β2-AGONISTS Use
β2-Agonists (e.g. salbutamol and the long-acting β2-agonist salmeterol) are used to treat the symptoms of bronchospasm in asthma (both in an acute attack and as maintenance ther- apy) and chronic obstructive pulmonary disease (COPD).
(Intravenoussalbutamolis also used in obstetric practice to inhibit premature labour). For asthma, β2-agonists are given via inhalation where possible, see also Table 33.1.
1. Inhalation formulations include:
• metered-dose inhaler – aerosol. Some patients are unable to master this technique;
• aerosol administered via a nebulizer;
• as a dry powder – almost all patients can use a dry- powder inhaler correctly.
2. Oral formulations, including slow-release preparations.
Intravenous administration
The increase in FEV1after inhaling salbutamolbegins within 5–15 minutes, peaks at 30–60 minutes and persists for 4–6 hours.
Pharmacological effects, mechanism of action and adverse effects
Agonists occupying β2-adrenoceptors increase cyclic adeno- sine monophosphate (cAMP) by stimulating adenylyl cyclase via stimulatory G-proteins. Cyclic AMP phosphorylates a
cascade of enzymes (see Figure 33.3). This causes a wide var- iety of effects including:
1. relaxation of smooth muscle including bronchial, uterine and vascular;
2. inhibition of release of inflammatory mediators;
3. increased mucociliary clearance;
4. increase in heart rate, force of myocardial contraction, speed of impulse conduction and enhanced production of ectopic foci in the myocardium and automaticity in pacemaker tissue. This can cause dysrhythmias and symptoms of palpitations;
5. muscle tremor;
6. vasodilatation in muscle, part of this effect is indirect, via activation of endothelial NO biosynthesis;
7. metabolic effects:
• hypokalaemia (via redistribution of Kinto cells);
• raised free fatty acid concentrations;
• hyperglycaemia due to a greater increase in glycogenolysis than in insulin secretion.
8. desensitization.
Pharmacokinetics
Salbutamolundergoes considerable presystemic metabolism in the intestinal mucosa (sulphation) and hepatic conjugation
to form an inactive metabolite that is excreted in the urine.
Most (approximately 90%) of the dose administered by aerosol is swallowed, but the 10–15% which is inhaled largely remains as free drug in the airways. The plasma elimination half-life (t1/2) is two to four hours.
Salmeterolis long acting, with a duration of action of at least 12 hours, allowing twice daily administration. The lipophilic side-chain of salmeterolbinds firmly to an exo-site that is adjacent to, but distinct from, the β2-agonist binding site. Consequently, salmeterol functions as an almost irre- versible agonist. The onset of bronchodilatation is slow (15–30 minutes). Salmeterol should not therefore be used to treat acute attacks of bronchospasm. It is now advised as first-line in prophylactic therapy, on a twice daily basis, with ‘top ups’
of short acting β2-agonists.Salmeterolshould be used in con- junction with inhaled glucocorticosteroids.
MUSCARINIC RECEPTOR ANTAGONISTS Use
Osler recommended stramonium– which contains atropine– in the form of cigarettes for asthmatics! In comparison to atropine, modern agents, e.g. ipratropium, are quaternary ammonium analogues and have reduced systemic absorption due to their positive charge. Ipratropiumis given three or four DRUGSUSED TOTREATASTHMA ANDCHRONICOBSTRUCTIVEPULMONARYDISEASE 237
Table 33.1:Comparative pharmacology of other β2-agonists
Drug Formulations Pharmacokinetics/ Other comments
available pharmacodynamics
Terbutaline Metered-dose inhaler Plasma t1/2is 3–4 h Similar to salbutamol Dry powder Gastro-intestinal and
Nebulizer solution hepatic metabolism Tablets/syrup
Slow-release tablets
Salmeterol Metered-dose inhaler Onset slow; 12 h duration Prophylaxis and exercise- of action. Hepatic metabolism induced asthma. Not
Dry powder for treatment of acute
bronchospasm
ATP GDP GTP
Myosin light↓ chain kinase Phosphorylase
kinase↑ Adenylyl
cyclase
Protein kinase A cAMP
Ca2
2-Agonist
2-Receptor
Bronchodilatation ↓ Mediator release ↓ Mucosal oedema Gi/Gs
Figure 33.3:Membrane and intracellular events triggered when β2-agonists stimulate β2-receptors.
Gi/Gs, inhibitory and stimulatory G-protein, GDP, guanosine diphosphate; GTP, guanosine triphosphate;
cAMP, 3,5-cyclic adenosine monophosphate.
METHYLXANTHINES Use
Aminophylline(theophylline, 80%; ethylene diamine, 20%) is occasionally used intravenously in patients with severe refrac- tory bronchospasm. Oral theophyllinemay be used for less severe symptoms or to reduce nocturnal asthma symptoms.
Recently, the use of theophyllinehas markedly declined, but it is still sometimes used in refractory cases.
For intravenous aminophylline, a loading dose given slowly (20–30 minutes) is followed by a maintenance infusion.
Oraltheophyllinesustained-release preparations can provide effective therapeutic concentrations for up to 12 hours follow- ing a single dose. Because of their slow release rate they have a reduced incidence of gastro-intestinal side effects.
Mechanism of action and pharmacological effects It is not clear exactly how theophylline produces broncho- dilation. Its pharmacological actions include the following:
• relaxation of airway smooth muscle and inhibition of mediator release (e.g. from mast cells). Theophylline raises intracellular cAMP by inhibiting phosphodiesterase.
However, phosphodiesterase inhibition is modest at therapeutic concentrations of theophylline;
• antagonism of adenosine (a potent bronchoconstrictor) at A2-receptors;
• anti-inflammatory activity on T-lymphocytes by reducing release of platelet-activating factor (PAF).
Adverse effects
The adverse effects of theophyllineare:
• Gastro-intestinal: nausea, vomiting, anorexia.
• Cardiovascular: (1) dilatation of vascular smooth muscle – headache, flushing and hypotension; (2) tachycardia and cardiac dysrhythmias (atrial and ventricular).
• Central nervous system: insomnia, anxiety, agitation, hyperventilation, headache and fits.
Pharmacokinetics
Theophyllineis well absorbed from the small intestine. It is 85–90% eliminated by hepatic metabolism (CYP1A2). The therapeutic concentration range is 5–20 mg/L, but it is prefer- able not to exceed 10 mg/L in children.
238 THERAPY OF ASTHMA,COPD AND OTHER RESPIRATORY DISORDERS times daily from a metered-dose inhaler or nebulizer. Inhaled muscarinic receptor antagonists are most effective in older patients with COPD. The degree and rate of onset of bron- chodilatation are less than those of salbutamol, but the dur- ation of response is longer. Ipratropium has a place in maintenance therapy and the treatment of acute severe attacks of asthma and chronic bronchitis. It is compatible with β2-agonists, and such combinations are additive. Tiotropium is a long-acting antimuscarinic bronchodilator administered by inhalation in the management of COPD patients. It is not used to treat acute bronchospasm.
Mechanism of action
There is increased parasympathetic activity in patients with reversible airways obstruction, resulting in bronchoconstric- tion through the effects of acetylcholine on the muscarinic (M2, M3) receptors in the bronchi. The final common pathway is via a membrane-bound G-protein which when stimulated leads to a fall in cAMP and increased intracellular calcium, with consequent bronchoconstriction. Antimuscarinic drugs block muscarinic receptors in the airways.
Adverse effects These include:
• bitter taste (this may compromise compliance);
• acute urinary retention (in patients with prostatic hypertrophy);
• acute glaucoma has been precipitated when nebulized doses are given via a face mask;
• paradoxical bronchoconstriction due to sensitivity to benzalkonium chloride, which is the preservative in the nebulizer solution.
Pharmacokinetics
When administered by aerosol, it is poorly absorbed system- ically. Plasma t1/2is three to four hours and inactive metab- olites are excreted in the urine.
Several formulations of β2-agonist combined with mus- carinic antagonist bronchodilators are available to simplify treatment regimens.
Key points
Bronchodilator agents
• β2-Agonists.
• Bronchodilate by increasing intracellular cAMP.
• Short-acting, rapid-onset agents (e.g. salbutamol) are used as needed to relieve bronchospasm in asthma.
• Long-acting, slower-onset agents (e.g. salmeterol) are used regularly twice daily.
• Common side effects include tremor, tachycardias, vasodilatation, hypokalaemia and hyperglycaemia.
Anticholinergics
• Antagonist at M2and M3muscarinic receptors in the bronchi, causing bronchodilatation.
• Slow onset of long-lasting bronchodilatation (given six- to eight-hourly), especially in older patients.
• Bitter taste.
• Little systemic absorption and side effects are rare (dry mouth, acute retention, exacerbation of glaucoma).
Theophylline
• Potent bronchodilator (also vasodilator).
• Aminophylline i.v. for acute severe episodes.
• Slow-release oral preparations for chronic therapy.
• Hepatic metabolism, multiple drug interactions (e.g.
clarithromycin, ciprofloxacin).
• Therapeutic drug monitoring of plasma concentrations.
• Side effects include gastro-intestinal disturbances, vasodilatation, dysrhythmias, seizures and sleep disturbance.
Drug interactions
Although synergism between β2-adrenergic agonists and theo- phyllinehas been demonstrated in vitro, clinically the effect of this combination is at best additive. Many drugs inhibit CYP1A2- mediated theophylline metabolism, e.g. erythromycin (and other macrolides), fluoroquinolones (e.g. ciprofloxacin),inter- feronandcimetidine, thus precipitating theophyllinetoxicity.
Theophyllinemetabolism is induced in the presence of hepatic CYP450-inducing agents, such as rifampicin.
GLUCOCORTICOSTEROIDS
Glucocorticosteroids are used in the treatment of asthma and in severe exacerbations of COPD because of their potent anti-inflammatory effect. This involves interaction with an intracellular glucocorticosteroid receptor that in turn interacts with nuclear DNA, altering the transcription of many genes and thus the synthesis of pro-inflammatory cytokines, β2-adrenocep- tors, tachykinin-degrading enzymes and lipocortin (an inhibitor of phospholipase A2, reducing free arachidonic acid and thus leukotriene synthesis). They are used both in maintenance ther- apy (prophylaxis) and in the treatment of the acute severe attack.
SYSTEMIC GLUCOCORTICOSTEROIDS
For more information on the use of systemic glucocortico- steroids, see Chapter 40.
Hydrocortisoneis given intravenously in urgent situations.
Improvement (a rise in FEV1and forced vital capacity, FVC) does not begin until after six hours, and is usually maximal 10–12 hours following the start of treatment. This delay is due to the action of glucocorticosteroids via altered gene transcription and subsequent modified protein synthesis. Oral glucocorticosteroids (e.g.prednisolone) are usually started within 12–24 hours.
INHALED GLUCOCORTICOSTEROIDS (E.G.
BECLOMETASONE, BUDESONIDE, FLUTICASONE, MOMETASONE)
Use
Modern inhalational devices deliver up to 20% of the admin- istered dose to the lungs.
Glucocorticosteroids can be administered via nebulizers,
‘spacer’ devices, metered-dose inhalers or as dry powders.
The fluorinated derivatives are extremely potent and mainly exert a local action because they are highly polar and hence only a small fraction of the dose is systemically absorbed.
Approximately 15–20% enters the lungs, the rest being swal- lowed and then rapidly converted to inactive metabolites by intestinal and hepatic CYP3A enzymes.
The comparative pharmacology of the commonly used inhaled glucocorticosteroids is summarized in Table 33.2.
Adverse effects of inhaled steroids
• At the lowest recommended daily dose for adults, there is no prolonged suppression of the hypothalamic–pituitary–
adrenal (HPA) axis. Higher doses can produce clinically important depression of adrenal function.
• Candidiasis of the pharynx or larynx occurs in 10–15% of patients. Using the minimum effective dose, or a ‘spacer device’, or gargling/using mouthwashes after dosing, minimizes this problem.
• A hoarse voice may develop due to a laryngeal myopathy at high doses. This is reversible and its occurrence is minimized by the use of a ‘spacer’.
• Bruising and skin atrophy occur at high doses.
• Inhibition of long bone growth during prolonged high- dose treatment in children.
• Posterior subcapsular cataracts may develop following prolonged use.
CROMOGLICATE AND NEDOCROMIL Use
Sodium cromoglicatemay be used to prevent exercise-induced asthma and as prophylaxis for allergic asthma in children. Its use as a prophylactic in children has been largely superseded by inhaled glucocorticosteroids which are more effective. It is used as a nasal spray for perennial and allergic rhin-itis, and as eyedrops in allergic conjunctivitis. Cromoglicateproduces no benefit during an acute asthmatic attack. Nedocromil sodium is an alternative to cromoglicate.
Mechanism of action
Cromoglicateandnedocromilinhibit mediator release from sensitized mast cells in vitro, and also reduce firing of sensory DRUGSUSED TOTREATASTHMA ANDCHRONICOBSTRUCTIVEPULMONARYDISEASE 239
Key points
Anti-inflammatory agents – cromoglicate and glucocorticosteroids
Sodium cromoglicate
• Its mechanism of action is unclear. It has an anti- inflammatory effect.
• Largely superseded in chronic prophylactic therapy of
‘allergic asthma’ by glucocorticosteroids.
• Prevents exercise-induced asthma.
• Inhaled therapy is administered via metered-dose inhaler or dry powder.
• Side-effects are minimal (headache, cough).
• Its use is very safe in children.
Glucocorticosteroids
• Mechanism is anti-inflammatory.
• They are administered systemically (i.v./p.o.) in severe acute and chronic asthma.
• They are inhaled topically or nebulized in chronic asthma.
• Glucocorticosteroids are well absorbed from the gastro- intestinal tract–hepatic (CYP3A) metabolism.
• Dosing is once daily for oral glucocorticosteroids and twice daily for inhaled agents.
• Side effects are minimal with topical therapy (oral thrush, hoarse voice, HPA suppression only at high dose).
• Side effects with systemic therapy are the features of Cushing’s syndrome.
240 THERAPY OF ASTHMA,COPD AND OTHER RESPIRATORY DISORDERS Table 33.2:Comparative pharmacology of some inhaled glucocorticosteroids
Drug Relative binding affinity Relative blanching Comments
to receptorsa potencya
Beclometasone 0.4 600 Equi-effective compared to
dipropionate budesonide. May be used in children
Budesonide 9.4 980 Nebulized formulation (0.5–1mg/2 mL)
available. May be used in children to avoid systemic steroids
Fluticasone 18 1200 May cause fewer systemic side
effects than others
aRelative to dexamethasone binding to glucocorticosteroid receptors in vitro and blanching of human skin in vitro.
receptor to cause bronchoconstriction, attraction of eosinophils and production of oedema.
LEUKOTRIENE C4AND D4ANTAGONISTS Use
Leukotriene receptor antagonists are used to treat asthma and are given orally, usually in the evening. Montelukastwas the first of these drugs to become available clinically. It reduced the requirement for glucocorticosteroid and improved symptoms in chronic asthma. It is also useful in the prophylaxis of exercise- or antigen-induced asthma. Montelukastis effective in aspirin- sensitive asthma, which is associated with diversion of arachi- donic acid from the cyclo-oxygenase pathway (blocked by aspirin) to the formation of leukotrienes via 5-lipoxygenase.
Mechanism of action
Montelukastis a competitive inhibitor of LTD4and LTC4at the Cys-LT1receptor.
Adverse effects
Montelukastis generally well tolerated, but side effects include:
• gastro-intestinal upsets;
• asthenia and drowsiness;
• rash, fever, arthralgias;
• elevation of serum transaminases.
Pharmacokinetics
This drug is rapidly absorbed from the gastro-intestinal tract. The mean plasma t1/2is 2.7–5.5 hours. It undergoes hepatic metab- olism by CYP 3A and 2C9, and is mainly excreted in the bile.
Drug interactions
No clinically important drug–drug interactions are currently recognized.
5-LIPOXYGENASE INHIBITORS
Zileuton(available in the USA) is a competitive inhibitor of the 5-lipoxygenase enzyme. It is used in asthma therapy and administered orally and undergoes hepatic metabolism. Its C-fibres in response to tachykinins (e.g. bradykinin). However,
the complete mechanism underlying their therapeutic efficacy is uncertain.
Adverse effects
• Sodium cromoglicateis virtually non-toxic. The powder can (very rarely) produce bronchospasm or hoarseness.
• Nausea and headache are rare adverse effects.
• Nedocromil has a bitter taste.
Pharmacokinetics
Sodium cromoglicate, an inhaled powder, undergoes little systemic absorption. Most of the powder is swallowed, about 10% reaching the alveoli. Nedocromil sodium has similarly low systemic bioavailability.
LEUKOTRIENE MODULATORS
These fall into two classes, namely leukotriene receptor antag- onists and 5-lipoxygenase inhibitors.
Leukotrienes (LT) are fatty acid-derived mediators contain- ing a conjugated triene structure. They are formed when arachidonic acid (Chapter 26) is liberated from the cell mem- brane of cells, as a result of cell activation by allergic or other noxious stimuli. 5-Lipoxygenase is the enzyme required for the synthesis of LTA4, which is an unstable epoxide precursor of the two subgroups of biologically important leukotrienes.
LTB4 is a dihydroxy 20-carbon-atom fatty acid which is a potent pro-inflammatory chemo-attractant. The other group is the cysteinyl leukotrienes (LTC4, LTD4and LTE4). LTC4is a conjugate of LTA4plus glutathione, a tripeptide which com- bines with LTA4via its cysteine residue. LTC4is converted to an active metabolite (LTD4) by the removal of the terminal amino acid in the peptide side-chain. Removal of a second amino acid results in a less active metabolite (LTE4). LTC4, LTD4 and LTE4, the ‘sulphidopeptide leukotrienes’ or ‘cys- teinyl leukotrienes’, collectively account for the activity that used to be referred to as ‘slow-reacting substance of anaphylaxis’
(SRS-A). They all (but especially LTD4) bind to the Cys-LT1
use in asthma has declined considerably, with the efficacy of the leukotriene receptor antagonists.
ANTI-IGE MONOCLONAL Ab
Omalizumabis a recombinant humanized IgG1 monoclonal anti-IgE antibody. It is used as additional therapy in patients with severe persistent allergic asthma due to IgE-mediated sensitivity to inhaled allergens and inadequately controlled by glucocorticosteroids plus long-acting β2-agonists. It binds to IgE at the same epitope on the Fc region that binds FcεRI, this means it cannot react with IgE already bound to the mast cell or basophils and is not anaphylactogenic. It is administered subcutaneously every two to four weeks. It causes a 80–90%
reduction in free IgE and it reduces FcεRI expression on inflammatory cells. It has a t1/2of 20–30 days and is cleared via the reticuloendothelial system. Side effects include rashes, urticaria, pruritus, sinusitis, gastro-intestinal upsets, injection site reactions and possibly secondary haematologic malignan- cies. It can be used in children, but is a very expensive therapy.
chronic asthmatics, but because of their long-term toxicities (Chapters 26 and 50), they are not used routinely.