Drugs Acting on the Respiratory System
DRUGS AFFECTING AIRWAY CALIBRE
Airway smooth muscle tone results from a balance between opposing sympathetic and parasympathetic influences (Fig. 9.1). Sympathetic activity causes bronchodilatation while cholinergic parasympathetic activity from the vagus nerve causes bronchoconstriction. Drugs which increase sympathetic influence or decrease cholinergic parasympathetic activity generally cause bronchodilatation by relaxation of airway smooth muscle, and so may be used in the management of asthma and chronic obstructive pulmonary disease (COPD). Sympathetic control is mediated at a cellular level by β2-receptors. Agonists such as adrenaline that bind to these G-protein coupled receptors (Gs) stimulate adenylate cyclase. This enzyme catalyses the conversion, within the cell, of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Through kinase enzyme systems, cAMP relaxes airway smooth muscle. Cyclic AMP is degraded to inactive 5′-AMP by the enzyme phosphodiesterase. Drugs that increase the concentration of cAMP within the cell relax airway smooth muscle (e.g. β2-agonists, phosphodiesterase inhibitors). Conversely, drugs which reduce the level of cAMP (e.g. β2-antagonists) may cause bronchoconstriction.
FIGURE 9.1 Summary of the three physiological systems that control airway smooth muscle contraction. See text for details. ACh, acetylcholine; Gq and Gs, G-proteins; PIP2, phosphatidylinositol biphosphate; IP3, inositol triphosphate; VIP, vasoactive intestinal peptide; NO, nitric oxide; cGMP, cyclic guanosine monophosphate; ATP, adenosine triphosphate; PKA, phosphokinase; cAMP, cyclic adenosine monophosphate.
Bronchodilators
β-Adrenergic Agonists
β-Adrenergic agonists are usually the first-line treatment for relieving bronchospasm in asthma and COPD. These drugs have additional beneficial effects in the management of asthma (Table 9.1). There are at least three subtypes of β-receptor in the body: β1 is found in cardiac tissue, β2 in pulmonary tissue and peripheral vasculature and β3 in adipose tissue. Although non- selective β-agonists such as adrenaline and ephedrine can be used as bronchodilators, their unwanted β1 action (e.g. tachycardia) has meant that β2-specific agonists are preferred. Salbutamol, a synthetic sympathomimetic amine, is the most commonly used selective β2-agonist. Although developed as a selective β2-agonist, salbutamol may have β1 side-effects in high doses or in the presence of hypoxaemia or hypercapnia. Salbutamol is a short-acting bronchodilator with a fast onset of action used for the relief of acute symptoms.
TABLE 9.1
Effects of β-Agonist Drugs on the Airways
Specific
Increase in intracellular cAMP and bronchodilatation
Non-Specific but Complementary
Inhibition of mast cell mediator release
Inhibition of plasma exudation and microvascular leakage
Prevention of airway oedema
Increased mucous secretion
Increased mucociliary clearance
Prevention of tissue damage mediated by oxygen free radicals
Decreased acetylcholine release in cholinergic nerves by an action on prejunctional β2-receptors
Route of Administration and Dose: Inhalation is usually the most appropriate route of administration of β2-agonists in order to minimize systemic side-effects. An inhaled drug may also be more effective, because it easily reaches the mast and epithelial cells of the airway which are relatively inaccessible to a drug administered systemically. Salbutamol is administered from a pressurized aerosol (100 μg per puff; 1 or 2 puffs four times daily). The effect lasts for 4–6 h. The drug may also be nebulized in inspired gases and inhaled via a face mask or added to the breathing system in patients undergoing artificial ventilation. For this purpose, a dose of 2.5–5 mg up to four times daily is used. In severe bronchospasm, up to 5 mg may be given as frequently as every 30 min initially. Side-effects are more likely when these drugs are nebulized as they deliver a larger dose of which a significant proportion is absorbed systemically.
Adverse Effects: Adverse effects of β-agonists include the following:
tachycardia/tachyarrhythmias (β1 effect)
decreased peripheral vascular resistance and postural hypotension (β2 effect)
muscle tremor – resulting from a direct effect on β2-receptors in skeletal muscle
hypokalaemia caused by increased uptake of potassium ions by skeletal muscles (β2 effect)
metabolic effects – increases in the plasma concentrations of free fatty acids, insulin, glucose, pyruvate and lactate (β3 effects)
Anticholinergic Drugs
Indications: Ipratropium is used as a second-line bronchodilator in acute exacerbations of asthma and COPD. It has an additive effect when used in combination with β-agonists. It is particularly effective in older patients with COPD. Tiotropium is prescribed to COPD patients with the aim of decreasing frequency of exacerbations; it is not useful in the treatment of acute bronchospasm.
Route of Administration and Dose: Ipratropium can be delivered from a metered dose inhaler (20–40 μg) or as a nebulizer (250–500 μg) up to four times daily. Tiotropium is delivered as a dry powder by a ‘Spiriva HandiHaler’ device; the dose is 18 μg once daily.
Adverse Effects: Dry mouth is the most commonly reported adverse effect of the antimuscarinic bronchodilators. Other less frequent side-effects include nausea, constipation and palpitations. The drugs are well known to precipitate acute urinary retention and so should be used with caution in patients with benign prostatic hypertrophy. They may also cause acute angle-closure glaucoma, particularly when given as a nebulizer (accidental instillation into the eye) with salbutamol.
Methylxanthines
phosphodiesterase inhibition, leading to increased intracellular cAMP
adenosine receptor antagonism, preventing mast cell degranulation
endogenous catecholamine release
interference with calcium mobilization
Indications: Methylxanthines are usually prescribed when inhaled therapies have failed or have been only partly effective. They are particularly useful in COPD. Recently, they have been shown to improve exercise tolerance in intensive care patients on a weaning programme.
Route of Administration and Dose: Theophylline may be used as a sustained release oral preparation for the prevention of acute exacerbations of COPD. The dose depends on the preparation being used and is given twice daily. Aminophylline is an intravenous preparation used for the relief of acute episodes of bronchospasm. It is a strong alkaline solution and should not be given intramuscularly or subcutaneously. A loading dose of 5 mg kg–1 should be given slowly over 20 min followed by an infusion of 0.5-0.7 mg kg–1 h–1. If the patient is already taking an oral theophylline, then the loading dose should be omitted.
There is a close relationship between the degree of bronchial dilatation and the plasma concentration of theophylline. A concentration of < 10 mg L–1 is associated with a mild effect and a concentration of > 25 mg L–1 with frequent side-effects. Consequently, the therapeutic window is narrow and the plasma concentration should be maintained within the range 10–20 mg L–1 (55–110 μmol L–1). Plasma assays should be performed 6 h after commencing an infusion or following a rate change and then every 24 h. Approximately 40% of the drug is protein-bound. Theophylline is metabolized mainly in the liver by cytochrome P450 microenzymes; 10% is excreted unchanged in urine. Factors which affect the activity of hepatic enzymes and thus the clearance of the drug are summarized in Table 9.2. The infusion rate of aminophylline should be adjusted accordingly (e.g. 1.6 times for smokers, 0.5 times for patients receiving erythromycin). The dose for obese patients should be based on ideal body weight and frequent estimation of plasma concentration is required to prevent ineffective therapy or toxicity.
TABLE 9.2
Factors Affecting the Plasma Concentration of Methylxanthines for a Given Dose
Factors Which Lower the Plasma Concentration:
Children
Smoking
Enzyme induction – rifampicin, chronic ethanol use, phenytoin, carbamazepine, barbiturates
High protein diet
Low carbohydrate diet
Factors Which Increase the Plasma Concentration:
Old age
Congestive heart failure
Enzyme inhibition – erythromycin, omeprazole, valproate, isoniazid, ciprofloxacin
High carbohydrate diet
Adverse Effects: Adverse effects of methylxanthines may be severe and are more likely to occur in patients also receiving a β-agonist bronchodilator or other sympathomimetic drugs.
Central nervous system effects: stimulation of the CNS may lead to nausea, restlessness, agitation, insomnia, tremor and seizures. Some CNS effects (e.g. tremor) may occur even with therapeutic plasma concentrations of the drug.
Cardiovascular effects: methylxanthines have positive chronotropic and inotropic effects on the heart. Tachyarrhythmias may occur with therapeutic doses, especially in the presence of halothane.