1. Introduction

Asthma may be defined as a syndrome in which there is recurrent 'reversible' obstruction of the airways in response to stimuli which are not in themselves noxious and which do not affect non-asthmatic subjects. The asthmatic subject has intermittent attacks of dyspnea, wheezing, and cough. Asthma affects over 5% of the population in industrialized countries. It is increasing in prevalence and severity and has a rising mortality despite a substantial increase in prescribed asthma treatment. Some physicians consider that this trend may be the result of the currently available therapy not being used optimally. If this is indeed so it may stem from the fact that recent advances in the understanding of the pathogenesis of asthma have not been universally appreciated. It is currently recognized that the characteristic features of asthma are bronchial hyperresponsiveness and inflammatory changes in the airways. The latter feature may well be causally related to the former, and is present even in patients with very mild asthma; in some individuals it may even precede the development of overt asthma. The term bronchial hyper-responsiveness (or hyper-reactivity) refers to abnormal sensitivity to a wide range of stimuli such as irritant chemicals, cold air, stimulant drugs and so on. Stimuli which cause the actual asthma attacks are many and various, and include allergens (in sensitized individuals), exercise (in which the stimulus may be cold air), respiratory infections and atmospheric pollutants such as sulfur dioxide. In many subjects the asthmatic attack consists of two main phases as can be demonstrated by tests of FEV :
· the immediate phase
· the late phase.

However, in some subjects, only one of the phases may be obvious. The full details of the complex events involved are still a matter of debate; the following represents a simplified synthesis of current ideas.

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 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'.

There are two categories of anti-asthma bronchodilators drugs and anti-inflammatory agents. Bronchodilators are effective in reversing the immediate response, antiinflammatory agents in inhibiting or preventing the later phase. It is probable that progression of the asthma, with increase in the severity of the attacks, is due to persistence of the late phase reaction and a gradual increase in the mucosal inflammation. Lack of understanding of this, with consequent over-reliance on bronchodilators which overcome the acute attacks without modifying the underlying inflammation, could have contributed to the increase in asthma morbidity and mortality. The problem of the combined use of these two categories of drugs in the clinical management of asthma is complex.

4.1 Bronchodilator drugs

b2-adrenoceptor agonists

b2-adrenoceptor agonists are the drugs of choice for the immediate phase of the asthmatic attack, and their mechanism of action is two-fold. The main effect is to dilate the bronchi by a direct action on the b2-adrenoceptors on the smooth muscle. These drugs can relax the bronchial muscle irrespective of the spasmogen involved. b2-adrenoceptor agonists also may inhibit mediator release from mast cells, and vagal tone. The main drugs used are salbutamol and terbutaline. These are usually given by inhalation (of aerosol, powder or nebulised solution), but some may be given orally. Salbutamol and terbutaline can be given by the parenteral route in severe attacks. Given by inhalation, salbutamol and terbutaline start to act within a few minutes and the effects last for 3 5 hours. Some degree of tolerance to the effects of these bronchodilators can develop if they are used for 2-3 weeks; the decreased responsiveness can be reversed by parenteral steroids. There have also been reports that a rebound bronchial hyper-reactivity has followed cessation of treatment after 2 weeks of continuous therapy. Salmeterol and formoterol are longer-acting b2-adrenoceptor agonists, producing effects for up to 12 hours.

Xanthine drugs

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 be used also as theophylline-ethylenediamine, known as aminophylline. Caffeine and theophylline are constituents of coffee and tea, and theobromine is a constituent of cocoa. Both theophylline and aminophylline have bronchodilator action, though they are rather less effective in this regard than b-adrenoceptor agonists. Several clinical studies have shown that xanthines can be effective both in relieving the acute attack and in the treatment of 'chronic asthma'. Actions in addition to bronchodilatation seem to be involved since there is some evidence that these agents can inhibit the late phase, as shown by measurement of FEV, after bronchial allergen challenge. However, they do not appear to prevent bronchial hyper-responsiveness.

The way in which this group of drugs produces its effects in asthma is still unclear. One proposed mode of action is competitive antagonism of adenosine at adenosine receptors, but enprofylline, which is a more potent bronchodilator, is not an adenosine antagonist. The relaxant effect on smooth muscle has been attributed to inhibition of phosphodiesterase with resultant increase in cyclic AMP. An increase in cyclic AMP could also inhibit activation of inflammatory cells. 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 cyclic GMP phosphodiesterase. 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, theophylline has a relatively low therapeutic index.

Muscarinic-receptor antagonists

The compound used specifically as an anti-asthmatic is ipratropium bromide. This drug is not particularly effective against allergen challenge and is only really of use in asthmatic attacks in which there is a distinct component of reflex bronchospasm mediated by parasympathetic nerves. This applies mainly to asthma produced by irritant stimuli. It can, however, be useful as an adjunct to other bronchodilator therapy, particularly in severe acute asthma. Its major clinical role is as a bronchodilator in some cases of chronic bronchitis and in asthma precipitated by b2-adrenoceptor antagonists.

4.2 Anti-inflammatory agents

Glucocorticoids

Glucocorticoids are not bronchodilators and are not effective in the treatment of the immediate response to the eliciting agent. Given prophylactically they inhibit the late phase response, and given continuously they may reduce bronchial hyper-reactivity, although there is some dispute on this point. Of relevance for asthma is the fact that they can inhibit the generation of PAF and eicosanoids, probably through the action of lipocortin on phospholipase A2 In experimental studies in animals, they inhibit the allergen-induced influx of inflammatory cells into the lung and reduce the blood eosinophilia. Unlike b2-adrenoceptor agonists they are not very effective at inhibiting release of mediators from human lung mast cells, but they do inhibit the activation of macrophages and mediator release from eosinophils. Glucocorticoids also reduce the formation of various cytokines; and the reduction in the synthesis of IL-3 (the lymphokine which regulates mast cell production) may explain why long-term steroid treatment eventually reduces the early-phase response to allergens and prevents exerciseinduced asthma.

The main compounds used are beclomethasone, betamethasone and budesonide, which are given by inhalation, the full effect being attained only after several days of therapy.

Glucocorticoids given by inhalation constitute a major advance in the overall management of asthma. They are able to control the disease without causing adverse systemic effects or adrenal suppression. For acute, severe or rapidly deteriorating asthma, a short course of an oral glucocorticoid (e.g. prednisolone) is indicated, combined with an inhaled steroid to reduce the oral dose required. 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, and necessitate the carrying of a 'steroid card.

Sodium cromoglycate and nedocromil

Sodium cromoglycate and nedocromil are unique in that they were first tested and its efficacy demonstrated-in allergic asthma in man, without prior testing in animals. They are not a bronchodilator and does not have any direct effects on smooth muscle, nor does they inhibit the actions of any of the known smooth muscle stimulants. If given prophylactically they can prevent both the immediate and the late-phase asthmatic responses. They were 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. It is generally said that children are more likely to respond, and they have become the anti-inflammatory drug of first choice in children. Pre-treatment before exposure to an eliciting stimulus may be dramatically effective in many young patients. Continuous treatment with cromoglycate or Nedocromil is thought to result in a decrease in bronchial hyper-reactivity. Their mechanism of action is a matter of debate. It was originally thought to act by preventing mediator release from mast cells and indeed it can be shown to have this effect in human lung mast cells in vitro and in animal models of Type 1 hypersensitivity. However, it is not very potent as a 'mast cell stabilising agent', being in fact 1000 times less effective than salbutamol in this respect.

Histamine H1-receptor antagonists

Although mast cell mediators are thought to play a part in the immediate phase of allergic asthma and in exercise-induced asthma, histamine H1-receptor antagonists have had no place in therapy.

Severe acute asthma is a medical emergency requiring hospitalization. Treatment includes oxygen, systemic glucocorticoids and bronchodilator drugs such as aminophylline given intravenously, or salbutamol given either intravenously or by inhalation.

Although there are several agents which can reverse the acute asthmatic attack and others which reduce the underlying inflammation and bronchial hyper-responsiveness, none is ideal in that none actually 'cures' all patients of the disease. Many pharmaceutical firms are trying new approaches in attempts to develop more effective anti-asthma drugs. One approach concentrates on the mediators now known to be of more significance than histamine, namely platelet-activating factor and the cysteinyl-leukotrienes (Cys-LT). The leukotriene antagonists are the first new class of anti-asthma drugs for more than 20 yrs. One of these compounds, zafirlukast (Accolate), is a potent antagonist of the Cys LT, receptors in human airways. Zafirlukast not only improves the symptoms associated with asthma, but also pulmonary function. These improvements are associated with a reduced need for use of b2-agonist. Zafirlukast is also well tolerated by most patients, and its oral route of administration may improve patients' ability to comply with their anti-asthma therapy. Recently, zafirlukast has been licensed and introduced in the USA, Ireland, and Finland.

Other approaches being explored are:
- Bronchodilatation by selective potassium channel activators
- New selective muscarinic M3 receptor antagonists and/or M2 receptor agonists
- Selective opioid receptor agonists to inhibit release of sensory neuropeptides
- Selective H3-receptor agonists to inhibit acetylcholine release.
- Inhibitors of phospholipase A2
- Inhibitors of 5-lipoxygenase or five lipoxygenase activating protein (FLAP)
- Selective phosphodiesterase inhibitors
- Anti-cytokines or anti-inflammatory cytokines (IL-10)
- Immunomodulating agents (Ciclosporine...)
- Anti-chemokines or antibody against adhesion molecules
- Antagonists of tachykinins (Substance P or neurokinin