those patients who cannot undergo surgical  interventions   In cases where there is joint deterioration, surgery  may be considered. Examples include hip and knee  replacement.   • Surgical procedure in which the diseased parts of  the hip are removed and replaced with an  artificial joint (prosthesis)   • Full recovery after surgery can take between  3 and 6 months   • Pharmacist intervention: use of heparin to  prevent thrombosis, pain management,  prevention of infection (see also Chapters 24, 31  and 34).   • Topical agents: application of products  containing methylsalicylate or capsaicin may be  considered as an adjuvant treatment to simple  analgesia   Gout is an abnormality in either the production  (associated with neoplastic diseases such as multiple  myeloma, leukaemias, lymphomas, Hodgkin’s  disease and myeloproliferative conditions such as    Weight reduction, exercises, glucosamine supplements,  paracetamol + NSAIDs in acute attack, topical NSAIDs    Figure 45.1 Management of osteoarthritis. ESR, erythrocyte sedimentation rate; NSAIDs, non-steroidal anti-inflammatory  drugs.   • Swelling and inflammation of a single joint  which usually involves the first  metatarsophalangeal joint, when it is referred to  as podagra. Recurrent attacks may be  polyarticular   • Occurrence of attacks may be associated with  increased episodes of physical exercise.    • May be precipitated by drugs such as diuretics  (bumetanide, furosemide, thiazides), ciclosporin,  ACE inhibitors (lisinopril, ramipril) and  cytotoxic chemotherapy (carboplatin, cisplatin,  cyclophosphamide, daunorubicin, vinblastine,  vincristine).    Patients presenting with an acute attack of  gout should have their blood pressure  measured and renal function assessed since  hypertension and impaired renal function are  common in patients with gout.   • Acute attack: high doses of NSAIDs (e.g.  diclofenac, naproxen, indometacin),  colchicine   • Affects mostly middle-aged men. If it occurs in  premenopausal women or in men younger than  30 years of age, further investigations are  required to evaluate underlying pathology.    “'Drugs used for long-term control may precipitate an  acute attack when they are introduced. They should  not be used to manage an acute attack, they should  be started within 2-3 weeks from an acute attack and  they are usually given in combination with NSAIDs  or colchicine for the first few weeks.   • Used in acute attacks of gout and in the short  term in the initial stages of prophylaxis with  allopurinol or uricosuric agents   • Its disadvantage is the occurrence of side-effects  particularly at high doses. Common side-effects  include nausea, vomiting and abdominal pain.  Other side-effects are profuse diarrhoea,  gastrointestinal haemorrhage, rash, renal and  hepatic damage. Rarely peripheral neuritis,  myopathy, alopecia, inhibition of  spermatogenesis and blood disorders may  occur   • It is preferred to NSAIDs in acute attacks in  patients where NSAIDs are contraindicated, in  patients who cannot tolerate NSAIDs, in patients  with heart failure and in patients receiving  anticoagulants.   • Inhibits synthesis of uric acid by competitively  inhibiting xanthine oxidase, which is the enzyme  catalysing the hypoxanthine-xanthine-uric acid  reaction   • Effect is dose related. It is started in a low dose  and dose increased according to required  outcome   • Side-effects: generally well tolerated with  gastrointestinal disturbances being the common  side-effects. However, occurrence of skin rashes  requires monitoring since treatment should be  withdrawn if recurrent and if it is due to a  hypersensitivity reaction.    Probenecid and sulfinpyrazone are uricosuric  drugs and they reduce serum urate concentra-  tion by increasing renal excretion of uric acid.   • Low doses used in initial stages of treatment to  avoid development of kidney stones. Patient  should be advised to maintain good fluid  intake   • Side-effects: gastrointestinal disturbances, urinary  frequency, headache, flushing, dizziness, alopecia,  anaemia, haemolytic anaemia, sore gums,  hypersensitivity reactions, rarely nephritic  syndrome, hepatic necrosis, leukopenia and  aplastic anaemia   • Since it may cause salt and water retention, it  should be used with caution in patients with  cardiovascular disease   • Side-effects: gastrointestinal disturbances, allergic  skin reactions, salt and water retention; rarely:  blood disorders, gastrointestinal ulceration and  bleeding, acute renal failure, raised liver enzymes,  jaundice and hepatitis   • In osteoarthritis, the use of paracetamol is  preferred to compound analgesics and NSAIDs  for long-term pain relief.   • Intra-articular corticosteroids reduce the pain  and inflammation in the joint affected with  osteoarthritis and need to be administered every  few months.   • When pain and joint deterioration is  considerable, surgery for joint replacement  should be considered in patients who are eligible  for the intervention (e.g. can undertake  anaesthesia, have no other complications).   • Patients receiving treatment for acute attacks of  gout or treatment for long-term control of gout  should be advised about the importance of  ensuring adequate fluid intake.   • Patients should be advised to avoid alcohol and  red meat.   1 Describe the clinical presentation of an acute  attack of gout.   2 When is allopurinol indicated in gout and what  advice should be given to patients receiving  allopurinol?   1 Acute onset of symptoms with a painful swelling  and inflammation of joints, characteristically the  metatarsophalangeal joint.   2 Allopurinol is used in the long-term  management of gout and should not be used    during the acute attack. Patients receiving  allopurinol should be advised to take product  with or after food with plenty of water.   Waddell D D and Bricker D C (2007). Total knee replace-  ment delayed with Hylan G-F 20 use in patients with  grade IV osteoarthritis. J Manag Care Pbarm 13:  113-121.   Bernard Coleiro, Consultant Physician and Rheumatologist,  Department of Medicine, Mater Dei Hospital, Malta.   • To appreciate lifestyle measures that are required in • To review background and drug therapy relevant to   • To develop skills required to counsel patients and  monitor patients receiving drugs for prophylaxis  and treatment of osteoporosis   • act as depot for calcium, phosphorus,  magnesium, sodium and carbonate.   • Cortical (compact): mid-shafts and outer  surfaces of long bones and on surface of flat  bones   • Trabecular (cancellous): inner aspect of  metaphyses of the long bones.   • Parathyroid hormone: increases calcium levels in  circulation by mobilising calcium from bone,    increases absorption of calcium from intestine  and reduces loss of calcium from kidney   • Vitamin D: metabolised to the active dihydroxy  form which increases absorption of calcium and  phosphate   • Osteopenia: significant decrease in bone mass  relative to normal values adjusted for race, age,  sex   • Osteomalacia: deficient mineralisation of bone  leading to an accumulation of unmineralised  osteoid   • Osteoporosis: progressive systemic skeletal  disease characterised by low bone mass and  micro-architectural deterioration of bone tissue,  with a consequent increase in bone fragility and  susceptibility to fracture, which typically involves  the wrist, spine or hip.    skeletal weakness and subsequent fracture. A major  complication is hip fracture. Preventive strategies are  important from an early age: regular exercise (e.g.  walking), smoking cessation and calcium supplemen-  tation.   Education on the importance of preventing  occurrence of osteoporosis particularly in  patients with osteopenia should be under-  taken, since if osteoporosis occurs this is a  progressive disease where the risk of fractures  increases. If fractures occur, in a large number  of cases they will lead to a degree of immo-  bility and sometimes may be associated with  the development of complications.   • Female sex: decline in oestrogen in the  postmenopausal phase is associated with  accelerated bone loss   • Disease: chronic liver disease, chronic  renal failure, hyperthyroidism, primary  hyperparathyroidism, Cushing’s  syndrome, gastrointestinal resection or  malabsorption.    In patients taking high doses of cortico-  steroids for long-term use, prophylaxis of  osteoporosis should be considered. This  could be undertaken using bisphosphonates,  calcitriol or hormone replacement therapy in  premenopausal women.   Diagnosis is based on bone densitometry measured at  the hip or spine using dual-energy X-ray absorptiom-  etry (DXA). The result compares a patient’s bone  mineral density (BMD) with that of a healthy young  adult, T score and takes into consideration previous  history of fracture. Interpretation of bone density  results is shown in Table 46.1.   Clinical features may indicate occurrence of  osteoporosis (e.g. loss of height).   • To alleviate fracture-related morbidity and  decrease risk of further fractures   Risk of fractures increases in patients who  have a history of fractures, with an alcohol  intake of 4 or more units per day, in patients  with rheumatoid arthritis and in patients on  long-term oral corticosteroids.   • The treatment plan for patients with  osteoporosis should also address  modifiable risk factors, namely muscle  weakness (increase exercise), abnormality  of gait or balance, poor eyesight (prevent  falls).   • Avoid drug therapy or limit use of drugs  that may increase risks (e.g. drugs that  induce sedation such as benzodiazepines,  hypnotics, diuretics, antidepressants).   • Ensure management of diseases that affect  mobility (e.g. arthritis and neurological  diseases such as stroke, Parkinson’s  disease).   Drug that has a dual action: preventing bone  loss and promoting bone formation   Patients receiving prophylactic therapy or  treatment for osteoporosis should be advised  to maintain an adequate intake of calcium  and vitamin D and to adopt prevention strate-  gies namely decrease smoking and undertake  regular non-impact exercise.   • Calcium absorption is influenced by level of  vitamin D which is necessary for absorption and  uptake into bone   • To be taken over several years to provide  prophylactic therapy   • Evidence of reduction in fracture rate in patients  with osteoporosis is limited.   These are analogues of pyrophosphate that have a  strong affinity for calcium phosphate. They decrease  osteoclast activity by preventing binding of osteoclasts  to bone resorption sites, thus decreasing resorption  rate.   • Released slowly from the skeleton and therefore  have a prolonged action.   • Studies report significant reductions in vertebral  and non-vertebral fracture rate in  postmenopausal women with osteoporosis after  1 year of treatment.   • Some (e.g. disodium pamidronate) are also used  in hypercalcaemia in malignancy and in bone  metastases in breast cancer.   • Contraindications: abnormalities of oesophagus,  hypocalcaemia, pregnancy, breast-feeding,  patients who cannot sit upright for 30 minutes  after ingesting the drug.   • Cautions: upper gastrointestinal disorders,  history of active gastrointestinal ulceration, renal  impairment, hypocalcaemia, vitamin D  deficiency, risk factors for osteonecrosis of the  jaw: cancer, chemotherapy treatment,  corticosteroid therapy, poor oral hygiene.    • Side-effects: oesophageal reactions, abdominal  pain, dyspepsia, regurgitation, melaena,  diarrhoea or constipation, flatulence,  musculoskeletal pain, headache, osteonecrosis of  the jaw especially with intravenous  administration.   • Counselling: swallow whole with plenty of water  in sitting or upright position and remain upright  for at least 30 minutes, to be taken on an empty  stomach 30 minutes before food, to maintain  oral hygiene.   • For oral administration: alendronate 70 mg once  weekly, alendronate in combination with  calcitriol (bisphosphonates do not work  optimally if there is vitamin D deficiency),  ibandronic acid 150 mg once a month,  risedronate 35 mg once weekly, tiludronic acid  400 mg daily for 12 weeks which may be  repeated after 6 months.   • Zoledronic acid 5 mg may be administered  intavenously once a year.    Some patients may be intolerant to oral  administration of bisphosphonates due to  the persistent occurrence of severe gastro-  intestinal disturbances that occur despite  patients following drug administration  instructions. In these patients other drugs such  as strontium ranelate could be considered.   • Side-effect: diarrhoea especially with initial  treatment, venous thromboembolism, headache,  dermatitis, eczema. Very rarely severe allergic  reactions presenting with drug rash, eosinophilia  and systemic symptoms (DRESS) which can be  fatal have been reported   • Available: granules in sachets and is relatively  well tolerated by patients    Avoid food intake 2 hours before and after  administration. Avoid concomitant  administration of calcium-, aluminium- or  magnesium-containing tablets. Stop medication  and consult a health professional if skin rash  develops.   This is a selective oestrogen receptor modulator  (SERM) and is preferred in the prophylaxis of osteo-  porosis when other menopausal symptoms, namely  vasomotor symptoms or genitourinary symptoms,  are predominant.   • Has an agonist effect on oestrogen receptors in  blood vessels and bone and an antagonist effect  on receptors in breast and uterus   • Contraindications: history of venous  thromboembolism, undiagnosed uterine bleeding,  endometrial carcinoma   • Cautions: venous thromboembolism, breast  cancer, history of oestrogen-induced hypertrigly-  ceridaemia   • Side-effects: venous thromboembolism, hot  flushes, leg cramps, peripheral oedema,  influenza-like symptoms.   This is a naturally occurring peptide hormone  produced by the parathyroid gland which decreases  osteoclastic activity. Since it is a polypeptide it cannot  be given orally. Route of administration is by injec-  tion or as a nasal spray. It has analgesic properties  and may be used in acute pain in collapsed vertebrae.  It is less effective than bisphosphonates in the  prophylaxis of osteoporosis. It is used in Paget’s  disease and in the treatment of hypercalcaemia  associated with malignancy.   • Patient monitoring: serum calcium level, renal  and liver function tests   • Side-effects: nausea, vomiting, diarrhoea,  abdominal pain, flushing, dizziness, headache,  taste disturbances, musculoskeletal pain.   This causes a decrease in bone resorption, an increase  in calcitriol concentration and an increase in calcium  absorption. It should be used when other options are  contraindicated, cannot be tolerated or when there is  lack of response (see also Chapter 39).   Treatment with bisphosphonates, strontium,  calcitonin and raloxifene is long term and  pharmacists should ensure that patient under-  stands the correct dosage regimen (particu-  larly relevant for bisphosphonates which are  not taken on a daily basis) and that patient is  taking the drug regularly and not attempting  to use it for symptomatic relief.   This is a recombinant fragment of the human  parathyroid hormone that promotes bone growth. It  is available as a subcutaneous injection administered  daily for 1 8 months for the treatment of osteoporosis  and corticosteroid-induced osteoporosis.   • Contraindications: hypercalcaemia, Paget’s  disease, previous radiation therapy to the  skeleton, skeletal malignancies or bone  metastases, unexplained raised alkaline  phosphatase, pregnancy and breast-feeding   • Side-effects: gastrointestinal disorders: nausea,  reflux, haemorrhoids, postural hypotension,  dyspnoea, depression, dizziness, vertigo, urinary  tract disorders, polyuria, muscle cramps,  irritation at injection site.   Since it is an amino acid peptide, parathyroid hormone  cannot be administered orally. Human recombinant  parathyroid hormone is available for subcutaneous  administration. It requires daily administration and  is also available as a pen device to facilitate self-  administration.    • Recommended duration of treatment not to  exceed 24 months; may be administered  intermittently   • Contraindications: hypercalcaemia, metabolic  disease including hyperparathyroidism and  Paget’s disease, previous radiation therapy to the  skeleton, unexplained raised alkaline  phosphatase, severe hepatic impairment,  pregnancy and breast-feeding   • Side-effects: nausea, vomiting, dyspepsia,  constipation, diarrhoea, palpitation, headache,  dizziness, fatigue, asthenia, transient hyper-  calcaemia, hypercalciuria, muscle cramp, pain in  extremities, back pain, injection site reactions.   After patients have taken maximum therapy  with teriparatide or parathyroid hormone,  long-term bisphosphonate therapy may be  considered.   This increases bone formation in cancellous bone  rather than cortical bone. It requires calcium supple-  mentation. However, concomitant administration of  fluoride with calcium may adversely affect fluoride   • In premenopausal women: HRT (discuss  risk - benefit profile with patient)   Calcium and vitamin D supplementation to  be considered in all scenarios    absorption. To date there is limited clinical experi-  ence with fluoride.   • Lifestyle changes are essential for the prophylaxis  and management of osteoporosis.   • Adequate daily calcium supplementation should  be ensured for all adults, particularly women.   • Weight-bearing exercises such as climbing stairs  and brisk walking help in the prevention and  deterioration of the condition.   • Fall and injuries prevention requires attention as  much as ensuring patient adherence to drug  therapy for the management of osteoporosis.  Strategies to make the home safer (e.g. removing  rugs, improving lighting, putting up bathroom  handles) as well as ensuring that patient  undertakes regular eye tests and wears foam  shields should be considered.    3 Describe monitoring requirements and lifestyle  changes to be suggested in the management of  osteoporosis.   1 Teriparatide is used in patients with severe  osteoporosis or patients who did not respond  to other drug therapy. The advantage of  teriparatide over bisphosphonates is that it  promotes bone growth. The disadvantages  are that it is available for parenteral  administration and treatment is comparatively  more expensive.   2 Side-effects include gastrointestinal (nausea,  gastro-oesophageal reflux), palpitations,  dyspnoea and headache.   3 Monitoring: bone density. Lifestyle  modifications: increase calcium intake, take up  exercise and prevent falls and injuries at home  (e.g. remove carpets, ensure availability of  handrails).   Cadarette S M, Katz J N, Brookhart A, Sturmer T, Stedman  M R and Solomon D H (2008). Relative effectiveness of  osteoporosis drugs for preventing nonvertebral fracture.  Ann Intern Med 148: 537-646.   Jarvinen T L, Sievanen H, Khan K M, Heinonen A and  Kannus P (2008). Shifting the focus in fracture preven-  tion from osteoporosis to falls. BMJ 336: 124-126.   Mulder J E, Kolatkar N S and LeBoff M S (2006). Drug  insight: existing and emerging therapies for osteo-  porosis. Nat Clin Pract Endocrinol Metab 2: 670-680.   National Institute for Health and Clinical Excellence  (2008). Technology appraisal guidance: Alendronate,  etidronate, risedronate, raloxifene and strontium  ranelate for the primary prevention of osteoporotic  fragility fractures in postmenopausal women.  http://www.nice.org.uk/Guidance/TA160.   1 When should teriparatide be used in  osteoporosis? What are the advantages of  teriparatide over bisphosphonates? What are  the disadvantages of teriparatide?   2 Mention four side-effects that could be expected  due to teriparatide.   • To consider different dosage forms for topical  application in the management of skin conditions   • To identify use of medications for the treatment  and management of particular conditions.   • Greasy preparations that are normally anhydrous  and insoluble in water   • Less greasy and less occlusive than ointments,  more cosmetically acceptable   • Less effective at hydrating stratum corneum, less  preferred when condition presents as very dry.   • May cause hypersensitivity and photosensitivity  The following factors should be considered when reactions,  choosing a product to use:   • Duration of effect is short and should be applied  frequently   • Considerations: ease of application and  appearance, smell, duration of effect, effect on  clothing, ease of removal.   • Causes dryness of area of application and this  may be a disadvantage if skin is dry   • Forms a thick dried paste that may not be  acceptable to patients.   Steroids consist of four fused rings of which one is a  five-membered cyclopentane ring. Glucocorticoid  activity is increased by the addition of a halogen atom  on carbon-9 and this is seen in the higher potency for  betamethasone (Figure 47.1), clobetasol (Figure 47.2),  dexamethasone, diflucortolone, triamcinolone (fluo-  rine) and beclometasone (chlorine) compared with  hydrocortisone (Figure 47.3). Products that contain a  second halogen atom, such as difluorinated products  (difluocortolone, fluorine on carbon-6) and the addi-  tion of chlorine atom as a 21-chloro group (clo-  betasol), result in increased topical glucocorticoid  activity compared with the other halogenated  compounds.    • The use of topical corticosteroids should  be limited as much as possible to avoid  occurrence of unwanted effects.   • The least potent corticosteroid that is  effective in controlling the symptoms  should be used for the shortest possible  period.   • Apply thinly to affected area using least potent  formulation; usually once to twice daily  application is recommended   • May be applied as combination products with  antifungals or antibacterial agents   • Avoid occlusion with dressings and plastic  nappies (the latter increase systemic  absorption)   This is an infection caused by Staphylococcus aureus  or Streptococcus pyogenes.   • Development of a sore, clusters or small vesicles  or pustules with a honey-yellow crust   • Clinical presentation: dry, itchy and flaky scalp;  very much limited to scalp.   • Pyrithione zinc: safe for children; to be used daily  until condition clears   • Selenium: not suitable for children under 5 years  of age. Avoid if broken or inflamed skin since  irritation may occur. Apply twice weekly for 2  weeks, then once weekly for 2 weeks and then as  necessary   • Ketoconazole shampoo: acute treatment - twice  weekly for 2-4 weeks. Prophylaxis - once every  1-2 weeks. Suitable for use in children.    Dandruff presents with flaky and itchy scalp.  However, usually there are no other skin  lesions and no redness in the area as may be  expected with other skin conditions such as  seborrhoeic dermatitis.   • Management: antifungal agents (e.g.  ketoconazole shampoo), use of almond oil or  olive oil to remove scales, particularly in young  children, and topical corticosteroids may be  considered for a short time due to the  inflammatory reaction.   • Identification of allergen to avoid re-occurrence.  Examples of allergens include detergents,  cosmetic preparations, jewellery, rubber gloves.   • May cause skin atrophy, acne-form  pustules, spreading of infection, contact  dermatitis, striae, mild depigmentation   • Creams indicated for moist lesions,  ointments preferred for dry scaly lesions.   This is a red, dry, scaly rash spreading to the flexures  in the neck, wrist, elbows and knees. Scratching due  to irritation and itchiness may lead to secondary  bacterial infection such as impetigo.   • Management: emollients to address dry skin,  topical corticosteroids to reduce inflammation  and calcineurin inhibitors.   • Calcineurin inhibitors (e.g. tacrolimus and  pimecrolimus) result in inhibition of  transcription of inflammatory genes   • Used for atopic eczema which is uncontrolled by  maximal topical treatment or if there is  intolerance to topical corticosteroids   • Side-effects: application site reactions (burning  sensations, rash); less common: herpes simplex  virus, skin malignancy.   • Emollients hydrate the skin and form an  occlusive barrier to prevent evaporation  of moisture   This condition is caused by the mite Sarcoptes  scabiei, which is transmitted by physical contact. The  female mite burrows in the stratum corneum and  deposits eggs, while the faecal pellets left in the  burrow cause a local hypersensitivity reaction.   • Occurrence generally limited to finger webs, sides  of fingers and wrists   • Caution: avoid contact with eyes, mouth; do not  use on broken skin.   Pruritus occurring with scabies may persist  for several weeks after the infestation has  been eliminated. Consider use of topical corti-  costeroids or oral antihistamines.   • Scalp hair transforms into vellus-like hair  follicles which are shorter due to preferential   • Causes hair loss at the front of the head in men  and in women causes generalised and diffuse hair  loss   • Minoxidil, a topical scalp solution, delays and  slows hair loss. Baldness returns upon  discontinuation of treatment, tailing off of effect  occurs and it is effective in a minority of  individuals. Applied twice daily.   • Finasteride is an anti-androgen that can be  used in men. Oral tablets are given for 3-6  months before evaluation of outcomes  can be carried out. Effects are reversed  6-12 months after treatment withdrawal (see  also Chapter 41).   This is a disorder of the sebaceous follicle that has  significant psychological impact on the patient.  During puberty, increased androgen levels in both  males and females stimulate enlargement of the seba-  ceous follicle resulting in enormous increase in sebum  production, leading to seborrhoea and the occur-  rence of greasy skin.   • Follicular hyperkeratosis may occur, resulting in  the characteristic comedo (blackhead) formation   • Excessive proliferation of the commensal  bacterium Propionibacterium acnes is associated  with occurrence of acne.   This is a potent bactericidal that acts against P.  acnes. It is effective in mild-to-moderate acne. Local  skin irritation, bleaching of hair and clothing may  occur. Start with a low dose and increase strength  gradually.   This may be preferred to benzoyl peroxide since it is  less likely to cause irritation than benzoyl peroxide.   Erythromycin, clindamycin and tetracycline are used.  Generally well tolerated, may cause irritation. Bacter-  ial resistance may be reduced by using benzoyl  peroxide concomitantly.   • Main side-effects: redness and skin peeling which  occurs to a lower extent with adapalene   • Erythromycin: increasing levels of P. acnes  resistance among acne patients limits its clinical  use   • Combined oral contraceptives: in androgen-  induced seborrhoea, oestrogens inhibit sebaceous  gland activity.    When combined oral contraceptives are  used, a preparation where the progestogen  component is either drospirenone, which is  anti-androgenic, or a low-dose progestogen  (progestogens have an androgenic effect)  should be chosen.   • Occurrence of side-effects: facial dermatitis,  epistaxis, conjunctivitis, dryness of mucous  membranes, psychiatric symptoms   • Teratogenicity: care with women patients;  pregnancy testing and contraception advice have  to be provided.   Clinical severity assessment using health-  related tools such as the American Academy  of Dermatology (AAD) classification and the  Acne Disability Index may be undertaken to  evaluate patient outcomes.   This is a genetically influenced chronic skin  disorder that is characterised by a hyperprolifera-  tive condition. It presents with well-demarcated red  plaques covered with a silvery-white scale, typically  affecting elbows, knees, scalp (scalp psoriasis) and  sacrum. It is a chronic relapsing condition that may  impact on patient’s social life and psychological  well-being.   • Drugs (e.g. lithium, antimalarials, beta-blockers,  NSAIDs, ACE inhibitors, withdrawal of  corticosteroids).   • Emollients: improve dryness, scaling and  cracking, useful in inflammatory psoriasis, used  as adjunct treatment   • Topical corticosteroids: used for specific sites to  counteract inflammatory reactions and for the  shortest time period possible   • Coal tar: has anti-inflammatory and anti-scaling  properties, useful in chronic plaque psoriasis.  Available also as shampoos and liquid bath  formulations. Disadvantage: smelly and may  stain clothing and skin, patient acceptability low   • Salicylic acid: used for its keratolytic properties.  Particularly used for psoriasis affecting the  scalp   • Dithranol: used in short term since it is  associated with skin irritation. To be applied on  chronic extensor plaques avoiding small lesions,  flexures or the face. Patients should be advised  about irritation and possibility of staining of skin  and clothing.   • Trunks and limbs: emollients, vitamin D  analogues, coal tar, topical corticosteroid   • Scalp: coal tar shampoo, corticosteroid lotion,  coal tar-salicylic acid-coconut oil ointment.   Patients using tar-based products, dithranol,  vitamin D analogues and tazarotene should  be advised about the risk of skin irritation  and to apply product specifically to the  affected areas as advised.   • Choice of dosage form of products used in the  management of the skin conditions may depend  on vehicles included in the preparation.   • Emollients soothe and hydrate the skin and can  be applied freely in any condition that is  associated with a dry and scaling presentation.   • Barrier preparations are used to prevent skin  deterioration due to increased moisture in the area.   • The use of calamine preparations and topical  antihistamines as antipruritics is limited due to  ineffectiveness and sensitisation for topical  antihistamines.   • Topical corticosteroids are used to relieve  symptoms of inflammation associated with acute  conditions (e.g. insect bites) or with chronic  conditions (e.g. eczema).   • In chronic skin disorders patient participation in  the use of medications and dose adjustments (e.g.  of topical corticosteroids) during flare-ups is  necessary.   1 What are the distinguishing characteristics of  absorption and fatty bases?   3 Compare the use of clobetasol and tacrolimus in  atopic eczema.   1 Fatty bases are very greasy and form an  occlusive layer on the skin. Absorption bases  absorb water and encourage hydration, spread  easily and are less occlusive than fatty bases.   • delays and slows hair loss, baldness returns  upon discontinuation of treatment, tailing  off of effect occurs   • given once daily for 3-6 months before  evaluation of treatment outcomes can be  carried out.   3 Clobetasol is a very potent topical corticosteroid  indicated for relief of symptoms in the acute  phase of atopic eczema. It may cause skin  atrophy, acne-form pustules, spreading of  infection, contact dermatitis, striae and mild  depigmentation. Topical corticosteroid creams  are indicated for moist lesions while ointments  are preferred for dry scaly lesions. It should be  applied thinly once or twice times daily for up  to 4 weeks. Tacrolimus is licensed for topical    use in moderate-to-severe atopic eczema. It is a  calcineurin inhibitor that inhibits transcription  of inflammatory genes (affects the immune  system). Tacrolimus is used for atopic eczema  which is uncontrolled by maximal topical  treatment or if there is intolerance to topical  steroids. In contrast to corticosteroids,  calcineurin inhibitors are not indicated for first-  line treatment. Treatment should be short term;  continuous long-term treatment should be  avoided. Side-effects include application site  reactions (burning sensation, rash) and less  commonly herpes simplex virus and skin  malignancy.   4 Permethrin is effective for the treatment of  scabies; malathion can be used if permethrin is  inappropriate. Aqueous preparations are  preferable to alcoholic lotions, which are not  recommended owing to skin irritation. Avoid  contact with eyes and mouth and do not use  formulations on broken skin. Pruritus occurring  with scabies may persist for several weeks after  the infestation has been eliminated. The use of  topical corticosteroids or oral sedating  antihistamines at night may be considered.   Clark C (2004). How to choose a suitable emollient? Pharm  J 273: 351-352.   Clark C (2007). Scalp problems in the pharmacy. Pharm J  278: 431-434.   Clark C (2009). Acne: causes and clinical features. Clin  Pharm 1: 163-166.   Jerram P (2008). Proprietary emollients: why pump  dispensers can complicate selection. Pharm J 281: 369.   Nathan A (2007). Advising on insect bites and stings.  Pharm J 278: 557-560.   Seaton R A (2009). Skin and soft tissue infection: diagnosis  and management. Clin Pharm 1: 13-19.   • To identify characteristics of wound dressings • To develop skills required in the handling of wound   • Wound: damage to the skin or mucous  membrane which may be caused by elective  trauma or accidental trauma   • Process of healing: replacement of damaged  tissue by new living material.   • Clean or contaminated: e.g. wound occurring  after an injury sustained in the fields or wound  sustained in the bathroom?   • Site of wound: e.g. bed sore occurring in the  sacral area, a wound occurring in the periphery  in a diabetic patient or wound occurring in the  thigh?   • Exudate: dry, necrotic, black or clean exuding  (granulating wound) or dry low exudates  (epithelialising wound)?   • Healing by first intention: healing takes place  from the internal layers outwards   Necrotic tissue presents as yellowish-brown to black  tissue. It is associated with chronic wounds (e.g. pres-  sure sores). The occurrence of necrotic tissue creates  concern since it delays healing and promotes infec-  tion. It may be removed by debridement. Dressings  used should promote rehydration and moisture  retention.   This is accumulation of dead cells in the exudate  from wounds. The exudate is yellowish and is  removed by desloughing. Dressings should promote  fluid and odour absorption if the wound is moist or  moisture retention and rehydration if the wound is  dry.   • Blood supply: compromised blood supply in area  of wound delays healing (e.g. in patients with  diabetes or in patients with peripheral circulation  disorders)   • Nutritional factors: malnourished patients have a  delay in wound healing   • Infection: occurrence of infection interferes with  process of healing and may lead to gangrene and  amputations of extremities   • Hypergranulation: leads to scar formation, some  individuals are prone to develop scars and  keloids   • Incontinence: increases risk of infection and  maceration of the area.   • Dressing: material that covers a wound should  not interfere negatively with the process of  healing   • Bandage: used to keep a dressing in place at the  site of the trauma (conforming-stretch bandage),  to immobilise a dry area or to provide  compression (elasticated tubular or support  bandages, compression bandages, adhesive  bandages)   • Surgical absorbents: e.g. swabs applied to the  wound to adsorb exudates. Care should be taken  since they may shed fibres into the wound or  adhere to the wound surface   • Adhesive tapes: used to keep dressing material in  place. May be of the hypoallergenic type to  decrease risk of skin irritation due to sensitivity  to material.    • Dressings used should not interfere with  the process of healing    • Surgical absorbents are preferred as  secondary dressings to manage heavily  exuding wounds where they are used on  top of the primary dressing. In this way  the risk of shedding fibres or adhering to  the wound surface is eliminated.   The traditional dressings (e.g. cotton wool, gauze,  lint) fail in a number of characteristics expected from  a dressing, including that they require frequent  changing, are not free from particulate contaminants  and are not impermeable to microorganisms.   They are used on clean, dry wounds and as  secondary dressings for absorbent and protective  functions.    There is no dressing that matches all the  criteria required of an ideal dressing. Choice  of dressing should be undertaken for each  individual scenario to identify priority  features required from the dressing.   • May be used as the first layer in contact with the  wound followed by other absorbent secondary  dressings   • May have adhesive border or else require use of  surgical tape to keep dressing in place   • Allow vapour and oxygen to be interchanged  across the dressing (water vapour  permeable)   • Provide a moist healing environment and  may provide a cooling of the wound  surface   • Suitable for mildly exuding wounds, to protect  minor skin damage in patients at risk and for  prophylaxis of pressure sores. Also used as  retention dressings for canulae and in stoma  care   • Disadvantage: excess exudate may accumulate as  a bubble under the film and this may cause skin  maceration; should be avoided in heavily exuding  wounds   • Consist of a large proportion of water (about  70-90% water)   • Non-adherent and usually are amorphous  materials that will take up the shape of the  wound. A secondary dressing to cover the area is  required   • Suitable for dry sloughy or necrotic wounds since  they promote debridement. May be used in  lightly exuding wounds since they absorb small  amounts of exudates   • Contain methylcellulose, pectin and gelatin  presented as a layer on a vapour-permeable film  or foam   - absorb fluid and form a gel which makes it  easy to clear during wound dressing   • Suitable in acute and chronic wounds which are  dry, sloughy or necrotic and light to moderately  exuding wounds   • Used for light-medium-highly exuding wounds  depending on the type of product used   • Reduce hypergranulation tissue and so are  indicated in patients with a tendency to develop  keloids   • The alginate component will gel when it comes  in contact with exudates   • Odour absorbing: contain charcoal that is used  to adsorb odour.   • Impregnated with an antiseptic (e.g.  chlorhexidine) or an antibacterial (e.g. fusidic  acid)    • Effectiveness over the application of the  medication and a separate wound dressing is still  not established.   • Products that do not have an alcoholic base are  preferred because there is a lower risk of  irritation   • Physiological saline is an effective, safe and  inexpensive product. Other products include  chlorhexidine, povidone - iodine and cetrimide.   • It is important that the type of dressing used  does not interfere with wound healing.   • Wound characteristics that influence choice of  dressing include site of wound, whether wound is  clean or infected and degree of exudate.   • Alginate dressings and foam dressings are  preferred in medium-heavy exuding wounds.  Hydrogel and hydrocolloid dressings are effective  in medium exuding wounds.   • The use of irritant antiseptics and cleansers is not  recommended; irrigation with physiological  saline is the usual practice.   3 What are the advantages and disadvantages of  povidone - iodine as an antiseptic?   2 Vapour-permeable adhesive films are suitable  for relatively shallow wounds; can be used  prophylactically to prevent pressure sores and  as retention dressings.   3 Advantages: broad spectrum - active against  most Gram-positive and -negative bacteria as  well as most fungi, protozoa and viruses;  indicated for skin disinfection, vaginal and oral  infections; available in numerous dosage forms  (e.g. solution, dry powder spray, mouthwash).  Disadvantages: may stain skin and clothing;  application of povidone-iodine to large wounds  or severe burns may produce systemic adverse  effects such as metabolic acidosis,  hypernatraemia and impairment of renal  function; regular use should be avoided in  patients with thyroid disorders or those  receiving lithium therapy.   Morgan DA (1999). Wound management products in the  Drug Tariff. Pharm J 263: 820-825.   Ohura T, Sanada H and Mino Y (2004). Clinical activity-  based cost effectiveness of traditional versus modern  wound management in patients with pressure ulcers.  Wounds 16: 157-163.   Parnes A and Lagan KM (2007). Larval therapy in wound  management: a review. Int J Clin Pract 61: 488-493.  Romanelli M, Dini V, Bertone M S and Brilli C (2007).  Measuring wound outcomes. Wounds 19: 294-298.   • To identify problems in the use of medicines in the • To develop skills required in medicines  elderly management in older persons.   Ageing is characterised by an inability to maintain  homeostasis under conditions of physiological stress.  This situation predisposes to health-related prob-  lems. Theories to describe the process of ageing  describe a deterioration of the protein-synthesising  mechanism.   Problems in the elderly that may  interfere with drug therapy and disease  progression    Factors responsible for increased incidence of  adverse drug reactions in the elderly   • Participate in appropriate drug selection:  consider other drugs being taken by patient,  assess pharmacokinetic profile and impact of  unwanted drug effects   • Ensure optimum use of medicines by patient:  provide patient counselling, facilitate drug taking  using medication reminder aids   • From time to time run medication reviews:  examine all medications taken by patient to  identify any duplication, conflicting therapy or  drugs that may be withdrawn or doses that can  be adjusted   • Identify drug-related problems: patient problems  with drug or occurrence of side-effects   When selecting drug therapy for the elderly, prefer-  ence of one drug over another may be based on the  pharmacokinetic profile of the drugs (e.g. lorazepam  is preferred to diazepam because of its shorter half-  life) or pharmacodynamic changes (e.g. calcium  channel blockers preferred to beta-blockers in the  management of hypertension in the elderly due to  decreased responsiveness to beta-blockers).   Age-related changes in upper gastrontestinal function  include altered gastric pH, diminished blood flow  and changes in motility. However, the significance of  these changes on clinical outcomes is minimal.   In older people, there is a decreased cardiac output  which may lead to a decreased hepatic and renal  blood flow. Changes in the body composition occur  leading to a decrease in lean body mass and an  increase in adipose tissues.   These changes will result in a decreased volume  of distribution for drugs that are distributed  primarily in water or lean body mass (e.g. digoxin -  requires lower dose in geriatric patients). The volume  of distribution of drugs that are primarily distributed  in fat may be increased (e.g. diazepam - results in  increased risk of accumulation with repeated use).  There is also a decrease in serum albumin concentra-  tion which may affect degree of protein binding (e.g.  phenytoin).   In older people, the total liver weight and the number  of functioning liver cells are decreased. In addition,  disease states and nutritional status may adversely  affect liver function. This may result in a decrease in  the elimination rate of drugs that are excreted in the  liver (e.g. warfarin, long-acting benzodiazepines).   Renal function decreases with age because there is a  decline in glomerular filtration rate, tubular secretion,  re-absorptive capacity and renal blood flow. Drugs  that are eliminated by the kidney such as aminoglyco-  sides, atenolol, digoxin, enalapril, fluconazole, fluoro-  quinolones, furosemide, lisinopril, methotrexate,  spironolactone and thiazides may have reduced clear-  ance in the elderly. Drugs where this factor may lead  to side-effects and drug-related problems require dose  adjustment (lower doses) in older people.   • Changes in receptor sensitivity (e.g. decreased  responsiveness to agonists and antagonists at  beta-adrenoceptors)   • Increased sensitivity to drug effects (e.g.  anticoagulant effects of warfarin)   • Decline in some pathways: decreased cholinergic  neurons in areas of the brain lead to a higher risk  of drugs with anticholinergic properties (e.g.  benzatropine, trihexyphenidyl, sedating  antihistamines, tricyclic antidepressants,  neuroleptics) inducing mental confusion   • Orthostatic hypotension: may be aggravated by  alpha-adrenergic blocking drugs, diuretics,  nitrates, phenothiazines, tricyclic antidepressants.   The use of drugs in the older patient is summarised  in Table 49.1.   The occurrence of side-effects is higher in  older patients. The reasons include:   • doses used are sometimes too high in  relation to reduced elimination   • doses used are sometimes too high in  relation to decreased physiological  responses (e.g. hypotensive drugs).   Adverse effects occurring in the elderly with  antibacterial treatment are listed in Table 49.2.   Avoid products with long half-life (e.g. piroxicam); increased risk of renal failure and gastrointestinal toxicity; may   Medicines with short half-life preferred to reduce risk of confusion and ataxia   - ability to administer medication: use of self-  injections, swallowing tablets or capsules,  using an inhaler device   • Consider preparing medicines in a pill box  where medicines are prepared according to the  dosage regimen (assess product stability); use a  memory aid to prompt patient to take  medicines; use printed leaflets to explain dosage  regimen.   • Identify literacy problems: ensure that  patient knows clearly how to take  medicines   • Number of prescribed and non-  prescription medications administered:  kept to a minimum   • Identify administration problems:  documentation necessary for patient to  access medications on NHS where  applicable, access to prescription    • Packaging and labelling: patient can  access packaging and label is large, clear  and can be read and understood by  patient   • Occurrence of side-effects and  identification of interactions: check  occurrence of unwanted effects, even  insignificant ones, that are bothering the  patient and interactions   • Social functioning: patient requires social  support and care at home to ensure  adequate nutrition and independent  living.   • Evaluate possibility of drug interacting with  another drug or a medical condition.   Discuss with patient medications used and health-  related issues to identify any drug-related problems.   • Medications Appropriateness Index:  evaluates process of prescribing and  administration of medicines   • Indicators of Preventable Drug Related  Morbidity: evaluates outcome  measurement, quality-of-life outcomes.   • Fall prevention: assessment of fall risks by  identifying risk factors and preparing a risk-  reduction strategy which includes patient support  and home help   • Fall management: in addition to looking into the  physical damage, when falls in older people  occur: pharmacist review of medications,  physiotherapists to support patient in physical  movements, social worker to assess patient needs  at home.   • When starting treatment, use a low dose and  increase slowly, if necessary.   • Keep treatment as simple as possible using the  minimum number of different drugs.   • Ensure that the patient or a responsible person  clearly understands the treatment schedule.   • Avoid childproof containers for those who are  unable to open them.    • Drugs may precipitate a health condition  particularly in elderly patients. When patient  presents with a condition and there is no obvious  reason for that, consider each drug used and  identify any correlation.   1 Why should diazepam be used with caution in  elderly patients?   2 What precautions are necessary when NSAIDs  are used in the elderly?   1 Diazepam has been shown to have an increased  volume of distribution in the elderly due to the  changes in the ratio of adipose tissue to lean  tissue. Also, rate of metabolism is slower  leading to increased risk of side-effects such as  drowsiness and light-headedness the next day,  confusion and ataxia.   2 Elderly patients have an increased risk of  developing gastrointestinal side-effects and renal    toxicity with NSAIDs. NSAIDs also cause fluid  retention and should not be given to patients  suffering from hypertension and/or heart failure.  Therefore in elderly patients products with a  short half-life should be adopted, use enteric-  coated preparations and advise patient to take  drug with or after food. NSAIDs should be  used for the short term.   Armour D and Cairns C (2001). Medicines in the Elderly.  London: Pharmaceutical Press.   Fialova D, Topinkova E, Gambassi G, Finne-Soveri H,  Jonsson P V, Carpenter I et al. (2005). Potentially  inappropriate medication use among elderly home care  patients in Europe. JAMA 293: 1348-1358.   Mansur N, Weiss A and Beloosesky Y (2009). Is there an  association between inappropriate prescription drug  use and adherence in discharged elderly patients? Ann  Pharmacother 43: 177-184.   Zermansky A G, Alldred D P, Petty D R, Raynor D K, Free-  mantle N, Eastaugh J et al. (2006). Clinical medication  review by a pharmacist of elderly people living in care  homes - randomised controlled trial. Age Ageing 35:  586-591.   Zhang M, Holman C D J, Price S D, Sanfilippo F M, Preen  D B and Bulsara M K (2009). Comorbidity and repeat  admission to hospital for adverse drug reactions in  older adults: retrospective cohort study. BMJ 338:  a2752.   • To recognise differences in the handling of drugs by  paediatric patients    • To grasp developments in the regulatory area with  regards to development of medicines for use in  paediatric patients.   A large number of clients at the pharmacy are  mothers of children who present common paediatric  conditions. The pharmacist must be able to distin-  guish between minor ailments and potentially serious  childhood conditions.   The average body weight at birth is 3.5 kg. A baby’s  body weight is monitored during the first year to  assess child’s growth. International agreement on age  range and definition is shown in Table 50.1.   • Meningococcal disease in children is caused by  Neisseria meningitidis serogroups B and C    • Immunisation provides long-term protection  against infection by serogroup C of Neisseria  meningitidis   • Indicated for children: doses given at 3 and 4  months; booster dose at 12 months   • Patients over 1 year up to 25 years: one dose.   • Recommended for childhood immunisation and in  patients at increased risk: elderly patients, diabetic  patients, patients with immune deficiency, chronic   Human papillomavirus vaccine: 3 doses: second dose given 1-2 months after first dose and third dose given 6 months    respiratory disease, cardiovascular disorders, renal  and liver disease, asplenia, splenic dysfunction and  cochlear implant   • Pneumococcal polysaccharide vaccine:  polysaccharide from each of 23 capsular types of  pneumococcus. Dose: single dose; recommended  for children over 5 years and adults   • Pneumococcal polysaccharide conjugate vaccine:  polysaccharide from each of seven capsular types  of pneumococcus (conjugated to diphtheria  toxoid) adsorbed onto aluminium phosphate.  Dose: 2 months, 4 months and 13 months    • There are two types of vaccine available: the  bivalent vaccine and the quadrivalent vaccine.  Since they are not interchangeable, repeated  doses should be carried out with the same type  of vaccine   • Prevents cervical cancer and other pre-cancerous  lesions caused by the human papillomavirus  (HPV) types 16 and 18   • The quadrivalent vaccine is also used for the  prevention of genital warts and pre-cancerous  lesions caused by HPV types 6, 11, 16   • The duration of protection from an entire  course is still not known but at least 6 years’  protection is given. If course is repeated  same dosage regimen has to be    • Since vaccines do not protect against all strains,  women should be advised that routine cervical  screening should still be carried out.   • Characterised by rhythmical bouts of screaming,  each lasting a few minutes, in an otherwise  thriving baby   • If baby is vomiting or crying persists for several  hours: refer   • Change size of bottle teat. Incidence of colic is  increased with the use of a teat with a large hole.  Advise on use of infant formula milks specifically  indicated to reduce colic   • If baby is breast-fed, then breast milk can be  given together with ORSs   • If baby is taking an infant formula milk, infant  formula milk should be stopped and instead a  soy-based formula introduced together with ORSs   • An oral vaccine against rotavirus which causes  gastroenteritis in children is available for  administration to infants over 6 weeks and  before 16-24 weeks. Consists of two doses given  with a 4-week interval.   • Occurs due to inadequate food or fluid intake,  withheld defecation and anal fissures    • Stool softeners (lactulose) or bulk-forming  laxatives (ispaghula) may be used, consider use  of glycerin suppositories. Short-term use of  stimulant laxative (senna) may be considered  especially in patients with anal fissures   • In many cases there is also occurrence of  candidiasis. This is detected by the occurrence of  white spots in the area. Antifungals, usually an  imidazole cream, are required.   • Low-strength topical corticosteroids for a short  time may be used to counteract inflammation.   Use of corticosteroids in napkin dermatitis  should be restricted as much as possible to  hydrocortisone and the product should be  used for only a few days. The occlusive effect  of the nappy increases absorption of the  steroid through the skin and increases risk of  systemic side-effects.   • Is a form of seborrhoeic dermatitis (see also  Chapter 47)   • Rubbing olive oil/almond oil/baby oil into the  scalp, leaving it overnight and then removing it  by shampooing    • Proprietary products are available which have an  emollient effect to counteract dryness associated  with cradle cap.   • Infestation spreads by head-to-head contact and  is more common when children are in close  contact (e.g. when children start school)   • Diagnosis is based on visual inspection and  through the use of nit combs to detect active  head lice and nits (eggs)   • Products used include carbaryl, dimeticone,  malathion, the pyrethroids (permethrin and  phenotrin)   • Resistance to anti-lice products develops and  departments of public policy issue guidelines on  effective products to use   • In addition to the use of medicated hair products  the use of nit combs to remove nits should be  emphasised.   • Choose aqueous-based preparations in  patients with atopic background, asthma  and young children.   This is the most accurate way of calculating dose  since many physical phenomena relate more closely  to body surface area than to weight. The average  BSA of a 70-kg human is 1.7 m 2 .   • Advantages: effective (kills in one application),  fast acting, treatment is complete with one  application    • Young children may require a higher  dose/kg than adults because of their  higher metabolic rates   • Obese children would get a much higher  dose than necessary when the dose is  calculated on the body weight.   • There are differences in gastrointestinal pH,  blood flow, intestinal integrity and motility in  neonates and children.    • Due to alkaline gastric pH in neonates,  bioavailability of acidic drugs (e.g. phenytoin)  may be decreased; bioavailability of weakly basic  drugs or acid-labile drugs (e.g. penicillins,  macrolides) is increased.   • Plasma protein binding is decreased due to a  lower concentration of binding proteins (during  the first year of life). Decreased protein binding  may occur with penicillins, diazepam, phenytoin  and sulphonamides.   • Neonates are at increased risk of displacement  of bilirubin from albumin-binding sites,  resulting in kernicterus or bilirubin  encephalopathy with administration of drugs  that have a molar concentration which is much  lower than that of albumin (e.g. ceftriaxone,  sulphonamides).   • Increased permeability of drugs into neonatal  tissues (e.g. distribution across the blood-brain  barrier) may lead to increased volume of  distribution and higher risk of unwanted central  effects.   • Hepatic metabolism is lower than for adults due  to decreased liver perfusion, hepatic enzyme  capacity and biliary excretion.   • Reduced clearance of drugs such as  chloramphenicol (decreased glucuronidation  leads to the ‘grey baby syndrome’),  corticosteroids, diazepam, metronidazole,  morphine, phenytoin and valproic   • In pre-term and neonates, glomerular filtration,  tubular secretion and tubular re-absorption are  decreased. These affect clearance of drugs such  as gentamicin (decreased glomerular filtration),  thiazides, morphine and penicillins (decreased  tubular secretion).   Adverse drug reactions occurring most frequently in  infants and children are listed in Table 50.3.   This is an acute illness encountered exclusively in chil-  dren and characterised by vomiting, central nervous  system damage, hepatic injury and hypoglycaemia  with a mortality rate of 50%. It is associated with  aspirin intake in children. Aspirin is contraindicated in  children.   • Use oral syringes to calculate doses  smaller than 5 mL.   • Liquid formulation is preferred. However, some  medicines, especially those that are not usually  used in children, are not available in a suitable  dosage form.    Table 50.3 Adverse drug reactions occurring  most frequently in infants and children    • Taste may affect acceptability of medicine by the  paediatric patient. Sometimes parents prefer a  specific brand of a product due to the flavour.   • Problems with product availability in terms of  presentation and formulation lead to  extemporaneous preparation of medicines for  children and to off-label use of medicines   • Use of orphan drugs (drugs intended for  diagnosis, prevention or treatment of diseases  that affect only a small number of patients):  many of these conditions are metabolic diseases  occurring in paediatric patients (e.g. urea cycle  disorders).   • There is a lack of clinical trials providing  evidence to support licensing applications for  paediatric drug use due to technical problems in  dosage form production and the expenses  incurred.   • The European Medicines Agency (EMEA) 1 has  issued new paediatric regulations: 2   As of 26 July 2008, for a valid application for a  Marketing Authorisation, it is an obligation to  submit results of studies conducted according to  a paediatric investigation plan.   As of 26 January 2009, for authorised,  patented medicinal products there will be an  obligation to submit results of studies for  paediatric use when seeking a variation or an  extension of the Marketing Authorisation for a  neiv indication, new route of administration or  new pharmaceutical formulation.   • Safe and effective therapeutic use of drugs in  paediatrics is difficult due to limited evidence  base and lack of appropriate dosage  formulations.    • Risks of medication errors in paediatric patients  are higher due to lack of appropriate dosing  information, the requirement to prepare  extemporaneous preparations for products that  are not commercially available and  miscalculation of doses.   • Pharmacokinetic changes in pre-term babies and  paediatrics need to be considered when  identifying medicines to be used in children.   1 Write briefly on (a) infantile colic and (b)  napkin dermatitis.   2 Give reasons why the following preparations  should be used with caution or are  contraindicated in paediatric patients: (a)  bisacodyl, (b) doxycycline, (c) prednisolone.   1 (a) Infantile colic is a common gastrointestinal  problem in the neonate. It is characterised by  rhythmic bouts of screaming, each lasting a  few minutes, in an otherwise thriving baby. If  baby is vomiting or crying persists for several  hours referral is indicated. Non-  pharmacotherapeutic measures could be  suggested to decrease incidence of colic.  Simeticone is used with feeds.   condition occurring in the nappy area  presenting with soreness and redness. It may  be aggravated with the occurrence of  bacterial or candidal infections. Parents  should be educated on measures to prevent  napkin dermatitis: frequent napkin change,  avoiding plastic occlusive pants and using a  barrier cream. If condition occurs, treatment  consists of using barrier and emollient  creams if area is very dry. The use of  imidazole creams should be considered when  candidiasis is suspected.    of causing electrolyte imbalance. Children are  more prone to developing electrolyte  imbalance.   2 (b) Doxycycline is a tetracycline that may cause  tooth staining, bulging fontanelle and  growth inhibition in children. Tetracyclines  are contraindicated in children under 12  years.   2 (c) Corticosteroids cause growth suppression  and are thus used with caution in children.   Ghaleb M A, Barber N, Franklin B D, Yeung V W S,  Khaki Z F and Wong I C K (2006). Systematic review  of medication errors in paediatric patients. Ann Phar-  macother 40: 1766-1776.    Jahnke C, Bauer E, Hengge U R and Feldmeier H (2009).  Accuracy of diagnosis of pediculosis capitis. Arch  Dermatol 145: 309-313.   Lowey A and Jackson M (2008). How to ensure the quality  and safety of unlicensed oral medicines. Pharm J 281:  240.   Visscher M O (2009). Recent advances in diaper dermatitis:  etiology and treatment. Pediatr Health 3: 81-99.   1 European Agency for the Evaluation of Medicinal Prod-  ucts. ICH Topic E 11. Note for guidance on clinical  investigation of medicinal products in the paediatric  population (CPMP/ICH/27 11/99). London: EMEA,  2000 .   2 Regulation (EC) No 1901/2006 and Amending Regula-  tion (EC) No 1902/2006 of the European Parliament  and of the Council.   • To appreciate good practice of use of drugs in • To develop skills to manage occurrence of minor   During pregnancy, drugs used may adversely effect  the developing fetus. Since the thalidomide tragedy in  the 1960s, drug use during pregnancy takes into  consideration the riskibenefit ratio due to passage of  the drug across the placenta. In breast-feeding, a  large number of drugs pass into breast milk and the  clinical consequences depend on the amounts and  type of drug used.   Since the thalidomide tragedy (see Chapter 1), medi-  cines regulatory authorities have required that before  becoming commercially available all medications are  tested for teratogenicity on animals.   • Teratogen: a chemical entity that when present  during critical periods of development is able to  produce a congenital defect   • Congenital defect: minor or major malformations  (anatomical or functional) in a baby which    deviate from the norm (e.g. cleft palate  associated with antiepileptic drugs).   Examples of drugs known or suspected  to be teratogenic in humans   • Time of exposure during pregnancy: greatest risk  is associated with drugs administered between  weeks 3 and 1 1 of pregnancy   Alcohol consumption, particularly regular intake, is  associated with fetal alcohol syndrome. A safe level  of alcohol consumption is not known. Pregnant  women should be advised to refrain from alcohol  consumption.   Intake of caffeine, which has stimulant effects,  should be moderate and possibly limited to not more  than three cups of coffee a day.   When using drugs in pregnancy, benefits  should outweigh risks of treatment. Drugs  should be avoided as much as possible, espe-  cially during the first trimester. Drugs that  have been used and are backed up with clin-  ical evidence and safety in pregnancy should  be preferred over new or untried drugs and  the lowest effective dose should be adopted.   Women planning a pregnancy and pregnant mothers  should receive advice on lifestyle modifications to  decrease risks to the fetus. They should consider  alcohol and caffeine consumption, smoking and  diet.   Children whose mothers smoked during pregnancy  were shown to lag behind non-exposed children in  development and were associated with a decreased  birth weight. The effects of smoking on the fetus  include:   • increased incidence of infant respiratory distress  syndrome (dyspnoea and cyanosis).   During pregnancy, women should be moti-  vated to quit smoking. Nicotine replacement  therapy is not recommended during preg-  nancy because of lack of safety data. In  patients who opt for nicotine replacement  therapy, inhalators, gums and sprays at the  lowest dose and frequency are the preferred  dosage forms.   Pregnant women should be advised on a healthy  balanced diet where calorie intake is increased during  the pregnancy. Food intake should include foods rich  in calcium and vitamin D (dairy products), iron (lean  red meat) and folate (green vegetables). Vitamin  supplementation, if used, should avoid excessive  amounts of vitamin A.   • To reduce incidence of neural tube defects (e.g.  spina bifida)   • Indicated as a supplement during pregnancy and  in women planning a pregnancy.   • Foods rich in iron: red meat, green vegetables,  nuts and beans   • The use of immunising agents during pregnancy  should be limited.   • Consider the use of tetanus toxoids (in case of  accidents) and influenza vaccines according to  the individual case.   • Rubella vaccination should be promoted to  women planning a pregnancy.   • Keep well hydrated, use oral rehydration salts if  vomiting occurs.   • Antacids that have a low sodium content may be  recommended.   • Recommend use of bulk-forming laxatives as  first-line treatment. An osmotic laxative may be  considered. Stimulant laxatives should be used if  a stimulant effect is necessary.   • External products are preferred as opposed to  suppositories. Astringents are preferred. Products  containing topical anaesthetics and  corticosteroids are to be used with caution.   • Prefer topical rather than systemic administration  of sympathomimetics (nasal decongestants). The  use of saline nasal drops is recommended.   • The use of imidazole intravaginal preparations  should be recommended by a specialist after  ensuring the safety of the application. Topical  administration of imidazole preparations is  preferred.   • Oral administration of itraconazole and  fluconazole is not recommended due to reported  toxicity in animal studies.   • Dose adjustments of antiepileptic agents  (there may be increased dosage requirements  during pregnancy) are required throughout  pregnancy.   • It is important that women taking antiepileptic  drugs who are planning a pregnancy are  counselled on the possible consequences and are  given folic acid supplementation during the  planning stage and continued during the  pregnancy.   • After birth, the neonate is at risk of  developing antiepileptic-associated neonatal  haemorrhage. This is counteracted by the  administration of vitamin K injection at  birth.   It has to be explained to the mother that  compliance to antiepileptic drug therapy is  essential for the well-being of fetus and  mother.   Blood glucose control is essential during pregnancy  and benefits of antidiabetic treatment overrule the  risks of therapy.   • Sulphonylureas and metformin are relatively  contraindicated during pregnancy (occurrence of  neonatal hypoglycaemia reported).   This is caused by the deposition of melanin in the  skin (melasma) during pregnancy. It may also occur  in patients using oral contraceptives. Dark-brown  patches occur on the face; these are accentuated by  exposure to sun.   • NSAIDs may cause delayed onset and increase  duration of labour if taken during the third  trimester.   • Drugs licensed for infants generally do  not pose a hazard   • Agents that are not absorbed such as bulk-  forming and osmotic agents are preferred.   • Short-term moderate use of stimulant laxatives  may sometimes be prescribed in moderate doses.   • COX-1 inhibitors: short-acting agents that do  not have an active metabolite are preferred (e.g.  diclofenac).   • Preferably use a minimally sedating agent with a  short half-life   • During lactation there is increased requirements  for some vitamins and minerals (folate, vitamin   • Use of drugs in pregnancy and lactating mothers  should be avoided as much as possible.   • Benefits of drugs used in pregnancy and lactating  mothers should outweigh risks to fetus and baby.   • Drugs used should be identified after careful  evaluation of the symptoms, patient background  and drug characteristics.   1 What advice should be given to a woman who  is planning a pregnancy?   2 Give one example of an antihistamine which  could be recommended to a lactating mother  for systemic use.   1 To take folic acid supplementation 0.4 mg daily  pre-conception until week 12 of pregnancy to  reduce incidence of neural tube defects such as    spina bifida. To take iron supplementation and  eat foods rich in iron such as red meat, green  vegetables, nuts and beans. Vitamin C enhances  iron absorption. Woman should be advised to  take up rubella vaccination prior to conception.  If woman is a smoker, advise patient on  importance of stopping smoking before  pregnancy. Advice on the use of nicotine  replacement therapy may be given for use  before conception.   2 Older-type antihistamines are used, preferably  a product with a short half-life such as  diphenhydramine. Advise on risk of sedation.   McElhatton P R (2003). General principles of drug use in  pregnancy. Pharm ] 270: 232-234.   McElhatton P R (2003). Drug use in pregnancy: part 1.  Pharm J 270: 270-272.   McElhatton P R (2003). Drug use in pregnancy: part 2.  Pharm J 270: 305-307.   Nathan A (2003). General care of pregnant women. Pharm  ] 270: 338-340.   • To appreciate use of parenteral preparations for • To develop skills required for using drugs and   • Deterioration may be due to pulmonary  oedema or pneumonia, and presents as  respiratory failure.   • Critical care is associated with dysfunction in  circulatory, respiratory, hepatic and renal systems.   • Routes of administration and doses of drugs  should be based on physiological status of the  individual patient.   • Critical care is more likely to be associated with  the occurrence of adverse drug reactions due to  number of medications used and type of  medications used (narrow therapeutic index  drugs).   • Prevent occurrence of complications —  infections, acute respiratory distress syndrome  (ARDS).   Pulmonary embolism occurs due to prolonged immo-  bility, tissue damage and activation of coagulation. In  patients with prolonged bed rest, who have under-  gone recent surgery or have suffered a head trauma  use heparin. Consider use of mattresses that avoid  occurrence of pressure sores (see also Chapter 24).   In critical care, patients may have inter-  related pathologies. Try to summarise the  information available and extract relevant  issues.   This condition is caused by loss of intravascular fluid  as a result of trauma, vomiting, diarrhoea, haemor-  rhage, burns or dehydration. Symptoms include  tachycardia and decreased urine output. Replacement  solutions are used to correct hypovolaemia. These  may be crystalloid solutions or colloid solutions.   • Sodium chloride 0.9%: may give rise to  hypernatraemia presenting with oedema; use  with caution in patients with impaired renal  function, hypertension, cardiac failure, peripheral  and pulmonary oedema.   • Lactated Ringer’s solution (compound sodium  lactate/Hartmann’s solution/Ringer lactate  solution): consists of sodium chloride 0.6%,  sodium lactate 0.25%, potassium chloride  0.04%, calcium chloride 0.027%.   • Intravenous glucose: rarely used alone in  hypovolaemia, usually used in combination with  sodium chloride when there is a combined water  and sodium depletion. Used alone when there is  loss of water with no significant loss of  electrolytes (e.g. hyperthyroidism,  hypercalcaemia); also used to correct    hypoglycaemia or for parenteral nutrition. When  used as monotherapy, care should be taken since  it may cause hyponatraemia and other electrolyte  disturbances. Available as glucose 5%, 25%, 50%  solutions or as solutions presenting a mixture of  sodium chloride and glucose (e.g. 0.9% NaCl,   These are solutions containing plasma proteins or  colloidal molecules. Since they contain large mole-  cules, a smaller volume of fluid is required to produce  the same volume expansion that would be obtained  with crystalloid solutions.   • Prepared from whole blood and contains soluble  proteins and electrolytes   • Since it does not contain blood group antibodies,  there is no need to match blood groups   • Used to expand blood volume (e.g. in shock due  to burns or septicaemia). They are also used  short term until blood is available for transfusion  after haemorrhage   • Caution: large volumes of some plasma  substitutes may increase risk of bleeding, cardiac  and liver disease, renal impairment   This condition is characterised by a potassium serum  level >5 mmol/L.    • Caution: usually there is concomitant  hyponatraemia; monitor serum sodium  electrolyte levels.   • Oral potassium solution is usually preferred  unless patient is unable to swallow;  gastrointestinal side-effects may occur.   20 mmol potassium in 1 mL mixed with sodium  chloride 0.9%. Monitoring required includes  ECG and serum potassium levels. Should not be  administered rapidly since rapid infusion is toxic  to the heart.   • Calcium gluconate or calcium chloride  (intravenous): aim is to maintain cardiac  function; prolonged use may cause  hypercalcaemia   • Sodium bicarbonate (intravenous): lowers  potassium levels; prolonged use may cause  sodium overload   • Glucose solutions: given in regimen with calcium  and bicarbonate and insulin in the emergency  management of hyperkalaemia. Potassium moves  across cell membranes with glucose in the  presence of insulin. Glucose/insulin  administration may be used for longer than the  calcium and bicarbonate components. Dextrose  20% or Dextrose 50% may be used.   • Signs and symptoms: cardiac abnormalities,  muscle weakness, paralysis, weak pulse   • Drug selection is based on: availability of dosage  forms, drug suitability according to patient’s  characteristics (e.g. renal and cardiac function),  drug interactions to be avoided   • Monitor use of parenteral solutions and assess  route of administration   • Monitor for drug incompatibilities in solution  and administration lines (e.g. drug-drug co-  precipitation: gentamicin (positive charge) with  cephalosporins/heparin (negative charge)   • Assess drug stability (e.g. intravenous co-  amoxiclav has to be administered immediately  after reconstitution)   • Follow up appropriate drug storage and labelling  to avoid medication errors   • Assess risk of infection and adopt prophylactic  therapy where appropriate: monitor anti-infective  drug use and check that dose given is sufficient  to ensure efficacy.   1 When hypokalaemia occurs, patient is at risk  of developing arrhythmias and muscle cramps.  Potassium supplementation is administered in  patients receiving diuretics or those with  hypokalaemia. Parenteral administration is  considered for acute management of  hypokalaemia when the risks of cardiac  arrhythmias are high, such as in patients with  very low serum potassium levels and  cardiovascular disease and patients in whom  administration of oral formulations is not  possible.   Anon (2009). Safe administration of intravenous potassium  for treating hypokalaemia in hospital. Clin Pharm 1:  40.   Hess M (2007). Integrating Critical Care Skills into Your  Practice: A case workbook. Bethesda, MA: American  Society of Health-System Pharmacists.   Sexton J and Rahman M H (2008). Parenteral replacement  of fluids and electrolytes: the basics. Pharm J 281:  571-574.   Bernard Coleiro, Consultant Physician, Department of  Medicine, Mater Dei Hospital, Malta.    • To highlight requirement to keep abreast of new  developments in pharmacy and the use of  medicines.   A large number of drugs that are used today have  been developed over the past 30 years (see also  Chapter 1). Drugs that were developed over the past  few years include:   • bisphosphonates for the prevention of fractures  in postmenopausal patients (e.g. alendronic acid)   • alpha-blockers to relax smooth muscle in benign  prostatic hyperplasia (e.g. alfuzosin).   • Two oral anticoagulants indicated for the  prevention of venous thromboembolism  following hip or knee replacement surgery.   • Dabigatran etexilate acts as a direct thrombin  inhibitor and rivaroxaban acts as a factor Xa  inhibitor.   • Indicated for the treatment of chronic stable  angina pectoris in patients who have  contraindication or intolerance to beta-blockers   • Lowers heart rate by its action on the sinus node   • Contraindications: severe bradycardia (less than  60 beats/min), recent myocardial infarction,  recent cerebrovascular accident, unstable angina.   • Oxazoline compound with antihypertensive  properties acting on medullary and peripheral  vasomotor structures   • Atypical antidepressant licensed for use as an aid  to smoking cessation programmes.   • An anticonvulsant agent that is a triazole  derivative making it structurally different to  other antiepileptic agents   • Marketed for patients with Lennox-Gastaut  syndrome, a severe and difficult-to-treat form of  epilepsy that usually begins in childhood.   • Centrally acting anti-obesity agent that inhibits  serotonin and noradrenaline re-uptake resulting  in decreased food intake.   • Protease inhibitors are metabolised by  cytochrome P450 enzyme systems and  therefore have a significant potential for drug  interactions   • Used with caution in hepatic impairment,  diabetes (associated with hyperglycaemia)  and haemophilia (increased risk of  bleeding).   • Raltegravir prevents the covalent insertion or  integration of the HIV genome into the host cell  genome   • Indicated for use in HIV-infected patients  showing HIV replication despite antiretroviral  therapy   • To be used in combination therapy with other  antiretroviral agents.   • Used for the systemic treatment of candidiasis  and for the prophylaxis of candidiasis in patients  undergoing haematopoietic stem cell  transplantation.   • It is a pleuromutilin derivative that has  bacteriostatic effects, particularly against  Staphylococcus aureus and Streptococcus  pyogenes.   • Increases insulin secretion, suppresses glucagon  secretion and slows gastric emptying.   • Increases incretin levels leading to increased  insulin secretion and lower glucagon secretion.   • To be used with care in patients with ischaemic  heart disease due to increased risk of heart  attack; risk of bone fracture increased.   • An oestrogen receptor antagonist without the  agonist effects seen with tamoxifen   • Licensed for oestrogen receptor-positive  metastatic breast cancer in postmenopausal  women   • In chronic myeloid leukaemia, there is a  chromosomal abnormality known as  Philadelphia chromosome leading to abnormal  tyrosine kinase activity.   • Imatinib is an oral signal transduction inhibitor  that specifically inhibits the abnormal kinase   • Oral protein kinase indicated for breast cancer  with overexpression of HER2   • It is compared with trastuzumab which is  available only for intravenous infusion.   • Monoclonal antibody that is indicated in  epidermal growth factor receptor (EGFR)-  expressing metastatic colorectal cancer   • Used as monotherapy. Increased risk of toxicity  when used in combination chemotherapy.   • A kinase inhibitor indicated for first-line  treatment in advanced renal cell carcinoma   • Monitoring required: full blood count, glucose  and lipid profiles, renal function, symptoms of  bowel perforation.   New therapies, particularly in the area of  malignancy, rely on pharmacogenetic expres-  sion of the disease. These treatment modali-  ties represent personalised medication and  apply particularly to patients who otherwise  may experience treatment failure.    • Clopidogrel: can be used in combination with  aspirin in patients eligible for thrombolytic  therapy, for the prevention of atherothrombotic  events in ST-segment elevation acute myocardial  infarction   • Pramipexole and ropinirole (antiparkinsonian  drugs): licensed for restless legs syndrome.   The originator company would like to retain market  share from a product as much as possible once  generic formulations become available soon after  patent expiry. Strategies that can be adopted are to  add value to the current patented product and there-  fore achieve an extension of the patent or post-patent  expiry to compete with the competing manufacturer.   • Look out for updated information on drug  profile for the first few years after release.   • Ensure patient safety and patient information  when switching to a newer drug.   1 What are the characteristics of the following  drugs: (a) aliskiren, (b) varenicline?   1 (a) Aliskiren interferes with the production of  angiotensin II which is a vasoconstrictor by  inhibiting renin. Its efficacy is similar to  ACE inhibitors and angiotensin II receptor  blockers (ARBs).   receptors in the brain and causing a reduction  of the craving sensation for nicotine and a  reduced satisfaction when smoking. The  drug is started 1 week before intended  smoking cessation. Suicidal thoughts and  behaviour have been reported. Patients  should be advised to report immediately  signs of these side-effects. The product  should be used with caution in patients with  a history of psychiatric illness, in renal  impairment and during breast-feeding.   Adcock H (2007). Clinical developments in 2006. Pharm J  278: 21-24.   Adcock H (2008). Clinical developments in 2007. Pharm J  280: 27-30.   Adcock H (2009). Clinical developments in 2008. Pharm J  282: 25-28.   • To understand common cold and drugs used in the • To recognise influenza and methods of prophylaxis,  management of symptoms   The common cold and influenza are two conditions  affecting the respiratory tract that are caused by a viral  infection. Both are generally self-limiting. However,  in some scenarios complications that have serious  implications may occur. Transmission is by droplet  inhalation.   Also referred to as acute coryza or infectious rhinitis,  this is a viral infection of the upper respiratory  tract.   • Symptoms: sore or tickly throat (pharyngitis),  sneezing, rhinorrhoea. Fever may occur in  children   • Complications: secondary bacterial infection,  otitis media particularly in children, sinusitis and  laryngitis.   • Factors that influence the body’s immune response  to the exposure to the virus include: nutrition,  stress, smoking, emotional disturbances.   • Air is colder and this may allow the virus to  replicate at a higher rate.   cells in the respiratory system, submucosal inflam-  mation and fluid extravasation occur.   • Incubation period: 1-4 days, average 2 days.  Onset is rapid    • Symptoms: fever, headache, myalgia, severe  malaise, non-productive cough, sore throat,  rhinitis.   • People in close or frequent contact with anyone  in the high-risk group.   • Cardiac complications especially in patients with  a history of cardiovascular disease    Croup (laryngotracheobronchitis) occurs  mainly in paediatric patients and presents as a  barking cough. Referral is recommended  since sometimes condition may become life  threatening.   Nasal decongestants are sympathomimetic agents  that act primarily on the alpha-adrenergic receptors  causing peripheral vasoconstriction. They offer symp-  tomatic relief from rhinorrhoea and nasal congestion.  The products may be administered either topically  (nasal administration) or orally (for a systemic effect).   • Disadvantage: rhinitis medicamentosa when  product is applied for a prolonged period of time    • Advise patient to use topical nasal decongestants  for a few days, usually not exceeding 7 days, to  avoid occurrence of rhinitis medicamentosa.   • Caution: cardiac disease, hypertension, diabetes,  hyperthyroidism, glaucoma, benign prostatic  hypertrophy   • May be found in combination with  antihistamines and cough preparations.   • Sodium chloride: 0.9%, safe product which can  be used in paediatric patients and during  pregnancy. Patient is advised to apply product as  required to provide relief from congestion.   • Steam inhalations: intended to provide relief  from nasal congestion. Volatile oils such as  camphor and menthol may be added to the  solution. Patient should be advised to be careful  when using hot or boiling water to avoid  injuries.   • Side-effects: sedation, dry mouth, blurred vision,  constipation, difficulty in urination   • The side-effect of sedation may be a required  effect to induce sleep. Occurrence of sedation  counteracts the side-effect of insomnia that is  associated with systemic administration of nasal  decongestants   • To be used only for dry non-productive cough.  Cough suppressants are contraindicated when  there is a chesty cough   • Opioids: e.g. codeine, pholcodine,  dextromethorphan (less potent, milder side-effect  profile)   • Caution: asthma, hepatic and renal impairment,  children, avoid under 1 year of age   Combined vs single therapy: combined prep-  arations may contain products that are not  relevant to a particular individual. Using  different single products may be preferred to  select active ingredients that are required  to counteract symptoms in a particular indi-  vidual. However, this approach is more expen-  sive than a combination product and increases  medicine handling requirements by patient.    Formulations that can be used with confidence  in adults are shown in Table 54.1.   • Not to use topical nasal decongestants for  longer than 5-7 days   • Not to use paracetamol with combination  cold preparations that already contain  paracetamol   • Drowsiness may occur with products  containing sedating antihistamines or  opioid antitussives.   Vitamin C (ascorbic acid) is an antioxidant that  neutralises the oxidising compounds released by  neutrophils during a viral infection. Doses of 1-4 g/  day decrease duration and severity of cold symptoms  by 10-30%.   • Care: at high doses it interferes with diabetes  urine tests and increases risk of production of  urinary oxalate leading to renal stones.   • According to the MHRA (UK), there is a  lack of evidence of benefits and reports of  side-effects from the use of sedating  antihistamines, antitussives, expectorants  and nasal decongestants in children under  6 years. 1   • In children under 6 years the use of the  following products is recommended:   - vapour rub: for children over 3 months  to relieve nasal congestion   • Inactivated vaccine containing different strains  that are identified every year as the predicted  predominant strains   • Route of administration: intramuscular injection.  A new formulation of the influenza vaccine has  been granted a marketing authorisation by  EMEA in 2008 for administration via the  intradermal route. It is suggested that the route  of administration allows for the antigen to be  deposited in the dermal layer of the skin which is  rich in dendritic cells that are associated with  stimulating an immune response   • When used within 48 hours of onset of  symptoms, reduce duration of symptoms   • Used for post-exposure prophylaxis of influenza.  They may be used to prevent influenza in an  epidemic.   • Cautions: asthma and chronic pulmonary disease  (avoid in severe disease), uncontrolled chronic  illness   • Patient advice: if used in patients with  asthma and chronic pulmonary disease, other  inhaled drugs should be administered before  zanamivir if concurrent administration is requires  and a short-acting bronchodilator should be  available to be used if bronchospasms occur.    The occurrence of fever warrants antipyretic  treatment. In children paracetamol and  ibuprofen are the drugs of choice; aspirin  should be avoided. Patients should be kept  well hydrated and in airy rooms. Avoid  smoking. Using multiple pillows to elevate the  head at night reduces the occurrence of post-  nasal drip.   • Management of the common cold is based on  counteracting symptoms presented.   • Topical nasal decongestants should not be used  for a prolonged period. Sodium chloride 0.9%  drops are preferred in very young children.   • Antitussive preparations should be used only  when there is dry cough and should be avoided  in patients with chronic respiratory disease and  children under 1 year of age.   • The influenza vaccine should be administered  yearly to patients at high risk of developing  complications of influenza.   1 What is a disadvantage of topical nasal  decongestants and what advice should be given  to the patient to minimise occurrence of this  unwanted effect?   2 Describe the nasal decongestant effect of  phenylephrine. Name two side-effects that could  occur with the systemic administration of  phenylephrine. Name four conditions when  phenylephrine should be used with caution.   1 Topical administration of nasal decongestants is  intended only for short-term use (not more than  7 consecutive days) as prolonged use can result  in rebound congestion (rhinitis medicamentosa).  Patients should be advised to use the product  for not more than 7 days.   2 Phenylephrine is a nasal decongestant that acts  as a sympathetic nervous system agonist  predominantly at the alpha receptors. It causes  vasoconstriction of the nasopharyngeal and  sinus passages, leading to relief from the  symptoms of rhinorrhoea and nasal congestion.  Side-effects include tachycardia and anxiety.  Phenylephrine should be used with caution in   Barrett B, Harahan B, Brown D, Zhang Z and Brown R  (2007). Sufficiently important difference for common  cold: severity reduction. Ann Fam Med 5: 216-233.  Fleming D (2007). Assessing the accuracy of influenza  diagnosis by community pharmacists. Pharm J 279:  441-444.    National Institute for Health and Clinical Evidence (2009).  Amantadine, oseltamivir and zanamivir for the  treatment of influenza: Review of NICE technology  appraisal guidance 58. http://www.nice.org. uk/TA168.  Perrie Y (2006). Influenza: treatment and prevention.  Pharm J 277: 399-402.   1 Anon. Cough and cold remedies no longer recom-  mended for children under six years. Pharm J 2009;  282: 237.   • To summarise use of topical agents in eye • To address management of glaucoma   Preparations for the eye should be sterile. Eye drops  in multiple-application containers used in domicil-  iary care should not be used for more than 4 weeks  after first opening.   • Eye drops: drugs penetrate the globe, probably  through the cornea; systemic effects may arise  from absorption of drugs into the general  circulation   Ocular symptoms most likely to be encoun-  tered in the pharmacy are red eyes, styes,  swollen, painful eyelids and sore, gritty eyes.  Responding to these symptoms requires  special care to differentiate between minor  disorders and potentially serious conditions  that could have significant consequences.   • Local pyogenic infection involving the follicle or  sebaceous gland of an eyelash   • Occurs on the outer surface of the eyelid as a  palpable, tender nodule   • Presents with painful swelling and inflammation  of the edge of the eyelid   • Management: hot compresses and application of  local antibacterial eye preparations.   • Occurs due to blockage of one of the meibomian  glands which lubricate the eyelid   • Management: surgical removal may be required,  local antibacterial preparations may be  considered if infection is suspected.   • Presentation: inflammation, scaling, pruritus,  oedema, yellow crusts form on the eyelashes   • Management: cleanse the eye with saline  solution and apply of local antibacterial  preparations.   Entropion and ectropion are conditions that occur in  old age and lead to eye discomfort and dryness.   • Refer in cases where metallic foreign bodies,  chemical exposure or thermal damage has  occurred.   This is inflammation of the membrane that lines the  eyelids (conjunctiva). It presents with erythema and  swelling of the lids and can be acute or chronic. It  may be due to:   • allergy: occurring in both eyes; watery discharge,  itchiness and rhinitis may be concomitant  symptoms.   • viral infection: occurring in both eyes; watery  discharge, gritty feeling and usually patient   • bacterial infection: initially presents in one eye  but may spread to both eyes; purulent discharge,  gritty feeling and not usually associated with  other symptoms.   • Presentation of mildly red eye, gritty feeling or  sensation of foreign body, excess tears   • Management: artificial tears which can be  applied as often as required.   • May develop at any age following minor trauma,  sneezing, coughing   • Eyelid irritation: with history of trauma  or with swelling and failed nodule  treatment   • Red eye: with pain, blurred vision,  photophobia, history of trauma, contact  lens wear, foreign body sensation and  possible contamination or vomiting.    • Dosing schedule normally requires  administration three to four times a day   • It is recommended to advise patient to continue  treatment 48 hours after healing, about careful  hand washing and to be careful when  administering the drops or ointment in the lower  conjunctival sac to avoid contamination of  dropper.   When the application of eye ointments is rele-  vant, it may be recommended to use the eye  ointment at night and then complement  therapy with the eye drops. Application of eye  ointments is associated with blurring of vision  and this may impact negatively on patient  compliance if three to four times daily  administration is requested.   • Use: allergy, herpes simplex keratitis ( +  aciclovir), post surgery   • Cautions: undiagnosed red eye since the use of  the steroid may clear the symptoms while the  underlying condition is not treated; precipitation  of steroid glaucoma, steroid cataract and  increased susceptibility to microbial infections.   • Chronic use may lead to rebound conjunctival  congestion (conjunctivitis medicamentosa)   • Care: may mask diagnostic signs since redness  and inflammation may be removed while  underlying condition is not treated.   • Astringents: distilled witch hazel used in eye  lotions for irrigation.   • Administration by intravenous infusion over 10  minutes and then light activated using non-  thermal laser   • The expense of drug therapy should be compared  with the cost of loss of productivity and quality  of life due to loss of peripheral vision.   Glaucoma describes a range of ocular conditions  where the intraocular pressure is too high for the eye  to withstand without damage to the structure or  impairment of function. The upper limit of normal  pressure is 21 mmHg. The condition is classified into  acute glaucoma (closed angle) and chronic glaucoma  (open angle).   • Act on ciliary muscle leading to opening  up of drainage channels in trabecular  meshwork, resulting in increased aqueous  flow   • Note: use in patients with asthma and  obstructive airway disease should be avoided due  to risk of bronchospasm if there is some degree  of systemic absorption    • side-effects: bitter taste, burning and stinging of  eyes common; other side-effects associated with  systemic activity may occur including  paraesthesia, flushing, headache, dizziness,  fatigue, irritability, thirst, polyuria   • Increase uveoscleral outflow and result in a  decreased intraocular pressure in open-angle  glaucoma   Glaucoma requires constant monitoring of  the outcomes of therapy by evaluating intra-  ocular pressure. When monotherapy is not  effective, rather than increasing dosing  frequency, combination therapy should be  adopted.   • Diabetic patients and immunocompromised  patients are at greater risk of developing eye  infections.   • Extended-wear disposable: discarded after  4 weeks, intended to avoid complications  associated with the accumulation of  deposits.   • Used for daily cleaning to remove fresh deposits  of lipids, proteins and other contaminants   • Applied to both surfaces of the lens and digital  pressure is used in a rotating manner in the palm  of the hand.   • Disinfectants: contain hydrogen peroxide. Lenses  should be rinsed before insertion into the eye.   Multi-purpose solutions present the steps of  rinsing, disinfection and storing in one  product. These solutions are preferred since  they are less time-consuming to use, only one  type of product needs to be purchased and  steps for maintenance and storage of the  lenses are easy to follow. Care should be  taken to use the solution that is appropriate  for the type of lenses used (hard or soft  lenses).   These are intended for instillation directly into the  eye with the lenses on. They provide fluid to main-  tain adequate lens hydration and improve comfort.   These are used periodically after cleaning and before  disinfection. They consist of proteolytic enzymes (e.g.  papain) as tablets that are dissolved in saline. The    lenses are soaked in this solution before being  cleaned and rinsed. Protein removal tablets are suit-  able for soft and hard lenses.   The use of extended-wear disposable products  eliminates the need for this step since at this stage the  lenses are discarded.   Most complications are self-limiting if the lens is  removed at the first sign of trouble. Complications  could be as a result of:   • Precipitating factors include overnight wear and  long intervals between cleaning.   • Reduced tolerance due to oral contraceptives:  oestrogen component causes eyelid oedema,  allergic conjunctivitis   • Aspirin: appears in tears and may be absorbed by  soft lenses resulting in ocular irritation and  redness.   • May damage contact lens and increase contact  time of the drug   • Eye drops should be administered 30 minutes  before inserting lens.   • Preparations administered in the eye should be  sterile. Eye drops in multi-dose containers for  domiciliary use should be discarded within 4  weeks of opening and those used in institutions  should be discarded within 1 week of opening.   • Patients should be advised on the correct  administration of eye drops and eye ointments.   • When using anti-infective preparations, care  should be taken not to contaminate dropper.   • Administration of corticosteroids should be  undertaken with care due to risk of misdiagnosis  and risk of side-effects.   • In glaucoma more than one type of drug may be  used to control intraocular pressure.   • Use of contact lenses requires strict adherence to  recommendations for storage and lens use to  avoid conditions related to contact lens wear.   2 What are the unwanted effects that could  result from topical ocular administration of  corticosteroids?   3 Giving examples, describe what is a miotic  agent and comment on its use in glaucoma.   1 Chalazion: inflammatory granulomatous  swelling on the eyelid or its margin. Occurs due  to blockage of one of the meibomian glands    which lubricate the eyelid. More common in  adults than in children. Management involves  surgical removal and anti-infective agents.  Blepharitis: inflammation of the eyelid margins  characterised by inflammation, scaling,  pruritus, oedema, formation of yellow crusts  on the eyelashes. Causes may be unknown but  may be associated with seborrhoeic dermatitis  and allergy. Management involves cleansing  the eye with saline solution and the use of  topical antibacterial preparations.   2 Undiagnosed red eye, steroid glaucoma, steroid  cataract, increased susceptibility to microbial  infections.   3 Miotics (pilocarpine, carbachol) are  parasympathomimetic drugs used in glaucoma.  They act on ciliary muscle leading to opening  up of drainage channels in trabecular  meshwork, resulting in increased aqueous flow  and a reduction in the intraocular pressure. A  disadvantage is the short duration of action  and products need to be applied four times  daily. Ocular side-effects include burning and    itching, blurred vision, conjunctival vascular  congestion, myopia, vitreous haemorrhage  and pupillary block.   Elton M (2007). Ocular conditions from A to Z (i). Pharm  J 278: 195-198.   Elton M (2007). Ocular conditions from A to Z (ii). Pharm  J 278: 255-258.   Haque K (2007). Macular degeneration: symptoms and  diagnosis. Hosp Pharm 14: 151-154.   Titcomb L C (2000). Topical ocular antibiotics: part 1.  Pharm J 264: 298-301.   Titcomb L C (2000). Topical ocular antibiotics: part 2.  Pharm J 264: 441-445.   Titcomb L C (1999). Treatment of glaucoma: part 1. Pharm  J 263: 324-329.   Titcomb L C (1999). Treatment of glaucoma: part 2. Pharm  J. 263: 526-530.   Pharmacists are involved in responding to common  dental problems such as tooth decay and gum  disease. Oral and dental problems may present  discomfort, interfere with food intake and pose social  problems. The relevance of good oral health is an  essential feature that needs to be emphasised.   • Present as round, single or clusters of greyish-  white or yellow craters surrounded with raised  red rim causing pain particularly on eating and  drinking   • Occurrence is related to stress, trauma, infection,  vitamin B and iron deficiency, and hormonal  changes   • Patient is diabetic or in children under  10 years of age   • Corticosteroids (e.g. hydrocortisone,  triamcinolone: available as an oral paste) reduce  inflammation.   • Benzydamine, available as an oral rinse or buccal  spray, reduces pain and discomfort.   • Choline salicylate, available as an oral gel,  produces an analgesic effect.   • Chlorhexidine used as a mouth rinse to disinfect  the oral cavity.   • Anaesthetic topical preparations (e.g. benzocaine)  can be applied every 20 minutes and are intended  to provide relief   • Paracetamol may be used as an analgesic and for  the associated pyrexia that may occur   • Non-pharmacotherapy: use teething accessories;  some products can be placed in the freezer  beforehand so as to provide a cooling effect  when the child handles them and bites on them.    antibacterial agents, patients with ill-fitting  dentures, immunocompromised patients, use of  inhaled corticosteroids.    This may occur after extraction or after a new filling  or due to an abscess. It may be triggered or worsened  by heat or cold. For an abscess, the patient may also  present with fever and facial swelling.   Referral should be considered if an abscess is  suspected since anti-infective agents are required.   • Systemic analgesics: paracetamol or NSAIDs  unless contraindicated (see Chapter 31)   • Inhibits biosynthesis of ergosterol which is a  constituent of the fungal cell membrane   • Gel has to be retained in mouth for as long as  possible   • Treatment to be continued for up to 2 days after  symptoms subside   • Absorption from oral mucosa may occur:  miconazole potentiates activity of warfarin,  should be used with caution in pregnancy and  breast-feeding, and is contraindicated in hepatic  impairment.   • Used in unresponsive infections and in chronic  hyperplastic candidiasis (leukoplakia).    Oral candidal infections cause oral thrush,  denture-induced stomatitis and angular cheilitis  Present with soreness, discomfort on eating and  bad taste    Miconazole may be used in combination with  fusidic acid and hydrocortisone when  concomitant bacterial infection is also  suspected (e.g. angular cheilitis).   This is a condition caused by herpes simplex type 1  virus. It occurs on areas around the lips, is recurrent  and is precipitated by stress, sun and the common  cold.   • Presents with a prodromal phase: burning,  tingling and numbness occur before the  occurrence of the cold sore.   Since exposure to the sun can precipitate the occur-  rence of cold sores, it is advisable to recommend the  use of UV-blocking lip-salve as a preventive measure.   Patients should be advised that the condition  is recurring and that they should recognise the  prodromal symptoms so as to commence  topical application of antiviral agent.   • Advise patients to use sugar-free lozenges,  salivary substitutes and to avoid alcoholic  mouthwashes   • Pilocarpine tablets are used in patients with dry  mouth following irradiation of head and neck  cancer or in Sjogren’s syndrome.   • Plaque: a film of soft material that forms on  teeth which is composed of microorganisms and  food. It calcifies by precipitating calcium salt  from saliva and forms calculus.    • Decreased salivary flow caused by salivary gland  disease, drugs, irradiation of head and neck   Proper oral hygiene is of great significance in  the management of gingivitis and periodontal  disease.   • Small head size to be able to approach all areas  of the mouth   • Lifespan: should be changed regularly (every 3  months or earlier if bristles are visible from the  sides when looking at the dorsal side of the  brush) to achieve effective toothbrushing  technique.   • Easier to handle for patients with reduced  manual dexterity (e.g. people with rheumatoid  arthritis).   • Good technique should be ensured to avoid  damage to buccal area.   • Use low abrasive dentifrices. Highly abrasive  agents should be used with caution since these  may damage dental enamel   • Assist in the removal of debris, mucus and  purulent secretions   • Chlorhexidine: cationic antibacterial agent,  proven activity against bacteria in dental plaque.  However, it stains teeth yellow-black colour and  therefore patients should be advised to rinse  mouth with water after use to minimise teeth  staining   • Other examples include: sodium chloride,  hydrogen peroxide, hexetidine and povidone-  iodine.   • Dentures should be cleaned out of the mouth  once or twice daily   • Squamous cell carcinoma: a rare condition that  may affect buccal mucosa which requires  immediate referral   • Lichen planus: erosive, ulcerated lesions on  gingival tissues and buccal mucosa; requires  administration of topical or systemic  corticosteroids.   • Mouth ulcers tend to be recurrent but their  repeated occurrence requires elimination of  underlying factors which may require referral.   • Teething in children may warrant use of systemic  analgesics in addition to topical anaesthetics and  may present with extra-buccal symptoms.   • In dental pain, occurrence of an infection should  be assessed.    • Occurrence of oral candidiasis may be related to  other drugs and to denture use.   • Cold sores are contagious and they are recurrent  since the herpes virus remains dormant in the  body.   • In oral hygiene, toothbrush used and proper  toothbrushing technique are key factors to ensure  maintenance of dental care.   1 What advice should be given to a patient who  is complaining of dry mouth?   1 Patients with a persistently dry mouth should be  advised on the importance of good oral hygiene.  Saliva lubricates the oral cavity and a dry mouth  is associated with a higher risk of dental  problems. Patients should be advised to adopt  regular daily toothbrushing (using an anti-caries  toothpaste, a medium textured small head  toothbrush, proper brushing technique). An  alcohol-free mouthwash helps to improve oral  hygiene and provides a refreshing sensation.  The use of sugar-free lozenges may help to  increase salivation.   2 Patients with gingivitis should be referred when  there is spontaneous gum bleeding to exclude  bleeding caused by medications, unexplained  bleeding and systemic illness.   Garwood D (2003). Oral problems. Pharm J 270: 574-576.  Garwood D (2003). Oral hygiene. Pharm J 270: 619-621.   • To present symptoms of foot problems • To identify management of foot problems.   Untreated foot conditions such as corns and calluses,  verrucae, athlete’s foot and onchomycosis can have a  negative impact on an individual’s lifestyle. The use  of support products to alleviate foot problems should  be encouraged. Care needs to be exercised in the  prevention and management of foot problems in  diabetics and patients with compromised peripheral  circulation.   • Corn: a small, raised, sharply demarcated  hyperkeratotic lesion with a central core; may be  soft (occurring mostly between toes) or hard  (occurring mostly on top of the toes)   • Callus: similar to a corn; ranges from a few  millimetres to several centimetres in diameter.  More common in adults   • Causes: pressure and friction; may be due to  inappropriate footwear, bad posture during  walking and activity.   • Contagious condition caused by human  papillomavirus commonly affecting the feet  as well as hands, anogenital region and  face   • Appearance: scaly, rough papules, greyish with a  black centre and a typical cauliflower-like  appearance   • Is the problem associated with a particular pair  of shoes?    Factors that differentiate warts from corns  and calluses are pain when pressure is applied  to the area and the cauliflower raised appear-  ance with reddish hue due to vascular damage  in the area.   • Salicylic acid in a plaster vehicle or salicylic acid  as a liquid for topical application   • Treatment duration for corns and calluses is  usually up to 14 days but for verrucae treatment  duration is longer, even up to 12 weeks   • In verrucae, if treatment fails, referral is required  for removal by cryotherapy.   • Is contraindicated in diabetics due to the risk of  irritation to the surrounding skin which may   • Advice: adjunctive therapy; application of  formulation containing salicylic acid should be  specific to lesion to avoid skin irritation.   • Epidermabrasion: using a foot file, scrape away  the excessive tissue   • Use of adhesive pads to alleviate pain due to  pressure   • In warts: patient should be advised on measures  to prevent spread of infection to other members  in the household and in common areas.    Irritation caused by the application of sali-  cyclic acid preparations may be avoided by  applying petroleum jelly to the area  surrounding the lesion to protect the skin  from coming in contact with salicylic acid.   • Protective pads may be used to reduce  inflammation over the area that generally causes  discomfort. Referral to a podiatrist may be  necessary for surgical correction.   This is a fungal infection characterised by macera-  tion, hyperkeratosis, pruritus, malodour, itching and  stinging sensation. It commonly affects toe webs but  may include sole, instep and toenails (onchomycosis).  In onchomycosis, the toenail changes appearance to  a yellowish colour. Systemic treatment is required in  onchomycosis.   • Did the problems begin with the use of new  shoes, socks or soap?: to identify occurrence of  contact dermatitis.   • Do you notice an odour when you take off your  shoes?   The presentation of athelete’s foot which has  an infective component needs to be differen-  tiated from hyperhidrosis and dermatitis.  Characteristic signs of a fungal infection  include itchiness and malodour.   • Vesicular eruptions with purulent discharge  due to probability of concomitant bacterial  infection   • Imidazoles (e.g. clotrimazole, econazole,  ketoconazole, miconazole) are effective. They  may be used in combination with a steroid  (hydrocortisone) for the first few days of  treatment to reduce symptoms of inflammation.   • Tolnaftate: not as effective as imidazoles in the  management of acute symptoms.   • Terbinafine (an allylamine): more effective than  the imidazoles, but more expensive.    Dosage forms for topical administration of  antifungals include creams, dusting powders  and sprays. Dusting powders are more effec-  tive for application to footwear. Sprays may  be easier to apply over a large area.   Systemic therapy may be required in toenail involve-  ment or when the correct use of topical treatment  failed.   • Tinea pedis: fluconazole (50 mg daily for 2-6  weeks) or itraconazole (100 mg daily for 30 days  or 200 mg for 7 days) or terbinafine (250 mg for  2-6 weeks)   • Onychomycosis: itraconazole (200 mg daily for  7 days repeated after 21 days for two more  courses) or terbinafine (250 mg daily for about  3 months).   • In fungal infections, treatment is for a minimum  of 2-4 weeks   • Proper foot hygiene: clean area regularly and dry  properly, reduce risk of contamination to other  members in the household   • Topical antifungal treatment in athlete’s  foot should be continued for a few days  after symptoms have cleared to prevent  re-infection   • Antifungal dusting powders containing  tolnaftate may be used in footwear to  prevent re-infection.   These occur when a section of the nail presses into  the soft tissue of the nail groove. The nail curves into    the flesh of the toe corners and becomes embedded  in the soft tissue of the toe, causing pain.   • Management: analgesia and refer for surgical  correction. Anti-infective agents may be required  if the area is infected.   Rubefacients (e.g. salicylates, nicotinates, capsicum,  camphor) provide symptomatic relief. They should not  be applied if the skin is broken. In cases where there is  broken skin, antiseptic creams are considered.   • Characterised by overactivity of the sweat  glands, resulting in excessive perspiration   • Management: use of talc and zinc oxide dusting  powders to adsorb excess sweat   • Advise patients to use non-occlusive footwear  which reduces morbidity due to hyperhidrosis  and decreases risk of athlete’s foot.   • Arterial thrombosis: pain and loss of blood  supply, cold and white in colour   • Care should be taken when conditions occur in  the feet in people with diabetes and in patients  with compromised peripheral circulation.   • Avoid products containing salicylic acid in people  with diabetes due to the risk of irritation that  may lead to infection and skin lesions.   • Refer when patient is complaining of severe pain  with sudden onset or if there is foot colour  change or appearance is abnormal.   • Advise on proper footwear (comfortable,  avoiding high heels and narrow pointed shoes)  and to use alternate pairs of shoes so as to  change footwear.   1 Explain what an ingrown toenail is and how  its occurrence can be prevented.   2 When should referral be considered when a  patient presents with a verruca?   1 An ingrown toenail occurs when a section of  the nail presses into the soft tissue of the nail  groove. The nail curves into the flesh of the  toe corners and becomes embedded in the soft  tissue of the toe, causing pain. An ingrown  toenail can be prevented by correct trimming  of the nails and avoidance of narrow tight-  fitting shoes.   2 Immediate referral when patients present with  verrucae that reportedly are changing in size    or colour and verrucae that itch or bleed  without provocation. Referral is also necessary  if patient has diabetes or peripheral circulatory  disorders, if there is haemorrhage or oozing, if  verruca is extensive and if proper self-  medication has already proved inadequate.   Keogh-Brown M R, Fordham R J, Thomas K S, Bachmann  M O, Holland R C, Avery A J, et al. (2007) To freeze  or not to freeze: A cost-effectiveness analysis of wart  treatment. Br J Dermatol 156: 687-692.   Younes D A and Ahmad A T (2006). Diabetic foot disease.  Endocr Bract 2006; 12: 583-592.   • To review characteristics of ear problems • To develop skills to reduce risk of ototoxicity.   The ear consists of three sections: the outer ear, the  middle ear and the inner ear. Besides being an organ  used to capture sounds, the ear (inner ear) is also a  sensory organ involved with balance. Ear disorders  may affect hearing or balance.   The auricle is a highly vascularized area. Its function  is to direct sound waves into the ear. Conditions  related to the auricle relate to skin disorders and  include trauma, boils (furuncles) which are more  common in young adults, dermatitis of the ear that  may be due to contact with jewellery or cosmetics  and itching or pruritus (see Chapter 47).   This is an inflammatory reaction that may be associ-  ated with infection due to bacteria (e.g. Pseudomonas  aeruginosa) and fungi (e.g. Aspergillus spp., Candida  albicans). It presents as a very painful condition in    which chewing and manipulation of the pinna may  exacerbate the pain. Oedema may occur and this may  interfere with hearing.   • Moisture increases infection and the condition is  associated with exposure to water (e.g.  swimming: swimmer’s ear).   Topical administration of antibacterial agents (e.g.  chloramphenicol, framycetin, gentamicin, neomycin  and ofloxacin) is required. The use of aminoglyco-  sides in patients with a ruptured tympanic membrane  should be avoided. Since the infection may also be  due to a fungal component and there is a risk of  promoting a fungal infection with the use of topical  antibacterial agents, a topical antifungal product  such as clotrimazole or clioquinol (not to be used in  perforated tympanic membrane) may be considered  either as monotherapy or in combination with  antibacterials.   • Topical corticosteroids: e.g. hydrocortisone,  betamethasone, dexamethasone, flumetasone,  prednisolone and triamcinolone. Corticosteroids  are used in combination with anti-infective  agents where inflammation and oedema are  prominent.    • Sodium chloride 0.9% wash: used to clean ear  from debris and as a soothing preparation.   • Aluminium acetate which has an astringent effect  and acetic acid drops which have antifungal and  antibacterial properties may be considered.   • Exclude occurrence of underlying chronic  otitis media before treating otitis externa   • In otitis externa, systemic analgesics may  be recommended in addition to topical  treatment to counteract the pain.   • Ear wax normally provides mechanical  protection of the tympanic membrane   • Occurrence of impacted cerumen may be due to  overactive ceruminous glands (some people are  more prone to develop this condition), congenital  anomalies (abnormally narrow ear canal),  learning disability and changes in the consistency  (drier) of the cerumen produced   • Presenting symptoms: ear discomfort and slight  hearing loss, sensation of fullness in the ear.  Symptoms may be precipitated by exposure to  water since the wax will adsorb water and inflate   • Patients should be advised to avoid getting water  in the ears (may use ear plugs during swimming  or showering) and not to use cotton buds to  remove impacted cerumen. The use of cotton  buds may cause damage to the tympanic  membrane since the impacted cerumen may be  pushed further inside into the middle ear.   • Patient is instructed to incline head and instil  drops and remain in this position for a few  minutes   • Fixed oils (olive oil and almond oil): to soften  the wax   • Cerumenolytics: very safe products, but may  cause irritation (e.g. docusate,  paradichlorobenzene in chlorbutol, urea-  hydrogen peroxide).    Advise patient that use of cerumenolytics may  not lead to an immediate effect and that  repeated administrations for a few days may  be required until cerumen is removed.   • Serous: sensation of fullness in ear and hearing  loss. Patient complains of popping and cracking  noise when swallowing or yawning. Commonly  occurs after a respiratory tract infection  particularly in children and usually resolves  spontaneously. It is due to the presence of fluid  in the middle ear which does not drain  completely. There are instances where the  condition develops into a chronic serous otitis  media (glue ear) where patient needs to be  referred and assessed for the need of surgical  draining. In children, occurrence of the chronic  serous condition may affect hearing to an extent  that it impinges on speech development. In  chronic serous otitis media pain is absent.   • Suppurative (purulent): acute otitis media. Idas  an inflammatory and an infective component.  Patient presents with pain, hearing loss, high  fever and feeling ill. More common in children.  Condition requires referral since systemic anti-  infective agents are required.   • Oral administration of antibacterials; considered  drugs are usually amoxicillin or macrolides in  penicillin-allergic individuals.   This occurs as a result of quick descent from a high  altitude during air travel or travel to high altitudes. It  results because the eustachian tube fails to ventilate,  resulting in negative pressure in the middle ear. This  causes suction and retraction of the tympanic  membrane, leading to pain.   • Management: use of nasal decongestants (topical  or systemic) to clear the condition. Products may  be used prophylactically by patients who are at  risk of developing barotrauma during travel   • Jaw movements such as chewing, swallowing and  blowing may help alleviate the condition   • Occurrence of nasal congestion in patients with  rhinitis (allergic or infective) predisposes to  development of barotrauma.   • Is the pain constant or worsened by  chewing or pulling at ears? (Pain that is  associated with pulling at ears or  touching auricle indicates an external ear  problem)   • Do you have fever? (More likely to  indicate otitis media)   • Have you attempted to remove ear wax  during the last few days? (Ear wax  removal with cotton buds or  cerumenolytics may lead to irritation)   • Are your ear canals dry and flaky or wet  and sticky? (Dry and flaky indicate an  allergic reaction whereas wet and sticky  indicate a purulent infection.)   This is immobilization of the stapes in the middle ear  due to abnormal formation of new bone. It causes  deafness.   • Management: advise patient to restrict water  entering ear and care should be adopted when  using ear drops, particularly those containing  aminoglycosides and clioquinol.   • Do you have a cold or influenza:  nasal congestion? (May affect middle  ear leading to temporary hearing  loss)   • Have you been swimming during the past  few days? (Increased risk of swimmer’s  ear)   • Are your eardrums damaged from a  previous illness or injury? (To eliminate  tympanic membrane damage)   • Have you been travelling recently? (To  establish occurrence of barotrauma)   • Are you taking any medications? (Some  medications may cause tinnitus and  ototoxicity.)   This is infection and inflammation of the inner ear.  It can cause loss of hearing, vertigo, nausea and  vomiting. The patient needs to be referred and  antibacterial treatment is considered.   This is a sensation of instability, loss of equilibrium  or rotation caused by a disturbance in the semi-  circular canal of the inner ear. It may be centrally  induced or is due to peripheral system disorders (e.g.  Meniere’s disease (labyrinthitis) and vestibular  neuronitis.   Antihistamine products are used in nausea and  vertigo (e.g. prochlorperazine, cinnarizine), as well as  betahistine which is an analogue of histamine that is  specifically indicated for vertigo, tinnitus and hearing  loss associated with Meniere’s disease (see also  Chapter 18).   • Do you have any ear pain? (Ear pain that  disappears with discharge indicates otitis  media with ruptured tympanic  membrane)   This is damage caused to structures within the  inner ear which may lead to hearing or balance  disorders.   • Cochlear damage: associated with tinnitus which  may be constant or alternating. Tinnitus is  described as a ringing or humming sensation   • Vestibular and stria vascularis damage: results in  dysequilibrium and nausea   • Aminoglycosides: cause damage to the cochlea  and stria vascularis, leading to deafness and  vestibular disorders    • Loop diuretics: affect stria vascularis and the  cochlea producing tinnitus and deafness   • Platinum compounds (antineoplastic agents):  cause damage to the cochlea and stria vascularis  leading to deafness. Risk is greater for cisplatin  than for carboplatin and oxaliplatin   • Salicylates: in high doses cause damage to the  cochlea, leading to tinnitus and hearing loss.    • As opposed to aminoglycosides,  quinolones (e.g. ofloxacin) are not  associated with ototoxicity. They may be  preferred for topical administration in  otitis externa where tympanic membrane  damage cannot be excluded.   • Toxicity with loop diuretics is more likely  with intravenous administration,  particularly in patients with impaired  renal function.   • The use of ototoxic products should be  avoided in patients with a history of  hearing loss and tinnitus.   • Analgesic ear drops should not be recommended  for earache. The underlying condition should be  identified.   • Cerumenolytic ear drops should not be  recommended unless the presence of excess ear  wax has been identified.   • Accompanying symptoms occurring with ear  disorders that require immediate referral include  nausea and vomiting (may be indicative of   2 Give one example of a product that could be  used in the management of Meniere’s disease.  Describe the characteristics of Meniere’s disease.   3 What advice should be given to a patient who  is complaining of impacted cerumen?   1 Barotrauma results when there is a quick  descent from high altitudes either during flying  or when travelling in mountainous areas. The  eustachian tube fails to ventilate, resulting in  negative pressure in the middle ear, causing  suction and retraction of the tympanic  membrane triggering pain. Barotrauma can be  minimised by using nasal decongestants either  topically or systemically in high-risk patients or    where nasal congestion is severe and by  chewing, blowing or swallowing.   2 The symptoms of Meniere’s disease are caused  by increased pressure of the fluid in the  labyrinth (consisting of the cochlea and  vestibular system). The cause of the condition is  not well understood. The patient suffers attacks  of vertigo which may increase in severity and  frequency. Patient presents with nausea and  vomiting, tinnitus and a perceptive deafness.  An example of a product that may be used is  betahistine, which is a drug that is specifically  indicated for Meniere’s disease. Antihistamines  and phenothiazines used in the management of  nausea and vomiting may be considered.   3 To avoid using cotton buds and getting water in  the ears since these may precipitate further the  symptoms of impacted cerumen. Advice may be  given on the use of cerumenolytic products.   Allen S (2006). Outer and middle ear problems. Pbarm J  276: 83-86.   Coco A S (2007). Cost-effectiveness analysis of treatment  options for acute otitis media. Ann Fam Med 5: 28-29.    • To appreciate implementation of pharmaco-  therapeutic and non-pharmacotherapeutic  approaches to musculoskeletal problems.   Musculoskeletal disorders can affect bones, muscles or  soft tissues (tendons, bursae). Pain is a characteristic  symptom of musculoskeletal disorders. Evaluating  onset and location of the pain helps to make a clinical  decision as to the most appropriate line of action.   • In sprains and strains, mobilisation,  strengthening and coordination exercises are  recommended to decrease risk of scar tissue  formation that may limit movement.   • Damage to the ligaments, vertebrae, spinal cord  or nerve roots in the neck region, caused by  sudden jerking back of the head and neck   • Injury to small spur of the vertebrae at the tip of  the spine, the coccyx   • Generally onset is insidious and it is usually  difficult for patient to recall injury.   • Excess force acting on the insertion of the  tendons of the forearm muscles   • May be related to repeated activities including  lifting heavy objects.   • Common condition that occurs after patient  carries out activities that are not normally  undertaken (e.g. exercise by an individual used to  a sedentary lifestyle).   • Commonly occurs in the knees (housemaid’s  knee) in individuals who tend to kneel regularly  and the elbows (student’s elbow) in individuals  who put pressure on their elbow while working  at a desk.   • Painful condition where there is a spasm of one  or more muscles in the neck due to straining of  muscles   • Neck mobilisation away from affected side is  possible, but there is difficulty and pain in  turning towards affected side   • Refer if patient has a history of arthritis or there  is presentation of sharp pain.   • Inflammation of the fibrous supporting tissue  surrounding the shoulder joint   • May lead to development of frozen  shoulder due to scarring or fibrosis of the  muscles.   • May occur after strenuous work (lumbago)  or when patient undertakes activities that  he or she is not used to doing (e.g.  gardening).   • If severe and debilitating, causing difficulty with  mobility or radiating from the back down to  the legs, referral is required since symptoms  indicate sciatica which requires further  evaluation.   • If pain is just below ribcage in the middle part to  side of back, or is associated with abnormality in  passing urine, refer for assessment of occurrence  of kidney problems.   • Chronic back pain (occurring for more than  3 months) indicates underlying pathologies  rather than injury. Examples include  osteoarthritis, inflammatory conditions (e.g.  arthritis, ankylosing spondylitis).   Occurrence of fever, bowel or bladder incon-  tinence, numbness, worsening pain or referred  pain to legs require referral.   • Advise patient on good posture and on exercise  where indicated   • Consider use of support products (e.g. soft  collars in whiplash, back supports in back pain,  compression supports in sprains, foam supports  in bursitis).   • Avoid sitting in same position for long  periods of time   • Prolonged rest for muscle injuries is usually  discouraged because the collagen scar tissue  formed is unable to contract and repair is  associated with some loss of flexibility.   • Administer cold pack for 30 minutes, repeating  every 2 hours   • Care should be employed not to damage skin  by application of cold compress. If ice is used,  this should not be applied directly to the skin  but first wrapped in cloth to avoid burning the  skin.   • Raise injured area to aid drainage of fluid and  reduce swelling.   • Use of NSAIDs is usually warranted due to  the requirement of an analgesic and an  anti-inflammatory component. They may   be used provided that patient is not asthmatic,  is not suffering from or has a past history  of peptic ulcer, and is not taking  warfarin.   • NSAIDs may be administered topically, thus  reducing risks with use of NSAIDs. Oral  administration is considered when local  administration is not providing the required pain  relief.   • Paracetamol and compound preparations  containing opioid analgesics may be considered  in patients where NSAIDs cannot be  recommended.   • Cause vasodilatation inducing a feeling of  warmth over the area   • The act of massage during the application of the  product is known to relax muscles and it may  disperse prostaglandins responsible for pain and  inflammation   • Disadvantage: strong smell associated with the  active ingredients may be unacceptable to  patients.   • Advise patient to drink water, exercise muscle to  relax it   • Sometimes application of cold compress may  offer relief and ibuprofen may be considered as  an analgesic.   Use of diuretics (not the potassium sparing  ones) may lead to potassium deficiency if  potassium supplementation is not adequate.  This may present with muscle cramps.   This is an area of skin discoloration caused by the  escape of blood from ruptured underlying blood  vessels as a result of injury. Skin discoloration is  initially red or pink, gradually becoming blue, green  and yellow.    • Topical application of heparinoids which disperse  oedematous fluid in swollen areas is considered.   a result of an injury of which the patient may not  be aware.   • Management of acute musculoskeletal problems  requires recommendations related to use of  support products and warrants referral to  physiotherapists to control pain associated with  the condition.   • Concomitant symptoms indicating organic illness  or chronic conditions require referral for further  assessment.   1 Write briefly on differential diagnosis of  sciatica and its management.   2 Give one example of a non-steroidal anti-  inflammatory drug that can be used topically  as well as systemically.   1 Lumbago, sciatica and kidney problems may  all present with back pain. Lumbago is back  pain that occurs after strenuous work. If back  pain is severe and debilitating, causing  difficulty in mobility or radiating from the  back down to the legs, then these factors are  used to indicate the possibility of sciatica and  the patient must be referred. If the back pain  is just below the ribcage in the middle part to  the side of the back or is associated with  abnormality in passing urine, this suggests a  kidney problem and the patient must be  referred. Sciatica is managed using non-  steroidal anti-inflammatory drugs such as    diclofenac as well as the B vitamins 1, 3 and  6 to strengthen the nervous system.   2 Diclofenac available as gel, gel patch,  cutaneous solution, eye drops, tablets,  dispersible tablets, capsules, suppositories  and injection.   Braund R (2006). Should NSAIDs be routinely used in the  treatment of sprains and strains? Pharm ] 276:  655-656.   Dickson J (2006). Promoting self care of joint pain. Pharm  ] 277: 285-288.   • To identify presentation of symptoms related to • To appreciate the use of non-prescription   • To develop skills required for the management of  these symptoms   The occurrence of abdominal pain is a symptom  relating to a multitude of diagnoses (e.g. gastro-  intestinal and urinary tract disorders) which requires  assessment to identify the system affected.   Table 60.1 lists the causes of abdominal pain and  diagnosis of upper and lower abdominal pain is  summarised in Figure 60.1.   • Onset is sudden in many cases occurring a few  hours after a meal; fatty foods aggravate the pain   • Pain has been present episodically for  more than 7 days   • Chronic back pain and occasional  fainting; history of myocardial infarction:  may indicate cardiovascular disorders.   Heartburn is the reflux of gastric contents  that are particularly acidic in pH into the  oesophagus, which cause an irritation of the  sensitive mucosal surface.    • Raise head of bed to decrease occurrence of  heartburn at night   Occurrence of heartburn in patients older  than 50 years who do not generally have a  history of heartburn or in patients where  symptom has a long-standing duration raises  concern. In these scenarios, referral should be  considered to investigate serious conditions  (e.g. carcinoma).   This is poorly localised abdominal discomfort  usually brought about by excess food and alcohol.  Management includes maintenance of good hydra-  tion, use of antacids to alleviate discomfort and if  gastric pain is present use of H 2 -receptor antagonists  (e.g. ranitidine).   • Ideally simple or functional constipation should  be corrected by increasing fibre and fluid intake.   • For long-term use, bulk-forming laxatives (e.g.  ispaghula husk) are preferred.   • Short-term use of stimulant laxatives (e.g.  bisacodyl, senna) is justified to re-establish a  bowel habit if dietary measures and bulk-forming  laxatives have failed.   • The use of laxatives in children is undesirable;  consider glycerin suppositories or enemas.   • Consider use of antispasmodic drugs (e.g.  hyoscine), especially in patients suffering from  gastrointestinal colic.   • Patients with diarrhoea should be  referred to a doctor if it persists for more  than:   - 2 days in children under 3 years and the  elderly   • Risk of dehydration is higher in children and  older persons.   • Oral rehydration salts are the mainstay of  treatment. They replace lost water and  electrolytes thus preventing dehydration.   • Loperamide may be used in adults as an adjunct  to oral rehydration salts to reduce discomfort  due to symptoms.    Patients presenting with a change in bowel  habit, bloody diarrhoea and signs of dehydra-  tion should be referred for further investi-  gation to assess for the occurrence of  inflammatory bowel disease and carcinoma.   This is inflammation of the bladder and urethra char-  acterised by frequent urge to pass urine with a  burning or stinging sensation on urination. It is  caused by a bacterial infection (common micro-  organisms involved include Escherichia coli, staphy-  lococci and enterococci).   • Commonly occurs in women; occurrence in  males is usually associated with underlying  pathology (e.g. benign prostatic hyperplasia).  Presentation in male patients requires referral.   • Alkalinising agents: salts consisting of sodium  bicarbonate, sodium citrate, potassium citrate   • Alkalinising agents are relatively safe and free  from unwanted side-effects. If condition does not  resolve, patient requires antibacterial treatment.  Usually trimethoprim, nitrofurantoin, co-  amoxiclav (unless patient is hypersensitive),  cephalosporins or quinolones are used    • Care when using alkalinising agents in patients  with uncontrolled hypertension or electrolyte  imbalance.    Occurrence of cystitis may lead to develop-  ment of pyelonephritis which presents with  symptoms of systemic infection including  fever, chills and pain. This scenario requires  referral. In acute pyelonephritis, antibacterial  therapy is required (e.g. quinolone).   This is an opportunistic infection caused by Candida  albicans occurring in women between 16 and 60 years  of age. Symptoms include itchiness, creamy-coloured  discharge and dysuria.   • Single-dose intravaginal imidazole preparations  (e.g. clotrimazole, econazole, miconazole).  Applied at night. Patient is advised to avoid  nylon underwear and to use unperfumed soap.  Imidazole creams are applied topically.   • Alternative option: povidone-iodine applied  twice daily for 14 days. Disadvantages of  povidone-iodine: it stains and inconvenience of  dosage regimen.   • Systemic treatment may be considered in severe  cases, in recurrent infection or failure of  treatment with imidazoles.   Topical imidazole preparations should be  recommended to the partner to avoid re-  infection.   • Diabetics: thrush may indicate  uncontrolled disease; suggest review of  diabetes control   • Strong smelly discharge: indicates  bacterial vaginosis or trichomoniasis  (where metronidazole or clindamycin is  recommended)   • Women under 16 or over 60 years: very  rare condition in these age groups.   • Swelling and dilatation of the veins that line the  anal canal   • Precipitating factors: long standing, constipation  or straining at stool, pregnancy.    Anal bleeding could be a sign of minor condi-  tions such as anal fissure but may indicate  gastrointestinal haemorrhage due to ulceration  or carcinoma.   • Anaesthetics (e.g. benzocaine): provide  temporary relief from pain and itching, may  cause sensitisation   • Other examples: shark liver oil, yeast cell extract:  provide a protective coat.   • Preparations with local anaesthetic or  astringents are preferred for routine use.   They may be applied twice daily and after  each bowel movement.   • Products containing hydrocortisone may  be useful when there is severe pruritus  and inflammation or when other products  were not effective. They should be used  short term.   • Oral phlebotropic drugs that protect the  endothelium, improve lymphatic drainage and  increase venous tone   • They may be recommended in acute attacks or  for chronic treatment.   • Females of the worm Enterobius vermicularis  migrate to the caecum and the anus at night to  lay their eggs in the perianal area. They attach to  the skin with a sticky, highly irritant fluid.   • Treatment offered to whole household due to  risk of cross-infection.   • Poorly absorbed from the gastrointestinal tract  and so associated with minimal side-effects.  Exerts a topical action on the organism in the  gastrointestinal tract   • Adults and children over 2 years: 100 mg  mebendazole stat dose, repeat after 2 weeks to  ensure eradication.   • Presentation of symptoms of abdominal pain  should be evaluated for signs of underlying  pathology.   • Repeated presentation of symptoms of  abdominal pain or perianal or perivulval pruritus  require further assessment.   • Where laxatives are required for chronic use,  bulk-forming laxatives or osmotic laxatives  should be considered. In children and the elderly  where faecal impaction is suspected, glycerin  suppositories should be the drug of choice.   • In diarrhoea, oral rehydration salts are the  mainstay of treatment and signs of dehydration  should be identified.   • Management of haemorrhoids requires routine  use of topical products or systemic phlebotropic  agents.   • In cystitis a short course (2 days) of alkalinising  agents is recommended together with advice to  increase fluid intake. If condition deteriorates or  symptoms do not subside, antibacterial therapy is  recommended.   • In vaginal thrush treatment is based on single-  dose intravaginal imidazole preparations with  topical imidazole creams or single-dose oral  fluconazole.   2 When is the use of a laxative not recommended  for the management of a patient presenting with  constipation?   3 Give one example of a topical agent and of a  systemic product that could be recommended in  vaginal thrush. For each example, state dosage  regimen.   1 An anal fissure is a small split or tear in the  anal mucosa that may cause painful bowel  movements and bleeding. There may be blood  on the outside of the stool or on the toilet tissue  following a bowel movement. Anal fissures are  extremely common in young infants but may  occur at any age. Most fissures heal on their  own and do not require treatment. The  incidence of anal fissures decreases rapidly with  age. Fissures are much less common among   In adults, fissures may be caused by  constipation, the passing of large, hard stools  or prolonged diarrhoea. They may occur after  pregnancy and in Crohn’s disease. Stool  softeners and increased fibre in the diet are  recommended.   2 No laxative should be recommended if  intestinal obstruction is suspected.   3 Topical product: miconazole, dosage regimen:  insert one ovule at night as a single dose.  Systemic product: fluconazole, dosage regimen:  stat dose 150 mg orally.   Mashburn J (2006). Etiology, diagnosis, and management  of vaginitis. J Midwifery Womens Health 51: 423-430.   Nickel J C (2005). Amoxicillin/clavulanate for the treat-  ment of uncomplicated cystitis in women: a historical  perspective. Nat Clin Pract Urol 2: 364-365.   Xu J, Schwartz K, Bartoces M, Monsur J, Severson R and  Sobel J D (2008). Effect of antibiotics on vulvovaginal  candidiasis: a metronet study. J Am Board Fam Med 21:  261-268.   • To develop skills required in the recommendation  of the preparation of medical first aid kits and the  use of medicines in the management of travel-  related disorders   Individuals need to receive information on  prevention of travel health risks, preparing medical  first aid kits and their use, and on the management of  health-related problems during travel.   The support and information required depend on  the destination (westernised countries or tropicals),  duration of travel and type of travel (e.g. skiing  holidays, back-packing, expedition).   When suggesting items for a medical kit, information  on destination is required. In some countries (e.g.  tropical or developing countries) it may be a problem  to purchase basic medical first aid items, including  bandages. Availability of medicines and quality of  medicines that are accessible may vary in developing  countries.   • Packaging: bulky packaging, liquid formulations  are difficult to carry (e.g. alcohol swabs are  preferred to surgical spirit)    • Controlled drugs: legal requirements between  countries vary (e.g. amounts of narcotic products  that can be carried may be restricted and need to  be declared)   • Prescription-only medicines such as antibacterial  agents (oral therapy, ear drops), prednisolone  tablets for ‘just-in-case’ scenarios particularly if  access to medicines may be limited in country  and area visited.   • Dermatological preparations: antifungal,  hydrocortisone, antiseptic, soothing (e.g.  calamine lotion) and moisturising cream.    • Hypersensitivity - if a medical first aid kit is  being prepared for a group of individuals then  one should consider possibility that some  members may be hypersensitive. In such a  scenario consider inclusion of macrolides   • Not expensive since product may not be used  at all   • Antibacterial agents considered: co-amoxiclav  and macrolides (respiratory and community-  acquired pneumonia, urinary tract infections and  wound damage), ciprofloxacin (bacterial  travellers’ diarrhoea and urinary tract infections),  metronidazole (to be used in protozoa-induced  travellers’ diarrhoea).   Accessibility to medications and to good-  quality medicines may vary when travelling  to foreign countries. Medical first aid kits  should be adapted for particular travellers  and specific type of travel.   • Patients may be referred to the national  immunisation centre for information on travel  vaccinations.   • Live-attenuated vaccines (e.g. Bacillus  Calmette-Guerin (BCG) vaccine, oral polio  vaccine) offer immediate protection and tend to  produce a more durable immunity than  inactivated vaccines.   • Side-effects: discomfort at site of injection, mild  fever and malaise. Some may produce a mild  form of the disease.   • Contraindications: acute illness, anaphylaxis with  a preceding dose of a vaccine, hypersensitivity to  egg. Live-attenuated vaccines should be avoided  in pregnant women.   Risk of hepatitis A infection is increased when  travelling to high-risk areas and frequent   In motion sickness, the brain is responding inappro-  priately to certain types of ‘unnatural’ forms of  motion. There is a physiological response to sensory  mismatch.   • Predisposing factors: gender (females), age (3-12  years), mental state (anxiety), external factors  (closed spaces)   • Sit in front seat when travelling in vehicles on the  road, on the ship go on deck and follow horizon   • Use of wrist bands, particularly useful in patients  who cannot tolerate medications or when  medications are contraindicated.   Motion sickness products are available in  different dosage forms, namely transdermal  patch, chewing gum and oral tablets. A dis-  advantage of motion sickness medications is  the occurrence of sedation as a side-effect.  Medication should be used to pre-empt  occurrence of nausea and vomiting before  there is onset of symptoms.   This occurs due to a disruption of the circadian  rhythm, probably as a result of the effect of light on  the retina which suppresses melatonin release from  the pineal gland.   • Recovery after eastward flight is longer than that  after westward travel.   • Adapt to local time and during flight adapt to  destination time   • Avoid large meals, excessive caffeine and alcohol  intake during flight   • Melatonin supplements are licensed for this  indication in some countries. Melatonin may be  used to relieve jet lag and is taken before bedtime  at the destination country.   When flying keep well hydrated, avoid  alcohol and large meals, wear comfortable  clothing and shoes, move around and perform  leg-wrist-neck exercises.   • Maintain mobility and undertake ankle and foot  movements during travel   75 mg daily dose started a few days before travel  and continued for a few days after reaching final  destination.   Recommendations to prevent travel-related  deep vein thrombosis should be presented to  all travellers. Emphasis should be given to  those undertaking travel that is of a longer  duration than 5 hours or those who have a  minor or moderate risk.   - effectiveness may deteriorate on storage; check  validity of product that has been opened for  some time   - protection against UVB and UVA (zinc oxide,  titanium dioxide, camphor derivatives,  benzophenones).   This occurs due to blockage of sweat glands and  leakage of sweat to surrounding epidermal tissue. It  affects skin folds.   • Management: calamine lotion which can be  applied repeatedly; hydrocortisone cream to be  applied to small areas to remove inflammation;  ascorbic acid supplementation for mucous  membranes.   This is a condition when sweat and thermoregulatory  mechanisms fail. It is characterised by a rapid rise in  body temperature.   • Symptoms: thirst, dry lips and mouth, decreased  urine output, giddiness, neuropathy, slight rise in  body temperature, rapid breathing, muscle  cramps   This is reported to occur at altitudes of >2000 m and   • Factors that increase risk: history of respiratory  disorders, speed of ascent, physical exertion,  cold   • Symptoms: headache, loss of appetite, nausea,  vomiting, insomnia, dizziness, chest tightness   • May develop into high altitude pulmonary  oedema, high altitude cerebral oedema   • Travellers should be advised on non-  pharmacotherapeutic measures to prevent  occurrence. They should be advised to seek  referral if condition occurs.    When travelling to areas where there is the  possibility of contaminated water:   • Information on vaccination required for travel  should be sought in advance of travelling since  some vaccinations are associated with a time lag  before immunity is achieved.   • Travellers should be advised to take the  required amount of chronic medication for the  duration of travel and also to take a supply of  any medications that are required occasionally.   It is advisable that chronic medications are  carried in the carry-on luggage to avoid  problems if checked-in luggage is mislaid or  delayed.   • Good travelling practice should be adopted when  flying to avoid dehydration, minimise impact of  jet lag where applicable and decrease risk of deep  vein thrombosis.   • When travelling to areas where there is a high  risk of contaminated water, food and water  hygiene are essential to minimise occurrence of  disease (e.g. diarrhoea, hepatitis A).   • During travel the body is exposed to increased  stress and individuals are at a higher risk of  developing infections (e.g. common cold). The  use of multivitamin preparations may be  considered for individuals who are undertaking  frequent travel, travelling to developing areas or  at increased risk of developing infections.   1 List four factors that present a moderate risk  of travel-related deep vein thrombosis (DVT).  What prophylactic measures could be followed?   2 What considerations are necessary when  recommending a product for prophylaxis of  motion sickness?   3 What advice should be given to patients who  present with prickly heat?   1 Recent heart disease, pregnancy, recent major  leg injury or surgery, family history of DVT.  Prophylaxis: consider use of support hosiery  (stockings), prophylactic aspirin; advise on  importance of proper hydration during travel  and to maintain mobility and carry out  ankle-foot exercises.   3 Use loose-fitting, light clothing. Apply  calamine lotion and prickly heat powders for  symptomatic relief, consider use of  hydrocortisone cream to reduce inflammation  and take ascorbic acid (vitamin C)  supplementation to prevent epidermal damage.   Goodyer L I (2004). Travel Medicine for Health  Professionals. London: Pharmaceutical Press.   • To appreciate use of pharmacy literature and • To develop skills to use information presented on   These are listings of drugs used in a particular  setting. For example, the British National Formulary  (BNF) is published jointly by the British Medical  Association and the Royal Pharmaceutical Society of  Great Britain in March and September every year.   The BNF includes key information on the  selection, prescribing, dispensing and admin-  istration of medicines. Medicines generally  prescribed in the UK are covered and those  considered less suitable for prescribing are  clearly identified. Little or no information is  included on medicines promoted for purchase  by the public. 1   • Notes on prescribing in palliative care, elderly  people, dental practice   Drug monographs provide information on indica-  tions, cautions, contraindications, side-effects and  dose. For preparations information on dosage forms  is available; manufacturer, prescription-only status  and price in sterling provided.   A pharmacopoeia is a compendium containing  descriptions, standards and official assays for medical  substances. The concept of pharmacopoeias has long  been established. The publication in Nuremberg,  Germany of the Dispensatorium Pbarmacorum  Omnium in 1546 is an early example and subse-  quently in 1561 in Basel such a publication was  prepared which carried for the first time the term  ‘pharmacopoeia’ in the title.   In 1618, the first London Pharmacopoeia was  published. It included 1028 drugs and 932  compounds. With time, national pharmacopoeias  replaced pharmacopoeias that were established for  districts or cities. In the UK the Medical Act of 1858  established that the British Pharmacopoeia (BP)  should be prepared as a single publication that  encompasses information presented by those of  London, Edinburgh and Dublin. More recently  regional pharmacopoeias replaced the national docu-  ment and today the European Pharmacopoeia (EP) is  adopted within member states of the European  Union. Attempts to harmonise the US Pharma-  copoeia, the Japanese Pharmacopoeia and the Euro-  pean Pharmacopoeia are ongoing. In addition the  World Elealth Organization issues the International  Pharmacopoeia.   • Published by the European Department for the  Quality of Medicines within the Council of  Europe.   • Establishes standard procedures for analysis and  specifications of active substances, excipients,  dosage forms and containers.   • Monographs are intended for regulatory  authorities, quality control laboratories,  manufacturers of active ingredients, excipients  and medicinal products.   The aim of Martindale is to provide healthcare  professionals with unbiased evaluated  information on drugs and medicines used  throughout the world. Martindale is based on  published information and more than 37 500  selected references are included. 2   • Pharmaceutical Journal (Pharm J): published  weekly by the Royal Pharmaceutical Society of  Great Britain   • American Journal of Health-System Pharmacy  ( AJHP ): published twice monthly by the  American Society of Health-System Pharmacists   • Journal of the American Pharmacists Association  (JAPhA): published twice monthly by the  American Pharmacists Association   • International Journal of Pharmacy Practice  (IJPP)\ published quarterly by Pharmaceutical  Press and presents reviews and original studies in  the areas of use of medicines and pharmacy  practice   • Clinical Pharmacist : published by Pharmaceutical  Press, United Kingdom and incorporates the  journal Hospital Pharmacist which was  published until 2008. It provides information on  current practice that is of direct relevance to  clinical pharmacy   • British Medical Journal (BMJ): published weekly  by the British Medical Association   • The Lancet: published weekly and presents  research studies in the medical and therapeutics  field   • Journal of the American Medical Association  (JAMA): published weekly by the American  Medical Association.   Traditional evaluation skills are necessary to assess  information from the internet. These include:   Limitations to using internet sources for retrieval  of drug information include that information may  not be peer reviewed and it may reflect the views of  the person or persons who posted the information.  Therefore it is essential that internet sources are first  evaluated prior to implementation.   • Interpretation and evaluation of literature  available should be carried out to support  pharmaceutical care programmes,   • Drug information services are intended to  provide adequate and timely drug information to  health professionals.   • Medical and pharmacy literature is used in the  preparation of educational programmes and  written educational materials that are intended to  be used by patients and their carers.   2 Give examples of publications that could be  used by a pharmacist when providing a drug  information service.   3 What action should be taken to ensure quality  service and reduce risks of errors in  documenting drug information?   1 A pharmacopoeia is a compendium containing  descriptions, standards and official assays for  medical substances. Examples include the  British Pharmacopoeia and the European  Pharmacopoeia.   2 British National Formulary, Martindale: The  Complete Drug Reference, British National  Formulary for Children, Stockley’s Drug  Interactions.   3 Define the information requested. Use robust  procedures in written format (e.g. use of check-  lists). Ensure that information given is accurate,  up to date and acquired from a reliable source.  Verify data given (safe). Comply with legal and  ethical requirements. Use resources of adequate  quality and extent. Personnel sourcing and  documenting drug information should be trained  in this activity. Document all steps carried out,  source of request, personnel pursuing the request.    Dunlop D M and Denston T C (1958). The history and  development of the British Pharmacopeia. BMJ ii:  1250-1252.   Kiley R (2003). Medical Information on the Internet: A  guide for health professionals , 3rd edn. London:  Churchill Livingstone.   Joint Formulary Committee (2008). British National  Formulary , 58th edn. British Medical Association and  Royal Pharmaceutical Society of Great Britain.  Paediatric Formulary Committee (2008). British National  Formulary for Children. London: Pharmaceutical  Press.    Sweetman S C, ed. (2007). Martindale: The Complete Drug  Reference , 35th edn. London: Pharmaceutical Press.   1 Joint Formulary Committee British National Formu-  lary, 57th edn. London: British Medical Association  and Royal Pharmaceutical Society of Great Britain,  2009.   2 Sweetman S C, ed. Martindale: The Complete Drug  Reference , 35th edn. London: Pharmaceutical Press,  2007.   • To describe the approach towards scientific writing • To develop skills of scientific report writing,  of abstracts and reports   • Review article: critical evaluation of material that  has already been published   • Original paper: an original study; usually  presented in the format of: Introduction,   An abstract is a summary describing the study and  presenting salient points from the research. It should  present:   Scientific reports should be based on unbiased back-  ground information. Sound methodology needs to be  presented. Data handling should be robust and  reliable. Salient observations are emphasised and  discussed.   • Table of contents: clear headings which indicate  a consistent and systematic approach   Report writing means rewriting. An attempt  to draw a first draft may be difficult initially  but once there is a draft it is easier to re-  arrange. Allocate enough time to be able to  review drafts.   • Should not be an exhaustive historical review  unless the report is looking at a review of works  done. Background to the study should be  presented.   • Include label and figures (numbers or percentage)  for each sector   • Use bar chart to compare groups or show  changes over time   • Adopt a horizontal positioning if using more  than six compartments   • Use line charts to compare results over many  points in time.   • Describe whether results support or do not  support original hypotheses   • Compare with other studies carried out  previously or in other scenarios   • For numbers greater than 100, report in  percentage and numbers   • Do not repeat data presented in figures or  tables in text or vice versa.   • Avoid plagiarism: direct quotations vs  paraphrasing. All quotations must be  acknowledged as being quotes by using quote  symbol and indicating source. For paraphrasing,  reference should be indicated.   • Document the write-up, report and paper with  regard to sources used to provide the necessary  background   • Provide the information necessary to identify and  retrieve every source   • Maintained by the International Committee of  Medical Journal Editors (ICMJE)    • Aims to maintain a standard approach to  documenting sources used in a scientific  report.   • Title of journal abbreviated according to Index  Medicus (see http://www.nlm.nih.gov).   Yeung V, Funnell R, Harrison R. Advice for  pharmacists who need to comply with clinical trials  regulations. Pbarm J 2008; 281: 193-195.   Royal Pharmaceutical Society of Great Britain.  Protocols and staff training to be added to Code of  Ethics. Pharm J 1996; 253: 124-127.   Anon. Creating a more professional image for a  pharmacy. Pbarm J 1991; 246: 304-305.   Kouimtzi M. Writing a research report. In: Stuart  MC, ed. The Complete Guide to Medical Writing.  London: Pharmaceutical Press; 2007, pp. 63-74.   Health Education Authority (UK). Helping People  Change: Audit tool guidelines. London: Health  Education Authority; 1995.   Mosby’s Medical, Nursing & Allied Health Diction-  ary, 5th edn. St Louis: Mosby; 1998. Bronchoscopy;  pp. 231-232.   Lowey AR, Jackson MN. A survey of extempora-  neous preparation in NHS trusts in Yorskshire, the  North-East and London. Hospital Pharmacist [serial  online] 2008; 15: 217-219 [cited 2008 September 9],  Available from: URL: http://www.pharmj.com/pdf/  hp/200806/hp_200806_papers.pdf.   • Vancouver system: numbered consecutively in the  order in which they are first mentioned in the  text; the references are listed consecutively by  number at the end of the text:   In 1968, Denzin and Mettlin described the  pharmacy profession as an occupation ‘which  has taken some, but not all, of the characteristics  commonly ascribed to the professions.’ 1 A study  to test whether this practice affects service  provided showed that pharmacists were similarly  motivated irrespective of their area of practice. 2   • Harvard system: author-date citation, the  references are listed in alphabetical order at the  end of the text:   In 1968, Denzin and Mettlin described the  pharmacy profession as an occupation ‘which  has taken some, but not all, of the characteristics  commonly ascribed to the professions.’   A study to test whether this practice affects  service provided showed that pharmacists were  similarly motivated irrespective of their area of  practice (Kronus, 1975).   The total cost spent on health-care in major  European countries has risen since the 1960s  ( Zayed and Manning, 1995).   Participation of community pharmacists in  practice-based research projects is a further  contribution to professional developments  (Ellerby et al, 1993).   Smith F. Referral of clients by community  pharmacists in primary care consultations. Int J  Pharm Pract 1993; 2: 86-89.   Smith F, Salkind MR. Counselling areas: views of  community pharmacists and clients. Pharm J  1988; 241(suppl): R7.   Smith F, Salkind MR. Presentation of clinical  symptoms to community pharmacists in London.  J Soc Admin Pharm 1990; 7: 221-224.   Smith F, Salkind MR, Jolly BC. Community  pharmacy: a method of assessing quality of care.  Soc Sci Med 1990; 31(5): 603-607.   • A literature search should be comprehensive and is  an ongoing process throughout the entire study.    • Scientific writing should be based on statements  that indicate facts and should avoid bias. Data  presented should be robust, reliable and valid.   1 To acknowledge the work of others and avoid  plagiarism. To indicate when one is quoting  other works, paraphrasing or summarising  ideas put forward by others. To identify the  reliability and the accuracy of the data, work  quoted and sources used. To allow reader to  locate sources used, read the original work and  confirm data from cited works. To support the  arguments made in the document. To identify  which literature was consulted in drawing of  conclusions. To follow harmonisation and  academic robustness in medical writing.   Stuart M C, ed. (2007). The Complete Guide to Medical  Writing. London: Pharmaceutical Press.   • To identify processes involved in planning of a  research study    • To develop skills required for oral communication  and poster preparation during dissemination of a  project.   In a research study, principles of rigour need to be  employed to ascertain a sound methodology and  validity of results.    The planning stage of the research study is an  important aspect since it may be very difficult  to remedy steps that were not considered at  this stage. For example, it would be impos-  sible to interview patients before an inter-  vention if the intervention has already  commenced.   • To contemplate advantages and disadvantages of  different approaches and make choices:   • A technique by which priorities of participants  can be identified and insights gained into their  reasoning and argument   • Interviewer needs to lead discussion and be able  to discover as many issues relating to the area of  study as possible   • The more concrete and detailed the account of  each issue the better.   • Data relate to actual events and not to estimates  or reports by participants.   • Major disadvantage is the ‘Hawthorne effect’  where participants being observed, knowingly or  unknowingly, modify their behaviour.   • Risk: the number of events that occur in a  defined time period divided by the average  population at risk   • Standardised mortality rate (SMR): the observed  crude death rate divided by the expected crude  death rate   • Cost-effectiveness analysis (CEA): the  examination of the costs of two or more  programmes that have the same clinical outcome  as measured in physical units (e.g. lives saved,  reduced morbidity)   • Cost-utility analysis: estimates patient preference  for a particular intervention in terms of the  patient’s state of well-being. The product of  utility and life-years gained provides the term  quality-adjusted life-years (QALY).    Quality-adjusted life-years (QALY) is a tech-  nique used to determine the most efficient and  effective treatment that should be made avail-  able to patients. QALY is meant to measure  outcomes of healthcare (e.g. pain relief,  anxiety reduction, morbidity improvement  and life extension). The use of QALY in deter-  mining benefit of drug action has to be made  in the light of ethical issues, social justice and  moral legitimacy.   • A clearly defined group of individuals studied in  a period of time   • Enables collection of data on the course of events  providing information on timing of events   • Limitations: time factor, follow-up and attrition,  expenses required to run the study for a long  period of time that is essential for follow-up.    • Use of table of random numbers or throwing a  dice to pick up sampling units that are selected   • Population is divided into subgroups or strata  (e.g. districts, age).   • Subgroups are identified from expert opinion,  literature review and should be related to  outcome of study.   • The method employed in simple random  sampling is undertaken for each subgroup.   • Advantage: better representation of elements in  the population that may affect the study  hypothesis.   • Double-blind: participants and researchers are  not aware of how the groups are divided   • Single-blind: participants do not know in which  group they are   • Matching between groups is required to  eliminate bias due to external factors (equating  experimental and control groups) (e.g. for age,  gender, level of education).   • Random (probability) sampling is desirable as  this allows the application of probability  statistics and generalisation of the data to the  population from which the sample is drawn  (Figure 64.2).   • Every sampling unit has an equal chance of being  selected   • Example: 200 patients are required from a  sample frame of 1000 patients   • Example: cluster shopping areas and then include  all units (pharmacies) in shopping areas  identified   • Increasing sample size leads to increase in  precision of results but may require more costs  and more time   • Sample size is estimated by deciding the level of  accuracy expected (standard error)   • When planning the study and recruiting sampling  units, it is essential to account for non-response  error (uninterviewable, not found, refusals, not  suitable for analysis). So a greater number of  sampling units should be used to make up for the  attrition that will occur during the study so as to  achieve the required sample size by the end of  the study.   • Identify larger number of eligible sampling  units than needed (a balance is required  since increasing the number increases the  costs)   • Always select a larger sample initially in  order to compensate for omissions   • Clusters of elements - sampling units  listed in clusters and identification  of individual sampling units is  impossible   • Blank elements - unlabelled sample for  analysis, small volume of sample to  enable analytical analysis, blank or  incomplete questionnaire.   • Clearly establish the objectives of the  questionnaire: what information is needed?  Refrain from asking questions that bring  information that is not related to these  objectives   • Adopt appearance and layout that make the  document easy to complete   • During the pilot phase assess applicability,  validity and reliability testing    When designing questionnaires bear in mind  the method of administration and data  analysis.   • Questionnaires may be carried out by interview:  formal, semi-structured, unstructured. The  interview method ensures response rate but more  time is required from the research group   These capture what people actually do, compared  with what people state that they do, which is reported  in a questionnaire.   Software packages, e.g. SPSS (Statistical Package  for the Social Sciences), BMDP (Biomedical Data  Package) and Minitab Statistical Software may be  used to calculate:    • Significance levels: Pearson’s chi-squared or  Mann- Whitney test on non-parametric  data (nominal or ordinal data); Student’s  t-test or analysis of variance (ANOVA) on  parametric data (interval and ratio    Significant testing is based on the laws of  probability which determine the probability  that the differences would have occurred in  any case (by chance). The probability level  usually accepted is expressed as P values less  than 0.05, implying that it is 95% certain that  the difference is not due to chance.   • Appropriate research design: methodology  adopted is sound and robust to generate data  that meet the specified objectives   • Research population: the study population  is a correct representation of the sampling  frame   • Validity and reliability of data: data collection  is validated (method of analysis used or the  questionnaire employed)   • Correct interpretation of results: extrapolation  of the inferences that can be drawn from   • Valid conclusion: conclusion reached is based on  the results obtained and links with the  established objectives.   • Undertaken in the form of: oral presentations,  posters, abstracts, journal articles, reports,  workshops and seminars   • Style, length, referencing system depends on type  of dissemination activity undertaken.   • Amount of time spent on various aspects of the  talk should be balanced, e.g. appropriate time  dedicated to the introduction, methodology,  results and discussion   • Practice: practise the presentation to identify  areas that are not clear   • Appropriate to the audience: direct level of detail  according to the audience background   • Enjoy it: being stressed and anxious makes it  difficult to achieve a good delivery.   • Use simple fonts such as Arial or Times New  Roman at a 24 font size, double spacing, bold  type   • Use a dark background and do not use more  than four colours per slide   • Each slide should contain only one main idea,  table or figure   • Do not write more than six to eight lines per  slide and use the middle area of the slide   • Organise the presentation according to a  systematic approach: Introduction, Aim(s),  Method, Results, Conclusion   • Use the audiovisual aids to keep track of the  stages within the structure of the presentation.   • For numbers greater than 100, report in  percentage and numbers.   Papers should be submitted according to the instruc-  tions to author provided by the identified journal.   • Population is divided into subgroups or  strata (e.g. districts, age)   • Subgroups are identified from expert  opinion, literature review and should be  related to outcome of study.   2 A focus group is based on a technique in which  priorities of participants can be identified and  insights gained into their reasoning and  argument. A discussion is undertaken and led by  the lead investigator to discover as many issues  relating to the area of study as possible. The  more concrete and detailed the account of each  issue, the better. Interventions by focus group  members should be recorded.   3 A sample is followed up for a period of time.   It enables collection of data on the course of  events providing information on timing of  events. Limitations: time factor, follow-up and  attrition, expenses.    These would include word count, number of figures  and tables, referencing system, structure of article  (e.g. abstract, keywords, introduction, methodology,  results and discussion) (see also Chapter 63).   • The proposal outlines objectives of the study,  methodology to be followed, expected results as  well as budget and timeplans.   • Dissemination of the project could be undertaken  through oral communication, posters and  abstracts. Relevant results should be identified  and emphasised.   • Every sampling unit has an equal chance of  being selected   Durham T A and Turner R J (2008). Introduction to  Statistics in Pharmaceutical Clinical Trials. London:  Pharmaceutical Press.   Edgar A, Salek S, Shickle D and Cohen D (1998). The  Ethical QALY: Ethical issues in healthcare resource  allocations. Surrey: Euromed Communications Ltd.  Smith F (2002). Research Methods in Pharmacy Practice.   Smith F, Francis S A and Schafheutle E (2008). International  Research in Healthcare. London: Pharmaceutical Press.  Stuart M C, ed. (2007). The Complete Guide to Medical  Writing. London: Pharmaceutical Press.   • To appreciate the expectations of society from • To identify pharmacist actions at the primary care   • Self-care: diagnosis, treatment and prevention of  disease conditions by the individuals themselves.   Improves the nation’s and the individual’s health not  only in the treatment of disease but also in the main-  tenance and promotion of health.   • To provide patients with the widest range of  choice in obtaining high-quality primary care    • To decrease the demand for secondary care in the  hospital setting.   • Treatment of ailments not requiring admission to  hospital or specialist treatment.    The pharmacist in primary healthcare collab-  orates with other healthcare professionals in  the sector and across the other levels of  service provision on a regular basis. The phar-  macist in primary healthcare is also the link  between different specialists participating in  patient care (e.g. the diabetologist and the  obstetrician and gynaecologist for pregnant  patients with diabetes).   Community pharmacists act as coordinators and  navigators of patient care within primary healthcare.  They also:   • participate in formulary development in  collaboration with prescribers in the area   • provide professional services to nursing and  residential homes in the area.   Delivery of home care medications, and monitoring  of patients receiving therapy at home including  patients receiving home intravenous therapy and home  parenteral fluid treatment.   Primary care-based services and services provided  from office-based specialists and hospital visits on an  outpatient basis.   • Healthcare expenditure: between 6% and 12%  of GDP is spent on healthcare.   Over the past few years the USA has decreased the  rise in healthcare costs by encouraging the population  to invest in managed care plans.   • Managed care: structured network of providers  of healthcare formed to offer quality care,  including preventive care at the lowest cost.   In the UK, supplementary prescribing role for the  pharmacist was established in 2003 and pharmacist  prescribing was established in 2005. Overview of  process:   • Documentation: care management plan which is  co-developed with a prescriber, identify clinical  guidelines followed (e.g. practice hypertension  protocol)   • Pharmacist actions at the primary healthcare  level include education about disease prevention  and healthy lifestyle, responding and managing  minor symptoms, recommending referral where  indicated and patient monitoring.   • By acting as navigators and coordinators of  patient care, pharmacists in the primary care  setting may contribute to increase collaboration  within the primary care level and with other care  levels. This will increase the provision of  seamless care and decrease risk of drug-related  problems due to the patient moving from one  interface to another.   1 What are the requirements for a screening  programme to be provided from a community  pharmacy as part of primary care health  services?   1 • Condition addressed must have serious  implications (e.g. produce significant  morbidity or mortality).   • There is effective therapy or action that can  be taken.    • Screening test must be safe and acceptable  to individual being screened and to the  pharmacist providing the service.   • Sensitivity, specificity and positive predictive  values must be known and acceptable.  Probability of occurrence of false positives  and false negatives must be within  reasonable, acceptable limits (see Chapter 11).   • Adequate and accessible information about  the condition and the screening test must be  provided.   • There must be adequate follow-up for  individuals with a positive result. A  pharmaceutical care plan needs to be drawn  up beforehand (see Chapter 12).   • Treatment or preventive measures  recommended should be acceptable to  individuals.   • The setting where the service is provided  should be adequate (see Chapter 5).   • Personnel providing the service and carrying  out the screening test should be properly  trained.   Examples of common screening programmes that  may be provided from community pharmacies  include hypertension, lipid profile, blood glucose.   Jepson G M H (2001). How do primary health care systems  compare across Western Europe? Pharm J 267:  269-273.   Lavender G (2005). Opportunities in primary care: diary of  a pharmacist supplementary prescriber. Pharm J 274:  151-152.   Smalley L (2005). Supplementary prescribing in action - an  example from primary care. Pharm J 274: 213-214.    • To develop skills essential in the management of  personnel, designing pharmacy layout and  handling of stock.   • Professional charge is not clear: patrons believe that  they can receive counselling without being charged   • Patients may feel more comfortable in a pharmacy  setting rather than a clinic environment   • Alternative dispensing systems: automated  dispensing, domiciliary services, mail order,  internet services   • Preservation of market share as opposed to  competition from supermarkets, internet  pharmacy and other sources to get drugs   • Keeping up with ethical and legal considerations;  the misconception that having a good business  aspect is inconsistent with good clinical practice  is very often discussed   • Use of computer technology to connect with  prescribers and maintain patient’s profile   • Time management to allow for new patient  contact interventions required.   • Appointing and dismissing of staff: issuing  contracts and drawing up job descriptions    Good management improves the satisfaction  of patients with professional pharmacy  services and meets expectations regarding the  quantity and quality of the care received.   • Stategic planning and identifying legal form of  business (proprietor, partnership, company)   and is being taken over, this step is essential to evaluate   • Review history: for already existing businesses,  the sales and profit; for a new pharmacy look at  potential for clients   • Assess condition of facilities and identify and  cost any upgrades necessary   • For already existing businesses, assess ability to  transfer goodwill to new owner.   • Identify targets according to timeframes where  the business should be   • Establish how to finance starting up business:  enquire with banks regarding loans and re-   - capital needed to get it started immediately  prior to opening or during the first few weeks   • Availability of physicians and primary care  clinics, collaboration with prescribers in the area   • Retail shops close by may serve as a positive  point in that the area is considered as a shopping  centre   • Traffic direction may hinder access to the  pharmacy or may have a positive influence on  patron’s choice, availability of parking space.   The accounting system for a pharmacy should  be developed in a way that it is easily under-  standable and serves the needs of the phar-  macy. Financial records are required both for  internal and for external reasons.   - not recommended to keep a product just in  case someone needs something because  overstocking may lead to money tied in stock  or to stock that will become shop soiled or  past its expiry date   • Identify prescribers in the area and define drugs  that they prescribe.   Specific policies and procedures are needed for specific  tasks to explain the procedure and who is authorised  to:   • Provision of domiciliary services and delivery to  institutions and house-bound patients   • Point-of-care testing: blood pressure monitoring,  blood tests (see Chapter 11)   • Promote atmosphere that is pleasing, conducive  to shopping and professional   • Psychological effect or feeling created by physical  characteristics of the pharmacy.   • Planning the internal arrangement of  departments and allocating the amount of space  for each department   • Most saleable and profitable items in the most  prominent locations    A large number of purchases from the phar-  macy with regard to non-prescription items  and parapharmaceuticals occur as a result of  impulse buying. Methods used to attract  clients to the pharmacy and to display the  stock, and the stock displayed, influence  impulse buying.   • Purchases journal: to record credit purchases  (supplier, amount, when payment is due)   A balance sheet is a statement of the financial condi-  tion of the business at a given point in time. It reflects  what is owned by the pharmacy, what it owes and  what the owner has invested.   • Current assets: convertible into cash within a  year (e.g. short-term stock)   • Fixed assets: not used within 1 year (e.g.  computer, office equipment)   • May be current liabilities (must be paid within  1 year) or long-term liabilities (e.g. bank  loans).   • Presenting point of access to patient information  on the web   • Keep up regular physical counts of stock and  expiry dates.   In converting from a manual system to a  computerised system or from one computer  system to another it is advisable to keep a  parallel version (the old system) for some  time. This reduces the risk of errors. However,  it is more expensive.   • Generates a large amount of information which  may be of little value to business but distracts  attention from major issue   • Investment required: computer hardware and  peripherals (e.g. printers), software, back-up and  storage.   • Identify the activities that will be carried  out with the computer system   • Select the vendor that provides the system  according to specifications required and  has after-sales services   • The financial aspect of a community pharmacy is  important to make the business viable.   • A sound working relationship with clients,  personnel and other health professionals  improves the running and development of the  business.   • Pharmacy layout, stock presentation and shop  window dressing influence the professional image  that is projected by the pharmacy.   • An understanding of the potential of computer-  driven technology within the business is essential    to identify activities that would be of benefit to  the pharmacy.   Desselle S P and Zgarrick D P (2005). Pharmacy Manage-  ment. New York: McGraw-Hill.   Tootelian D H and Gaedake R M (1993). Essentials of  Pharmacy Management. St Louis: Mosby.   • To become familiar with professional pharmacy • To identify pharmacist actions within hospital   • Enteral and parenteral infusion pumps  (e.g. patient-controlled analgesia pump, see  Chapter 31)   • Developing systems of seamless care: integrating  community and hospital pharmaceutical services.   • prescription sheet design to ensure an easy-to-  follow documentation of medicines to be  administered   • Topping up of ward stock: maintain practical  stock levels to ensure that wards have the  required medicines in the appropriate amounts  and avoid hoarding, stock wastage, pilferage   • Consider unit-dose dispensing: may lead to  increased pharmacist time during dispensing of  medicines to wards but it is an efficient system  that reduces medication errors. Cost-  effectiveness of the system employed needs to be  assessed.    • Pharmacists must ensure that the quality  of the medicines used in the hospital  remains intact until they are administered  to the patient. This is achieved by  ensuring proper storage and handling of  medicines even in the wards (e.g. rotation    of stock, removal of damaged or expired  products, stability and incompatibility of  parenteral admixtures).   • The pharmacists’ approach towards  nurses should be based on a teamwork  approach inviting nurses to ask questions  when they require information and to  cooperate to ensure appropriate  management of drugs on the wards.   • Medicines where at least five or six patients are  receiving it at the same time   • No major contraindications to their use and no  requirements for specialist care and supervision   • Label: name of drug, strength, instructions for  use (e.g. dilution/reconstitution), storage  requirements, no dosage instructions and patient  names   • Stock record books are kept. Unused stock of  these books should be kept in a secure place   • Refrigerator to store drugs: temperature  controlled with thermometer being used  calibrated, clean and lockable   • Pharmacy staff should establish a working  relationship with nurses and ward manager    • Drugs to be stored in a refrigerator  include total parenteral nutrition (TPN)  solutions, reconstituted antibacterial  suspensions and cytotoxic drugs, insulin,  vaccines   • Items and drugs that are not to be stored  in refrigerator include heparin, blood and  urine specimens, food, inflammables   • A good procedure is to prepare a list on  the door of the refrigerator of all the  items that require storage in a  refrigerator   • Check that all items in the refrigerator  require to be stored in a refrigerator  (usually between 2 and 8°C).   • Eyes are at greater risk of developing an infection  when an injury has occurred or a surgical  intervention was carried out   but some preparations may not be available in  this presentation and costings have to be  considered   • For preparations presented as multiple dose, the  product should not be used for more than 1  week; separate bottles are used for each eye, and  new bottles used postoperatively    Pharmacists' actions in the development of  protocols to standardise practical nursing  techniques on the wards   • to develop and implement policies on drug use  including, for example, generic substitution,  therapeutic guidelines and cost-containment  policies.   • to develop and implement policies and guidelines  regarding the use of anti-infective agents   • to respond to queries from different departments  and other care settings   • to investigate drug activity and coordinate  clinical trials activity (this activity may be shared  with the quality assurance unit)   • to coordinate reporting programmes for adverse  drug reactions and medication errors   • to liaise with the infections control committee to  identify antibacterial agents that are less likely to  develop bacterial resistance   Pharmacists should use their professional knowledge  to foster the safe and appropriate use of drugs by  patients in a teamwork approach. They should also  aim to solve medication errors, detect drug-drug  interactions and identify drug-induced disease.  Services provided include:   • Pharmacy services are provided to support the  rational and safe use of medicines and to ensure  teamwork in the therapeutic process.   • Pharmacists can give advice on storage of  medicines, stock levels for ward stock,  information on methods of drug use and drug  administration, participate in development of  therapeutic protocols and in clinical trials, and  participate in patient care and patient monitoring.   • Pharmacists practising in a hospital involved in  the clinical pharmacy services are in a position to  promote seamless care when the patient is  transferred back to the primary care level.   • Pharmacists in the hospital setting should be  involved in the wards and outpatient clinics to  establish collaboration with the prescribers and  nursing staff so as to liaise with them as a team  when providing the pharmacy professional  services.   1 How can a hospital pharmacist monitor the  proper storage of ward stocks?   • Ensure appropriate storage including the  refrigerator used for medicinal products   • Check for proper labelling and identify  sources of contamination or mixing up of  drugs.   • To review processes required for the development • To identify benefits and controversies associated  and maintenance of formularies with formulary systems.   A formulary is a continually updated list of  medications and related information, repre-  senting the clinical judgement of physicians,  pharmacists and other experts in the diag-  nosis, prophylaxis or treatment of disease and  promotion of health. A formulary includes,  but is not limited to, a list of medications and  medication-associated products or devices,  medication-use policies, important ancillary  drug information, decision-support tools, and  organizational guidelines. 1   1954 Hospital Formulary for Selected Drugs  for the University of Michigan Hospital  1959 American Society of Health-System   Pharmacists (ASHP) issued the American  Hospital Formulary Service in loose leaf  format so as to retain the idea of  selectivity for specific institutions.   Essential Drugs - a list of drugs necessary  for the provision of basic healthcare  1978 ASHP produced guidelines on production   and maintenance of a formulary system  which were subsequently updated regularly.   • Open formulary system-, the formulary  recommends drugs and non-formulary drugs are  still routinely available   • Closed formulary system: restricted drug list:  only medicines included in the formulary may be  used.   • A formulary for general practice should  include enough drugs to treat 80-90% of  all common conditions met in the practice  in addition to emergency drugs.   • Having too many drugs in a formulary  defeats its purpose of cost-reduction,  effective and rational selection.   • Having too few drugs in the formulary  makes the formulary an ineffective and  useless resource.   • To ensure quality and appropriateness of  drug use in a particular practice   • To teach appropriate drug therapy  especially relevant for junior doctors   • To cut down on the range of drugs in use   • Use of a restricted range of drugs results in better  knowledge of drug use   • Promotes seamless care between hospital  practitioners and primary care  practitioners.   • Decision whether to adapt another formulary or  develop a completely new formulary   • Should be flexible and adapt to ongoing needs of  prescribers and patients.   • Process to monitor drug use and establish  policies on drug use   • Regular updates to reflect current practice (e.g.  biannual or annual editions)   • Inclusion of new drugs released on the market:  consider issue of safety, cost, indications, me-too  drugs   • Follow a basic drug information system (e.g.  reference to British National Formulary)   • Binding: loose-leaf allows for flexible adaptations  but may present problems with long-term use   • Formulary system may provide for generic  substitution or therapeutic substitution   • Interactions with the pharmaceutical industry  may influence the formulary system.   At the macro level, prescribing trends that influence  the individual prescriber include:   • traditions and education of society (e.g. may  influence dosage form selection)   This is the dispensing of a different brand or an  unbranded drug product for the drug product  prescribed.   This is the dispensing of a particular drug entity in  place of a therapeutically similar but chemically  different drug product.   • clinical studies suggesting that not all drugs of  similar classes are equivalent   • A formulary provides information on the drugs  and medical devices that are used in a particular  institution.   • For successful implementation, the formulary  requires regular updating, and participation of  different members of the health professions in  decisions relating to its development and  maintenance.   • Presentation of the formulary should be easy to  use and follow, and attractive. Electronic access  to the formulary should be supported.   • Pharmacokinetic profile (e.g. include drugs  with short half-lives, include drugs  minimally affected by hepatic or renal  impairment)   • Formulations available (e.g. drugs available  for both oral and parenteral administration  allow for smooth transition from parenteral  to oral therapy)   • Use (e.g. certain categories of drugs such as  anaesthetics may not be relevant to the  formulary setting)   Serracino Inglott A, Azzopardi L M, Zarb Adami M and  Camilleri J (1999). Analysis of a formulary for a geriatric  hospital. Pharm J 263: R43.   Winfield A J and Richards M E ed. (2002). Pharmaceutical  Practice , 3rd edn. London: Churchill Livingstone.   • Toxicity (e.g. for equally effective drugs,  select the least toxic)   • Adverse effects (e.g. include drugs with same  indication but different side-effect profiles)   1 American Society of Health-System Pharmacists  (ASHP) Expert Panel on Lormulary Management.  ASHP Guidelines on the Pharmacy and Therapeutics  Committee and the Lormulary System. Am J Health-  Syst Pharm 2008; 65: 1272-1283.   • To introduce principles of regulatory affairs for • To identify interventions of qualified persons,   • To appreciate requirements of EU Good  Manufacturing Practice, EU Good Distribution  Practice and EU Good Clinical Practice   Within the pharmaceutical industry, regulatory  considerations are implemented across all stages of  the development of a medicinal product (from the  investigational medicinal product stage to the distri-  bution stage). The main principle underlying the  regulatory framework is to ensure safety, quality and  efficacy of the product.   • Forms part of a network of national agencies, is  a service provider for the network and has a  coordinating role within the network   • Mainly responsibile for the protection and  promotion of public and animal health, through  the evaluation and supervision of medicines for  human and veterinary use   • Responsible for scientific evaluation of  applications for a European marketing  authorisation (centralised procedure) for  medicinal products   • Coordinates good manufacturing practice,  product- and process-related inspections at  manufacturing sites run by national regulatory  bodies (e.g. MHRA in the UK)   • Liaises with other international medicines  regulatory bodies (e.g. in the USA, Canada and  Japan)   • Manufacturers of medicinal products must  hold a marketing authorisation for each  product manufactured and sold for human  consumption   • Medicinal products are granted a marketing  authorisation to ensure their efficacy, safety and  quality   - either as a national procedure at the level of  the national agency   - or as a European procedure at the level of the  EMEA - centralised procedure 1    • In an attempt to harmonise the presentation of  data for the application for registration of  medicinal products for human use in the EU,  the USA and Japan, the Common Technical  Document (CTD) was developed. This document  compiles the data required to be presented for an  application for a marketing authorisation into  five sections: administrative and prescribing  information, summaries and overview,  information on product quality, non-clinical  study reports and clinical study reports.   • The pharmaceutical company files one  application and if the application is successful  receives marketing authorisation in all EU  member states, Norway, Iceland and  Lichtenstein.   • The Committee for Medicinal Products for  Human Use (CHMP) is responsible for carrying  out assessment of the applications and handling  post-authorisation requests for variations or  extensions to existing marketing authorisations.   • For medicinal products for human use, the  centralised procedure is obligatory for products  derived from high-technology or biotechnology,  products used in rare diseases (orphan drugs),  products used in AIDS, cancer, neurodegenerative  disorders, diabetes, and autoimmune and viral  disease.   substances and products that bring therapeutic or  scientific progress and for generic medicines once  data exclusivity periods granted to originator  products authorised through centralised  procedure expire (10 years).   Counterfeit medicinal products are products  that are deliberately and fraudulently mis-  labelled with respect to identity, amount or  source of drug. This is an escalating global  problem. All stakeholders involved with the  manufacture, distribution and use of medic-  inal products are responsible for combatting  medicines counterfeiting by reporting any  incidents to the national medicines regulatory  authorities.   This ensures that medicinal products are consistently  produced and controlled to the quality standards  appropriate to their intended use and as required by  the marketing authorisation.   • Pharmaceutical manufacturers require a  manufacturing licence (ML) which is renewable  periodically and is issued by the regulatory  authority.   • Quality system (standard operating procedures  [SOPs], documentation, records, internal audits,  batch release).    A pharmaceutical manufacturer in the EU  producing medicinal products and investiga-  tional medicinal products for human use  cannot function without a manufacturing  licence.   The primary legal responsibility of the QP is to  release batches of medicinal product prior to use in a  clinical trial (investigational medicinal product; IMP)  or prior to release for sale.   • to ensure that standards of good practice in  manufacturing are complied with at all times   • to ensure that each batch of medicinal products  has been manufactured and tested, and complies  with EU directive and EU GMP   • to ensure that each batch of medicinal  products has been manufactured in accordance  with the requirements of the marketing  authorisation.   • Directive 2003/94/EC 2 also takes into  consideration manufacture of investigational  medicinal products.   • This ensures that trial participants are not placed  at risk and that the results of clinical trials   are not affected by inadequate safety, quality  or efficacy arising from unsatisfactory  manufacture.   • It ensures consistency between batches and that  changes during the development of an IMP are  adequately documented and justified.   • Regulated by Directive 2001/20/EC 3 and  Directive 2005/28/EC 4 , which stipulate  requirements related to clinical trials   • Compliance by pharmaceutical sponsor  (paying for the trial), contract research  organisation (handling the trial), investigational  trial sites (where clinical tests are carried out)  and clinical trial laboratories (where analysis is  carried out).   Ihis ensures that medicinal products are consis-  will be used by patients and that it is impor- , , , , , ,, , , , ,    • Wholesalers have to appoint a responsible person  (RP) who is responsible for ensuring that EU  GDP is implemented.   All pharmaceutical distributors in the EU  should hold a licence for wholesale dealing in  medicinal products. 6   • The Marketing Authorisation holders must  ensure that they have an appropriate system of  pharmacovigilance in order to assume  responsibility and liability for their products on  the market and to ensure that appropriate action  can be taken when necessary   • Marketing Authorisation holders should have at  their disposal a person responsible for  pharmacovigilance in the different states    allow healthcare professionals, including  pharmacists, to report adverse drug reactions  to a central agency. In the UK, suspected drug  adverse reactions may be reported by  completing the Yellow Card, copies of which  are available with the British National  Formulary.   • Pharmaceutical manufacturers and regulatory  authorities have a duty to ensure that patients  are properly protected and that medicinal  products meet appropriate requirements for  safety, quality and efficacy.   • Key personnel should have access and be familiar  with European and national guidance documents  and legislation relating to the manufacture,  clinical trials and distribution of medicinal  products for human use.   2 Summarise the requirements to comply with EU  Good Distribution Practice.   1 Medicines are granted a marketing  authorisation to ensure their efficacy, safety  and quality. The national procedure to obtain  a marketing authorisation is in agreement  with the national agency while the European  procedure is an EMEA-centralised procedure.   2 EU Good Distribution Practice ensures that the  quality, efficacy and safety of the product is  maintained during the distribution chain. A  quality system is required to outline standard  operating procedures (SOPs) for all processes    carried out in the wholesale activity. Personnel  should receive training in the processes and the  SOPs which has to be documented.  Documentation of all processes (receipt, sale,  recall of medicines) has to be kept and a  tracing system for the products handled is  required. Premises and equipment used for  storage should be controlled, including cold  storage in the store and during transportation.  The wholesaler has to appoint a responsible  person who is responsible for overseeing the  implementation of EU GDP.   Department of Essential Drugs and Other Medicines, World  Health Organization (1999). Counterfeit Drugs: Guide-  lines for the development of measures to combat  counterfeit drugs. Geneva: World Health Organization.   Franklin N (2007). Effective compliance with EU GMP Part  II in active substance manufacture: How did these GMP  requirements arise? Indust Pharm 14: 6-9.   Medicines and Healthcare products Regulatory Agency  (2007). Rules and Guidance for Pharmaceutical  Distributors. London: Pharmaceutical Press.   Medicines and Healthcare products Regulatory Agency  (2007). Rules and Guidance for Pharmaceutical Manu-  facturers and Distributors. London: Pharmaceutical  Press.    Robson A S, Bawden D and Judd A, eds. (2001). Pharma-  ceutical and Medicines Information Management: Infor-  mation management. London: Churchill Livingstone.   1 Regulation (EC) No. 726/2004 of the European Parlia-  ment and of the Council of 31 March 2004 laying  down Community procedures for the authorisation and  supervision of medicinal products for human and  veterinary use and establishing a European Medicines  Agency.   2 Directive 2003/94/EC of 8 October 2003 laying down  the principles and guidelines of good manufacturing  practice in respect of medicinal products for human use  and investigational medicinal products for human use.   3 Directive 2001/20/EC of the European Parliament and  of the Council of 4 April 2001 on the approximation of  the laws, regulations and administrative provisions of the  Member States relating to the implementation of good  clinical practice in the conduct of clinical trials on  medicinal products for human use.   4 Commission Directive 2005/28/EC of 8 April 2005  laying down principles and detailed guidelines for good  clinical practice as regards investigational medicinal  products for human use, as well as the requirements for  authorisation of the manufacturing or importation of  such products.   5 Directive 92/25/EEC of 31 March 1992 on the whole-  sale distribution of medicinal products for human use.   6 Directive 2001/83/EC of the European Parliament and  of the Council of 6 November 2001 on the Community  code relating to medicinal products for human use as  amended by Directives 2002/98/EC, 2004/24/EC,  2004/27/EEC.   • To appreciate the need for quality standards • To review issues that are assessed in quality care   A number of questions are posed by healthcare regu-  lators, financing agents and consumers regarding the  assessment and evaluation of professional pharmacy  services provided from community pharmacy. Two  main issues are whether professional services provided  from community pharmacies meet the required  standards and then what the required standards are.    In today’s market-oriented, economics-driven  society, all professions face the question:  what do I do for my customers that makes  my contribution unique? (Peter Kielgast,  Past-President, International Pharmaceutical  Federation) 1    A basic critical analysis of community pharmacy  identifies two strengths and three weaknesses:   1 A large number of pharmacists are practising in  this sector   1 The apparent loss of the traditional role when  compounding was replaced with industrial  manufacturing   • Quality policy and assessment for professional  services identified by professional bodies (e.g.  International Pharmaceutical Federation)   • Inclusion of perception of consumers and other  health professionals in the quality assessment for  some standards.   1997 In Vancouver presentation of revised  version endorsed by the WHO Expert  Committee on Specifications for  Pharmaceutical Preparations 1   1998 In The Hague adoption of the guidelines  on Good Pharmacy Practice in  Developing Countries 3   Within the scenario where the community pharma-  cist is participating in all aspects of drug therapy,  from evaluating a prescription to monitoring the  effectiveness of a patient’s treatment and to piloting  changes in pharmacotherapy, standards of care are  required to ensure that this is a valid contribution.   Quality care standards look at administration  and infrastructure of the pharmacy and at pro-  fessional services such as pharmacist interaction  with patients, recommendation of non-prescription  medicines, dispensing of prescription medicines,  diagnosis and pharmacotherapy monitoring, and  planning.   Quality care standards and pharmacist actions  when dispensing prescription medicines are shown in  Figure 70.1.    approach where particular professional services are  addressed or whether a generic approach is adopted.  For a generic approach standards are intended to  address more than one type of service.   Quality care standards and pharmacist actions  when responding to symptoms are shown in Figure  70.2.   • Drug information and counselling developed by  the Nordic Pharmacy Association 5   • Provision of pharmacist-recommended medicines  developed by the Pharmaceutical Society,  Australia 6   • Prevention of errors in drug dispensing developed  by the Japan Pharmaceutical Association. 7    The description of quality care standards can be Figure 70.2 Quality care standards and pharmacist actions  based on whether they are adopting an area-specific when responding to symptoms.   The presentation of standards can be described as  guidelines or as an audit tool.   Guidelines are presented to create a quality environ-  ment, to promote responsibility for quality, to present  aims and objectives of service provided and to present  standard procedures.   Extract from Dutch Pharmacy Standard by the Royal  Dutch Association for the Advancement of Pharmacy  (KNMP): 8   The pharmacist supports the client to make  well considered decisions regarding the use of  medicines and health care products.   Extract from the standard by the American Pharma-  ceutical Association (APhA): 9   The pharmacist evaluates the subjective and  objective information collected from the  patient and other sources then forms conclu-  sions regarding: (1) opportunities to improve  and/or assure the safety, effectiveness, and/or  economy of current or planned drug therapy;   (2) opportunities to minimize current or  potential future drug or health-related prob-  lems; and (3) the timing of any necessary  future pharmacist consultation.   Standards that are presented as audits outline proce-  dures to be followed and adopt a quantitative  approach. After using the standards as an audit tool  a score is obtained providing tangible results.   Extract from the standard Validation of Community  Pharmacy Method developed by the Department of  Pharmacy, University of Malta: 1   1. The pharmacist gives immediate attention  to the patient in an orderly way   IV. The pharmacist is recognised by the  patient or introduces himself to the patient   The FIP report by the Working Group on Quality Care  Standards 4 analysed 1 8 generic standards submitted by  international pharmacy organisations and identified  the areas included in the generic standards as listed in  Table 70.1.   Example from the standards developed by the Indian  Pharmaceutical Association: 10   Written standard operating procedures as  well as standard formulations should be  maintained for commonly made extempor-  aneous preparations.   Batch numbers of each medicine used for  compounding should be recorded.   Example from the standards developed by the  National Association of Pharmacy Regulatory  Authorities in Canada (NAPRA): 11   Pharmacists manage drug distribution by  performing or supervising the functions of    acquisition, preparation, and distribution of  drugs to ensure the safety, accuracy and  quality of supplied products.   Example from the standards developed by the Royal  Pharmaceutical Society of Great Britain, UK : 12   [Pharmacists] must ensure that pharmaceu-  tical stock is stored under suitable conditions,  taking into consideration the stability of the  drug.   Example from the standards developed by the Indian  Pharmaceutical Association : 10    The pharmacist must work out strategies to  make time to provide professional counselling  with regard to use of medicines and related  products, so as to improve the quality of the  patient’s life.   Example from Validation of Community Pharmacy  Method, Department of Pharmacy, University of  Malta : 1   Example from the standards developed by the Royal  Pharmaceutical Society of Great Britain, UK : 12   [Pharmacists must ensure that ] when a patient  or their carer requests advice on treatment,  sufficient information is obtained to enable an  assessment to be made of ivhether self-care  is appropriate, and to enable a suitable  product(s) to be recommended.   Example from standards developed by the Pharma-  ceutical Association of Israel : 13   The pharmacy externally should have a  professional appearance, in such a way that  it can be easily distinguished as being a  pharmacy.   A predominant sign should indicate it is a  pharmacy in at least two of the major ethnic  languages used in the location.   Example from standards developed by the Pharma-  ceutical Society of Uganda : 14    A pharmacist or his/her designee must see  every prescription for a medicine and make a  judgement as to what action is necessary.   For each prescription, the date of issue, the  quantity of drug supplied, the balance due  and the signature of who dispenses the  prescription must be indicated in red ink.   Example from standards developed by the Association  of Finnish Pharmacies: 15   • Who should run the method: the profession or  an outside body?   • Cost of quality system: costings of the system,  how are these going to be shared?   • Voluntary or mandatory: it is recommended to  start off on a voluntary basis with a lot of  incentives, otherwise success rate may be low.   • Reward for improving quality: to support  pharmacies to undertake required upgrading.    Health promotion is an important aspect  of the activity of a community pharmacy.  Prevention of diseases and health promotion  are among the central objectives of Finnish  health policy.   Example from standards developed by the Association  of Finnish Pharmacies: 15   Part of the herbal drugs and homeopathic  products are sold exclusively from phar-  macies. Therefore, the staff shall also get  acquainted with the use of these products.   Example from the standards developed by the Royal  Pharmaceutical Society of Great Britain, UK: 12   Patients must be readily able to identify who  is operating an internet site from a registered  pharmacy premises.   • Prepare standard operating procedures for  specific areas such as preparation of  extemporaneous preparations   • Carry out a self-assessment audit on a  specific process (e.g. steps carried out  during dispensing a prescription).   • Community pharmacists contribute to patient  care in multiple processes by identifying,  resolving and preventing medicine-related  problems and facilitating access to safe and  effective pharmacotherapy. Such interventions  can be provided by the pharmacist as distinct  from those by other skilled people because of the  scientific approach given to pharmacists during  their pharmacy education.   • Quality care standards are processes carried out  to confirm the effectiveness of the pharmacist in  a community setting.   1 List four salient points that may be  evaluated in the process of greeting the patient  at a pharmacy.   2 List five essential steps to be evaluated in  quality assessment of the process of  dispensing a prescription in a community  pharmacy setting.   1 Patient is given immediate attention; patient is  greeted in a friendly message; if patient is  known to pharmacist, he or she is addressed by  name; pharmacist is wearing professional attire  and can be identified by the patient.    2 Prescription is evaluated, checked for validity  (date of issue, prescriber), drug required  identified, quantity to be dispensed prepared  and patient advised on use of medication  according to instructions on prescription.   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London: Pharmaceutical Press.   neural blockade 189  in osteoarthritis 276-277  palliative care 261-262  paracetamol 186  patient-controlled analgesia  (PCA) 189-190  in peripheral neuropathy 235  during pregnancy 315  transcutaneous electrical nerve  stimulation (TENS) 192  see also non-steroidal anti-  inflammatory drugs, opioids  analgesic ladder 190  analytical evaluation 73  anaphylactic shock 104, 106, 144  androgenetic alopecia (male-pattern  baldness) 291, 294  aneroid sphygmomanometers 56  angina pectoris 102, 121-122  drugs that may worsen  symptoms 124-125  treatment 122-124  angioedema 144  angiography, coronary 102  angiotensin II receptor antagonists  (ARBs)   avoidance during pregnancy 117  in congestive heart failure 130  contraindications 116  drug interactions 117  in hypertension 109, 114-115  angiotensin-converting enzyme (ACE)  inhibitors   counselling 42  dabigatran etexilate 321  fondaparinux 140  heparins 139-140  INR monitoring 58, 142  rivaroxaban 321  warfarin 103, 140-141  anticonvulsants see antiepileptics  antidepressants 159-161, 163-164  in anxiety disorders 166, 167,  168, 169   drug interactions 162  hyponatraemia 162-163  in neuropathic pain 189  for nocturnal enuresis 254  in panic disorder 168  in post-traumatic stress disorder  169   in premenstrual syndrome 244  side-effects 161  antidiabetic drugs see oral  hypoglycaemic agents  anti-diarrhoeals 84, 93, 95  antidotes to poisons 26  antiemetics 97-98   in allergic rhinitis 146, 147, 149  as antiemetics 98, 99  in anxiety disorders 167  and breast-feeding 315, 316  cautions and contraindications  145   antihypertensive drugs 110—111, 119  ACE inhibitors 113-114  ARBs 114-115  beta-blockers 112-113  calcium channel blockers 115  contraindications and cautions  116   in dental conditions 341  in surgery 214  use during pregnancy 315  see also antibacterial drugs;  antifungals; antihelminthic  drugs; antiprotozoal agents;  antiviral agents  anti-inflammatory agents 187    see also corticosteroids; non-  steroidal anti-inflammatory  drugs (NSAIDs)  antimicrobial prophylaxis 203  antimicrobials, definition 203  antimotility drugs 84   bronchodilators 147  in urinary frequency and  incontinence 253, 254  anti-obesity drugs 180-181  antiplatelet drugs 103, 141-142  antiprotozoal agents 213  antipruritics 288   antipsychotic drugs 103, 104, 151  in anxiety disorders 169  ariprazole 322  butyrophenones 153  cautions 155  chlorpromazine 156  clozapine 154  comparison of agents 152  compliance 155  in dementia 196-197  depot injections 155  drug interactions 146, 155  emergency administration 155  haloperidol 157  initiation of therapy 154  patient counselling and  monitoring 154-155  phenothiazines 152-153  response to medication 154  risperidone 154  side-effects 152, 153, 155-156  thioxanthines 153  trifluoperazine 157  withdrawal of treatment 155  antipyretics 192, 331   see also analgesic drugs  antiretroviral therapy 216-218,  219-220  antiseptics 298  antispasmodics 95, 190  antituberculous drugs 211-212  antitussives 329, 330, 331  antiviral agents 212-213  in chronic hepatitis 223  for cold sores 342   see also anti-arrhythmic drugs  arterial thromboembolism 138, 141  antiplatelet drugs 141-142  arthralgia 135, 184, 356  arthropathy 184  arthroplasty 277, 279  ascorbic acid (vitamin C) 330, 371,  372 
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