Pharmacology of asthma treatment: an overview.

The major advance in the last decade in treating asthma is the realisation that it is primarily an inflammatory process in the airways and not a bronchial smooth-muscle disease. Accordingly, much more emphasis is being placed on the early introduction of regular anti-inflammatory therapy, greatly facilitated by the development of inhaled steroid products. Despite this, inhaled beta 2-agonists remain the other major therapy in modern asthma treatment because of their ability to provide rapid relief from potentially life-threatening bronchoconstriction. At present, there is a tendency to avoid regular daily use of beta 2-agonists alone for persistent symptoms. Theophylline is still used, despite concern about its toxicity. However, it does have pharmacological effects in addition to bronchodilatation that may give it an additional therapeutic role in asthma therapy. It seems unlikely that the search for new single-mediator antagonists or synthesis inhibitors will result in the development of a new, effective asthma treatment.

Adrenoceptors in airway smooth muscle.

This review examines the roles and functional significance of alpha and beta-adrenoceptor subtypes in airway smooth muscle, with emphasis on human airway function and the influence of asthma. Specifically, we have examined the distribution of beta-adrenoceptors in lung and the influence of age, the epithelium, respiratory viruses and inflammation associated with asthma on airway smooth muscle beta-adrenoceptor function. Sites of action, beta 2-selectivity, efficacy and tolerance are also examined in relation to the use of beta 2-agonists in man. In addition, alpha-adrenoceptor function in airway smooth muscle has been reviewed, with some emphasis on comparing observations made in airway smooth muscle with those in animal models.

An overview of the current status of the drug therapy of asthma.

The importance of inflammation as the central lesion in asthma is being increasingly recognised and it is proposed that the emphasis of therapy should be altered from simply treating symptoms, to trying to control inflammation at an early stage of the disease. A "tight control" treatment program to achieve this is outlined. Treatment regimes for asthma may therefore need to be re-assessed, although the most commonly used drugs (beta 2-adrenoceptor agonists, theophylline, corticosteroids and cromoglycate) are effective if used properly. For the majority of patients management is grossly inadequate in terms of diagnosis, assessment of disease severity and treatment. The death rate from asthma still remains unacceptably high and some strategies are outlined for the identification of patients at risk and the improvement of their management. This overview considers four central issues: (1) the lesions that should be the target for drug treatment; (2) an outline of the available drug treatment; (3) the aims of treatment and (4) the success of drug treatment in terms of morbidity and mortality.

In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, beta-adrenoceptor agonists and theophylline.

Responses of human bronchial strip preparations to contractile and relaxant agonists were measured in preparations from non-diseased and from asthmatic lung obtained 3-15 h post-mortem. The potencies of carbachol and histamine were approximately two times less in asthmatic than in non-diseased bronchi. This was statistically significant for carbachol (P less than 0.05), but not for histamine (P greater than 0.05). These results clearly indicate that the bronchial hyperreactivity to airway spasmogens observed in asthma is exclusively an in vivo phenomenon not involving increasing sensitivity of bronchial smooth muscle. The potencies of the beta-adrenoceptor agonists isoprenaline, fenoterol and terbutaline were significantly reduced by 4-5 fold in asthmatic bronchi compared with non-diseased airways. In contrast, theophylline was equipotent in the two populations of airway preparations. Thus, it appears that severe asthma is associated with decreased bronchial smooth muscle beta 2-adrenoceptor function.

Adverse reactions to beta 2-agonist bronchodilators.

Beta 2-Agonists are safe and effective bronchodilator drugs. Their major adverse effects of skeletal muscle tremor, tachycardia and various metabolic effects are mediated by beta-adrenoceptor stimulation and are reversible. Skeletal muscle tremor is the most frequent dose-limiting side effect. It may be reduced by commencing treatment with a low dose and if it persists another beta 2-agonist may be tried. Other side effects such as cardiac arrhythmias and reduction in PaO2 are a serious potential problem in some susceptible asthmatics. However, they are infrequent or of a mild degree and are generally outweighed by the good control of asthma produced by beta 2-agonists. Side effects from beta 2-agonist therapy can be minimised by use of the inhaled route which selectively delivers the drug to the airways. Furthermore, selective tolerance develops to their side effects. The dose of a beta 2-agonist should be assessed on the basis of therapeutic effect and the level of tolerance to its side effects. Recommended doses of beta 2-agonists used for long term therapy do not cause clinically significant desensitisation of airway beta-adrenoceptors, although this may become a relevant problem in patients who are regularly receiving very high doses. Intravenous beta 2-agonists have a place in the treatment of severe asthma not responding to nebuliser therapy. In this life-threatening situation with severe airflow obstruction, monitoring of heart rate, PaO2, plasma potassium and the electrocardiogram should be mandatory and supplemental oxygen given so that serious adverse effects are presented.

Experimental testing of Mackay's model for functional antagonism in the isolated costo-uterus of the rat.

Several key predictions of a recently developed model for functional antagonism (Mackay, 1981) were experimentally tested using the rat isolated costo-uterine preparation. In the presence of the functional antagonist fenoterol (Fen), the functional constants (KAF) for carbachol and oxotremorine (Oxo) were respectively 9.9 and 3.4 fold greater than their corresponding affinity constants (KA). According to Mackay's model for functional antagonism, the higher KAF/KA ratio for carbachol indicates that this cholinoceptor agonist has a greater efficacy than Oxo. This was confirmed by using conventional pharmacological methods. As predicted from the model of functional antagonism, the plot of KAF/KA-1 against the fraction of cholinoceptors not irreversibly blocked by phenoxybenzamine (Pbz) was linear for both carbachol and Oxo and the lines of best fit crossed the axes at a point not significantly different from the origin. The value of 4.6 for the relative efficacy of carbachol to Oxo estimated from functional antagonism studies was comparable to the value of 5.6 calculated using the method of irreversible antagonism proposed by Furchgott (1966).

An in vitro study of various drugs on central and peripheral airways of the rat: a comparison with human airways.

1 The effect of histamine and other drugs on the central and peripheral airways of the rat was studied by applying them directly to isolated tracheal and lung strip preparations. These effects were then compared with those observed on human isolated bronchial muscle preparations. 2 Acetylcholine and 5-hydroxytryptamine (5-HT) both contracted the lung strip and trachea of the rat, and both were more potent on the trachea than the lung strip. 3 Histamine and prostaglandins E2 (PGF2) or F2 tau (PGF2 tau) produced no effect on either the lung strip or trachea of the rat. 4 On the human isolated bronchial preparation, in contrast to the rat airways, both histamine and PGF2 tau produced marked concentration-dependent contractions and 5-HT either produced no response or a slight relaxation. 5 In view of these results, the use of anaphylactic bronchoconstriction in the rat as a model for the study of asthma in man is questioned.

The isolated lung strip and single open tracheal ring: a convenient combination for characterizing Schultz Dale anaphylactic contractions in the peripheral and central airways of the guinea-pig.

1. The use of the isolated lung strip and single open tracheal ring for studying Schultz Dale anaphylactic contractions in both the peripheral and central airways is described. 2. This method is particularly relevant to studies of anaphylaxis because many preparations may be obtained from a single sensitized animal. 3. Isolated preparations from control guinea-pigs did not respond to ovalbumin, whereas the lung strip and trachea taken from guinea-pigs sensitized to ovalbumin, contracted markedly to that antigen. 4. The peripheral and central airways from sensitized animals responded in the same way to antigen challenge.

The cat lung strip as an in vitro preparation of peripheral airways: a comparison of beta-adrenoceptor agonists, autacoids and anaphylactic challenge on the lung strip and trachea.

1 A new in vitro preparation, the isolated lung strip of the cat, is described for investigating the direct effect of drugs on the smooth muscle of the peripheral airways of the lung. The preparation comprises a thin strip of lung parenchyma which can be mounted in a conventional organ bath for isometric tension recording. Its pharmacological responses have been characterized and compared with the isolated tracheal preparation of the cat. 2 The lung strip exhibited an intrinsic tone which was relaxed by catecholamines, aminophylline and flufenamate. It was contracted strongly by histamine, prostaglandin F2alpha, acetylcholine, compound 48/80, potassium depolarizing solution and alternating current field stimulation. In contrast, the cat trachea was unresponsive to histamine and prostaglandin F2alpha and did not exhibit an intrinsic tone. 3 (-)-Isoprenaline and (-)-adrenaline were much more potent in relaxing the lung strip than the trachea. The potency order of relaxation responses to isoprenaline, adrenaline and (+/-)-noradrenaline in the lung strip was isoprenaline greater than adrenaline greater than noradrenaline but in the trachea was isoprenaline greater than noradrenaline greater than or equal to adrenaline. 4 beta2-Adrenoceptor selective agonists salbutamol and terbutaline were more potent in the lung strip than the trachea, suggesting beta2-adrenoceptors predominated in the lung strip. Propranolol was equipotent in inhibiting isoprenaline relexations of the lung strip and trachea, whereas practolol was much less effective in inhibiting lung strip than trachea, further supporting a predominance of beta2-adrenoceptors in lung strip and beta1-adrenoceptors in trachea. 5 Strong Schultz-Dale type contractions were elicited in both lung strips and trachea by Ascaris lumbricoides antigen in actively sensitized cats. The initial phase of the contractile response of the lung strip following challenge was shown to be due to histamine release and was absent in the trachea. The delayed phase of the contraction which took several minutes to develop in both the mepyramine-treated lung strip and trachea was not due to prostaglandins E1, F2alpha or bradykinin, the probable mediator being slow reacting substance of anaphylaxis (SRS-A). 6 It is concluded that the isolated lung strip of the cat is useful as an in vitro model for investigating the effect of drugs on the smooth muscle of the peripheral airways of the lungs.