Cough originating below the larynx is often relieved by water aerosol inhalations and a warm environment – the archetypal ‘steam’ inhalation. Compound benzoin tincture ⁴ may be used to give the inhalation a therapeutic smell (aromatic inhalation). This manoeuvre may have more than a placebo effect by promoting secretion of a dilute mucus that gives a protective coating to the inflamed mucous membrane. Menthol and eucalyptus are alternatives. The efficacy of menthol may be explained by the discovery that it can block the ion channel TRPV1, which is activated by capsaicin, the ‘hot chilli’ component of Capsicum species and a potent trigger for cough.

Local anaesthetics can also be used topically in the airways to block the mucosal cough receptors (modified stretch receptors and C-fibre endings) directly. Nebulised lidocaine, for example, reduces coughing during fibreoptic bronchoscopy and is also effective in the intractable cough that may accompany bronchial carcinoma.

Respiratory stimulants

The drugs used (analeptics) are central nervous system (CNS) stimulants capable of causing convulsions in doses just above those used therapeutically. Hence, their use must be monitored carefully.

Doxapram

increases the rate and depth of respiration by stimulating the medullary respiratory centres both directly and reflexly through the carotid body. A continuous i.v. infusion of 1.5–4.0 mg/min is given according to the patient’s response. Coughing and laryngospasm that develop after its use may represent a return of normal protective responses. Doxapram is also an effective inhibitor of shivering following general anaesthesia.

Adverse effects include restlessness, twitching, itching, vomiting, flushing, bronchospasm and cardiac arrhythmias, and in addition doxapram causes patients to experience a feeling of perineal warmth; in high doses it raises blood pressure.

Aminophylline

(a complex of theophylline and EDTA) in addition to its other actions (see also p. 154) is a respiratory stimulant and may be infused slowly i.v. (500 mg in 6 h).

Uses

Respiratory stimulants have a considerably reduced role in the management of acute ventilatory failure, following the increased use of non-invasive nasal positive-pressure ventilation for respiratory failure. Situations where they may still be encountered are:

• Acute exacerbations of chronic lung disease with hypercapnia, drowsiness and inability to cough or to tolerate low (24%) concentrations of inspired oxygen (air is 21 % oxygen). A respiratory stimulant can arouse the patient sufficiently to allow effective physiotherapy and, by stimulating respiration, can improve ventilation–perfusion matching. As a short-term measure, this may be used in conjunction with assisted ventilation without tracheal intubation (BIPAP ⁵), and thereby ‘buy time’ for chemotherapy to control infection and avoid full tracheal intubation and mechanical ventilation.

• Apnoea in premature infants; aminophylline and caffeine may benefit some cases.

• The manufacturer’s data sheet suggests the use of doxapram for buprenorphine overdoses where the respiratory depression is not responsive to naloxone.

Avoid respiratory stimulants in patients with epilepsy (risk of convulsions). Other relative contraindications include ischaemic heart disease, acute severe asthma (‘status asthmaticus’), severe hypertension and thyrotoxicosis.

Irritant vapours, to be inhaled, have an analeptic effect in fainting, especially if it is psychogenic, e.g. aromatic solution of ammonia (Sal Volatile). No doubt they sometimes ‘recall the exorbitant and deserting spirits to their proper stations’.⁶

Pulmonary surfactant

The endogenous surfactant system produces stable low surface tension in the alveoli, preventing their collapse. Failure of production of natural surfactant occurs in respiratory distress syndrome (RDS), including that in the neonate. Synthetic phospholipids are now available for intratracheal instillation to act as surfactants: colfosceril palmitate, poractant-α and beractant. These need to be stored chilled, and the manufacturers’ instructions followed carefully, because on reaching body temperature their physicochemical properties change rapidly. Their function is to coat the surface of the alveoli and maintain their patency, and their administration to premature neonates with RDS is a key part in reducing mortality and long-term complications in this condition.

Oxygen therapy

Oxygen used in therapy should be prescribed with the same care as any drug, including its specific inclusion on the patient’s drug chart; there should be a well-defined purpose and its effects should be monitored objectively.

The absolute indication to supplement inspired air is inadequate tissue oxygenation. As clinical signs may be imprecise, arterial blood gases should be measured whenever suspicion arises. An elevated serum lactate is also a useful marker. Nevertheless, tissue hypoxia should be assumed when the PaO₂ falls below 6.7 kPa (50 mmHg) in a previously normal acutely ill patient, e.g. with myocardial infarction, acute pulmonary disorder, drug overdose, musculoskeletal or head trauma. Chronically hypoxic patients may maintain adequate tissue oxygenation with a Pao₂ below 6.7 kPa by compensatory adaptations, including an increased red cell mass and altered haemoglobin–oxygen binding characteristics. Oxygen therapy is used as follows:

• High-concentration oxygen therapy is reserved for a state of low PaO₂ in association with normal or low Paco₂ (type I respiratory failure), as in: pulmonary embolism, pneumonia, pulmonary oedema, myocardial infarction and young patients with acute severe asthma. Concentrations of oxygen up to 100% may be used for short periods, as there is little risk of inducing hypoventilation and carbon dioxide retention.

• Low-concentration oxygen therapy is reserved for a state of low PaO₂ in association with a raised Paco₂ (type II failure), typically seen during exacerbations of chronic obstructive pulmonary disease. The normal stimulus to respiration is an increase in Paco₂, but this control is blunted in chronically hypercapnic patients whose respiratory drive comes from hypoxia. Increasing the Pao₂ in such patients by giving them high concentrations of oxygen removes their stimulus to ventilate, exaggerates carbon dioxide retention and may cause fatal respiratory acidosis. The objective of therapy in such patients is to provide just enough oxygen to alleviate hypoxia without exaggerating the hypercapnia and respiratory acidosis; normally the inspired oxygen concentration should not exceed 28%, and in some 24% may be sufficient.

• Continuous long-term domiciliary oxygen therapy (LTOT) is given to patients with severe persistent hypoxaemia and cor pulmonale due to chronic obstructive pulmonary disease (see below). Patients are provided with an oxygen concentrator. Clinical trial evidence indicates that taking oxygen for more than 15 h per day improves survival.

Histamine, antihistamines and allergies

Histamine is a naturally occurring amine that has long fascinated pharmacologists and physicians. It is found in most tissues in an inactive bound form, and pharmacologically active free histamine, released in response to stimuli such as physical trauma or immunoglobulin (Ig) E-mediated activation, is an important component of the acute inflammatory response.

The physiological functions of histamine are suggested by its distribution in the body, in:

• body epithelia (the gut, the respiratory tract and in the skin), where it is released in response to invasion by foreign substances

• glands (gastric, intestinal, lachrymal, salivary), where it mediates part of the normal secretory process

• mast cells near blood vessels, where it plays a role in regulating the microcirculation.

Actions

Histamine acts as a local hormone (autacoid) similarly to serotonin or prostaglandins, i.e. it functions within the immediate vicinity of its site of release. With gastric secretion, for example, stimulation of receptors on the histamine-containing cell causes release of histamine, which in turn acts on receptors on parietal cells which then secrete hydrogen ions (see Gastric secretion, Ch. 32). The actions of histamine that are clinically important are those on:

Smooth muscle. In general, histamine causes smooth muscle to contract (excepting arterioles, but including the larger arteries). Stimulation of the pregnant human uterus is insignificant. A brisk attack of bronchospasm may be induced in subjects who have any allergy, particularly asthma.

Blood vessels. Arterioles are dilated, with a consequent fall in blood pressure. This action is due partly to nitric oxide release from the vascular endothelium of the arterioles in response to histamine receptor activation. Capillary permeability also increases, especially at postcapillary venules, causing oedema. These effects on arterioles and capillaries represent the flush and the wheal components of the triple response described by Thomas Lewis.⁷ The third part, the flare, is arteriolar dilatation due to an axon reflex releasing neuropeptides from C-fibre endings.

Skin. Histamine release in the skin can cause itch.

Gastric secretion. Histamine increases the acid and pepsin content of gastric secretion.

As may be anticipated from the above actions, anaphylactic shock, which is due in large part to histamine release, is characterised by circulatory collapse and bronchoconstriction. The most rapidly effective antidote is adrenaline/epinephrine (see below), and an antihistamine (H₁ receptor) may be given as well.

Various chemicals can cause release of histamine. The more powerful of these (proteolytic enzymes and snake venoms) have no place in therapeutics, but a number of useful drugs, such as D-tubocurarine and morphine, and even some antihistamines, cause histamine release. This anaphylactoid (i.e. IgE independent) effect is usually clinically mild with a transient reduction in blood pressure or a local skin reaction, but significant bronchospasm may occur in asthmatics.

Metabolism

Histamine is formed from the amino acid histidine and is inactivated largely by deamination and methylation. In common with other local hormones, this process is extremely rapid.

Histamine receptors

Histamine binds to H₁, H₂ and H₃ receptors, all of which are G-protein coupled. The H₁ receptor is largely responsible for mediating its pro-inflammatory effects, including the vasomotor changes, increased vascular permeability and up-regulation of adhesion molecules on vascular endothelium (see p. 400), i.e. it mediates the oedema and vascular effects of histamine. H₂ receptors mediate release of gastric acid (see p. 528). Blockade of histamine H₁ and H₂ receptors has substantial therapeutic utility.

H₃ receptors are expressed in a wide range of tissues including brain and nerve endings, and function as feedback inhibitors for histamine and other neurotransmitters. More recently identified is the H₄ receptor, which is involved in leucocyte chemotaxis.

Histamine antagonism and H₁– and H₂-receptor antagonists

The effects of histamine can be opposed in three ways:

• By using a drug with opposing effects. Histamine constricts bronchi, causes vasodilatation and increases capillary permeability; adrenaline/epinephrine, by activating α- and β₂-adrenoceptors, produces opposite effects – referred to as physiological antagonism.

• By blocking histamine binding to its site of action (receptors), i.e. using competitive H₁-and H₂-receptor antagonists.

• By preventing the release of histamine from storage cells. Glucocorticoids and sodium cromoglicate can suppress IgE-induced release from mast cells; β₂ agonists have a similar effect.

Drugs that competitively block H₁-histamine receptors were the first to be introduced and are conventionally called the ‘antihistamines’. They effectively inhibit the components of the triple response and partially prevent the hypotensive effect of histamine, but they have no effect on histamine-induced gastric secretion which is suppressed by blockade of histamine H₂ receptors. Thus, histamine antagonists are classified as:

• histamine H₁-receptor antagonists (see below)

• histamine H₂-receptor antagonists: cimetidine, famotidine, nizatidine, ranitidine (see Ch. 32).

The selectivity implied by the term ‘antihistamine’ is unsatisfactory because the older first-generation antagonists (see below) show considerable blocking activity against muscarinic receptors, and often serotonin and α-adrenergic receptors as well. These features are a disadvantage when H₁ antihistamines are used specifically to antagonise the effects of histamine, e.g. for allergies. Hence the appearance of second-generation H₁ antagonists that are more selective for H₁ receptors and largely free of antimuscarinic and sedative effects (see below) has been an important advance. They can be discussed together.

Actions

H₁-receptor antihistamines oppose, to varying degrees, the effects of liberated histamine. They are generally competitive, surmountable inhibitors and strongly block all components of the triple response (a pure H₁-receptor effect), but only partially counteract the hypotensive effect of high-dose histamine (a mixed H₁– and H₂-receptor effect). H₁ antihistamines are of negligible use in asthma, in which non-histamine mediators, such as the cysteinyl-leukotrienes, are the predominant constrictors. They are more effective if used before histamine has been liberated, and reversal of effects of free histamine is more readily achieved by physiological antagonism with adrenaline/epinephrine, which is used first in life-threatening allergic reactions.

The older first-generation H₁ antihistamines cause drowsiness and patients should be warned of this, e.g. about driving or operating machinery, and about additive effects with alcohol. Paradoxically, they can increase seizure activity in epileptics, especially children, and can cause seizures in non-epileptic subjects if taken in overdose. The newer second-generation H₁ antihistamines penetrate the blood–brain barrier less readily and are largely devoid of such central effects. Antimuscarinic effects of first-generation H₁ antihistamines are sometimes put to therapeutic advantage in parkinsonism and motion sickness.

Pharmacokinetics

H₁ antihistamines taken orally are readily absorbed. They are metabolised mainly in the liver. Excretion in the breast milk may be sufficient to cause sedation in infants. They are generally administered orally and can also be given intramuscularly or intravenously.

Uses

The H₁ antihistamines are used for symptomatic relief of allergies such as hay fever and urticaria (see below). They are of broadly similar therapeutic efficacy.

Individual H₁-receptor antihistamines

Non-sedative second-generation drugs

These newer drugs are relatively selective for H₁ receptors, enter the brain less readily than do the earlier antihistamines, and lack the unwanted antimuscarinic effects. Differences lie principally in their duration of action.

Cetirizine (t_½ 7 h), loratadine (t_½ 15 h) and terfenadine (t_½ 20 h) are effective taken once daily and are suitable for general use. Acrivastine (t_½ 2 h) is so short acting that it is best reserved for intermittent therapy, e.g. when breakthrough symptoms occur in a patient using topical therapy for hay fever. Other non-sedating antihistamines are desloratadine, fexofenadine, levocetirizine and mizolastine.

Adverse effects

The second-generation antihistamines are well tolerated but an important adverse effect occurs with terfenadine. This drug can prolong the QTc interval on the surface ECG by blocking a potassium channel in the heart (the rapid component of delayed rectifier potassium current, I_Kr), which triggers a characteristic ventricular tachycardia (torsade de pointes, see p. 442) and probably explains the sudden deaths reported during early use of terfenadine (and prompted its withdrawal from North American markets). It is associated with either high doses of terfenadine or inhibition of its metabolism. Terfenadine depends solely on the 3A4 isoform of cytochrome P450, and inhibiting drugs include erythromycin, ketoconazole and even grapefruit juice. Fexofenadine, the active metabolite, has a much lower affinity for the I_Kr channel and does not cause QTc prolongation.

Sedative first-generation agents

Chlorphenamine (t_½ 20 h) is effective when urticaria is prominent, and its sedative effect is then useful.

Diphenhydramine (t_½ 32 h) is strongly sedative and has antimuscarinic effects; it is also used in parkinsonism and motion sickness.

Promethazine (t_½ 12 h) is so strongly sedative that it is used as a hypnotic in adults and children.

Alimemazine, azatadine, brompheniramine, clemastine, cyproheptadine, diphenylpyraline, doxylamine, hydroxyzine and triprolidine are similar.

Adverse effects

Apart from sedation, these include: dizziness, fatigue, insomnia, nervousness, tremors and antimuscarinic effects, e.g. dry mouth, blurred vision and gastrointestinal disturbance. Dermatitis and agranulocytosis can occur. Severe poisoning due to overdose results in coma and sometimes in convulsions.

Drug management of some allergic states

Histamine is released in many allergic states, but it is not the sole cause of symptoms, other chemical mediators, e.g. leukotrienes and prostaglandins, also being involved. Hence the usefulness of H₁-receptor antihistamines in allergic states is variable, depending on the extent to which histamine, rather than other mediators, is the cause of the clinical manifestations.

Note also that H₂-receptor antagonists (separate from their role in reducing gastric acid secretion) can be used to reduce the effects of a type I hypersensitivity response, e.g. rhinitis, urticaria and conjunctivitis.

Hay fever

If symptoms are limited to rhinitis, a glucocorticoid (beclometasone, betamethasone, budesonide, flunisolide or triamcinolone), ipratropium or sodium cromoglicate applied topically as a spray or insufflation is often all that is required. Ocular symptoms alone respond well to sodium cromoglicate drops. When both nasal and ocular symptoms occur, or there is itching of the palate and ears as well, a systemic non-sedative H₁-receptor antihistamine is indicated. Sympathomimetic vasoconstrictors, e.g. ephedrine, are immediately effective when applied topically, but rebound swelling of the nasal mucous membrane occurs when medication is stopped. Rarely, a systemic glucocorticoid, e.g. prednisolone, is justified for a severely affected patient to provide relief for a short period, e.g. during academic examinations.⁸

Hyposensitisation, by subcutaneous injection of graded and increasing amounts of grass and tree pollen extracts, is an option for seasonal allergic hay fever due to pollens (which has not responded to antiallergy drugs), and of bee and wasp allergen extracts for people who exhibit allergy to these venoms (exposure to which can be life-threatening). If hyposensitisation is undertaken, facilities for immediate cardiopulmonary resuscitation must be available because of the risk of anaphylaxis. A sublingual tablet containing a very low dose grass pollen extract (Grazax) is also now available to effect similar desensitisation. It has to be taken daily before and throughout the grass pollen season but does not cause anaphylaxis. Another strategy for subjects with very severe atopic and extrinsic asthma is to use a monocloncal antibody against IgE (omalizumab), which causes a rapid, dose-related and sustained fall in plasma IgE concentrations. The antibody is designed to bind to the part of the IgE molecule that interacts with the high-affinity IgE receptor (FcRI) on mast cells and basophils, thus preventing the activation of these cells by cross-linking of bound IgE.

Urticaria

See page 273.

Anaphylactic shock

See page 116.

Bronchial asthma

Asthma affects 10–15% of the UK population; this figure is increasing.

Some pathophysiology

The bronchi become hyperreactive as a result of a persistent inflammatory process in response to a number of stimuli that include biological agents, e.g. allergens, viruses, and environmental chemicals such as ozone and glutaraldehyde. Inflammatory mediators are liberated from mast cells, eosinophils, neutrophils, monocytes and macrophages. Some mediators such as histamine are preformed and their release causes an immediate bronchial reaction. Others are formed after activation of cells and produce more sustained bronchoconstriction; these include metabolites of arachidonic acid from both the cyclo-oxygenase, e.g. prostaglandin D₂ and lipo-oxygenase, e.g. cysteinyl-leukotrienes C₄ and D₄, pathways. In addition platelet activating factor (PAF) is being recognised increasingly as an important mediator (see Ch. 16, p. 242).

The relative importance of many of the mediators is not defined precisely but they interact to produce mucosal oedema, mucus secretion and damage to the ciliated epithelium. Breaching of the protective epithelial barrier allows hyperreactivity to be maintained by bronchoconstrictor substances or by local axon reflexes through exposed nerve fibres. Wheezing and breathlessness result. The bronchial changes also obstruct access of inhaled drug to the periphery, which is why they can fail to give full relief.

Asthma, like many of the common chronic disorders (hypertension, diabetes mellitus), is a polygenic disorder, and already genetic loci linked to either increased production of IgE or bronchial hyperreactivity have been reported in some families with an increased incidence of asthma.

Early in an attack there is hyperventilation so that PaO₂ is maintained and Paco₂ is lowered, but with increasing airways obstruction the Pao₂ declines and Paco₂ rises, signifying a serious asthmatic episode.

Types of asthma

Asthma associated with specific allergic reactions

This extrinsic type is the commonest and occurs in patients who develop allergy to inhaled antigenic substances. They are also frequently atopic, showing positive responses to skin prick testing with the same antigens. The hypersensitivity reaction in the lung (and skin) is of the immediate type (type I) involving IgE-mediated mast cell activation. Allergen avoidance is particularly relevant to managing this type of asthma.

Asthma not associated with known allergy

Some patients exhibit wheeze and breathlessness in the absence of an obvious allergen or atopy. They are considered to have intrinsic asthma and, because of a lack of an identifiable allergen, allergen avoidance has no place in their management.

Exercise-induced asthma

Some patients develop wheeze that regularly follows within a few minutes of exercise. A similar response occurs following the inhalation of cold air, as the common mechanism appears to be airway drying. Inhalation of a β₂-adrenoceptor agonist, sodium cromoglicate (see below) or one of the newer leukotriene receptor antagonists (see below) prior to either challenge prevents bronchoconstriction.

Asthma associated with chronic obstructive pulmonary disease

A number of patients with persistent airflow obstruction exhibit substantial variation in airways resistance and in the extent to which they benefit from bronchodilator drugs. It is important to recognise that asthma may coexist with chronic obstructive pulmonary disease, and to assess their responses to bronchodilators or glucocorticoids over a period of time (as formal tests of respiratory function may not reliably predict clinical response in this setting).

Approaches to treatment

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. Identification of 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, i.e. the RAST test (RadioAllergoSorbent Test). Avoiding an allergen may be feasible when it is related to some 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. 242) 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 that these mediators cause. Glucocorticoids used in asthma include prednisolone (orally), and beclometasone, fluticasone and budesonide (by inhalation) (see Ch. 35).

Sodium cromoglicate

(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 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.

As it does not antagonise the bronchoconstrictor effect of the mediators after they have been released, cromoglicate is not effective at terminating an existing attack, i.e. it prevents bronchoconstriction rather than inducing bronchodilation. Special formulations are used for allergic rhinitis and allergic conjunctivitis.

Sodium cromoglicate is effective in extrinsic (allergic) asthma, including asthma in children and exercise-induced asthma, but its use has declined since the efficacy and safety of low-dose inhaled corticosteroid have become apparent.

It is remarkably non-toxic. 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 H₁-receptor blocker that may also have some anti-asthma effects but its benefit has not been demonstrated conclusively. In common with other antihistamines it causes drowsiness.

Dilatation of narrowed bronchi

This is achieved most effectively 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).

β₂–Adrenoceptor agonists

The predominant adrenoceptors in bronchi are of the β₂ type and their stimulation causes bronchial muscle to relax. β₂-Adrenoceptor activation also stabilises mast cells. Agonists in widespread use include salbutamol, terbutaline, fenoterol, eformoterol and salmeterol, and are discussed in Chapter 23. 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. α-Adrenoceptor activity contributes to bronchoconstriction, but α-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 bronchodilating 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 t_½ is 8 h, with substantial variation. It is prolonged in patients with severe cardiopulmonary disease and cirrhosis; obesity and prematurity are associated with reduced rates of elimination; tobacco smoking enhances theophylline clearance by inducing hepatic P450 enzymes. These pharmacokinetic factors and the low therapeutic index render necessary the therapeutic monitoring of the plasma theophylline to achieve the best outcome; the desired concentration range is 10–20 mg/L (55–110 micromol/L).

Theophylline is relatively insoluble and is formulated either as a salt with choline (choline theophyllinate) or complexed with EDTA (aminophylline). Aminophylline is sufficiently soluble to permit intravenous use of theophylline in acute severe asthma (status asthmaticus). Rapid intravenous injection will induce unwanted effects (below) by exposing the heart and brain to high concentrations before distribution is complete. Intravenous 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 methylxanthine preparation (always enquire about this before injecting the loading dose!).

There are numerous sustained-release oral forms for use in chronic asthma, but because they are not bio-equivalent patients should not switch between them once they are stabilised on a particular preparation.

Adverse effects. At high therapeutic doses some patients experience nausea and diarrhoea, and plasma concentrations above the recommended range risk cardiac arrhythmia and seizures. 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 that 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, hypokalaemia and seizures. Activated charcoal should be given every 2–4 h until the plasma concentration is below 20 mg/L. Potassium replacement is important to prevent arrhythmias, and a benzodiazepine (e.g. 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 bronchodilatation, although the preferred antimuscarinics in clinical practice are inhaled ipratropium, oxitropium or the long-acting tiotropium (its effects last for up to 24 h). These synthetic compounds, unlike atropine, are permanently charged molecules that resist significant absorption after inhalation and thus minimise antimuscarinic effects outside of the lung. They are used mostly in older patients with chronic obstructive pulmonary disease, but are useful in acute severe asthma when combined with β₂-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 bronchoconstrictor effects of cysteinyl-leukotrienes (C₄, D₄ and E₄) by blocking their common cysLT1 receptor. They have similar efficacy to low-dose inhaled glucocorticoid. The scarcity 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 five-step regimen for asthma (see Fig. 28.1). 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.

Fig. 28.1 A five-step management scheme for chronic asthma (British Thoracic Society 2008). β₂, β₂-Adrenoceptor agonist; GCC, glucocorticoid, e.g. beclometasone, budesonide or fluticasone.

Montelukast is given once per day and zafirlukast twice daily. 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.

Drug therapy by inhalation

The inhaled route has been developed to advantage because the undesirable effects of systemic exposure to drugs, especially glucocorticoids, are substantially reduced. The pharmacokinetic advantages of using the inhaled versus the oral route are apparent from the substantially reduced dose requirement: salbutamol 100 micrograms from an aerosol inhaler will provide bronchodilatation similar to 2000 micrograms by mouth.

Before a drug can be inhaled, it must first be converted into particulate form; the optimum particle size to reach and be deposited in the small bronchi is around 2 μm. Such particles are delivered to the lung as an aerosol, i.e. dispersed in a gas, which can be produced in a number of different ways:

Pressurised aerosol

Drug is dissolved in a low boiling point liquid in a canister under pressure. Opening the valve releases a metered dose of liquid that is ejected into the atmosphere; the carrier liquid evaporates instantly, leaving an aerosol of the drug that is inhaled. Until recently the vehicle has been a CFC (chlorofluorocarbon), but due to concerns over depletion of atmospheric ozone these are being replaced by hydrofluoroalkanes (HFAs), which are ozone friendly. This switch has introduced a noticeable change in the taste of some inhalers, but more importantly it has changed the bio-equivalence of inhaled glucocorticoids. HFA-based glucocorticoid inhalers are generally more potent than a CFC-based inhaler delivering the same dose at the lips (typically the efficacy is doubled).

To ensure optimal drug delivery, it is necessary to coordinate activation of the inhaler with inspiration and a final hold of breath. Many patients, especially the young and the elderly, find this very difficult and ‘spacer’ devices are often used between the inhaler and lips; these act as an aerosol reservoir and also reduce impaction of aerosol in the oropharynx. Topical deposition can cause local side-effects in the mouth, particularly candida with inhaled glucocorticoids; a spacer abolishes this problem.

Nebulisers

convert a solution or suspension of drug into an aerosol. Jet nebulisers require a driving gas, usually air from a compressor unit for home use, or oxygen in hospital; the solution in the nebulising chamber is broken into droplets by the jet and the larger droplets are filtered off leaving the smaller ones to be inhaled. Ultrasonic nebulisers convert a solution into particles of uniform size by vibrations created by a piezoelectric crystal (which converts electricity into mechanical vibration). With either method the aerosol is delivered to the patient by a mouthpiece or facemask, so no coordination is called for, and the dose can be altered by changing the strength of the solution. Much larger doses can be administered by nebuliser than by pressurised aerosol.

Dry powder inhalers

The drug is formulated as a micronised powder and placed in a device, e.g. a spin-haler or diskhaler, from which it is inhaled. Patients can often use these when they fail with metered-dose aerosols. Inhalation of powder occasionally causes transient bronchoconstriction.

Drug treatment

This varies with the severity and type of asthma. It is a general rule that the effectiveness of changes in drug and dose should be monitored by serial measurements of the simple respiratory function tests such as peak expiratory flow rate (PEFR) or forced expiratory volume in 1 s (FEV₁). Neither the patient’s feelings nor physical examination are alone sufficient to determine whether there is still room for improvement. When an asthmatic attack is severe, arterial blood gases must also be measured.

Constant and intermittent asthma

The 2008 British Thoracic Society guidelines recommend a five-step approach ⁹ (summarised in Fig. 28.1) to the drug management of chronic asthma. The scheme starts with a patient requiring occasional β₂-adrenoceptor agonist and follows an escalating plan of add-on anti-inflammatory treatment. Points to emphasise are:

1. Short-acting β₂-adrenoceptor agonists are used throughout as rescue therapy for acute symptoms.

2. Patients must be reviewed regularly as they can move up or down the scheme.

3. Particular attention should be paid to inhaler technique, as this is an important cause of treatment failure. Patients who cannot manage inhaled therapy, even with the addition of a spacer device or use of a dry-powder device, can be given oral therapy, although this will be accompanied by more systemic side-effects.

An inhaled β₂-adrenoceptor agonist

should be used initially. Salbutamol or terbutaline (1–2 puffs up to four times daily) are typical short-acting β₂-adrenoceptor agonists whose bronchodilator effect is prompt in onset (within a few minutes) and lasts 4–6 h. Salmeterol and formoterol have a much longer duration of effect (12–24 h), making them useful for nocturnal symptoms; they should not be used as ‘rescue’ bronchodilator (salmeterol in particular, because its bronchodilating action takes 15–30 min to emerge) nor as a replacement for inhaled glucocorticoid (see Step 3). β₂-Adrenoceptor agonists all cause dose-dependent tremor, especially if given orally rather than inhaled.

Anti-inflammatory agents

can commence either with sodium cromoglicate or low-dose inhaled glucocorticoid (Step 2). The inhaled glucocorticoids in current use (beclometasone, budesonide and fluticasone) are characterised by low oral bio-availability because of high first-pass metabolism in the liver (almost 100% for fluticasone). This property is important, as it minimises the systemic effects of inhaled glucocorticoid, 80–90% of which is actually swallowed. Precisely for this reason, prednisolone or hydrocortisone would have less advantage (over oral administration) if inhaled, because they are absorbed from the gut and enter the circulation with relatively little pre-systemic metabolism. Inhaled glucocorticoids also exhibit higher lipid solubility and potency than those usually administered orally. Potency (the physical mass of drug in relation to its effect, see p. 78) is generally unimportant in comparisons of oral drugs, but is essential for locally administered drugs.

Inhaled glucocorticoids

are generally safe at low doses. Topical effects (oral candida and hoarseness) are eliminated by using a spacer device and rinsing the mouth. High doses (> 2000 micrograms/day) are reported to carry a slightly increased risk of cataract and glaucoma; this may reflect local aerosol deposition rather than a true systemic effect. Bone turnover is also increased in adults, suggesting a long-term risk of accelerated osteoporosis, and bone growth may be reduced in children (although evidence indicates that normal adult height can be attained ¹⁰). Therefore, it is important that patients are maintained on the minimum dose of inhaled glucocorticoid necessary for symptom control.

Oral prednisolone

is very effective for severe exacerbations and short courses (e.g. 30 mg daily for 5–7 days) are frequently given. Provided symptoms and peak flows respond promptly, more prolonged courses or prolonged reduction of dose are unnecessary. When oral glucocorticoids are used long term (Step 5), doses should be adjusted much more slowly. Adverse corticosteroid effects may also be minimised by administering a single morning dose to coincide with the normal peak cortisol concentration (and thus the least suppression of feedback to the hypothalamic–adrenal axis). This is possible because of the long duration of their biological effect (18–36 h) compared with plasma t_½ (3 h for prednisolone). Morning dosing with inhaled glucocorticoid may also have a prednisolone-sparing effect. Some patients may get further prednisolone-sparing by addition of nebulised high-dose budesonide, 1–2 mg twice daily or fluticasone 500 micrograms twice daily.

Chest infections in asthma

Antimicrobials are over-prescribed for exacerbations of asthma. Respiratory tract infections do cause increased airflow obstruction and bronchial hyperresponsiveness, but viral not bacterial pathogens are the commonest culprits. Antimicrobials should be prescribed only if there is high suspicion of a bacterial respiratory tract infection, e.g. purulent sputum. Note that macrolide antibiotics, such as erythromycin and clarithromycin, interfere with theophylline metabolism.

Acute severe asthma (‘status asthmaticus’)

This is a life-threatening emergency requiring rapid aggressive treatment. The airways may become refractory to β₂-adrenoceptor agonists after 36–48 h, partly for pharmacological reasons (possibly receptor desensitisation) and partly due to the prolonged respiratory acidosis. The mucous plugs, which are the hallmark of the condition, may also prevent inhaled drugs from reaching the distal airways.

The following lists, with some explanation, the recommendations of the British Thoracic Society⁹ for managing acute severe asthma:

Immediate treatment

• Oxygen by mask (humidified, to help liquefy mucus). Carbon dioxide narcosis is rare in asthma and 60% can be used if the diagnosis is not in doubt. In older patients, or when there is any concern about chronic carbon dioxide retention, start with 28% oxygen and check that the PaCO₂ has not risen before delivering 35% oxygen.

• Salbutamol by nebuliser in a dose of 2.5–5 mg over about 3 min, repeated in 15 min. Terbutaline 5–10 mg is an alternative.

• Prednisolone 30–60 mg by mouth or hydrocortisone 100 mg i.v.

• Avoid sedation of any kind.

• Chest radiography is required to exclude pneumothorax.

If life-threatening features are present (absent breath sounds, cyanosis, bradycardia, exhausted appearance, PEFR < 33% predicted or best, arterial oxygen saturation of < 92%):

• Ipratropium 0.5 mg should be added to the nebulised β₂ agonist.

• Consider i.v. magnesium sulphate (1.2–2 g over 20 min).¹¹

• Alert the intensive care unit.

Subsequent management

If the patient is improving, continue:

• 40–60% oxygen.

• Prednisolone 30–60 mg daily or hydrocortisone 100–200 mg 6-hourly.

• Nebulised salbutamol or terbutaline 4-hourly.

If the patient is not improving after 15–30 min:

• Continue oxygen and glucocorticoid.

• Give nebulised β₂-adrenoceptor agonist more frequently, e.g. salbutamol up to 10 mg/h.

• Add ipratropium 0.5 mg to nebuliser and repeat 6-hourly until patient is improving.

If the patient is still not improving:

• Consider intravenous infusion of aminophylline (0.9 micrograms/kg/min)¹¹ or

• Consider as an alternative intravenous β₂-adrenoceptor agonist (as above), e.g. salbutamol 250 micrograms over 10 min, then up to 20 micrograms/min as an infusion (as nebulised salbutamol may not be reaching the distal airways).

• Contact the intensive care unit to discuss intubation and mechanical ventilation.

Monitoring response to treatment

• By peak expiratory flow rate (PEFR) every 15–30 min.

• Oxygen saturation: maintain > 92%. Repeat blood gas measurements if initial PaO₂ < 8 kPa (60 mmHg) and/or initial Paco₂ is normal or raised (the tachypnoea is expected to reduce Paco₂ in most patients).

Treatment in intensive care unit

Transfer (accompanied by doctor with facilities for intubation) is required if:

• any of the above deteriorates, despite maximal treatment

• the patient becomes exhausted, drowsy, or confused

• coma or respiratory arrest occurs.

Treatment at discharge from hospital

Patients should:

• continue high-dose inhaled glucocorticoid and complete course of oral prednisolone

• be instructed to monitor their own PEFR and not to reduce dose if the PEFR falls, or there is a recurrence of early morning dipping in the reading (patients should not generally be discharged until there is less than 25% diurnal variation in PEFR readings).

Warnings

Asthma may be precipitated by β-adrenoceptor blockade and the use of β-adrenoceptor antagonists is contraindicated in asthmatics; fatal asthma has been precipitated by β-blocker eye drops, even allegedly β₁-selective agents.

Overuse

of β₂-adrenergic agonists is dangerous. In the mid-1960s, there was an epidemic of sudden deaths in young asthmatics outside hospital. It was associated with the introduction of a high-dose, metered aerosol of isoprenaline (β₁ and β₂ agonist); it did not occur in countries where the high concentration was not marketed.¹² The epidemic declined in Britain when the profession was warned, and the aerosols were restricted to prescription only. Though the relationship between the use of β₂-receptor agonists and death is presumed to be causal, the actual mechanism of death is uncertain; overdose causing cardiac arrhythmia is not the sole factor. The subsequent development of selective β₂-receptor agonists was a contribution to safety, but a review in New Zealand during the 1980s found that the use of fenoterol (β₂ selective) by metered-dose inhalation was associated with increased risk of death in severe asthma,¹³ and later analysis concluded that it was the most likely cause.¹⁴ A further cause for concern comes from a meta-analysis of 19 clinical trials which concluded that long-acting β agonists (LABAs) increased severe and life-threatening asthma exacerbations, as well as asthma-related deaths.¹⁵ The US Food and Drug Administration has recently confirmed their belief that the benefits of LABAs still outweigh these risks but have opted for a more cautious labelling policy.¹⁶