Pulmonary pharmacology concerns the effects of drugs on the lungs and understanding how drugs used to treat patients with pulmonary diseases work. Much of this pharmacology concerns drugs used to treat obstructive airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD).
Two types of drugs are used in the treatment of obstructive airway diseases:
1. Relievers (bronchodilators) give immediate reversal of airway obstruction, largely by directly relaxing airway smooth muscle.
2. Controllers (preventers) suppress the underlying disease process and provide long-term control of symptoms. These drugs include anti inﬂammatory treatments, such as corticosteroids.
Both asthma and COPD are characterized by airway narrowing secondary to a chronic inﬂammatory process. In asthma, eosinophilic (and sometimes neutrophilic) inﬂammation occurs throughout the respiratory tract, although the proximal airways are predominantly affected. In COPD, there is inﬂammation and narrowing of small airways (chronic obstructive bronchiolitis) and destruction of lung parenchyma (emphysema), resulting in loss of support for the airways, early closure on expiration, and air trapping.
Bronchodilators cause immediate reversal of airway obstruction as a result of a relaxing effect on airway smooth muscle. However, other pharmacologic effects of bronchodilator drugs on other airway cells (reduced microvascular leakage, reduced release of bronchoconstrictor mediators from inﬂammatory cells) may contribute to the reduction in airway narrowing. Three classes of bronchodilators are in current clinical use for the treatment of obstructive airway diseases: β2- agonists, theophylline, and anticholinergics.
Inhaled β2-agonists are the bronchodilator treatment of choice for patients with asthma because they are the most effective bronchodilators, reverse all known bronchoconstrictor mechanisms, and have minimal side effects when used correctly. Short-acting and nonselectiveagonists (e.g., isoproterenol) have no role.
Mode of Action
β2-Agonists produce bronchodilatation by directly stimulating β2-receptors on airway smooth muscle cells, which leads to relaxation of central and peripheral airways. β2-agonists act as “functional antagonists” and reverse bronchoconstriction irrespective of the contractile agent; this is important in asthma because many bronchoconstrictor mechanisms (neural and mediators) are likely to constrict airways. In COPD, their major effect is reversal of cholinergic neural tone. Occupation of β2-receptors by agonists results in the activation of adenylyl cyclase via the stimulatory G-protein (Gs), which increases intracellular cyclic AMP (cAMP), leading to relaxation through inhibition of the contractile machinery.
β2-receptors are localized to several types of airway cells, and β2-agonists may have additional effects.β2-agonists may cause bronchodilatation, not only by a direct action on airway smooth muscle but also indirectly by inhibiting the release of bronchoconstrictor mediators from mast cells and of bronchoconstrictor neurotransmitters from airway nerves. β2-agonists have an inhibitory effect on mast cell mediator release and microvascular leakage, suggesting they may inhibit acute inﬂammation. However, β2-agonists do not have a signiﬁcant inhibitory effect on the chronic inﬂammation of asthmatic airways and do not reduce airway hyperresponsiveness, which is a clinical manifestation of inﬂammation in asthma.
Short-acting inhaled β2-agonists (e.g., albuterol, terbutaline) are the most widely used bronchodilators. Their duration of action is 3 to 4 hours (less in severe asthma). When inhaled from pressurized metered dose inhalers (pMDIs) in standard doses, they are convenient, easy to use, rapid in onset, and without signiﬁcant side effects. They also protect against bronchoconstrictor stimuli such as exercise, cold air, and allergens. They are the bronchodilators of choice in acute severe asthma, in which the nebulized route of administration is as effective as intravenous use. The inhaled route of administration is preferable to the oral route because side effects are less common and because it may be more effective (better access to surface cells such as mast cells). Short-acting inhaled β2-agonists should be used as required by symptoms and not on a regular basis; increased usage indicates a need for more antiinﬂammatory therapy.
Long-Acting Inhaled 2-Agonists
The long-acting inhaled β2-agonists (LABAs) salmeterol and formoterol are a signiﬁcant advance in the treatment of patients with asthma and COPD. Both drugs have a bronchodilator action, protect against bronchoconstriction for more than 12 hours, and provide better symptom control (when given twice daily) than regular treatment with short-acting β2- agonists (four times daily). Formoterol has a more rapid onset of action but is a fuller agonist than salmeterol, so tolerance is more likely. Inhaled long-actingβ2-agonists may be added to low or moderate doses of inhaled corticosteroids if asthma is not controlled, and this is more effective than increasing the dose of inhaled corticosteroids. Long-acting inhaled β2-agonists should be used only in patients who are taking inhaled corticosteroids because these drugs do not have an antiinﬂammatory action and are potentially dangerous without corticosteroids. Combination inhalers with a long-acting β2-agonist and corticosteroid (ﬂuticasone/ salmeterol, and budesonide/formoterol) are an effective and convenient way to control asthma and are useful in COPD.
Unwanted effects result from stimulation of extrapulmonary β-receptors and include tachycardia, tremors, and palpitations. Side effects are uncommon with inhaled therapy but more common with oral or intravenous administration.
A large trial in the United States showed that salmeterol increased mortality in patients with asthma, but this was mainly in patients who were not using concomitant inhaled corticosteroids. This provides a strong argument for only prescribing long-actingβ2-agonists in a combination inhaler.
Continuous treatment with an agonist often leads to tolerance (desensitization), which may result from uncoupling or downregulation (or both) of the receptor. Tolerance of non-airway β-receptor responses (e.g., tremor, cardiovascular and metabolic responses) is readily observed. Loss of bronchodilator action is minimal, but there is some loss of bronchoprotective effect against, for example, exercise. This is incomplete and not progressive and does not appear to be a clinical problem.
Worldwide, theophylline remains the most widely used antiasthma therapy because it is inexpensive, but the greater incidence of side effects with theophylline and the greater efﬁcacy of 2-agonists and inhaled corticosteroids have reduced its use (see Plate 5-2). It still remains a useful drug in patients with severe asthma and COPD. There is increasing evidence that low-dose theophylline (plasma concentration, 5-10 mg/L) has an anti inﬂammatory or immunomodulatory effect and may be effective in combination with inhaled corticosteroids.
Mode of Action
Despite extensive study, it has been difﬁcult to elucidate the molecular mechanisms of the antiasthma actions of theophylline. It is possible that any beneﬁcial effect in asthma is related to its action on other cells (e.g., plate- lets, T lymphocytes, macrophages) or on airway micro- vascular leak and edema in addition to airway smooth muscle relaxation. Theophylline is a relatively ineffective bronchodilator, and high doses are needed for its bronchodilator action. Its antiasthma effect is more likely to be explained by other effects (e.g., immunomodulation). Several molecular modes of action have been proposed.
Inhibition of Phosphodiesterases
Phosphodiesterases (PDEs) break down cAMP in the cell; their inhibition leads to an increase in intracellular cAMP concentrations (see Plate 5-2). PDE inhibition is likely to account for the bronchodilator action of theophylline, but the degree of inhibition is relatively small at concentrations of theophylline within the therapeutic range. PDE inhibition also accounts for the side effects of nausea and headaches.
Adenosine Receptor Antagonism
Adenosine is a bronchoconstrictor in asthmatic patients via activation of mast cells (A2B receptors). Adenosine antagonism may account for some side effects of theophylline (e.g., central nervous system [CNS] stimulation, cardiac arrhythmias, diuresis).
Histone Deacetylase Activation
Therapeutic concentrations of theophylline activate histone deacetylases in the nucleus, resulting in the switching off of inﬂammatory genes and enhancing the antiinﬂammatory action of corticosteroids, especially when there is corticosteroid resistance.
|METHYLXANTHINES: ADVERSE EFFECTS|
In patients with acute asthma, intravenous aminophylline is less effective than nebulized β2-agonists and should therefore be reserved for the few patients who fail to respond to β-agonists. (Aminophylline is a stable mixture or combination of theophylline and ethylenediamine, which confers greater solubility.) Theophylline is less effective as a bronchodilator than inhaled β2- agonists and is more likely to have side effects. There is increasing evidence that low doses (giving plasma concentrations of 5-10 mg/L) may be useful when added to inhaled corticosteroids, particularly in more severe asthma. Theophylline is also useful as an additional bronchodilator in COPD, reducing hyperinﬂation and improving dyspnea.
Theophylline is readily and reliably absorbed from the gastrointestinal tract, but many factors affect plasma clearance, and thereby plasma concentration, that make the drug relatively difﬁcult to use.
Adverse effects are usually related to plasma concentration and tend to occur when plasma levels exceed 20 mg/L, although some patients develop them at lower plasma concentrations. The severity of side effects may be reduced by gradually increasing the dose until therapeutic concentrations are achieved. The most common side effects are headache, nausea and vomiting, abdominal discomfort, and restlessness, which are likely caused by PDE inhibition and at higher concentrations cardiac arrhythmias and seizures caused by antagonists of adenosine A1-receptors. Theophylline also has many interactions with other drugs because of alterations in liver enzyme metabolism.
Atropine is a naturally occurring compound that was introduced for the treatment of asthma but because of side effects (particularly drying of secretions), less soluble quaternary compounds (e.g., ipratropium bromide) were developed.
Mode of Action
Anticholinergics are speciﬁc antagonists of muscarinic receptors and inhibit cholinergic nerve-induced bronchoconstriction. A small degree of resting bronchomotor tone is present because of tonic cholinergic nerve impulses, which release acetylcholine in the vicinity of airway smooth muscle, and cholinergic reﬂex bronchoconstriction may be initiated by irritants, cold air, and stress. Although anticholinergics protect against acute challenge by sulfur dioxide and emotional factors, they are less effective against antigen, exercise, and fog; they inhibit reﬂex cholinergic bronchoconstriction only and have no signiﬁcant blocking effect on the direct effects of inﬂammatory mediators, such as histamine and leukotrienes. In COPD, cholinergic tone is the major reversible element of airway narrowing.
Whereas ipratropium bromide and oxitropium bromide are administered three or four times daily via inhalation, tiotropium bromide is given once daily. In patients with asthma, anticholinergic drugs are less effective than β2-agonists and offer less protection against various bronchial challenges. Nebulized anticholinergics are effective in acute severe asthma but less effective thanβ2-agonists. Nevertheless, anticholinergic drugs may have an additive effect with β2-agonists in acute and chronic treatment and should therefore be considered when control of asthma is inadequate, particularly when there are side effects with theophylline or inhaled β-agonists.
Anticholinergic drugs are the bronchodilators of choice in COPD, and once-daily tiotropium bromide is the most effective bronchodilator for COPD.
Inhaled anticholinergic drugs are well tolerated, and systemic side effects are uncommon because almost no systemic absorption occurs. Ipratropium bromide, even in high doses, has no detectable effect on airway secretions. Nebulized ipratropium bromide may precipitate glaucoma in elderly patients as a result of a direct effect of the nebulized drug on the eye; this is avoided by use of a mouthpiece rather than a face mask. Paradoxic bronchoconstriction with ipratropium bromide, particularly when given by nebulizer, was largely explained by the hypotonicity of an earlier nebulizer solution and by antibacterial additives such as benzalkonium chloride; this problem is avoided with current preparations. Dry mouth occurs in about 10% of patients taking tiotropium bromide but rarely requires discontinuation of treatment.
Corticosteroids are the most effective therapy available for asthma (see Plates 5-5 and 5-6). Inhaled corticosteroids have revolutionized the management of patients with chronic asthma and are now used as ﬁrst-line therapy in all patients with persistent symptoms.
Mode of Action
Corticosteroids enter target cells and bind to glucocorticoid receptors in the cytoplasm. The corticosteroidreceptor complex is transported to the nucleus, where it binds to speciﬁc sequences on the upstream regulatory element of certain target genes, resulting in increased or decreased transcription of the gene and increased or decreased protein synthesis. Glucocorticoid receptors may also inhibit transcription factors, such as nuclear factor-ƘB and activator protein-1, which regulate inﬂammatory gene expression by a nongenomic mechanism. Corticosteroids inhibit acetylation of core histones and thereby inﬂammatory gene expression by recruiting histone deacetylase-2 to the activated transcriptional complex.
The mechanism of action of corticosteroids in asthma is most likely related to their antiinﬂammatory properties. Corticosteroids have widespread effects on gene transcription, increasing transcription of antiinﬂammatory genes and more importantly suppressing transcription of multiple inﬂammatory genes. At a cellular level, they have inhibitory effects on many inﬂammatory and structural cells that are activated in asthma. The inhibitory action of inhaled corticosteroids on airway epithelial cells may be particularly important; this results in a reduction in airway hyperresponsiveness, but in long-standing asthma, airway hyperresponsiveness may not return to normal because of irreversible structural changes in airways.
Systemic corticosteroids are used in acute asthma and accelerate its resolution. There is no advantage with very high doses of intravenous corticosteroids (e.g., methylprednisolone, 1 g). Prednisolone or prednisone (40-60 mg orally) has an effect similar to intravenous hydrocortisone and is easier to administer.
Maintenance doses of oral corticosteroids are reserved for patients whose asthma cannot be controlled on other therapy; the dose is titrated to the lowest that provides acceptable symptom control. In any patient taking regular oral corticosteroids, objective evidence of corticosteroid responsiveness should be obtained before maintenance therapy is instituted. Short courses of oral corticosteroids (prednisolone, 30-40 mg/d for 1-2 weeks) are indicated for exacerbations of asthma; the dose may be tapered over 1 week after the exacerbation is resolved. (The tapering period is not strictly necessary, but patients ﬁnd it reassuring.) Inhaled corticosteroids are currently recommended as ﬁrst-line therapy in all patients with persistent asthma. Inhaled corticosteroids, such as beclomethasone dipropionate, budesonide, ﬂuticasone propionate, triamcinolone, mometasone furoate, and ciclesonide, act topically on the inﬂammation in the airways of asthmatic patients. They may be started in any patient who needs to use a β2-agonist inhaler for symptom control more than twice a week. In most patients, inhaled corticosteroids are used twice daily; this improves compliance after control of asthma has been achieved. If a dose of more than 800 µg of budesonide or equivalent daily via MDI is administered, a spacer should be used to reduce the risk of oropharyngeal side effects and of absorption from the gastrointestinal tract. Inhaled corticosteroids at doses of 400 µg/d or less may be used safely in children.
Rarely, patients with severe asthma fail to respond to corticosteroids. Corticosteroid-resistant asthma is likely to be caused by several molecular mechanisms, including defective translocation of the glucocorticoid receptor as a result of activated kinases or reduced histone deacetylase-2 activity. COPD patients occasionally respond well to corticosteroids; these patients are likely to have undiagnosed asthma. Patients with COPD show a poor response to corticosteroids, and the inﬂammation is essentially steroid resistant. The steroid resistance in COPD appears to be caused by a marked reduction in histone deacetylase-2 in inﬂammatory cells, such as macrophages. Inhaled corticosteroids have no effect on the progression of COPD but reduce exacerbations in patients who have severe disease and frequent exacerbations. Inhaled corticosteroids do not reduce mortality in COPD, and recent evidence suggests that in high doses, they may increase the risk of developing pneumonia.
Side Eﬀects (see Plate 5-7)
Corticosteroids inhibit cortisol secretion by a negative feedback effect on the pituitary gland. Hypothalamopituitary–adrenal axis suppression is dependent on dose and usually occurs when a dose of prednisone of more than 7.5-10 mg/d is used. Signiﬁcant suppression after short courses of corticosteroid therapy is not usually a problem, but prolonged suppression may occur after several months or years; corticosteroid doses after prolonged oral therapy must therefore be reduced slowly. Symptoms of “corticosteroid withdrawal syndrome” include lassitude, musculoskeletal pains, and occasionally fever.
Side effects of long-term oral corticosteroid therapy include ﬂuid retention, increased appetite, weight gain, osteoporosis, capillary fragility, hypertension, peptic ulceration, diabetes, cataracts, and psychosis. The incidence tends to increase with age.
Systemic side effects of inhaled corticosteroids have been investigated extensively. Effects such as cataract formation and osteoporosis are reported but often in patients who are also receiving oral corticosteroids. There has been particular concern about growth suppression in children using inhaled corticosteroids, but in most studies, doses of 400 µg or less have not been associated with impaired growth, and there may even be a growth spurt because asthma is better controlled. The fraction of corticosteroid inhaled into the lungs acts locally on the airway mucosa and may be absorbed from the airway and alveolar surface, thereby reaching the systemic circulation. The fraction of inhaled corticosteroid deposited in the oropharynx is swallowed and absorbed from the gut. The absorbed fraction may be metabolized in the liver before it reaches the systemic circulation. Budesonide and ﬂuticasone propionate have a greater ﬁrst-pass metabolism than beclomethasone dipropionate and are therefore less likely to produce systemic effects at high inhaled doses. The use of a large volume spacer reduces oropharyngeal deposition, thereby reducing systemic absorption of corticosteroid.
· Initial studies suggested that adrenal suppression occurred only when inhaled doses of more than 1500 µg/d were used.
· More sensitive measurements of systemic effects include indices of bone metabolism (e.g., serum osteocalcin, urinary pyridinium cross-links), 24-hour plasma cortisol proﬁles and, in children, short-term growth of the lower leg, which may be affected by inhaled doses as low as 800 µg. The clinical relevance of these measurements is unclear. Nevertheless, it is important to reduce the risk of systemic effects by using the lowest dose of inhaled corticosteroid needed to control the asthma and by use of a large-volume spacer to reduce oropharyngeal deposition.
Inhaled corticosteroids may have local side effects caused by deposition of corticosteroid in the oropharynx. These side effects include oral thrush caused by overgrowth of Candida spp., throat irritation, and changes in voice caused by vocal cord irritation and weakness.
Cromones include cromolyn sodium and the structurally related nedocromil sodium.
Mode of Action
Initial investigations suggested that cromoglycate acts as a mast cell stabilizer, but this effect is weak in human mast cells. Cromones inhibit bronchoconstriction induced by sulfur dioxide, metabisulﬁte, and bradykinin, which are believed to act through activation of sensory nerves in the airways. Cromones have variable inhibitory actions on other inﬂammatory cells that may participate in allergic inﬂammation, including macrophages and eosinophils.
Cromoglycate blocks the early response to allergen (mediated by mast cells) and the late response and airway hyperresponsiveness, which are more likely to be mediated by macrophage and eosinophil interactions. The molecular mechanism of cromone action is not understood; evidence suggests they may block a type of chloride channel that may be expressed in sensory nerves, mast cells, and other inﬂammatory cells.
Cromones are prophylactic treatments and must be given regularly. They protect against indirect bronchoconstrictor stimuli, such as exercise, allergens, and fog. Cromones are poorly effective compared with low doses of inhaled corticosteroids, and recent systematic reviews concluded that they provide little beneﬁt in chronic asthma in children. Cromones are administered four times daily and may also be taken before exercise in children with exercise-induced asthma. There has been an increasing tendency to substitute low-dose inhaled corticosteroids for cromoglycate in adults and children, so they are now rarely used and are not recommended in most guidelines. There is no role for cromones in the management of patients with COPD.
Cromoglycate is one of the safest drugs available, and side effects are extremely rare. The dry-powder inhaler may cause throat irritation; coughing; and, occasionally, wheezing, but this is usually prevented by prior administration of a β-agonist inhaler. Very rarely, a transient rash and urticaria or pulmonary eosinophilia are seen; these result from hypersensitivity. Side effects are not usually a problem with nedocromil, although some patients have noticed a sensation of ﬂushing after using the inhaler.
Antileukotrienes (leukotriene receptor antagonists) are less effective than inhaled corticosteroids in the control of asthma but have been widely used because they are effective by mouth and have few side effects (see Plates 5-8 and 5-9).
Mode of Action
Elevated levels of leukotrienes are detectable in bronchoalveolar lavage ﬂuid, exhaled breath condensate, sputum, and urine of asthmatic patients. Cysteinyl-leukotrienes (cys-LTs) are generated from arachidonic acid by the rate-limiting enzyme 5-lipoxygenase. Cys-LTs are potent constrictors of human airways in vitro and in vivo, cause airway microvascular leakage in animals, and stimulate airway mucus secretion. These effects are all mediated in human airways via cys-LT1 receptors. Montelukast and zaﬁrlukast are potent cys-LT1 receptor antagonists that markedly inhibit the bronchoconstrictor response to inhaled leukotrienes; reduce allergen-induced, exercise-induced, and cold air–induced asthma by about 50% to 70%; and inhibit aspirin-induced responses in aspirin-sensitive asthmatics almost completely. The only 5-lipoxygenase inhibitor clinically available is zileuton, the efﬁcacy of which is similar to that of receptor antagonists. Antileukotrienes have also been shown to have weak antiinﬂammatory effects and reduce eosinophilic inﬂammation, which may be provoked by cys-LTs.
Antileukotrienes may have a small and variable bronchodilator effect, indicating that leukotrienes may contribute to baseline bronchoconstriction in asthma. Long-term administration reduces asthma symptoms and the need for rescue 2-agonists and improves lung function. However, their effects are signiﬁcantly less than those with low-dose inhaled corticosteroids in terms of symptom control, improvement in lung function, and reduction in exacerbations. Antileukotrienes are not as effective as inhaled corticosteroids in the management of mild asthma and are not the preferred therapy. They may be useful in some patients whose asthma is not controlled on inhaled corticosteroids as an add-on therapy to inhaled corticosteroids but are less effective in this respect than a long- acting β2-agonist or low-dose theophylline. They are effective in some but not all patients with aspirinsensitive asthma. Patients appear to differ in their response to antileukotrienes, and it is impossible to predict which patients will respond best even when genetic polymorphisms of the leukotriene pathways are elucidated.
A major advantage of antileukotrienes is that they are orally active, and this is likely to improve compliance with long-term therapy. However, they are expensive, and a trial of therapy is indicated to determine which patients will beneﬁt most.
Adverse effects are uncommon. Zaﬁrlukast may produce mild hepatic dysfunction, so regular liver function tests are important. Several cases of Churg-Strauss syndrome (systemic vasculitis with eosinophilia and asthma) have been observed in patients taking antileukotrienes, but this is likely to be because a concomitant reduction in oral corticosteroids (made possible by the antileukotriene) allows the vasculitis to ﬂare up.
Mode of Action
Omalizumab is a humanized recombinant monoclonal antibody that binds to circulating IgE and thus blocks it from activating high-afﬁnity IgE receptors on mast cells and low-afﬁnity IgE receptors on other inﬂammatory cells. This results in reduced responses to allergens. Over time, the blocking of IgE reduces its synthesis from B cells and results in a sustained reduction in IgE.
Omalizumab reduces airway inﬂammation in patients with mild to moderate asthma and reduces the incidence of asthma exacerbations with improved control of asthma in patients maintained on reduced doses of inhaled corticosteroids. Omalizumab is most useful in patients with severe asthma who are not controlled with maximal doses of inhaled therapy because it reduces exacerbations and improves asthma control. Fewer than 30% of patients show a good response, and this is not predictable by any clinical features; therefore, a trial of therapy over 4 months is indicated. Omalizumab should be given only to patients with serum IgE levels of 20 to 700 IU/mL; above these levels, it is not possible to give enough antibody to neutralize IgE. The dose of omalizumab is determined by the serum IgE levels and is given either once or twice a month. Because of its high cost only patients at steps 4 (severe) and 5 (very severe) of the Global Initiative for Asthma (GINA) Guidelines who have frequent exacerbations are suitable for this therapy.
Omalizumab is well tolerated. Occasionally, local reactions occur at the injection sites, and very rarely, anaphylactic reactions have been seen.
Immunosuppressive therapy has been considered in asthma when other treatments have been unsuccessful or when a reduction in the dosage of oral corticosteroids is required; it is therefore indicated in very few (1%) asthmatic patients at present.
Low-dose methotrexate, 15 mg weekly, has a corticosteroid-sparing effect in some patients with asthma, but side effects are relatively common and include nausea (reduced if methotrexate is given as a weekly injection), blood dyscrasia, hepatic damage, and pulmonary ﬁbrosis. Careful monitoring (monthly blood counts and liver enzymes) is essential.
Gold has long been used in the treatment of patients with chronic arthritis. A controlled trial of an oral gold preparation (auranoﬁn) demonstrated some corticosteroid-sparing effect in chronic asthmatic patients maintained on oral corticosteroids, but side effects (skin rashes and nephropathy) are a limiting factor.
Low-dose oral cyclosporine A in patients with corticosteroid-dependent asthma is reported to improve control of symptoms, but in clinical practice, it is unimpressive, and its use is limited by severe side effects (nephrotoxicity, hypertension).
Despite the fact that cough is a common symptom of airway disease, its mechanisms are poorly understood, and current treatment in unsatisfactory (see Plate 5-10). Because cough is a defensive reﬂex, its suppression may be inappropriate in those with bacterial lung infections. Before treatment with antitussives, it is important to identify underlying causal mechanisms that may require therapy. Treatments such as opioids may act centrally on the “cough center,” but other treatments such as local anesthetics may act on airway sensory nerves.
Opiates have a central mechanism of action on the medullary cough center, but some evidence suggests that they may have additional peripheral action on cough receptors in the proximal airways. Codeine and dextromethorphan are commonly used, but there is little evidence that they are clinically effective. Morphine and methadone are effective but are only indicated in patients with intractable cough associated with bronchial carcinoma.
Asthma commonly presents as cough, and the cough usually responds to bronchodilators and inhaled corticosteroids. A syndrome characterized by cough in association with sputum eosinophilia but no airway hyperresponsiveness and termed eosinophilic bronchitis responds to inhaled corticosteroids and may be regarded as pre-asthma. Nonasthmatic cough does not respond to inhaled steroids but sometimes responds to cromones or anticholinergic therapy. The cough associated with postnasal drip of sinusitis responds to antibiotics, nasal decongestants, and intranasal steroids. The cough associated with angiotensin-converting enzyme inhibitors responds to withdrawal of the drug (or a switch to an angiotensin receptor antagonist) and to cromones. In some patients, there may be underlying gastroesophageal reﬂux, which leads to cough by a reﬂex mechanism and occasionally by acid aspiration. This cough responds to effective suppression of gastric acid with an H2-receptor antagonist or more effectively to a proton pump inhibitor, such as omeprazole.
Some patients have an intractable cough that often starts after a severe respiratory tract infection. When no other causes for this cough are found, it is termed idiopathic and may be caused by hyperesthesia of airway sensory nerves. This is supported by the fact that these patients have an increased responsiveness to tussive stimuli such as capsaicin. This form of cough is difﬁcult to manage. It may respond to nebulized lidocaine, but this is not practical for long-term management, and novel therapies are needed.
There is a need to develop new, more effective therapies for cough, particularly drugs that act peripherally. There are close analogies between chronic cough and sensory hyperesthesia, so it is likely that new therapies are likely to arise from pain research.
DRUGS FOR DYSPNEA
Bronchodilators should reduce breathlessness, and chronic oxygen may have some effect, but in a few patients, breathlessness may be extreme. Drugs that have been shown to reduce breathlessness may also depress ventilation in parallel and may be dangerous in those with severe asthma and COPD. Some patients show a beneﬁcial response to dihydrocodeine and diazepam, but these drugs must be used with caution. Slow-release morphine tablets may also be helpful in COPD patients with extreme dyspnea. Nebulized morphine may also reduce breathlessness in COPD and could act in part on opioid receptors in the lung.
Several classes of drug stimulate ventilation and are indicated when ventilatory drive is inadequate rather than stimulating ventilation when the respiratory pump is failing. Nikethamide and ethamivan were originally introduced as respiratory stimulants, but doses stimulating ventilation are close to those causing convulsions, so their use has been abandoned. More selective respiratory stimulants have now been developed and are indicated if ventilation is impaired as a result of over-dose with sedatives, postanesthetic respiratory depression, and in idiopathic hypoventilation. Respiratory stimulants are rarely indicated in patients with COPD because respiratory drive is already maximal, and further stimulation of ventilation may be counterproductive because of the increase in energy expenditure caused by the drugs.
At low doses (0.5 mg/kg intravenously), doxapram stimulates carotid chemoreceptors, but at higher doses, it stimulates medullary respiratory centers. Its effect is transient, and it must therefore be administered by intravenous infusion (0.3-3.0 mg/kg/min). The use of doxapram to treat ventilatory failure in patients with COPD has largely now been replaced by noninvasive ventilation. Unwanted effects include nausea, sweating, anxiety, and hallucinations. At higher doses, increased pulmonary and systemic pressures may occur.
Doxapram is metabolized in the liver and should be used with caution if hepatic function is impaired.
The carbonic anhydrase inhibitor acetazolamide induces metabolic acidosis and thereby stimulates ventilation, but it is not widely used because the metabolic imbalance it produces may be detrimental in the face of respiratory acidosis. It has a very small beneﬁcial effect in respiratory failure in COPD patients. The drug has proven useful in the prevention of high- altitude sickness.
Naloxone is a competitive opioid antagonist that is only indicated if ventilatory depression is caused by overdose of opioids.
Flumazenil is a CNS benzodiazepine receptor antagonist and can reverse respiratory depression caused by overdose of benzodiazepines.
Protryptiline has been used in the treatment of patients with sleep apnea syndromes, but its mode of action is unclear. It appears to stimulate activity of upper airway muscles via some central effect.
Modaﬁnil is a nonamphetamine CNS stimulant occasionally used to treat drowsiness in patients with obstructive sleep apnea syndrome as an adjust to continuous positive airway pressure therapy. ide effects include insomnia, anxiety, and tachycardia.