THERAPIES AND THERAPEUTIC PROCEDURES

Mode of Action

β ₂ -Agonists produce bronchodilatation by directly stimulating β ₂ -receptors on airway smooth muscle cells, which leads to relaxation of central and peripheral airways. β ₂ -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 β ₂ -receptors by agonists results in the activation of adenylyl cyclase via the stimulatory G-protein (G _s ), which increases intracellular cyclic AMP (cAMP), leading to relaxation through inhibition of the contractile machinery.

β ₂ -receptors are localized to several types of airway cells, and β ₂ -agonists may have additional effects. β ₂ -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. β ₂ -agonists have an inhibitory effect on mast cell mediator release and microvascular leakage, suggesting they may inhibit acute inflammation. However, β ₂ -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.

Clinical Use

Short-acting inhaled β ₂ -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 β ₂ -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 β ₂ -Agonists

The long-acting inhaled β ₂ -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 β ₂ 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-acting β ₂ -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 β ₂ -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 β ₂ -agonist and corticosteroid (fluticasone/salmeterol, and budesonide/formoterol) are an effective and convenient way to control asthma and are useful in COPD.

Side Effects

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.

Long-Term Safety

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-acting β ₂ -agonists in a combination inhaler.

Tolerance

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.

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., platelets, T lymphocytes, macrophages) or on airway microvascular 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 (A _2B 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.

Clinical Use

In patients with acute asthma, intravenous aminophylline is less effective than nebulized β ₂ -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 β ₂ 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.

Side Effects

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 A ₁ -receptors. Theophylline also has many interactions with other drugs because of alterations in liver enzyme metabolism.

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.

Clinical Use

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 β ₂ -agonists and offer less protection against various bronchial challenges. Nebulized anticholinergics are effective in acute severe asthma but less effective than β ₂ -agonists. Nevertheless, anticholinergic drugs may have an additive effect with β ₂ -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.

Side Effects

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.

Mode of Action

Corticosteroids enter target cells and bind to glucocorticoid receptors in the cytoplasm. The corticosteroid-receptor 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-κB 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.

Clinical Use

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 β ₂ -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. Hypothalamo–pituitary–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.

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.