Asthma may be loosely defined as a condition in which there is recurrent reversible obstruction of the airflow in the airways in response to stimuli which do not affect non-asthmatic subjects. Reversal of the obstruction generally requires drug treatment. The condition affects over 5-10% of the population in industrialised countries. Most authorities agree that it is increasing in prevalence and severity.
In chronic asthma, the individual has intermittent attacks of dyspnoea (disorder of breathing), wheezing, and cough, the dyspnoea consisting of difficulty in breathing out. Acute severe asthma, conversely, is not easily reversed. It can be fatal and requires prompt and energetic treatment. Hospitalization may be necessary.
The term bronchial hyper-reactivity (or hyper-responsiveness) refers to abnormal sensitivity to a wide range of stimuli such as irritant chemicals, cold air, stimulant drugs, etc., all of which can result in bronchoconstriction. Stimuli that cause the actual asthma attacks are many and varied and include allergens (in sensitised individuals), exercise (in which the stimulus may be cold air), respiratory infections and atmospheric pollutants such as sulfur dioxide. The non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, can precipitate asthma in sensitive individuals.
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The development of allergic asthma probably involves both genetic and environmental factors, and the asthmatic attack itself consists, in many subjects, of two main phases-the immediate phase and the late (or delayed) phase.
The Immediate Phase
The immediate phase, i.e. the initial response, occurs abruptly and is due mainly to spasm of the bronchial smooth muscle. The cells involved in this phase are predominantly mast cells (activated to release histamine, in the case of allergic asthma, by interaction of allergen with cell-fixed IgE), but other cells could contribute. Both platelets and macrophages have receptors for IgE, albeit of low affinity, and there is clinical evidence of platelet activation in vivo during allergic bronchospasm. It is possible that in nonallergic asthma, irritants may stimulate the irritant receptors and cause release of peptide mediators by antidromic impulses in sensory nerve fibers, and that these mediators then activate mast cells and other cells. Exercise induced asthma appears to involve only the phenomena of this first phase.
The Late Phase
The second, late-phase response, i.e. the delayed response, occurs at a variable time after exposure to the eliciting stimulus and may be nocturnal. This phase is in essence an acute inflammatory reaction. The inflammation has special characteristics because asthma is not consistently associated with the inflammation seen, for example in bronchitis. There is infiltration not only by the usual inflammatory cells but also, and more specifically, by eosinophils and platelets. There is usually a blood eosinophilia and also some degree of loss of bronchial epithelium. In view of the increasing evidence for the seminal role of the eosinophils and the epithelial loss, some authorities have stated that asthma should be redefined as 'chronic, desquamating eosinophilic bronchiolitis'.
Classes Used in Treatment
There are two categories of anti-asthma drugs: bronchodilators and anti-inflammatory agents. Bronchodilators are effective in reversing the bronchospasm of the immediate phase; anti-inflammatory agents are effective in preventing the inflammatory components of both phases. But note that these two categories are not mutually exclusive: some drugs classified as bronchodilators may also have some effect on inflammatory cells.
Drugs used as bronchodilators include β2-adrenoceptor agonists, xanthines, cysteinyl-leukotriene receptor antagonists and muscarinic receptor antagonists.
The β2-adrenoceptor agonists
Their primary effect in asthma is to dilate the bronchi by a direct action on the β2-adrenoceptors on the smooth muscle. They relax the bronchial muscle. They also inhibit mediator release from mast cells and the release from monocytes of one of the primary mediators of inflammation. In addition, they may increase mucus clearance by an action on cilia.
These drugs are usually given by inhalation of aerosol, powder or nebulised solution, but some may be given orally or by injection. A metered-dose inhaler is used for aerosol preparations. If patients (e.g. children, the elderly) have problems using these, a 'spacer' device can be used instead.
Two categories of β2-adrenoceptor agonists are used in asthma:
Short-acting agents: salbutamol and terbutaline. These are given by inhalation, the maximum effect occurs within 30 minutes and the duration of action is 4-6 hours; they are usually used on an 'as needed' basis to control symptoms. Bambuterol, a pro-drug of terbutaline, is also now available.
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Longer-acting agents: e.g. salmeterol. These are given by inhalation and the duration of action is 12 hours. They are not used 'as needed' but are given regularly, twice daily, as adjunctive therapy in patients whose asthma is inadequately controlled by glucocorticoids. Other long-acting agents are formoterol, fenoterol, pirbuterol and reprotelol.
The unwanted effects of β2-adrenoceptor agonists result from systemic absorption. In the context of their use in asthma, the commonest adverse effect is tremor. There is some evidence that β2-agonist tolerance can occur in asthmatic airways and that steroids can reduce the development of tolerance because they inhibit β2-adrenoceptor downregulation. Other side effects include tachycardia and hypokalaemia.
Short-acting drugs (salbutamol or terbutaline, usually by inhalation) to prevent or treat wheeze in patients with reversible obstructive airways disease.
Salmeterol (long-acting bronchodilator) to prevent bronchospasm (e.g. at night or with exercise) in patients requiring long-term bronchodilator therapy.
There are three pharmacologically active, naturally occurring methylxanthines: theophylline, theobromine and caffeine. The xanthine usually employed in clinical medicine is theophylline (1,3-dimethylxanthine), which can also be used as theophylline ethylenediamine. Caffeine and theophylline are constituents of coffee and tea, and theobromine is a constituent of cocoa. Theophylline has bronchodilator action, though it is rather less effective than the β2-adrenoceptor agonists.
Mechanism of Action
Anti-asthmatic actions- Xanthines have long been used as bronchodilators. Actions in addition to bronchodilatation seem to be involved since there is some evidence that theophylline can inhibit some aspects of the late phase. The way in which the xanthine drugs produce effects in asthma is still unclear. The relaxant effect on smooth muscle has been attributed to inhibition of the phosphodiesterase (PDE) isoenzymes, with resultant increase in cAMP. However, the concentrations necessary to inhibit the isolated enzyme greatly exceed the therapeutic range. There is some evidence that the smooth muscle relaxation could be related to an effect on a cGMP PDE. Another proposed mode of action is competitive antagonism of adenosine at adenosine receptors, but the PDE inhibitor enprofylline, which is a more potent bronchodilator, is not an adenosine antagonist.
Actions on the central nervous system- The methylxanthines have a stimulant effect on the CNS, causing increased alertness. They can cause tremor and nervousness and can interfere with sleep and have a stimulant action on respiration.
Actions on the cardiovascular system- All the xanthines stimulate the heart, having positive chronotropic and inotropic actions. They cause vasodilatation in most blood vessels, though some can cause constriction in some vascular beds, more particularly cerebral blood vessels.
Actions on the renal system- Methylxanthines have a weak diuretic effect, involving both increased glomerular filtration rate and reduced reabsorption in the tubules.
When theophylline is used in asthma, most of its other effects, such as those on the CNS, cardiovascular system and gastrointestinal tract, are unwanted side-effects. Furthermore, the plasma concentration range for an optimum therapeutic effect is 30-100 μmol/l, and adverse effects are likely to occur with concentrations greater than 110 μmol/l; thus, there is a relatively small therapeutic window. Measurements of the plasma concentration are necessary when the drug is given intravenously for treatment of status asthmaticus and are advisable to optimise therapy at high oral doses.
Gastrointestinal symptoms (anorexia, nausea and vomiting) and nervousness and tremor are sometimes seen with concentrations only slightly higher than the clinically effective levels. Serious cardiovascular and CNS effects can occur when the plasma concentration exceeds 200 μmol/l. The most serious cardiovascular effect is dysrhythmia, which can be fatal. In children, seizures can occur with theophylline concentrations at or slightly above the upper limit of the therapeutic range. Seizures can be fatal in patients with respiratory compromise due to severe asthma.
Clinical Uses of Theophylline
As a second-line drug, in additon to steroids, in patients whose asthma does not respond adequately to β2-adrenoceptor agonists.
Intravenously in acute severe asthma.
To reduce symptoms of chronic obstructive pulmonary disease.
Muscarinic Receptor Antagonist
The main compound used specifically as an anti-asthmatic is ipratropium. Oxitropium is also available. Ipratropium relaxes bronchial constriction caused by parasympathetic stimulation, which occurs particularly in asthma produced by irritant stimuli and can occur in allergic asthma.
Mechanism of Action
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Vagolytic action by competitive inhibition of muscarinic receptors on airway smooth muscle (M3-type) leading to bronchodilatation. It is given by aerosol inhalation. It is not well absorbed into the circulation and thus does not have much action at muscarinic receptors other than those in the bronchi. The maximum effect occurs after 30 minutes or so but then lasts for 3-5 hours. It has few unwanted effects and is, in general, safe and well tolerated. It can be used with β2-adrenoceptor agonists.
High doses occasionally cause typical atropine-like effects:
Mydriasis (usually a topical action of the aerosol!)
Cysteinyl-Leukotriene Receptor Antagonists
Cysteinyl-leukotriene receptor antagonists include montelucast and zafirlukast. The cysteinyl-leukotriene receptor antagonists prevent aspirin-sensitive asthma, inhibit exercise-induced asthma and decrease both early and late responses to inhaled allergen. They relax the airways in mild asthma, the bronchodilator activity being one third that of salbutamol. Their action is additive with β2-adrenoceptor agonists. They also reduce sputum eosinophilia, but so far there is no clear evidence that they modify the underlying inflammatory process in chronic asthma.
These are in general few, consisting mainly of headache and gastrointestinal disturbances. A few subjects have developed Churg-Strauss syndrome possibly precipitated by withdrawal of the concomitant corticosteroid.
The main drugs used for their anti-inflammatory action in asthma are the glucocorticoids. Cromoglicate and nedocromil also have some anti-inflammatory action.
Glucocorticoids are not bronchodilators and are not effective in the treatment of the immediate response to the eliciting agent. They are used in the management of chronic asthma, in which there is a predominant inflammatory component.
Mechanism of Action
An important action, of relevance for asthma, is that they decrease formation of cytokines in particular the Th2 cytokines that recruit and activate eosinophils and are responsible for promoting the production of IgE and the expression of IgE receptors. Glucocorticoids also inhibit the generation of the vasodilators PGE2 and PGI2, by inhibiting induction of cyclooxygenase-2.
Unwanted effects are uncommon with inhaled steroids. Oropharyngeal candidiasis can occur, as can dysphonia (voice problems), but these are less likely to occur if 'spacing' devices are used, which decrease oropharyngeal deposition of the drug and increase airway deposition. Regular large doses can produce adrenal suppression, particularly in children
Cromoglicate is unique in that it was first tested-and its efficacy demonstrated-in allergic asthma in humans, without prior testing in animals.
Mechanism of Action
Cromoglicate and the related drug nedocromil sodium are not bronchodilators; they do not have any direct effects on smooth muscle, nor do they inhibit the actions of any of the known smooth muscle stimulants. If given prophylactically, they can reduce both the immediate and the late-phase asthmatic responses and reduce bronchial hyper-reactivity. They are effective in antigen-induced, exercise-induced and irritant-induced asthma, though not all asthmatic subjects respond, and it is not possible to predict which patients will benefit. Children are more likely to respond than adults.
The mechanism of action is not fully understood. Cromoglicate was originally thought to act as a 'mast cell stabiliser', preventing histamine release from mast cells. However, although it has this effect it is clearly not the basis of its action in asthma because many other compounds have been produced which are equally or more potent than cromoglicate at inhibiting mast cell histamine release but none has proved to have any anti-asthmatic effect at all in humans.
Unwanted effects are few and consist mostly of the effects of irritation in the upper respiratory tract. Hypersensitivity reactions have been reported (urticaria, anaphylaxis), but are rare.