Respiratory system

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Chapter 28 Respiratory system

Kevin M. O’Shaughnessy

• Cough: modes of action and uses of antitussives.

• Respiratory stimulants: their place in therapy.

• Pulmonary surfactant.

• Oxygen therapy: its uses and dangers.

• Histamine, antihistamines and allergies.

• Bronchial asthma: types, modes of prevention, agents used for treatment and their use in asthma of varying degrees of severity.

• Infections (see Ch. 14).

Cough

There are two sorts of cough: the useful and the useless. Cough is useful when it effectively expels secretions or foreign objects from the respiratory tract, i.e. when it is productive; it is useless when it is unproductive and persistent. Useful cough should be allowed to serve its purpose and suppressed only when it is exhausting the patient or is dangerous, e.g. after eye surgery. Useless persistent cough should be stopped. Asthma, rhinosinusitis (causing postnasal drip) and oesophageal reflux are the commonest causes of persistent cough. Recently, eosinophilic bronchitis has been recognised as a possibly significant cause; it responds well to inhaled or oral corticosteroid. Clearly the overall approach to persistent cough must involve attention to underlying factors. The British Thoracic Society publishes guidelines on cough and its management that are available online.¹

Sites of action for treatment

Peripheral sites

On the afferent side of the cough reflex: by reducing input of stimuli from throat, larynx, trachea, a warm moist atmosphere has a demulcent effect on the pharynx.

On the efferent side of the cough reflex: measures to render secretions more easily removable (mucolytics, postural drainage) will reduce the amount of coughing needed, by increasing its efficiency.

The best antitussive of all is removal of the cause of the cough itself, i.e. treatment of underlying conditions (above). In patients with hypertension or cardiac failure, a common cause of a dry cough is treatment with an angiotensin-converting enzyme (ACE) inhibitor. This can be stopped by switching to an angiotensin II receptor blocker (ARB), e.g. losartan.

Central nervous system

Agents may act on the:

• medullary paths of the cough reflex (opioids)

• cerebral cortex

• subcortical paths (opioids and sedatives in general).

Cough is also under substantial voluntary control and can be inducible by psychogenic factors (e.g. the anxiety not to cough during the quiet parts of a musical concert) and reduced by a placebo. Considerations such as these are relevant to practical therapeutics.

Cough suppression

Antitussives that act peripherally

Smokers should stop smoking.

Cough originating above the larynx often benefits from syrups and lozenges that glutinously and soothingly coat the pharynx (demulcents ²), e.g. simple linctus (mainly sugar-based syrup). Small children are prone to swallow lozenges, so a sweet on a stick may be preferred.

Linctuses are demulcent preparations that can be used alone and as vehicles for other specific antitussive agents. Their exact constitution is not critical, and medical students in 1896 were taught the following:

Many of you know that this (simple) linctus used to be very much thicker than it is now, and very likely the thicker linctus was more efficacious. The reason why it was made thinner was this. It was discovered that a large number of children came to the surgery complaining of cough, and they were given the linctus, but instead of their using it as a medicine, they took it to an old woman out in Smithfield, who gave them each a penny, took their linctus, and made jam tarts with it.³

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.

Antitussives that act centrally

The most consistent means of suppressing cough irrespective of its cause is blockade of the medullary cough centre itself. Opioids, such as methadone and codeine, are very effective, although part of this antitussive effect could reflect their sedatory effect on higher nervous centres; nevertheless antitussive potency of an opiate is generally poorly correlated with its potency at causing respiratory depression.

As dextromethorphan (the D-isomer of the codeine analogue levorphanol) and pholcodine also have an antitussive effect that is not blocked by naloxone, non-μ-type opiate receptors are probably involved (and dubbed σ-type). It is not surprising, then, that these opiates also have no significant analgesic or respiratory-depressant effects at the doses required for their antitussive action.

Opioids are usually formulated as linctuses for antitussive use. Deciding on which agent to use depends largely on whether sedation and analgesia may be useful actions of the linctus. Hence methadone or diamorphine linctus may be preferred in patients with advanced bronchial carcinoma. In contrast, dextromethorphan, being non-sedating and non-addictive, is widely incorporated into over-the-counter linctuses (see Table 4 in footnote 1).

Sedation generally reduces the sensitivity of the cough reflex. Hence older sedating antihistamines, e.g. diphenhydramine, can suppress cough by non-H₁-receptor actions; often the doses needed cause substantial drowsiness so that combination with other drugs, such as pholcodine and dextromethorphan, is common in over-the-counter cough remedies.

Mucolytics and expectorants

Normally about 100 mL fluid is produced from the respiratory tract each day and most of it is swallowed. Respiratory mucus consists largely of water and its slimy character is due to glycoproteins cross-linked together by disulphide bonds. In pathological states much more mucus may be produced; an exudate of plasma proteins that bond with glycoproteins and form larger polymers results in the mucus becoming more viscous. Patients with chest diseases such as cystic fibrosis (CF) and bronchiectasis have difficulty in clearing their chest of viscous sputum by cough because the bronchial cilia are rendered ineffective. Drugs that liquefy mucus can provide benefit.

Mucolytics

Carbocisteine and mecysteine have free sulphydryl groups that open disulphide bonds in mucus and reduce its viscosity. They are given orally or by inhalation (or instillation) and may be useful chiefly where particularly viscous secretion is a problem (cystic fibrosis, care of tracheostomies). Mucolytics may cause gastrointestinal irritation and allergic reaction.

Water inhalation via an aerosol (breathing over a hot basin) is a cheap and effective expectorant therapy in bronchiectasis. Simply hydrating a dehydrated patient can also have a beneficial effect in lowering sputum viscosity.

Dornase α is phosphorylated glycosylated recombinant human deoxyribonuclease. It is given daily by inhalation of a nebulised solution containing 2500 units (2.5 mg). It is of modest value only in patients with cystic fibrosis, whose genetic defect in chloride transport causes particularly viscous sputum. The blocked airways, as well as the sputum itself, are a trap for pathogens, and the lysis of invading neutrophils leads to substantial levels of free and very viscous DNA within the CF airways.

Expectorants

These are said to encourage productive cough by increasing the volume of bronchial secretion; there is little clinical evidence to support this, and they may be of no more value than placebo. The group includes squill, guaiphenesin, ipecacuanha, creosotes and volatile oils.

Cough mixtures

Every formulary is replete with combinations of antitussives, expectorants, mucolytics, bronchodilators and sedatives. Although choice is not critical, knowledge of the active ingredients is important, as some contain sedative antimuscarinic antihistamines or phenylpropanolamines (which may antagonise antihypertensives). Use of glycerol or syrup as a demulcent cough preparation, or of simple linctus (citric acid), is probably defensible.

Choice of drug therapy for cough

As always, it is necessary to have a clear idea of the underlying problem before starting any therapy. For example, the approach to cough due to invasion of a bronchus by a neoplasm differs from that due to postnasal drip from chronic sinusitis or to that due to chronic bronchitis. The following are general recommendations.

Simple suppression of useless cough

Codeine, pholcodine, dextromethorphan and methadone linctuses can be used in large, infrequent doses. In children, cough is nearly always useful and sedation at night is more effective to give rest. A sedative antihistamine is convenient (e.g. promethazine), although sputum thickening may be a disadvantage. In pertussis infection (whooping cough), codeine and atropine methonitrate may be tried.

To increase bronchial secretion slightly and to liquefy what is there

Water aerosol with or without menthol and benzoin inhalation, or menthol and eucalyptus inhalation may provide comfort harmlessly.

Carbocysteine or another mucolytic orally may occasionally be useful.

Preparations containing any drug with antimuscarinic action are undesirable because this thickens bronchial secretion. Oxygen inhalation dries secretions, so rendering them even more viscous; oxygen must be bubbled through water, and patients having oxygen may need measures to liquefy sputum.

Cough originating in the pharyngeal region

Glutinous sweets or lozenges (demulcents), incorporating a cough suppressant or not, as appropriate, are used.

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).

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