With the foregoing discussion in mind, the following approaches to treatment are logical:
• Prevention of exposure to allergen(s)
• Reduction of the bronchial inflammation and hyperreactivity
• Dilatation of narrowed bronchi.
These objectives may be achieved as follows:
Prevention of exposure to allergen(s)
This approach is appropriate for extrinsic asthmatics. Identifying an allergen may be aided by the patient's history (wheezing in response to contact with grasses, pollens, animals), by intradermal skin prick injection of selected allergen or by demonstrating specific IgE antibodies in the patient's serum (RAST testing). Avoiding an allergen may be feasible when it is related to some a specific situation, e.g. occupation, but is less feasible if it is widespread, as with house-dust mite.
Reduction of the bronchial inflammation and hyperreactivity
As persistent inflammation is central to bronchial hyperreactivity, the use of anti-inflammatory drugs is logical.
Glucocorticoids (see p. 665) bring about a gradual reduction in bronchial hyperreactivity. They are the mainstay of asthma treatment. The exact mechanisms are still disputed but probably include: inhibition of the influx of inflammatory cells into the lung after allergen exposure; inhibition of the release of mediators from macrophages and eosinophils and reduction of the microvascular leakage which these mediators cause. Glucocorticoids used in asthma include prednisolone (orally), and beclomethasone, fluticasone and budesonide (by inhalation) (see Ch. 34).
Sodium cromoglicate8 (cromolyn, Intal) impairs the immediate response to allergen and was formerly thought to act by inhibiting the release of mediators from mast cells. Evidence now suggests that the late allergic response and bronchial hyperreactivity are also inhibited, and points to effects of cromoglicate on other inflammatory cells and also on local axon reflexes. Cromoglicate is poorly absorbed from the gastrointestinal tract but is well absorbed from the lung, and it is given by inhalation (as powder, aerosol or nebuliser); it is eliminated unchanged in the urine and bile.
8 Cromoglicate was introduced in 1968 as the culmination of work carried out by the asthmatic research director of the company (REC Altounyan) on himself. We can admire Dr Altounyan without recommending this as the best way of screening new chemical entities.
Since it does not antagonise the broncho-constrictor effect of the mediators after they have been released, cromoglicate is not effective at terminating an existing attack, i.e. it prevents broncho-constriction rather than induces bronchodilation. Special formulations are used for allergic rhinitis and allergic conjunctivitis.
Sodium cromoglicate is effective in extrinsic (allergic) asthma including asthma in children, and in exercise-induced asthma but its use has declined since the efficacy and safety of low dose inhaled corticosteroid have become apparent.
It is remarkably nontoxic. Apart from cough and bronchospasm induced by the powder it may rarely cause allergic reactions. Application to the eye may produce a local stinging sensation and the oral form may cause nausea.
Nedocromil sodium (Tilade) is structurally unrelated to cromoglicate but has a similar profile of actions and can be used by metered aerosol in place of cromoglicate.
Other drugs. Ketotifen is a histamine Hj-receptor blocker which may also have some antiasthma effects but its benefit has not been conclusively demonstrated. In common with other antihistamines it causes drowsiness.
This is most effectively achieved by physiological antagonism of bronchial muscle contraction, namely by stimulation of adrenergic bronchodilator mechanisms. Pharmacological antagonism of specific bronchoconstrictors is less effective either because individual mediators are not on their own responsible for a large part of the bronchoconstriction (acetylcholine, adenosine, leukotrienes) or because the mediator is not even secreted during asthma attacks (histamine).
(^-adrenoceptor agonists. The predominant adrenoceptors in bronchi are of the p2 type and their stimulation causes bronchial muscle to relax. (32-adrenoceptor activation also stabilises mast cells. Agonists in widespread use include: salbutamol, terbutaline, fenoterol, eformoterol and salmeterol, and are discussed in Chapter 22. Salmeterol is longer-
acting because its lipophilic side chain anchors the drug in the membrane adjacent to the receptor, slowing tissue washout.
Less selective adrenoceptor agonists such as adrenaline (epinephrine), ephedrine, isoetharine, isoprenaline and orciprenaline are less safe, being more likely to cause cardiac arrhythmias, a-adrenoceptor activity contributes to bronchoconstriction but a-adrenoceptor antagonists have not proved effective in practice.
Theophylline, a methylxanthine, relaxes bronchial muscle, although its precise mode of action is still debated. Inhibition of phosphodiesterase (PDE), especially its type 4 isoform now seems the most likely explanation for its bronchodilator and more recently reported anti-inflammatory effects. Blockade of adenosine receptors is probably unimportant. Other actions of theophylline include chronotropic and inotropic effects on the heart and a direct effect on the rate of urine production (diuresis).
Absorption of theophylline from the gastrointestinal tract is usually rapid and complete. Some 90% is metabolised by the liver and there is evidence that the process is saturable at therapeutic doses. The tV2 is 8 h, with substantial variation, and it is prolonged in patients with severe cardiopulmonary disease and cirrhosis. Obesity and prematurity are associated with reduced rates of elimination, whereas tobacco smoking enhances theophylline clearance by inducing hepatic P450 enzymes. Because of these pharmacokinetic factors and low therapeutic index, monitoring of the plasma theophylline concentration is necessary to optimise its therapeutic effect and minimise the risk of adverse reactions; the optimum concentration range is 10-20 mg/1 (55-110 mmol/1).
Theophylline is relatively insoluble and it is formulated either as a salt with choline (choline theophyllinate) or complexed with EDTA (amino-phylline). Aminophylline is sufficiently soluble to permit i.v. use of theophylline in status asthmaticus. There are numerous sustained-release oral forms for use in chronic asthma. These are not bio-equivalent and patients should not switch between them once they are stabilised on a particular preparation. It has also been used in the past for the emergency treatment of left ventricular failure (see p. 518). At high therapeutic doses some patients experience nausea and diarrhoea, and plasma concentrations above the recommended range risk cardiac arrhythmia and seizures. The latter are prone to occur with rapid intravenous injection, which exposes the heart and brain to high concentrations before distribution is complete. It follows that i.v. injection must be slow (a loading dose of 5 mg/kg over 20 min followed by an infusion of 0.9 mg/kg/h adjusted according to subsequent plasma theophylline concentrations). The loading dose should be avoided in any patient who is already taking a xanthine preparation (always enquire about this before injecting). Enzyme inhibition by erythromycin, ciprofloxacin, allopurinol or oral contraceptives increases the plasma concentration of theophylline; enzyme inducers such as carbamazepine, phenytoin and rifampicin reduce the concentration.
Overdose with theophylline has assumed greater importance with the advent of sustained-release preparations which prolong toxic effects, with peak plasma concentrations being reached 12-24 h after ingestion. Vomiting may be severe but the chief dangers are cardiac arrhythmia, hypotension, hypokalemia and seizures. Activated charcoal should be given every 2-4 h until the plasma concentration is below 20 mg/1. Potassium replacement is important to prevent arrhythmias. Diazepam is used to control convulsions.
Antimuscarinic bronchodilators. Release of acetylcholine from vagal nerve endings in the airways activates muscarinic (M3) receptors on bronchial smooth muscle causing bronchoconstriction. Blockade of these receptors with atropine causes bron-chodilation, although the preferred antimuscarinics in clinical practise are inhaled ipratropium or oxitropium. These synthetic compounds, unlike atropine, are permanently charged molecules, which prevents significant absorption after inhalation and thus minimises antimuscarinic effects outside of the lung. They are mostly used in older patients with chronic obstructive pulmonary disease, but are useful in acute severe asthma when combined with P2-adrenoceptor agonists. Vagally-mediated bronchoconstriction appears to be important in acute asthma, but relatively unimportant for most chronic stable asthmatics.
Leukotriene receptor antagonists e.g. montelukast and zafirlukast, competitively prevent the broncho-constrictor effects of cysteinyl-leukotrienes (C4, D4 and E4) by blocking their common cysLTl receptor. They have similar efficacy to low-dose inhaled glucocorticoid. The paucity of comparisons with established medications consigns them to a second or third line role in treatment. They could be substituted at step 2 or later stages of the current 5-step regimen for asthma (see Fig. 27.1). There are no studies to justify their use as steroid sparing (far less, replacement) therapy. When used occasionally in this way in patients unwilling or unable to use metered-dose inhalers, serial monitoring of spirometry is essential. Montelukast is given once per day and zafirlukast twice per day. Leukotriene receptor antagonists are generally well tolerated, although Churg-Strauss syndrome has been reported rarely with their use. This probably represents unmasking of the disease as glucocorticoids are withdrawn following addition of the leukotriene receptor antagonist. Alerting features to this development are vasculitic rash, eosinophilia, worsening respiratory symptoms, cardiac complications and peripheral neuropathy.
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