ALLERGIC RHINITIS (UK) Seasonal Perennial Epidemiology The problem is seen worldwide. Prevalence has increased in the industrialized \200\230West \200\231. Around 20% of the UK popula- tion have allergic rhinitis. A familia l pattern of predisposi- tion is recognized, but the speci \201 c genetic factors have not been fully de \201 ned. Spring (tree) Summer (grass) Autumn (fungal) Work Domestic Dust mite Pets Fig. 4.2.1 Diagnostic algorithm. Rhinitis and asthma It is increasingly clear, that allergic rhinitis is a risk factor for a sthma. The supporting evidence includes: \200 KEY POINT Non-specific irritants do exacerbate true allergic rhinitis. Perennial rhinitis is an independent risk factor for asthma. Asthma is commoner in patients with perennial rhinitis, irrespective of whether they are atopic individuals. Children, wh o develop seasonal rhinitis, are more likely to develop asthma, but the risk is reduced if the seasonal allergic rhinitis is adequately treated. In patients with both asthma and rhin itis, there are fewer seasonal admissions for asthma, if the rhinitis is adequately treated . Bronchial hyper-reactivity increases in the hay fever season. One key clue is whether symptoms are all year round (per- ennial), seasonal, or perennial w ith seasonal exacerbation (e.g. house dust mite (HDM) with grass pollen sensitivity). Anoth er consideration is whether symptoms suggest a domestic- or work-related trigger. Work-rela ted symptoms (which may be due to true allergy or non-allergic irrita- tion) would reduce a t weekends and evenings typically, and be maximal towards the end of the working day. Examp les might include vets, bakers ( \202 our dust), latex (hospital staff), and chemicals / p aints. In the UK, seasonal allergic rhinitis may be due to \200 \200 \200 \200 Aspirin sensitivity/nasal polyps and asthma \200\230Samter \200\231s \200\231 triad. Rhini tis is often the \201 rst symptom. All non-steroidal anti-in \202 ammatories should be a voided. Nasal polyposis can be reduced medically (nasal corticos- teroid) or surgically. Ac cidental exposure to aspirin (or similar drugs) can provoke life-threatening adverse effect s. Clinical features can include urticaria, and angioedema, as well as asthma. Tree pollen: February \200\223May. Grass pollen: May \200\223August. Fungal spores: July \200\223September. Weed pollen: April \200\223September. Differential diagnosis Pointers against allergy include: \200 \200 Most seasonal rhinitis in the UK will be tree and or grass (weed and fungal spores are less of a problem) Asymmetric/unilateral symptoms/signs. Symptoms which fail to respond to adequate doses of c orticosteroid (see Treatment p.65). Mid-life onset with no previous allergic problems and n o family history of atopy. Diagnostic tests Skin prick tests These tests detect functional IgE speci \201 c antibody, in vivo. They are sensitive and at least for the common inhaled allergens (including HDM, pollens, pets) are reliable with sensitivity and specificity both approaching 80 \200\22390 %. Puri \201 ed allergen is applied externally to the patients skin, and the allergen is s cratched into the epidermis by gentle use of a sharp sterile blade. Positive results (itchy wheal and \202 are reactions) develop within 15 minutes, and the patient can leave the c linic knowing their results. This test has an extremely good safety record. Non-allergic diagnoses \200 \200 Congenital defects (e.g. ciliary dysmotility) \200\223 rare. Infection \200\223 common bu t typically acute/short lived, and with associated systemic features (malaise, fever, \200 \230 \202 u-like symptoms \200\231). Iatrogenic \200\223 medical (e.g. excessive deconges tant medi- cation). Iatrogenic \200\223 surgical. Autoimmune (Wegener \200\231s \200\223 rare). \200 Speci \201 c IgE blood tests Originally \200\230RAST \200\231 tests were performed. Nowad ays simpler non-radioactive assays are performed. Puri \201 ed allergen in vitro is used t o detect small amounts of Non-allergic irritation/in \202 ammation Cigarette smoke, pungent inhaled chemicals (e.g. perfumes), dusty environments (building sites), and chemical contact CHAPTER 4.2 Allergic rhinitis 65 allergen speci \201 c IgE. A sample of clotted blood (serum) is required by the laboratory , and results are routinely available the same day. Table 4.2.1 Topical medications Sneez Drip Blockage Total serum IgE This test is of little value. Elevated levels point to an allergic (atopic) tendency but elevated IgE per se does not prove allergic rhinitis. Results from skin prick tests and from allergen speci \201 c IgE blood tests largely agree with one another, and costs are comparable. Saline douches ++ Decongestant +++ Anti-histamine ++ + Ipatropium bromide +++ Topical corticosteroid +++ +++ +++ Chromoglycate ++ + + Provocation tests Allergen challenge, to determine if symptoms are reliably provoked is rar ely necessary, and in some circumstances (e.g. asthmatics) carries some risk. In the same way that many asthma suffers may not have been taught how to optimally use thei r inhalers, the major- ity of patients with allergic rhinitis do not employ the correct del ivery technique. A \200\230head down \200\231 position (with the head bent forward, akin t o kneeling on a prayer mat) helps ensure that medication does not simply drip into the oro- pharynx. Administration should be passive (no violent snif \201 ng). Systemic decongestant s are often less effective than topical equivalents and are best avoided. Both preparations risk rebound congestion if overused (more than 1 week). Ephedrine is the safest topical sy mpathomimetic, and can be effective within hours. Treatment Allergen avoidance This can be dif \201 cult or near impossible. Some situations are easier to manage than others \200\223 e.g. removing feather pillows from the home. KEY POINT Some pet epithelial allergens, (notoriously cat), can per- sist for many years af ter a cat has died or been removed, despite house cleaning. Mild rhinitis Often, the \201 rst step should be to try saline washouts and or topical de congestants (e.g. ephedrine). These sim- ple treatments with or without anti histamine (ant i-H1 receptor) topically or orally may be sufficient on an as required basis. Oral anti-his tamines have few side effects and are easier to administer than their topical counterparts. HDM \200\223 a very common culprit Typical features include: \200 \200 \200 Symptoms worst \201 rst thing in the morning. Tendency to wake with nasal obstruction. Sy mptoms with vacuum cleaning / dusting. KEY POINT HDM can be strangly limked to eczema and reduced exporure can lead to improvement of eczema in many cases. Moderately severe rhinitis For more severe symptoms, (see Table 4.2.1), topically administe red corticosteroid is the gold standard. Aim to use the lowest effective doses topically. C oncurrent anti- histamine will usually also be required. HDM reduction measures include: \200 Severe rhinitis Treatment options include addition of: \200 \200 Purchase of barrier bedding (pillow cases and sheets). HDM feeds on shed human epithelium, and large reser- voirs of HDM are found in bedding. Use of chemicals (acaricides), which ki ll HDM. Maintaining a domestic environment which is unfavour- able to HDM (increased ventil ation, low humidity, use of air \201 lters). Topical chromoglycate. Topical ipatropium bromide \200\223 very useful for vasomotor drip. Oral leukotriene antagonists (reduce obstruction/ dripping). \200 Oral corticosteroid Under certain circumstances, it is generally agreed that oral prednisol one or similar, can be justi \201 ed to cover short periods of either severe symptoms, or where avoidance of symptoms needs to be guaranteed (e.g. weddings, exam- inations). Doses w ould be similar to those used to control asthma exacerbations. Clinical trials of these methods have suffered from design limitations. Isolated use of bar rier bedding is unlikely to be successful. In the UK, in the winter especially, low humidit y is hard to achieve. Acaricides offer most promise. Combining interventions may prove to b e most effective, but again the evidence base is poor. Irritant avoidance Non-speci \201 c irritants (cigarette smoke, dust, swimming pools (chlo rine, perfumes)) can exacerbate allergic rhinitis and should be avoided. Prophylaxis/prevention Where problems can be predicted (e.g. hay fever) it is good practice to start treatment a week or two before onset of symptoms, and maintain it daily throughou t the season. KEY POINT The commonest reason for treatment failure is non- compliance or inappropriate dr ug administration. Drugs will not work if the nasal passages are blocked in the first place (here use of topical decongestant drops helps open up the airways before switching to topi cal corticosteroid and or other medications). Bene \201 t/harmful effects The estimated minimum number of treated patients required to d emonstrate bene \201 t (5 patients for topical anti-H1 or for injection immunotherapy, and 15 for oral monteleukast), can be contrasted with the number of J UNSWORTH 66 patients on the same medication before signi \201 cant side effects are noted (approximate ly 15, 25, 150 respectively). Thus monteleukast is \200\230safer \200\231 but less effecti ve than topical steroid. Results to date suggest improved outcomes when com- pared to placebo, but further studies a re required. Pollen sensitivity and \200\230oral allergy \200\231 (pollen/food allergy) syndrome A sub- group of pollen-sensitive individuals develop addi- tional food-related problems typically several years after onset of their hay fever. Immunological hypersensitivity to particular pollen proteins (namely profilins) leads to speci \201 c and predictable cross \200\223 r eactions and immediate \200\230oral \200\231 or throat symptoms when certain foods (which contain the shared allergen) are handled or eaten. The problem relates to \200 \200 \200 Desensitization This involves planned, controlled, cautious, repeated expo- sure to puri \201 ed allergen (e.g. grass pollen prior to the hay fever season) administered in such a w ay that the resulting immunological response favors \200\230tolerance \200\231 with reduce d symptoms, and reduced need for rescue medication. The ef \201 cacy is dose dependant. Subcutaneous injection This has been most used over the last 25 years. Recently, better de \201 ned allergen preparations, exclusion of brittle asthmatics, and limitation to experie nced secondary care centers, has led to fewer severe side effects. Consent for desensitizat ion by injection must highlight the following considerations: \200 Fruits (apples, cherries, peaches and several others). Vegetables (potatoes, celery, carrot s and others). Some tree nuts (hazelnut, walnut and almond). KEY POINT With the exception of nuts (which may resist cooking) pro \201 lin proteins are heat sensitive and easily destroyed by cooking/tinning/microwaving. Only successful in approximately 75% patients (varies according to the allergen). minor/loc al injection site irritation (25% or more). Severe systemic immediate hypersensitivity reac tions in fewer than 5% (risks reduced if asthmatic patients are excluded). Patients must be detained for observation for 1 hour post treatment. \200 Further reading Durham SR. Allergen immunotherapy (desensitization) for allergic diseases. Clin Med 2006; 6: 348 \200\223351. Leynaert B, Bousquet J, Neukirch C, et al. Perennial rhinitis: an inde- pendent risk factor for asthma in non-atopic subjects. J Allergy Clin Immunol 1999; 104: 301 \200\223304. Madonini E, Briatico-Vangosa G, Pappacoda A, et al. Seasonal increase of bronchial reactivi ty in allergic rhinitis. J Allergy Clin Immunol 1987; 79: 358 \200\223363. Note percentages quoted here vary, with some allergens (e.g. cat epithelium) being more lik ely to provoke adverse reactions than other allergens. Portnoy J M, Van Osdol T, Brock Williams P. Evidence based strate- gies for the treatment o f allergic rhinitis. Curr Allergy Asthma Rep 2004; 6: 439 \200\223446. Oral desensitization Immunological tolerance can be generated by mucosal (e.g. oral) antige n / allergen exposure, rather than by subcutaneous injection. This logistically easier appr oach shows promise, and early observations suggest that adverse hypersensitivity reactions are less than with subcutaneous immunotherapies. This approach offers the prospect of poten tially safe home therapy. However, direct compari- sons of subcutaneous and oral delivery e mploying the same allergen preparations are awaited. This page intentionally left blank P BARNES 68 4.3 Pharmacology The pharmacology of asthma largely involves the use of drugs to treat airway obstruction. T wo types of drug are used in its treatment: \200 Mode of action B2-agonists produce bronchodilatation by: \200 Directly by stimulating B2-receptors in airway smooth muscle, leading to relaxation of cent ral and peripheral airways. B2-agonists act as \200\230functional antagonists \200\231 and reverse bronchoconstriction irrespective of the contractile agent; this is important in as thma, because many bronchoconstrictor mechanisms (neural and mediators) are likely to const rict airways. Occupation of B2-receptors by agonists results in the activation of adenylyl cyclase via the stimulatory G-protein (Gs), which increases intra-cellular cAMP, leading to relaxation. Indirectly by inhibiting mast cell mediator release, cholin- ergic neurotransm ission and microvascular leakage. 2-adrenoceptors B By binding to B 2-agonists activate ade nylate cyclase resulting in an increase in intracellular cyclic AMP (cAMP) (Fig. 4.3.1). B2 -agonists relax airway smooth muscle via several mecha- nisms: \200 Relievers (bronchodilators) give immediate reversal of airway obstruction, largely by relax ing airway smooth muscle. Controllers (preventers) suppress the underlying disease process and provide long-term control of symptoms. These drugs include anti-inflammatory treatments . Asthma is characterized by airway narrowing secondary to a chronic in \202 ammatory proces s. Eosinophilic and some- times neutrophilic) in \202 ammation occurs throughout the respi ratory tract. Bronchodilators cause immediate reversal of airway obstruction as a result of an effect on airway smooth muscle; other pharmacological effects on other airway cells (re duced micro-vascular leakage, reduced release of bronchoconstrictor mediators from in \202 ammatory cells) may contribute to the reduction in air- way narrowing. Lowering of intracellular calcium ion (Ca2+) concentra- tion by active removal of Ca2+ from the cell and into intracellular stores. Inhibitory effect on phosphoinositide hydrolysis. Inhibition of myosin light chain kinase. Activation of myosin light chain phosphatase. b2-adrenoceptor agonists Inhaled B2-agonists are the bronchodilator treatment of choice in asthma because they are the most effective bron- chodilators, reverse all known bronchocons trictor mecha- nisms and have minimal side-effects when used correctly. Short-acting and no n-selective B-agonists (e.g. isoprena- line, orciprenaline) have no role. \200 \200 K+ 2-agonist Blocked by iberiotoxin 2-adrenoceptor Cell membrane AC s s Ca2+-activated K+ channel activation Gs Gs d PI hydrolysis Cyclic 3 5 AMP ATP i Na+/Ca2+ exchange i Na+/K+ ATPase PKA i MLCK Fig. 4.3.1 Molecular mechanism of action of 2-agonists on airway smooth muscle cells. Ac tivation of 2-adrenoceptors results in activation of adenylyl cyclase (AC) via a stimula tory G-protein (Gs) and increase in cyclic 3 \200\2315 \200\231 adenosine monophosphate (AM P). This activates protein kinase A (PKA) which then phosphorylates several target proteins which result in opening of calcium-activated potassium channels (KCa) or maxi-K channels, decreased phosphoinositide (PI) hydrolysis, increase sodium/calcium ion (Na+/Ca2+) exchange , increase Na+/K+ ATPase and decrease myosin light chain kinase (MLCK) activity. In additio n, 2-receptors may be coupled directly via Gs to KCa. (ATP = adenosine trithosphate). CHAPTER 4.3 Pharmacology 69 Opening of a large conductance calcium-activated potassium channels (KCa) which repolarise the smooth muscle cell Safety A recent large trial in the USA showed that salmeterol increased mortality in asthma tic patients, but this was mainly in poor patients who were not using concomitant inhaled c orticosteroids. This provides a strong argument for only prescribing long-acting B2-agonist s in a combination inhaler. B2-agonists have no signi \201 cant inhibitory effects on the chronic in \202 ammation of asthmatic airways, and do not reduce airway hyperresponsiveness in asthma. Clinical use Short-acting inhaled B2-agonists (e.g. salbutamol, terbuta- line) have a durat ion of action is 3 \200\2234 hours (less in severe asthma). They are convenient, easy to us e, rapid in onset and without significant side effects. They also protect against bronchoco nstrictor stimuli such as exercise, cold air and allergen. They are the bronchodilators of choice in acute severe asthma, in which the nebulised route of administration is as effecti ve as IV use. The inhaled route of administration is preferable to the oral route because s ide effects are less common, and because it may be more effec- tive (better access to surfa ce cells such as mast cells). Short-acting inhaled B2-agonists should be used as required b y symptoms, and not on a regular basis. Increased usage indicates a need for more anti-in \202 ammatory therapy. Long-acting inhaled B2-agonists (e.g. salmeterol and formoterol) hav e a bronchodilator action and protect against bronchoconstriction for more than 12 hours, a nd provide better symptom control (given twice daily) than regular treatment with short-act ing B2-agonists (four times daily). \200 Tolerance Continuous treatment with an agonist often leads to toler- ance (desensitization) , which may result from uncoupling and/or down-regulation of the receptor. Tolerance of non - airway B-receptor responses (e.g. tremor, cardiovascular and metabolic responses) is read ily observed. Loss of bronchodilator action is minimal, but there is some loss of bronchopr otective effect against exercise. This is incom- plete and not progressive, and is not a cl inical problem. Theophylline Theophylline remains the most widely used anti-asthma therapy worldwide becaus e it is inexpensive, but the greater incidence of side effects with theophylline and the gr eater ef \201 cacy of B-agonists and inhaled corticosteroids have reduced its use. It stil l remains a useful drug in patients with severe asthma.There is increasing evidence that lo w- dose theophylline (plasma concentration 5 \200\22310mg/L) has an anti-in \202 ammatory or immunomodulatory effect and may be effective in combination with inhaled corticosteroids . Mode of action Theophylline is a bronchodilator only at high doses (>10mg/L) when side effe cts are common and its anti- asthma effect is more likely to be explained other effects (e. g. immunomodulation). Several modes of action have been proposed: \200 Formoterol has a more rapid onset of action than salmeterol and formoterol, but not salmete rol, is more effective as a reliever than short-acting B2-agonists. Inhaled long-acting B2- agonists may be added to low or moderate doses of inhaled corticosteroids if asthma is not controlled, and this is more effective than increasing the dose of inhaled corticosteroids. Long-acting inhaled B2-agonists should be used only in patients who are taking inhaled cor ticosteroids, because these drugs have no anti-in \202 ammatory action and are potentially dangerous without corticosteroids. Combination inhalers with a long-acting 2-agonist and corticosteroid ( \202 uticasone/salmeterol, budesonide/ formoterol, budesonide beclometha sone dipropionate) are an effective and convenient way to control asthma Budesonide/formote rol is very effective as a reliever when added to maintenance treatment with the same drug (allowing single inhaler therapy). Inhibition of phosphodiesterases, which break down cAMP leads to an increase in intracellul ar cAMP concentrations. This accounts for the bronchodilator action of theophyl- line, but also for the side effects of nausea and headaches. Adenosine receptor antagonism \200\223 adenosine is a bron- choconstrictor in asthmatic patients, via activation of mast cells (A2 B receptors). Adenosine antagonism may account for some side effects of theophylline (e.g. seizures, cardiac arrhythmias, diuresis). Histone deacetylase activation \200\223 therapeu tic concentra- tions of theophylline activate histone deacetylases in the nucleus, resultin g in the switching off of in \202 ammatory genes and enhancing the anti-in \202 ammatory action of corticosteroids. Side effects Unwanted effects result from stimulation of extra-pulmonary B-receptors. Side effects are uncommon with inhaled therapy, but more common with oral or IV administration ( Table 4.3.1). Clinical use In patients with acute asthma, IV aminophylline (combina- tion of theophylline and ethylenediamine) is less effective than nebulised B2-agonists, and should therefore be reserved for the few patients who fail to respond to B-agonists. Theophylline is less effe ctive as a bronchodila- tor than inhaled B2-agonists and is more likely to have side- effec ts. Low doses (plasma concentrations of 5 \200\22310mg/L) may be useful when added to inhal ed corticosteroids, particularly in more severe asthma. Theophylline is readily and reliabl y absorbed from the gas- trointestinal tract, but there are many factors affecting plasma c learance, and thereby plasma concentration, that make the drug relatively dif \201 cult to use (Table 4.3.2). Table 4.3.1 Side effects of 2-agonists Muscle tremor \200\223 direct effect on skeletal muscle B2-receptors Tachycardia \200\223 direct effect on atrial B2-receptors, re \202 ex effect from increased peripheral vasodil atation via B2-receptors Hypokalaemia \200\223 direct effect on skeletal muscle uptake of K+ via B2-receptors Restlessness Hypoxaemia \200\223 increased V/Q mismatch because of pul monary vasodilatation \200 \200 P BARNES 70 Side effects Side effects are usually related to plasma concentration and occur when plasma levels exceed 20mg/liter, though many patients develop them at lower plasma concentra- tio ns. The severity of side effects may be reduced by gradu- ally increasing the dose until th erapeutic concentrations are achieved. The most common side-effects are nausea and vomiting , headache, abdominal discomfort and rest- lessness. The most severe side effects are cardi ac arrhyth- mias and seizures. Side effects \200 Inhaled anticholinergic drugs are well tolerated, and systemic side-effects are uncommon be cause almost no systemic absorption occurs. Ipratropium bromide, even in high doses, has no detect- able effect on airway secretions. Nebulised ipratropium bromide may precipitate gl aucoma in elderly patients as a result of a direct effect of the nebulised drug on the eye; this is avoided by use of a mouthpiece rather than a face-mask. Paradoxical bronchoconstri ction with ipratropium bro- mide, particularly when given by nebuliser, was largely explain ed by the hypotonicity of an earlier nebuliser solution and by antibacterial additives such as benzalko- nium chloride; this problem is avoided with current preparations. Table 4.3.2 Factors affecting theophylline clearance Increased clearance \200 \200 \200 \200 \200 Enzyme induction (rifampicin, phenobarbitone, ethanol) Smoking (tobacco, marijuana) High-pr otein, low-carbohydrate diet Barbecued meat In children Corticosteroids Corticosteroids are the most effective therapy available for asthma. Inhale d corticosteroids have revolutionized the management of chronic asthma and are now used as \201 rst- line therapy in all patients with persistent symptoms. By contrast they are poo rly effective in COPD, cystic \201 brosis and interstitial lung disease. Decreased clearance \200 Enzyme inhibition (cimetidine, erythromycin, cipro \202 oxacin, allopurinol, za \201 rluk ast) Congestive heart failure Liver disease Pneumonia Viral infection and vaccination High- carbohydrate diet \200 \200 \200 \200 Mode of action Corticosteroids enter target cells and bind to glucocorti- coid receptors (G R) in the cytoplasm. Activated GR are transported to the nucleus, where they: \200 Anticholinergics Atropine is a naturally occurring compound that was intro- duced for the t reatment of asthma but, because of side effects (particularly drying of secretions), less s oluble qua- ternary compounds (e.g. ipratropium bromide) were developed. Bind to speci \201 c sequences on the upstream regulatory element of certain target genes, resulting in increased or decreased transcription of the gene and increased or decreased p rotein synthesis. Inhibit proin \202 ammatory transcription factors, such as nuclear facto r- B and activator protein-1, which regulate in \202 ammatory gene expression by a non-ge nomic mecha- nism. Inhibit acetylation of core histones that results in increased in \202 ammatory gene expression by recruiting histone deacetylase-2 to the transcriptional complex (Fig. 4.3.2). The mechanism of action of corticosteroids in asthma is most likely to be re lated to their anti-in \202 am- matory properties. Corticosteroids have widespread effects on gene transcription, increasing transcription of anti-in \202 ammatory genes and, more importantly, sup- pressing transcription of many in \202 ammatory genes. They also have in hibitory effects on many in \202 ammatory and structural cells that are activated in asthm a (Fig. 4.3.4). The inhibitory action of inhaled corticosteroids on air- way epithelial cel ls may be particularly important; this results in a reduction in airway hyper-responsivenes s, though in long-standing asthma airway responsiveness may not return to normal because of irreversible struc- tural changes in airways. Mode of action Anticholinergics are speci \201 c antagonists of muscarinic receptors and i nhibit cholinergic nerve-induced bronchoc- onstriction. A small degree of resting bronchomo tor tone is present because of tonic cholinergic nerve impulses, which release acetylcholin e in the vicinity of airway smooth muscle, and cholinergic reflex bronchocon- striction may be initiated by irritants, cold air and stress. Although anticholinergics protect against acute challenge by sulfur dioxide and emotional factors, they are less effective against an tigen, exercise and fog \200\223 they inhibit reflex cholinergic bronchoconstriction only and have no signi \201 cant blocking effect on the direct effects of inflammatory mediator s such as histamine and leukotrienes. Clinical use Ipratropium bromide and oxitropium bromide are admin- istered three or four ti mes daily via inhalation, whereas tiotropium bromide is given once daily. \200 In asthmatics, anticholinergic drugs are less effective than B2-agonists and offer less pro tection against various bronchial challenges. Nebulised anticholinergics are effective in a cute severe asthma, but less effective than B2-agonists. Anticholiner- gic drugs may have a n additive effect with B2-agonists in acute and chronic treatment and should therefore be c onsidered when control of asthma is inadequate, par- ticularly when there are side-effects with theophylline or inhaled B-agonists. Clinical use \200 Systemic corticosteroids are used in acute asthma and accelerate their resolution. There is no advantage to very high doses of IV corticosteroids (e.g. methyl- prednisolone 1g). Pred nisolone (30 \200\22360 mg orally) has an effect similar to IV hydrocortisone and is easier to administer. Regular oral corticosteroids are reserved for patients whose asthma cannot be controlled on other therapy; the dose is titrated to the lowest that provides acceptable CHAPTER 4.3 Pharmacology 71 Inflammatory stimuli e.g. IL-1 , TNF- Corticosteroids Theophylline NF- B p65 GR + p50 Inflammatory protein (e.g. GM-CSF, IL-8) Co-activators CBP p65 GR HDAC p50 HAT Acetylation Deacetylation d Inflammatory gene transcription i Inflammatory gene transcription Gene activation Gene repression Fig. 4.3.2 Corticosteroids suppresses in \202 ammation by switching off the transcription of multiple activated in \202 ammatory genes. In \202 ammatory genes are switched on by i n \202 ammatory stimuli through the activation the transcription factor nuclear factor B (NF- B). NF- B translocates to the nucleus and binds to speci \201 c recognition sites on in \202 ammatory genes and also to coactivators, such as CREB- binding protein (CBP), w hich has intrinsic histone acetyltransferase (HAT) activity. This leads to acetylation of c ore histones, resulting in increased expression of genes encoding multiple in \202 ammator y proteins such as cytokines. Glucocorticoid receptors (GR) after activation by corticoster oids also translocate to the nucleus and bind to coactivators to inhibit HAT activity direc tly and more importantly by recruiting histone deacetylase-2 (HDAC2), which reverses histon e acetylation leading in suppression of these activated in \202 ammatory genes. HDAC2 is m arkedly reduced in COPD, accounting for the corticosteroid resistance in this disease. Inflammatory cells Structural cells Eosinophil Numbers (apoptosis) Epithelial cell d Cytokines Mediators d T-lymphocyte d Cytokines Endothelial cell d Leak Mast cell CORTICOSTEROIDS d Numbers Airway smooth muscle i \2372-Receptors Cytokines Macrophage d d Cytokines Mucus gland Dendritic cell Mucus secretion d d Numbers Fig. 4.3.3 Effect of corticosteroids on in \202 ammatory and structural cells in the airwa ys. P BARNES 72 symptom control. Objective evidence of corticosteroid responsiveness should be obtained bef ore maintenance therapy is instituted. Short courses of oral corticosteroids (prednisolone, 30 \200\22340 mg daily for 1 \200\2232 weeks) are indicated for exacer- bations of asthma. The dose may be tapered over 1 week once the exacerbation is resolved. Inhaled corticoster oids are currently recommended as \201 rst-line therapy in all patients with persistent a sthma. They may be started in any patient who needs to use a B2-agonist inhaler for symptom control more than twice a week. In most patients, inhaled corticosteroids are used twice d aily. Some patients with severe asthma fail to respond to corticosteroids and may require o ral corticosteroids. using inhaled corticosteroids, but in most studies doses of 400mcg daily or less have not b een associated with impaired growth, and there may even be a growth spurt because asthma is better controlled. Tabl e 4.3.3 Side effects of inhaled corticosteroids Local side effects \200 Dysphonia \200 Oropharyngeal candidiasis \200 Cough Systemic side effects \200 Adrenal suppression \200 Growth suppression \200 Bruising \200 Osteoporosis \200 Cataracts \200 Glaucoma \200 Metabolic abnormalities (glucos e, insulin, triglycerides) \200 Psychiatric disturbances Side effects \200 Corticosteroids inhibit cortisol secretion by a negative feedback effect on the pituitary g land. Hypothalamo \200\223 pituitary \200\223adrenal axis suppression is dependent on dose, and usually occurs when a dose of prednisolone of >7.5 mg daily is used. Significant suppr ession after short courses of corticosteroid therapy is not usually a prob- lem, but prolon ged suppression may occur after several months or years; corticosteroid doses after prolong ed oral therapy must therefore be reduced slowly. Symptoms of \200\230corticosteroid withd rawal syndrome \200\231 include lassitude, musculoskeletal pains and occasionally fever. Si de-effects of long-term oral corticosteroid therapy include \202 uid retention, increased appetite, weight gain, osteoporosis, capillary fragility, hypertension, peptic ulceration, diabetes, cataracts and psychosis. The inci- dence increases with age. Systemic side-effec ts, such as cataract formation and osteoporosis are reported but often in patients who are also receiving oral corticosteroids. There has been par- ticular concern about growth suppr ession in children The fraction of corticosteroid inhaled into the lungs acts locally on the airway mucosa and may be absorbed from the airway and alveolar surface, thereby reaching the sys- temic circ ulation. The fraction of inhaled corticosteroid deposited in the oropharynx is swallowed an d absorbed from the gut (Fig. 4.3.4). The absorbed fraction may be metabolized in the liver before it reaches the systemic circulation. Budesonide and \202 uticasone have a greater \201 rst-pass metabolism than beclomethasone dipropion- ate and are therefore less likel y to produce systemic effects at high inhaled doses. The use of a spacer reduces oropharyng eal deposition, thereby reducing systemic absorption of corticosteroid Inhaled corticostero ids may have local side-effects caused by deposition of corticosteroid in the orophar- ynx, including dysphonia, oral candidiasis and dry cough. MDI 10-20% inhaled Mouth and pharynx Lungs Systemic circulation 80-90% swallowed ( \206\223 spacer/mouth-wash) Absorption from GI tract Liver GI tract Systemic side effects Inactivation in liver \200\234first pass \200\235 Fig. 4.3.4 Pharmacokinetics of inhaled glucocorticoids (GI = gastrointestinal). CHAPTER 4.3 Pharmacology 73 Cromones Cromones include sodium cromoglycate, and the structurally- related nedocromil sod ium. The dry-powder inhaler may cause throat irritation, coughing and, occasionally, wheezing, b ut this is usually prevented by prior administration of a B-agonist inhaler. Very rarely, a transient rash and urticaria or pulmonary eosinophilia are seen as a result of hypersensit ivity. Side effects are not usually a problem with nedocromil, though some patients have no ticed a sensation of \202 ush- ing after using the inhaler. Mode of action \200 Initial investigations suggested that cromoglycate acts as a mast-cell stabilizer, but this effect is weak in human mast cells. Cromoglycate blocks the early response to allergen, wh ich is mediated by mast cells, Cromones also inhibit bronchoconstriction induced by sulfur dioxide, metabisulphite and bradykinin, which are believed to act through activation of sen sory nerves in the airways. Cromones have variable inhibitory actions on other in \202 amm atory cells that may participate in allergic in \202 am- mation, including macrophages and eosinophils and inhibits the late response to allergen. The molecular mechanism of cromone action is not understood; recent evidence suggests they may block a type of chloride chann el that may be expressed in sensory nerves, mast cells and other in \202 ammatory cells. Anti-leukotrienes Anti-leukotrienes (leukotriene receptor antagonists), such as montelukast and za \201 rlukast, are much less effective than inhaled corticosteroids in the control of asthma. Mode of action Elevated levels of leukotrienes are detectable in broncho- alveolar lavage \202 uid, exhaled breath condensate, sputum and urine of asthmatic patients. Cysteinyl-leu kotrienes (cys-LTs) are generated from arachidonic acid by the rate- limiting enzyme 5-lipo xygenase (5 -LO)(Fig. 4.3.5). Cys-LTs are potent constrictors of human airways in vitro and in vivo, cause airway microvascular leakage in animals, and stimulate airway mucus secreti on. These effects are all mediated in human airways via cys-LT1-receptors. Montelukast and za \201 rlukast are potent cys-LT1-receptor antagonists that markedly inhibit the bronchoc onstrictor response to inhaled leukotrienes, reduce allergen-induced, exercise-induced and cold air-induced asthma by about 50 \200\22370%, and inhibit aspirin-induced responses in a spirin- sensitive asthmatics almost completely. 5 -LO inhibitors (e.g. zileuton) have a sim ilar inhibitory and clinical effect but are not currently available outside the USA. Clinical use Cromones are prophylactic treatments and must be given regularly. They protect against indirect bronchoconstrictor stimuli such as exercise, allergen and fog. Cromones a re poorly effective compared to low doses of inhaled corti- costeroids as they have a very short duration of action and systematic reviews show that they provide little bene \201 t in chronic asthma. Cromones are administered four times daily and may also be taken before exercise in children with exercise-induced asthma. There has been an increas- ing tendency to substitute low dose inhaled corticoster- oids for cromoglycate in adults and children so they are now rarely used. Clinical use Anti-leukotrienes may have a small and variable bronchodi- lator effect, indic ating that leukotrienes may contribute to baseline bronchoconstriction in asthma. Long-term admin- istration reduces asthma symptoms and the need for rescue B2-agonists, and improves lung function. However, their effects are signi \201 cantly less than with inhaled cortic osteroids Side effects Cromoglycate is one of the safest drugs available and side effects are extreme ly rare. Cold air Allergen Exercise PAF MC Eos Aspirin (ASA patients) SO2 Arachidonic acid 5 \200\231-lipoxygenase 5-LO inhibitors zileuton Cysteinyl-leukotrienes (LTC4, LTD4, LTE4) LT-antagonist montelukast pranlukast zafirlukast Plasma exudation Cys-LT1 receptors Bronchoconstriction Mucus secretion Eos recruitment Fig. 4.3.5 Effects of cysteinyl-leukotrienes on the airways and their inhibition by anti-le ukotrienes (LT = leukotriene; 5-LO = 5 -lipoxygenase; ASA = aspirin sensitive asthmatic). P BARNES 74 in terms of symptom control, improvement in lung function and reduction in exacerbations. A nti-leukotrienes are not as effective as inhaled corticosteroids in the management of mild asthma and are not the preferred therapy. They may be useful in some patients whose asthma is not con- trolled on inhaled corticosteroids as an add-on therapy to inhaled corticostero ids, but are less effective in this respect than a long-acting B2-agonist or low dose theop hylline. They are effective in some but not all patients with aspirin- sensitive asthma. Pa tients appear differ in their response to anti-leukotrienes, and it is impossible to predic t which patients will respond best. A major advantage of anti-leukotrienes is that they are orally active, and this is likely to improve compliance with long-term therapy. However, t hey are expensive, and a trial of therapy is indicated to determine which patients will ben e \201 t most. blocking of IgE reduces its synthesis from B-lymphocytes results in a sustained reduction i n IgE (Fig. 4.3.6).