Antiasthmatic Drugs I: Pathophysiological and Clinical Pharmacological Aspects
Tóm tắt
The fundamental abnormality in asthma is bronchial reactivity. Airways obstruction and flow limitation arise as a result of viscid bronchial secretions, oedema of the walls of airways and some bronchial muscle contraction. During attacks, patients breathe at increased lung volume, as airways closure occurs within the normal tidal range. In severe asthma, total lung capacity is increased and there is a loss of elastic recoil of the lungs. Ventilation is poorly distributed so that it becomes mismatched with pulmonary blood flow. This mismatching results in arterial hypoxaemia, even in mild attacks. Despite increased work of breathing, patients most commonly maintain a normal or even increased alveolar ventilation. The arterial carbon dioxide tension is thus frequently low or normal, despite a marked reduction in forced expired volume. Hypercapnia usually indicates that airways obstruction is extremely severe. When carbon dioxide retention occurs during mild asthma, patients will usually be found to have impaired ventilatory control even in symptom-free periods. As the essential feature of an asthmatic attack is airways obstruction or flow limitation, tests such as forced expired volume in one second and maximum midexpiratory flow rate are sensitive indices of the degree of abnormality present and are essential in the proper continued management of patients with asthma. Control of airways calibre is maintained by an interplay between autonomic balance, local gas tensions and humoral factors. The humoral factors, including slow reacting substance of anaphylaxis, kinins, prostaglandins and histamine, are released from sensitised or damaged mast cells. There are two types of bronchodilator drug: the sympathomimetic amines, which stimulate β-adrenergic receptors, by activating the enzyme adenyl cyclase to bring about increased concentrations of intracellular cyclic AMP; and the xanthine derivatives, which also increase levels of cyclic AMP by competitively inhibiting the enzyme cyclic nucleotide phosphodiesterase which breaks down cyclic AMP. Sympathomimetic amines stimulate both β1-adrenergic (myocardium) and β2 -adrenergic receptor sites (bronchial smooth muscle). Modification of the chemical structure of isoprenaline has produced substances which have more ‘specific’ β2 -receptor (bronchial) activity. Sodium cromoglycate stabilises airways against a variety of insults without any known influence on the adenyl cyclase cyclic AMP system. It is most effective in preventing allergic asthma, inhibiting the release of histamine and slow reacting substance of anaphylaxis after antigen-reagin combination. The corticosteroids exert most of their effect in asthma by their anti-inflammatory activity, but they also act on airways to enhance the release of adenyl cyclase induced by catecholamines, and so increase the responsiveness of β-adrenergic receptors to sympathomimetic amines. Corticosteroids are carried in plasma both protein bound and in a free form: this has important clinical implications if serum albumin levels are reduced, when it is advisable to use lower than normal doses. On the other hand, larger than normal doses are necessary in severe attacks of asthma in steroid-treated patients because of the increased metabolic clearance rate of cortisol; perhaps due to hypoxaemia stimulating hepatic microsomal enzymes, a phenomenon which does seem to account for the reduced effectiveness of
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