Drugs Acting on the Respiratory System
DRUGS AFFECTING AIRWAY CALIBRE
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
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.
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.