 \200 ANTI-ARRHYTHMICS 273 Modes of action (Vaughan \200\223Williams classi \201 cation) Class I Action Reduces rate of rise of action potential: Ia: Increases action potential duration Ib : Shortens duration Ic: Little effect Reduces rate of pacemaker discharge Prolongs duration of action potential and hence length of refractory period Examples Ia: disopyramide Ib: lidocaine Ic: \202 ecainide B-blockers Amiodarone Sotalol Verapamil Diltiazem II III IV Antagonizes transportation of calcium across cell membrane Drug dosages Adenosine 6mg rapid IV bolus. If no response after 1min, give 12mg. If no response after 1min, repeat 12mg. 5mg/kg over 20min (or 150 \200\223300mg over 3min in emergency), then IV infusion of 15mg/kg/24h in 5% glucose via central vein. Reduce thereafter to 10mg/kg/24h (approx. 600m g/d) for 3 \200\2237d, then maintain at 5mg/kg/24h (300 \200\223400mg/d). Esmolol: A titrat ed loading dose regimen is commenced followed by an infusion rate of 50 \200\223200mcg/kg/m in. Propranolol: Initially given as slow IV boluses of 1mg, repeated at 2min intervals to a maximum of 5mg. Labetalol: 0.25 \200\2232mg/min Sotalol: Dosage range is 20 \200\223120mg IV (0.5 \200\2231.5mg/kg) administered over 10min. Repeat 6-hourly, if necessary. Metoprolo l: 2.5 \200\2235 mg injected IV at rate of 1 \200\2232mg/min, repeated at 5min intervals un til satisfactory response is seen or total dose of 10 \200\22315mg given. Atenolol: 2.5mg I V over 2.5min, repeated at 5min intervals until response is seen or maximum of 10mg In emer gency, 5mg/kg by rapid IV bolus. If no response after 5min, repeat or increase to 10mg/kg. 0.5mg given IV over 10 \200\22320min. Repeat at 4 \200\2238h intervals until loading achiev ed (assessed by clinical response). Maintenance dose thereafter is 0.0625 \200\2230.25mg/d, depending on plasma levels and clinical response. 1mg/kg slow IV bolus for loading, then 2 \200\2234mg/min infusion. Should be weaned slowly over 24h. 10 \200\22320mmol over 1 \200 \2232h (over 5min in emergency). 2.5mg slow IV. If no response, repeat to a maximum of 20mg . An IV infusion of 1 \200\22310mg/h may be tried. 10% calcium gluconate solution should be readily available. Amiodarone B-blockers Bretylium Digoxin Lidocaine MgSO4 Verapamil See also: Electrical cardioversion, p94; ECG monitoring, p162; Cardiac arrest, p340; Tachya rrhythmias, p384. 274 CHAPTER 15 Cardiovascular drugs Chronotropes Types \200 Anticholinergic, e.g. atropine, glycopyrronium bromide. Modes of action \200 The anticholinergic drugs act by competitive antagonism of acetylcholine at peripheral musc arinic receptors and decreases atrioventricular conduction time. Uses \200 \200 All types of bradycardia including 3* heart block. High dose atropine is used in cardiopulm onary resuscitation protocols for treatment of asystole. Side effects/complications \200 Anticholinergic drugs produce dry mouth, reduction and thickening of bronchial secretions, and inhibition of sweating. Urinary retention may occur, but parenteral administration does not lead to glaucoma. Notes \200 The anticholinergic agents are usually given by IV bolus, repeated as necessary. They are f requently used as a bridge to temporary pacing, but should not be considered a substitute. External or internal pacing should be readily accessible. Atropine nebulisers have been use d successfully in patients developing symptomatic bradycardia during endotracheal suction. Neurological effects may be seen with atropine but not glycopyrronium bromide. CHRONOTROPES 275 Drug dosages Atropine 0.3 \200\2230.6mg IV bolus. 3mg is needed for complete vagal blockade or cardiopulmonary re suscitation. 0.2 \200\2230.4mg IV bolus Glycopyrronium bromide See also: Temporary pacing (1), p96; Temporary pacing (2), p98; ECG monitoring, p162; Cardi ac arrest, p340; Bradyarrhythmias, p386. 276 CHAPTER 15 Cardiovascular drugs Anti-anginal agents Types \200 \200 \200 \200 Vasodilators, e.g. nitrates, calcium antagonists. B-blockers. Potassium channel openers, e. g. nicorandil. Antiplatelet/anticoagulant agents: aspirin, heparin, clopidogrel. Modes of action \200 Calcium channel blockers cause competitive blockade of cell membrane, slow calcium channels leading to decreased in \202 ux of calcium ions into cells. This leads to inhibition of c ontraction and relaxation of cardiac and smooth muscle \201 bres, resulting in coronary a nd systemic vasodilatation. Nitrates may cause ef \202 ux of calcium ions from smooth musc le and cardiac cells, and also increases cGMP synthesis resulting in coronary and systemic vasodilatation. B-blockers inhibit B-adrenoreceptor stimulation, reducing myocardial work a nd oxygen consumption. This effect is somewhat offset by compensatory peripheral vasoconstr iction. Potassium channel openers vasodilate by relaxation of vascular smooth muscle. The p otassium channel opening action works on the arterial circulation while a nitrate-type acti on provides some venodilatation. Though aspirin, heparin, and clopidogrel have no direct an ti-anginal effect, patients with unstable angina bene \201 t from the reduction in platele t aggregation and thrombus formation. Uses \200 Angina pectoris. Side effects/complications \200 \200 See Dilators, Hypotensive agents. Nicorandil is contraindicated in hypotension and cardioge nic shock. It should be avoided in hypovolaemia. Headache and \202 ushing are the major r eported side effects. Rapid and severe hyperkalaemia has been reported after cardiac surger y. Notes \200 Combination therapy involving nitrates, B-blockade, aspirin, clopidogrel 9 heparin 9 calciu m antagonists 9 glycoprotein IIb/IIIa antagonists are used in acute coronary syndromes; thr ombolytic therapy confers no added advantage. Local guidelines should be consulted. Potassi um channel openers belong to a new class of drug yet to be extensively evaluated in critica lly ill patients and should be thus used with caution, especially when hyperkalaemia is a c oncern. Angina may occasionally be worsened by a \200\230coronary steal \200\231 phenomeno n where blood \202 ow is diverted away from stenosed coronary vessels. This does not occu r with nicorandil. ANTI-ANGINAL AGENTS 277 Drug dosages Glyceryl trinitrate 0.3mg sublingually, 0.4 \200\2230.8mg by buccal spray, 2 \200\22340mg/h by IV infusion 10 \200\22320mg tds orally, 2 \200\22340mg/h by IV infusion 5 \200\22320mg PO. The capsule \202 uid can be aspirated then injected down nasogastric tube or given sublingually. Given either orally at doses of 10 \200\223100mg tds or IV as slow boluses of 1mg, repeated at 2m in intervals to a maximum of 5mg until effect is seen. This can be repeated 2 \200\2234 hou rly as necessary. 10 \200\22320mg PO bd 300mg PO loading dose, then 75mg PO od 75 \200\2231 50mg PO od Isosorbide dinitrate Nifedipine Propranolol Nicorandil Clopidogrel Aspirin See also: Coronary revascularisation techniques, p104; Echocardiography, p192; Vasodilators , p266; Acute coronary syndrome (2), p390. This page intentionally left blank 279 Chapter 16 Renal drugs Diuretics 280 Dopamine 282 280 CHAPTER 16 Renal drugs Diuretics Types \200 \200 \200 \200 Loop diuretics, e.g. furosemide, bumetanide. Osmotic diuretics, e.g. mannitol. Thiazides, e .g. metolazone. Potassium-sparing diuretics, e.g. amiloride, spironolactone, potassium canr enoate. Uses \200 \200 \200 \200 To increase urine volume. Control of chronic oedema (thiazides, loop diuretics). Control of hypertension (thiazides). To promote renal excretion (e.g. forced diuresis, hypercalcaemia ). Routes \200 \200 IV (mannitol, furosemide, bumetanide, potassium canrenoate). PO (metolazone, furosemide, bu metanide, amiloride, spironolactone). Modes of action \200 \200 Osmotic diuretics \200\224reduce distal tubular water reabsorption. Thiazides \200\224inhib it distal tubular Na+ loss and carbonic anhydrase, and increase Na+ and K+ exchange. This r educes the supply of H+ ions for exchange with Na+ ions, producing an alkaline natriuresis with potassium loss. Loop diuretics \200\224inhibit Na+ and Cl \200\223 reabsorption in the ascending loop of Henl . Potassium-sparing diuretics \200\224inhibit distal tubular Na+ a nd K+ exchange. Side effects \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Hypovolaemia. Hyponatraemia or hypernatraemia. Hypokalaemia. Hyperkalaemia with potassium-s paring diuretics. Oedema formation (mannitol). Reduced catecholamine effect (thiazides). Hy perglycaemia (thiazides). Metabolic alkalosis (loop diuretics). Hypomagnesaemia (loop diure tics). Pancreatitis (furosemide). Notes \200 It is important to correct pre-renal causes of oliguria before resorting to diuretic use. D iuretics do not prevent renal failure, but may convert oliguric to polyuric renal failure. If there is inadequate glomerular \201 ltration, mannitol is retained and passes to the e xtracellular \202 uid to promote oedema formation. Potassium-sparing diuretics should be avoided with ACE inhibitors as there is an increased risk of hyperkalaemia. DIURETICS 281 Drug dosages Oral IV 100g over 20min 6-hourly Infusion Mannitol Metolazone Furosemide Bumetanide Amiloride Spironolactone K+ canrenoate 5 \200\22310mg od 20 \200\22340mg 6 \200\22324 hourly 0.5 \200\2231mg 6-24 hourly 5 \200 \22310mg 12 \200\22324 hourly 100 \200\223400mg od 5 \200\22380mg 6 \200\22324 hourly 0.5 \200\2232mg 6 \200\22324 hourly 1 \200\22310mg/h 1 \200\2235mg/h 200 \200\223400mg od See also: Electrolytes (Na+, K+, Cl \200\223, HCO3 Pancreatitis, p424; Hyponatraemia, p484; Hypokalaemia, p488; Metabolic alkalosis, p504. \200\223), p212; Fluid challenge, p342; Hypertension, p382; Oliguria, p398; 282 CHAPTER 16 Renal drugs Dopamine The effects of dopamine are dependent on the dose infused. Dopamine was used widel y at low doses in an attempt to secure preferential DA1 stimulation and increase renal perf usion. However, a large, multicentre, randomized, controlled study comparing \200\230renal dose \200\231 dopamine and diuretics showed no difference in the incidence of renal failur e. The pre- vious widespread use of low dose dopamine (<3mcg/kg/min) has thus diminished co nsiderably. Higher doses increase cardiac contractility via B1 stimulation and produce vaso constriction via A stimulation. Where vaso- constriction is inappropriate, this will reduce renal perfusion. However, there is evidence of natriuresis and diuresis by enhanced Na+ tr ansportation in the ascending loop of Henl . This effect is similar to that of a loop diur etic. In addition to the renal effects of DA1 stimulation, there may be preferen- tial perf usion of the splanchnic bed though any bene \201 ts to patients have yet to be shown. DOPAMINE 283 Key paper Bellomo R for the Australian and New Zealand Intensive Care Society (ANZICS) Clin ical Trials Group. (2000) Low-dose dopamine in patients with early renal dysfunction: a pla cebo-controlled randomized trial. Lancet 356: 2139 \200\22343. This page intentionally left blank 285 Chapter 17 Gastrointestinal drugs H2 blockers and proton pump inhibitors 286 Sucralfate 288 Antacids 290 Anti-emetics 292 Gut motility agents 294 Anti-diarrhoeals 296 Anti-constipation agents 298 286 CHAPTER 17 Gastrointestinal drugs H2 blockers and proton pump inhibitors Types \200 \200 H2-antagonists, e.g. ranitidine, cimetidine. Proton pump inhibitors, e.g. omeprazole, panto prazole. Modes of action These agents inhibit secretion of gastric acid, reducing both volume and ac id content, either by antagonism of the histamine H2 receptor or by inhibiting H+K+-ATPase which fuels the parietal cell proton pump on which acid secretion depends. Uses \200 \200 \200 \200 \200 Peptic ulceration, gastritis, duodenitis. Re \202 ux oesophagitis. Prophylaxis against str ess ulceration. Upper gastrointestinal hemorrhage of peptic/stress ulcer origin. With non-s teroidal anti-in \202 ammatory agents in patients with dyspepsia. Side effects/complications \200 The major concern voiced against these agents is the increased risk of nosocomial pneumonia by removal of the acid barrier. However, a multicentre randomized controlled trial (RCT) c omparing ranitidine with sucralfate showed no difference in pneumonia rate and a lower inci dence of GI bleeding. H2-antagonists: rare but include arrhythmias, altered liver function tests, confusion (in the elderly). Proton pump inhibitors: altered liver function tests. Notes \200 Although licensed and frequently used for stress ulcer prophylaxis, overwhelming supportive evidence is scanty. Enteral nutrition has been shown to be as effective. No adequately pow ered study of proton pump inhibitors has yet been performed in ICU patients. Some studies h ave shown ef \201 cacy in upper gastrointestinal hemorrhage secondary to stress ulceration or peptic ulceration. Dosages should be modi \201 ed in renal failure. Cimetidine can aff ect metabolism of other drugs, in particular, warfarin, phenytoin, theophylline, and lidoca ine (related to hepatic cytochrome P450-linked enzyme systems). This does not occur with ra nitidine. Omeprazole can delay elimination of diazepam, phenytoin, and warfarin. \200 H2 BLOCKERS AND PROTON PUMP INHIBITORS 287 Drug dosages Ranitidine Cimetidine Omeprazole Pantoprazole 50mg tds by slow IV bolus, 150mg bd PO 200 \200\223400mg qds by slow IV bolus, 400mg bd PO 40mg od IV(over 20 \200\22330min) or 20 \200\22340mg od PO 40mg od PO or slow IV Key paper Cook D, Guyatt G, Marshall J, et al. (1998) A comparison of sucralfate and raniti dine for the pre- vention of upper gastrointestinal bleeding in patients requiring mechanic al ventilation. Canadian Critical Care Trials Group. N Engl J Med 338: 791 \200\2237. See also: Upper gastrointestinal hemorrhage, p412. 288 CHAPTER 17 Gastrointestinal drugs Sucralfate Modes of action \200 Sucralfate is a basic aluminum salt of sucrose octasulphate and is probably not absorbed fr om the gastrointestinal tract. Exerts a cytoprotective effect by preventing mucosal injury. A protective barrier is formed both over normal mucosa and any ulcer lesion providing prot ection against penetration of gastric acid, bile, and pepsin as well as irritants such as a spirin and alcohol. Directly inhibits pepsin activity and absorbs bile salts. Weak antacid activity. \200 Uses \200 \200 \200 Peptic ulceration, gastritis, duodenitis. Re \202 ux oesophagitis. Prophylaxis against str ess ulceration. Side effects/complications \200 \200 Constipation. Reduced bioavailability of some drugs given orally, e.g. digoxin, phenytoin. Can be overcome by giving agents at least 2h apart. Use with caution in renal failure due t o risk of increased aluminum absorption. Notes \200 Although licensed and frequently used for stress ulcer prophylaxis, overwhelming supportive evidence is scanty. Enteral nutrition and gastric acid blockers have been shown to be as e ffective. Evidence for a reduced incidence of nosocomial pneumonia compared to H2 blocker t herapy is also con \202 icting. Signi \201 cant reduction in nosocomial pneumonia has bee n shown compared to a combination of H2 blocker plus antacid, but not against H2 blocker al one. Indeed, a large multicentre RCT comparing ranitidine with sucralfate showed no differe nce in pneumonia rate and a lower incidence of GI bleeding with ranitidine. Antacids should not be given for 30min before and after sucralfate. SUCRALFATE 289 Drug dosage Sucralfate 1g six times a day PO or via NG tube. Key paper Cook D, Guyatt G, Marshall J, et al. (1998) A comparison of sucralfate and raniti dine for the pre- vention of upper gastrointestinal bleeding in patients requiring mechanic al ventilation. Canadian Critical Care Trials Group. N Engl J Med 338: 791 \200\2237. See also: Upper gastrointestinal hemorrhage, p412 290 CHAPTER 17 Gastrointestinal drugs Antacids Types \200 \200 \200 \200 Sodium bicarbonate. Magnesium-based antacids, e.g. magnesium trisilicate. Aluminum-based an tacids, e.g. aluminum hydroxide. Proprietary combinations, e.g. Gaviscon . Modes of action \200 \200 Neutralizes gastric acid. Provides protective coating on upper gastrointestinal mucosa. Uses \200 \200 Symptomatic relief of gastritis, duodenitis, oesophagitis. Stress ulcer prophylaxis (conten tious). Side effects/complications \200 \200 Possible increased risk of nosocomial pneumonia. Aluminum toxicity (if aluminum-containing antacids are used long-term in patients with renal dysfunction). Diarrhea (magnesium-based antacids). Constipation (aluminum-based antacids). Metabolic alkalosis if large amounts are administered. Milk-alkali syndrome resulting in hypercalcaemia, metabolic alkalosis, and r enal failure is very rare. \200 \200 \200 Notes \200 As their main use is for symptomatic relief, antacids are rarely needed in mechanically ven tilated patients. Continual nasogastric infusion of a weak sodium bicarbonate solution has been used successfully in treating stress ulcer-related hemorrhage. ANTACIDS 291 Drug dosages Magnesium trisilicate Aluminum hydroxide Gaviscon 10 \200\22320mL qds 10 \200\22320mL qds 10 \200\22320mL qds See also: Upper gastrointestinal hemorrhage, p412. 292 CHAPTER 17 Gastrointestinal drugs Anti-emetics Types \200 \200 \200 \200 Phenothiazines, e.g. prochlorperazine, chlorpromazine. Dopamine receptor blocker, e.g. meto clopramide, domperidone. Anti-histamines, e.g. cyclizine. 5HT3 receptor antagonists, e.g. o ndansetron, granisetron. Modes of action \200 Phenothiazines increase the threshold for vomiting at the chemo- receptor trigger zone via central DA2 dopaminergic blockade; at higher doses, there may also be some effect on the vo miting center. Metoclopramide acts centrally and by increasing gastric motility. Cyclizine increases lower oesophageal sphincter tone and may inhibit the midbrain emetic center. Onda nsetron is a highly selective 5HT3 receptor antagonist; its precise mode of action is unkno wn, but may act both centrally and peripherally. \200 Uses \200 \200 Nausea. Vomiting. Side effects/complications \200 Dystonic or dyskinetic reactions, oculogyric crises (prochlorperazine, metoclopramide). Arr hythmias (metoclopramide, prochlorperazine). Headaches, \202 ushing (ondansetron). Urtica ria, drowsiness, dry mouth, blurred vision, urinary retention (cyclizine). Postural hypoten sion (prochlorperazine, cyclizine). Rarely neuroleptic malignant syndrome (prochlorperazine , metoclopramide). \200 \200 \200 Notes \200 The initial choice should fall between prochlorperazine, metoclopramide, or cyclizine. Proc hlorperazine and cyclizine are preferable when vomiting is related to drugs and metabolic d isturbances acting at the chemoreceptor trigger zone while metoclopramide or domperidone sh ould be tried \201 rst if a gastrointestinal cause is implicated. Metoclopramide and proc hlorperazine dosage should be reduced in renal and hepatic failure. Ondansetron dosage shou ld be reduced in hepatic failure. ANTI-EMETICS 293 Drug dosages Prochlorperazine 5 \200\22310mg tds PO, 12.5mg qds IM or by slow IV bolus (note: not licensed for IV use) 10 mg tds by slow IV bolus, IM, or PO 50mg tds slow IV bolus, IM, or PO 4 \200\2238mg tds by s low IV bolus, IM, or PO 1 \200\2233mg by slow IV bolus up to max 9mg/24h Metoclopramide Cyclizine Ondansetron Granisetron See also: Enteral nutrition,p128; Vomiting/gastric stasis, p406. 294 CHAPTER 17 Gastrointestinal drugs Gut motility agents Types \200 \200 \200 Metoclopramide. Domperidone. Erythromycin. Modes of action \200 Metoclopramide and domperidone probably act by blocking peripheral DA2 dopaminergic recepto rs. Erythromycin is a motilin agonist acting on antral enteric neurons. Uses \200 \200 Ileus, large nasogastric aspirates. Vomiting. Side effects/complications \200 \200 \200 Dystonic or dyskinetic reactions, oculogyric crises (metoclopramide). Arrhythmias (metoclop ramide and erythromycin). Cholestatic jaundice (erythromycin). Notes \200 Metoclopramide dosing should be reduced in renal failure and hepatic failure, while erythro mycin dosing should be reduced in hepatic failure. GUT MOTILITY AGENTS 295 Drug dosages Metoclopramide Erythromycin 10mg tds by slow IV bolus, IM, or PO 250mg qds PO or IV See also: Enteral nutrition, p128; Vomiting/gastric stasis, p406. 296 CHAPTER 17 Gastrointestinal drugs Anti-diarrhoeals Types \200 \200 Loperamide. Codeine phosphate. Modes of action Loperamide and codeine phosphate bind to gut wall opiate receptors, reducin g propulsive peristalsis and increasing anal sphincter tone. Side effects/complications \200 Abdominal cramps, bloating. \200 Constipation (if exces sive amounts given). Notes \200 Should not be used when abdominal distension develops, particularly with ulcerative colitis or pseudomembranous colitis. Avoid in infective diarrhea as may prolong illness. Caution w ith loperamide in liver failure and codeine in renal failure. \200 ANTI-DIARRHOEALS 297 Drug dosages Loperamide 2 capsules (20mL) initially, then 1 capsule (10mL) after every loose stool for up to 5 days 30 \200\22360mg 4 \200\2236 hourly PO, IM, or by slow IV bolus Codeine phosphate See also: Enteral nutrition, p128; Diarrhea, p406. 298 CHAPTER 17 Gastrointestinal drugs Anti-constipation agents Types \200 \200 Laxatives, e.g. lactulose, propantheline, mebeverine. Bulking agents, e.g. dietary \201 b re (bran), hemicelluloses (methylcellulose, ispaghula husk). Suppositories, e.g. glycerin. Enemata, e.g. warmed normal saline, olive oil, or arachis oil retention enemata. \200 Modes of action \200 Laxatives include: \200 Anti-spasmodic agents such as anticholinergics (e.g. propantheline) and mebeverine (a pheny lethylamine derivative of reserpine). Non-absorbable disaccharides (e.g. lactulose) which s often the stool by an osmotic effect and by lactic acid production from a bacterial ferment ing effect. Irritants, such as castor oil, which is hydrolysed in the small intestine, rele asing ricinoleic acid. Bulking agents are hydrophilic and thus increase water content of the stool. Side effects/complications \200 \200 Bloating and abdominal distension. Diarrhea if excessive amounts given. Notes \200 Surgical causes presenting as constipation such as bowel obstruction must be excluded. Othe r measures should be taken if possible to improve bowel function e.g. reducing concurrent o piate dosage, starting enteral nutrition. The agent of choice is lactulose. Larger doses of lactulose are used in hepatic failure as the pH of the colonic contents is reduced; this l owers formation and absorption of ammonium ions and other nitrogenous products into the por tal circulation. Bene \201 t in patients has not been shown. Anthraquinone glycosides (e.g . senna) and liquid paraf \201 n are no longer recommended for routine use. \200 ANTI-CONSTIPATION AGENTS 299 Drug dosage Lactulose 15 \200\22350mL tds PO See also: Failure to open bowels, p410. This page intentionally left blank 301 Chapter 18 Neurological drugs Non-opioid analgesics 302 Opioid analgesics 304 Epidural analgesia 306 Sedatives and tranqu ilisers 308 Muscle relaxants 310 Anticonvulsants 312 Neuroprotective agents 314 302 CHAPTER 18 Neurological drugs Non-opioid analgesics Types \200 \200 Paracetamol. Non-steroidal anti-in \202 ammatory drugs (NSAIDs): e.g. aspirin, ibuprofen, indometacin, diclofenac, ketorolac, sulindac. Ketamine. Nitrous oxide. Local anesthetics, e .g. lidocaine, bupivacaine. A2 agonists \200\224clonidine, dexmedetomidine (see under sedat ives). \200 \200 \200 Uses \200 \200 Pain associated with in \202 ammatory conditions (aspirin, NSAIDs). Post-operative pain an d musculoskeletal pain (aspirin, NSAIDs, paracetamol, ketamine, nitrous oxide, lidocaine, b upivicaine). Opiate-sparing effect (aspirin, paracetamol, NSAIDs). Antipyretic (aspirin, pa racetamol, NSAIDs). \200 Routes \200 \200 \200 \200 \200 \200 IV (paracetamol, ketamine). IM (diclofenac, ketamine). PO (aspirin, NSAIDs, paracetamol). P R (aspirin, diclofenac, paracetamol). Local/regional (lidocaine, bupivacaine). Inhaled (nit rous oxide). Side effects \200 \200 \200 \200 \200 \200 \200 \200 Gastrointestinal bleeding (aspirin, indometacin, diclofenac). Renal dysfunction (indometaci n, diclofenac if any hypovolaemia). Reduced platelet aggregation (aspirin, indometacin, dic lofenac). Reduced prothrombin formation (aspirin, indometacin, diclofenac). Myocardial depr ession (lidocaine, bupivacaine). Hypertension and tachycardia (ketamine). Seizures (lidocai ne, bupivacaine). Hallucinations and psychotic tendencies (ketamine \200\224prevented by co ncurrent use of benzodiazepines or droperidol). Notes \200 The WHO analgesia ladder concept requires mild to moderate pain to be managed with simple a nalgesics, progressing to opioids if pain relief is not adequate. Non-steroidal anti-in \202 ammatory agents should be generally avoided in patients with renal dysfunction, GI ble eding, or coagulopathy. In sub-anesthetic doses, ketamine is a powerful analgesic. It is as sociated with good airway maintenance, allows spontaneous respiration, and provides cardiov ascular stimulation. It is also a bronchodilator. Nitrous oxide is a powerful, short-acting analgesic used with 50% oxygen (Entonox) to cover short, painful procedures. Do not use in cases of undrained pneumothorax since it may diffuse into the pneumothorax, resulting in t ension. Cox-2 inhibitors are not currently recommended by the authors due to emerging evide nce of cardiovascular side effects. Clonidine and dexmedetomidine have intrinsic analgesic properties. NON-OPIOID ANALGESICS 303 Drug dosages Aspirin Ibuprofen Indometacin Diclofenac 600mg PO/PR 4-hourly 400mg PO 4 \200\2238 hourly 50 \200\223100mg PO/PR 12-hourly 25 \200 \22350mg PO 8-hourly, 100mg PR 12 \200\22324 hourly, 75mg IM 12-hourly 10mg PO 4 \200\2236 hourly, 10 \200\22330mg IV/IM 4 \200\2236 hourly 200mg PO 12-hourly 0.5 \200\2231g PO/PR/IV 4 \200\2236 hourly 5 \200\22325mcg/kg/min IV or 0.5 \200\2231.0mg/kg IM 100 \200\223150mcg /min 1mcg/kg over 10min, followed by a maintenance infusion of 0.2 to 0.7mcg/kg/h Maximum 2 00mg Maximum 150mg* Ketorolac Sulindac Paracetamol Ketamine Clonidine Dexmedetomidine Lidocaine Bupivacaine *Local anesthetic doses vary according to area to be anesthetized. Ma ximum doses may be increased if epinephrine is used locally. See also: Opioid analgesics, p304; Rheumatic disorders, p572; Pyrexia \200\224management, p 604; Pain, p618; Post-operative critical care, p620; Pain and comfort, p624. 304 CHAPTER 18 Neurological drugs Opioid analgesics Types \200 \200 \200 Natural opiates, e.g. morphine, codeine. Semi-synthetic, e.g. diamorphine, dihydrocodeine. Synthetic, e.g. pethidine, fentanyl, alfentanil, remifentanil, tramadol. Uses \200 Analgesia: Strong analgesics are extracts from opium or synthetic substances with similar p roperties. They are more useful for continuous pain rather than sharp, intermittent pain. S edation. Anxiolysis in heart failure (diamorphine, morphine). Anti-diarrhoeal (codeine). \200 \200 Routes \200 IV (morphine, diamorphine, papaveretum, pethidine, fentanyl, alfentanil, remifentanil, tram adol). IM/SC (morphine, codeine, diamorphine, dihydrocodeine, pethidine, tramadol). PO (mor phine, codeine, diamorphine, dihydrocodeine, pethidine, tramadol). Percutaneous (fentanyl). Side effects \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Respiratory depression. Central nervous system depression. Stimulation of the vomiting cent er. Decreased gastric emptying and gut motility, constipation. Histamine release and itchin g. Dry mouth. Increased muscular tone. Appetite loss. Withdrawal syndrome (withdraw slowly) . Addiction (rare in the critically ill). Notes \200 Mild to moderate pain requiring opioids is usually treated with less potent drugs such as c odeine, dihydrocodeine, or tramadol. Morphine is poorly absorbed from the gastrointestinal tract, and therefore, is usually administered parenterally. It is metabolized to morphine-6 -glucuronide in the liver which is six times more potent than morphine and accumulates in r enal failure. Pethidine has local anesthetic properties associated with cardiac depression and vasodilatation. It is metabolized to norpethidine which may lead to seizures on accumul ation. Respiratory depression occurs despite maintenance of respiratory rate. Fentanyl and alfentanil are good, short-acting analgesics with poor sedative quality. However, long-term infusion leads to accumulation. They cause severe respiratory depression and muscular rigi dity. Remifentanil is ultra short-acting, and the patient may suffer from rebound pain if t he infusion is stopped temporarily. OPIOID ANALGESICS 305 Drug dosages Intravenous Bolus 0.1 \200\2230.2mg/kg 0.05 \200\2230.1mg/kg 0.5mg/kg 5 \200\2237.5mcg/kg 15 \200\22330 mcg/kg 1mcg/kg 50 \200\223100mg 4 \200\2236 hourly Infusion 0.05 \200\2230.07mg/kg/h 0.03 \200\2230.06mg/kg/h 0.1 \200\2230.3mg/kg/h 5 \200 \22320mcg/kg/h 20 \200\223120mcg/kg/h 0.05 \200\2232mcg/kg/min Morphine Diamorphine Pethidine Fentanyl Alfentanil Remifentanil Tramadol Other routes Morphine Codeine Diamorphine Dihydrocodeine Pethidine Tramadol Fentanyl Note the above dose s are a guide only and may need to be altered widely according to individual circumstances. The correct dose of an opiate analgesic is generally enough to ablate pain. 10mg IM/SC 4-hourly 30 \200\22360mg IM 4-hourly 5mg IM/SC 4-hourly 50mg IM/SC 4 \200\2236 h ourly 25 \200\223100mg IM/SC 4-hourly 50 \200\223100mg IM 4 \200\2236 hourly 12 \200\223100 mcg/h percutaneous 5 \200\22320mg PO 4-hourly 30 \200\22360mg PO 4-hourly 5 \200\22310mg PO 4-hourly 30mg PO 4 \200\2236 hourly 50 \200\223150mg PO 4-hourly 50 \200\223100mg PO 4 \200\2236 hourly See also: Non-opioid analgesics, p302; Pain, p618; Post-operative critical care, p620; Pain and comfort, p624. 306 CHAPTER 18 Neurological drugs Epidural analgesia Types \200 \200 \200 Opioid analgesics (morphine, diamorphine, fentanyl, alfentanil). Local anesthetics (bupivac aine). Adjuvants (clonidine). Uses \200 \200 Post-operative analgesia. Regional anesthesia. Side effects \200 As lower doses of opioids are required to achieve effective analgesia, there is a lower inc idence of opioid-related side effects. Hypotension (local anesthetics, clonidine). Bradycar dia (local anesthetic with a high block above T4). Central nervous system and respiratory d epression (opioids). Stimulation of the vomiting center (opioids). Appetite loss (opioids). Dry mouth (opioids). Decreased gastric emptying and gut motility (opioids). Histamine rele ase and itching (opioids). Increased muscular tone (opioids). Motor blockade (local anesthe tics). Urinary retention (opioids, local anesthetics). Headache (dural puncture). Abscess o r haematoma (catheter-related). Total spinal block (profound hypotension, apnoea, unconscio usness and dilated pupils due to inadvertent spinal injection of epidural dose). \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Notes \200 The epidural catheter should typically be placed in the mid-dermatome range of the site of the pain. Fentanyl is more lipid-soluble than non-synthetic opioids so gains faster access to opioid receptors. Low bupivacaine concentrations are less likely to block larger diamete r motor \201 bres allowing the patient to mobilize. It is usual to infuse combinations of drugs in lower doses to maximize the analgesic effect while minimizing side effects. Highe r volume infusions block a greater range of nerve routes. A bolus of 1 \200\2232mL of local anesthetic will typically block one dermatome. Age reduces the volume required. Inadequate block may respond to a bolus dose or increasing the infusion rate. Clonidine may enhance a nalgesia provided by epidural opioids and local anesthetics. Coagulation should be checked before removing an epidural catheter to avoid haematoma. At least 12 hours should be left a fter the last dose of low molecular weight heparin. EPIDURAL ANALGESIA 307 Drug dosages Concentration 2 \200\2234mcg/mL 50mcg/mL 20mcg/mL 0.1 \200\2230.125% 2mcg/mL Dose 0 \200\22340mcg/h 0 \200\2230.5mg/h 0 \200\2230.2mg/h 12.5mg/h 15 \200\22320mcg/h Fentanyl Morphine Diamorphine Bupivacaine Clonidine See also: Non-opioid analgesics, p302; Opioid analgesics, p304; Respiratory failure, p350; Hypotension, p380; Bradyarrhythmias, p386. 308 CHAPTER 18 Neurological drugs Sedatives and tranquilisers Types \200 \200 \200 \200 Benzodiazepines, e.g. diazepam, midazolam, lorazepam. Major tranquilizers, e.g. chlorpromaz ine, haloperidol. Anesthetic agents, e.g. propofol, iso \202 urane. A2 agonists, e.g. clon idine, dexmedetomidine. Uses \200 Sedation and anxiolysis. Routes \200 \200 \200 \200 IV (benzodiazepines, haloperidol, propofol, clonidine, dexmedetomidine). IM (benzodiazepine s, chlorpromazine, haloperidol). PO (diazepam, lorazepam, chlorpromazine, haloperidol, clon idine). Inhaled (iso \202 urane). Side effects \200 Hypotension (benzodiazepines, chlorpromazine, haloperidol, propofol, clonidine, dexmedetomi dine). Respiratory depression (benzodiazepines, chlorpromazine, haloperidol, propofol). Arr hythmias (chlorpromazine, haloperidol). Dry mouth (clonidine, dexmedetomidine). Extrapyrami dal disorder (chlorpromazine, haloperidol). Fluoride toxicity (iso \202 urane). Rebound ag itation on drug withdrawal (benzodiazepines). \200 \200 \200 \200 Notes \200 Sedative drugs have cardiovascular and respiratory side effects. Objective assessment of th e depth of sedation is necessary to ensure comfort does not give way to excessive sedation. All sedatives are cumulative so doses must be kept to a minimum. Stopping sedation daily h as been shown to reduce critical care stay. Benzodiazepines have an advantage of being amne sic. Midazolam is slowly metabolized in 10% of patients. All benzodiazepines accumulate in renal failure; care must be taken to avoid excessive dosage by regular reassessment of need . Propofol in sub-anesthetic doses is short-acting, but effects are cumulative with prolong ed infusion or with coexisting hepatic/renal failure. Large dose propofol may contribute si gni \201 cantly to calorie intake via the fat emulsion. As chlorpromazine and haloperidol antagonize catecholamines, they may cause vasodilatation and hypotension. Dystonic reaction s and arrhythmias (e.g. torsade de pointes) are also occasionally seen. A2 antagonists offe r both analgesia and sedation, and are synergistic with opiates. Dexmedetomidine causes min imal respiratory depression and the patient is easily rousable. Bradycardia and hypotension may occur, especially with the loading dose. Iso \202 urane is short-acting although cumu lative effects have been recorded with prolonged use that also carries the theoretical risk of \202 uoride toxicity. Exhaled iso \202 urane should be adequately scavenged. \200 \200 SEDATIVES AND TRANQUILISERS 309 Drug dosages Bolus 0.05 \200\2230.15mg/kg IV/IM 50mcg/kg IV/IM 1mg IV 0.5 \200\2232mg/kg IV 25 \200\2235 0mg IM 2 \200\22310mg IV/IM Infusion Too long-acting 10 \200\22350mcg/kg/h Too long-acting 1 \200\2233mg/kg/h Too long- acting Too long-acting 100 \200\223150mcg/h Diazepam Midazolam Lorazepam Propofol Chlorpromazine Haloperidol Clonidine Dexmedetomidine Loading infusion of 6.0mcg/kg/h over 10min, followed by maintenance infusion of 0.2 \200 \2230.7mcg/kg/h. Note that the above doses are a guide only and may need to be altered widely according to i ndividual circumstances. Key papers Kress JP, Pohlman AS, O Connor MF, et al. (2000) Daily interruption of sedative infusions in criti- cally ill patients undergoing mechanical ventilation. N Engl J Med 342: 1471 \200\2237. Pandharipande PP, Pun BT, Herr DL, et al. (2007) Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS random ized controlled trial. JAMA 298: 2644 \200\22353. Girard TD, Kress JP, Fuchs BD, et al. (2008) Ef \201 cacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awa kening and Breathing Controlled trial): a randomized controlled trial. Lancet 371: 126 \200 \22334. Monitoring sedation Frequent, objective reassessment of sedation depth and degree of agita- tion with corresponding adjustment of infusion doses is necessary to avoid severe cardiova scular and respiratory depression. Simple sedation scores are available to aid assessment, e.g. Riker Score, CAM-ICU. UCL Hospitals Sedation Score Agitated and restless Awake and uncomfortable Aware but calm R oused by voice, remains calm Roused by movement Roused by painful or noxious stimuli Unrous able Natural sleep Sedation doses are adjusted to achieve a score as close as possible to. Positive scores require increased sedation doses and negative scores require reduced sedati on doses. +3 +2 +1 0 \200\2231 \200\2232 \200\2233 A See also: IPPV \200\224failure to tolerate ventilation, p52; IPPV \200\224assessment of wea ning, p60; EEG/CFM moni- toring, p204; Respiratory stimulants, p256; Delirium, p442. 310 CHAPTER 18 Neurological drugs Muscle relaxants Types \200 \200 Depolarising, e.g. suxamethonium. Non-depolarising, e.g. pancuronium, atracurium, cisatracu rium, vecuronium, rocuronium. Mode of action \200 Suxamethonium is structurally related to acetylcholine and causes initial stimulation of mu scular contraction seen clinically as fasciculation. During this process, continued stimula tion leads to desensitization of the post- synaptic membrane of the neuromuscular junction with ef \202 ux of K+ ions. Subsequent \202 accid paralysis is short-acting (2 \200\2233 min) and cannot be reversed (is actually potentiated) by anticholinesterase drugs. Prolonge d effects occur with congenital or acquired pseudo-cholinesterase de \201 ciency. Non-depo larising muscle relaxants prevent acetylcholine from depolarising the post-synaptic membran e of the neuromuscular junction by competitive blockade. Reversal of paralysis is achieved by anticholinesterase drugs such as neostigmine. They have a slower onset and longer durati on of action than the depolarising agents. Uses \200 \200 To facilitate endotracheal intubation. To facilitate mechanical ventilation where optimal s edation does not prevent patient interference with the function of the ventilator. Routes \200 IV. Side effects \200 \200 \200 \200 Hypertension (suxamethonium, pancuronium). Bradycardia (suxamethonium). Tachycardia (pancur onium). Hyperkalaemia (suxamethonium). Notes \200 