Drugs Acting on the Respiratory System

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Drugs Acting on the Respiratory System

An understanding of how drugs interact with the respiratory system is vital for anaesthetists and those working in critical care. Knowledge of the drugs discussed in this chapter will facilitate effective management of common, potentially life-threatening medical emergencies. An appreciation of the steps in the British Thoracic Society guidelines on asthma management may help risk-stratify and optimize asthmatic patients in the perioperative period. Oxygen is increasingly being considered as a therapeutic agent or drug requiring a written prescription. Nearly 300 serious incidents associated with oxygen misuse, including nine deaths, were reported to the National Patient Safety Agency (NPSA) over a 5-year period. Anaesthetists are well placed to lead implementation of the NPSA’s recent guidance and assist in the education of other healthcare staff regarding the safe use of oxygen.

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 (G_s) 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; G_q and G_s, 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.

The cholinergic parasympathetic system is mediated through several subtypes of muscarinic receptor. The most common subtype found in pulmonary tissue is the M₃ receptor. This is also a G-protein coupled receptor (G_q) but one which, when activated, stimulates phospholipase C to produce inositol triphosphate, which then binds to sarcoplasmic reticulum receptors causing release of calcium from intracellular stores, and so results in smooth muscle contraction and bronchoconstriction. Therefore muscarinic agonists cause bronchoconstriction and anticholinergic drugs cause bronchodilatation.

A third, minor, neural pathway also exists, referred to as the non-cholinergic parasympathetic system. This is a bronchodilator pathway which has vasoactive intestinal peptide (VIP) as its neurotransmitter and nitric oxide (NO) as the second messenger. The physiological significance of this in humans is unknown.

Histamine and other mediators also play an important role in promoting bronchial constriction via H₁-receptors, especially during anaphylaxis, drug reactions, allergy, asthma and respiratory infections. Anti-inflammatory agents (e.g. steroids) and membrane stabilizers (e.g. sodium cromoglicate) may reduce or prevent bronchoconstriction in these conditions.

Bronchodilators

Bronchodilators are used commonly in the management of acute asthma or an exacerbation of COPD with the aim of reversing the abnormal bronchospasm that occurs in these potentially life-threatening conditions. All doctors working in acute specialties need to be familiar with their use. Anaesthetists, by ensuring optimal bronchodilator therapy, may avoid the need for invasive ventilation in some patients. In addition to alleviating the symptoms of wheeze and dyspnoea, bronchodilators improve the adequacy of ventilation and decrease the work of breathing.

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

Indications:

Asthma

COPD

Hyper-reactive airways in patients undergoing mechanical ventilation

Bronchospasm caused by allergic reactions and anaphylaxis

Bronchospasm following aspiration or inhalation of toxins.

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.

Oral administration has no advantage over the inhalational route and is associated with a greater incidence of adverse-effects. Intravenous administration is used occasionally, as a last resort, when bronchospasm is so severe that an aerosol or nebulizer is unlikely to deliver the drug to the narrowed airways or when inhalational therapy has failed. Intravenous administration is associated with more frequent systemic side-effects and should be used only when the patient is appropriately monitored.

Salmeterol is a more potent, longer acting β₂-agonist than salbutamol. Its effects last up to 12 h, allowing twice daily administration for the prevention of asthma attacks. It is available as an aerosol inhaler (dose: 50–100 μg twice daily).

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)

potentiation of non-depolarizing muscle relaxants.

Bronchodilatation may lead to transient hypoxaemia due to increased mismatch and inhibition of the normal hypoxic pulmonary vasoconstriction mechanism. This may be overcome easily by supplying supplementary oxygen. β₂-agonists also cause relaxation of the gravid uterus and may be used in the management of pre-term labour.

Anticholinergic Drugs

The use of anticholinergic agents for their bronchodilator properties dates back two centuries when Datura plants were smoked for the relief of asthma. As an anticholinergic, atropine does cause bronchodilatation but side-effects such as tachycardia and dry mucous membranes limit its usefulness. Anticholinergic drugs are usually used as second-line agents in the management of acute bronchospasm and are very effective in reducing the frequency of acute exacerbations of COPD when taken regularly. One of the most commonly used drugs is ipratropium bromide. It is a synthetic quaternary ammonium compound derived from atropine. Ipratropium is active topically and there is little systemic absorption from the respiratory tract. Mast cell stabilization has also been proposed as a complementary mechanism of action. Maximum effect occurs 30–60 min after inhalation and may continue for up to 8 h. Tiotropium is a more recently introduced antimuscarinic bronchodilator with a longer duration of action that allows once daily administration.

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

The bronchodilator effect of strong coffee was first described in the 19th century. Methylxanthines, which are chemically related to caffeine, have been used to manage obstructive airways disease since the 1930s. Theophylline is the most commonly used methylxanthine and is available as an oral modified-release preparation. Aminophylline is a water-soluble salt which is used as an injectable form of theophylline. Methylxanthines have widespread effects involving multiple organ systems. With regard to their bronchodilator effects, the following mechanisms have been proposed:

phosphodiesterase inhibition, leading to increased intracellular cAMP

adenosine receptor antagonism, preventing mast cell degranulation

endogenous catecholamine release

prostaglandin inhibition

interference with calcium mobilization

potentiation of β₂-agonists.

Methylxanthines also increase cardiac output and the efficiency of the respiratory muscles, including improved diaphragmatic contractility. Aminophylline has been used occasionally in the management of heart failure and is known to reduce the frequency of apnoea in the premature neonate.

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.