This chapter discusses the pharmacotherapy of obstructive airways disease, particularly bronchodilators, which act mainly by reversing airway smooth muscle contraction, and anti-inflammatory drugs, which suppress the inflammatory response in the airways. The chapter focuses on the pulmonary pharmacology of β2 agonists and corticosteroids; their basic pharmacology is presented elsewhere (see Chapters 12 and 42). This chapter also discusses other drugs used to treat obstructive airway diseases, such as mucolytics and respiratory stimulants, and covers the drug therapy of cough, the most common respiratory symptom, as well as drugs used to treat pulmonary hypertension. Drugs used in the treatment of lung infections, including tuberculosis (see Chapter 56), are covered elsewhere.
MECHANISMS OF ASTHMA
Asthma is a chronic inflammatory disease of the airways that is characterized by activation of mast cells (generally present in increased numbers), infiltration of eosinophils, and T helper 2 (TH2)lymphocytes (Figure 36–1). Mast cell activation by allergens and physical stimuli releases bronchoconstrictor mediators, such as histamine, leukotriene D4, and PGD2, which cause bronchoconstriction, microvascular leakage, and plasma exudation (see Chapters 32 and 33). Many of the symptoms of asthma are due to airway smooth muscle contraction; thus, bronchodilators are important as symptom relievers. Whether airway smooth muscle is intrinsically abnormal in asthma is not clear, but increased contractility of airway smooth muscle may contribute to airway hyperresponsiveness, the physiological hallmark of asthma. The mechanism of chronic inflammation in asthma is still not well understood. It may initially be driven by allergen exposure, but it appears to become autonomous so that asthma is essentially incurable. The inflammation may be orchestrated by dendritic cells that regulate TH2 cells that drive eosinophilic inflammation and IgE formation by B lymphocytes. Airway epithelium plays an important role through the release of myriad inflammatory mediators and through the release of growth factors in an attempt to repair the damage caused by inflammation.
Figure 36–1 Cellular mechanisms of asthma. Myriad inflammatory cells are recruited and activated in the airways, where they release multiple inflammatory mediators, which can also arise from structural cells. These mediators lead to bronchoconstriction, plasma exudation and edema, vasodilation, mucus hypersecretion, and activation of sensory nerves. Chronic inflammation leads to structural changes, including subepithelial fibrosis (basement membrane thickening), airway smooth muscle hypertrophy and hyperplasia, angiogenesis, and hyperplasia of mucus-secreting cells.
Chronic inflammation may lead to structural changes in the airways, including an increase in the number and size of airway smooth muscle cells, blood vessels, and mucus-secreting cells. A characteristic histological feature of asthma is collagen deposition (fibrosis) below the basement membrane of the airway epithelium (see Figure 36–1).
MECHANISMS OF COPD
COPD involves inflammation of the respiratory tract with a pattern that differs from that of asthma. In COPD, there is a predominance of neutrophils, macrophages, and cytotoxic T-lymphocytes (Tcl cells). The inflammation predominantly affects small airways, resulting in progressive small airway narrowing and fibrosis (chronic obstructive bronchiolitis) and destruction of the lung parenchyma with destruction of the alveolar walls (emphysema) (Figure 36–2). These pathological changes result in airway closure on expiration, leading to air trapping and hyperinflation, particularly on exercise. This accounts for shortness of breath on exertion and exercise limitation that are characteristic symptoms of COPD.
Figure 36–2 Cellular mechanisms in chronic obstructive pulmonary disease. Cigarette smoke and other irritants activate epithelial cells and macrophages in the lung to release mediators that attract circulating inflammatory cells, including monocytes (which differentiate to macrophages within the lung), neutrophils, and T lymphocytes (TH1 and TC1 cells). Fibrogenic factors released from epithelial cells and macrophages lead to fibrosis of small airways. Release of proteases results in alveolar wall destruction (emphysema) and mucus hypersecretion (chronic bronchitis).
Bronchodilators reduce air trapping by dilating peripheral airways and are the mainstay of treatment in COPD. In contrast to asthma, the airflow obstruction of COPD tends to be progressive. A discrete pattern of inflammatory mediators and cytokines mediates the inflammation in the peripheral lung of COPD patients. In contrast to asthma, the inflammation of COPD is largely corticosteroid-resistant, and there are currently no effective anti-inflammatory treatments. Many patients with COPD have systemic manifestations (skeletal muscle wasting, weight loss, depression, osteoporosis, anemia) and comorbid diseases (ischemic heart disease, hypertension, congestive heart failure, diabetes). Whether these are due to spillover of inflammatory mediators from the lung or due to common causal mechanisms (such as smoking) is not yet clear, but it may be important to treat the systemic components in the overall management of COPD.
ROUTES OF DRUG DELIVERY TO THE LUNGS
Inhalation (Figure 36–3) is the preferred mode of delivery of many drugs with a direct effect on airways, particularly for asthma and COPD. The major advantage of inhalation is the delivery of drug to the airways in doses that are effective with a much lower risk of systemic side effects. This is particularly important with the use of inhaled corticosteroids (ICS), which largely avoids systemic side effects. In addition, inhaled bronchodilators have a more rapid onset of action than when taken orally.
Figure 36–3 Deposition of inhaled drugs (e.g., corticosteroids, β2 agonists). Inhalation therapy deposits drugs directly, but not exclusively, in the lungs. Distribution between lungs and oropharynx depends mostly on the particle size and the efficiency of the delivery method. Most material will be swallowed and absorbed, entering systemic circulation after undergoing the first-pass effect in the liver. Some drug will also be absorbed into the systemic circulation from the lungs. Use of a large-volume spacer will reduce the amount of drug deposited on oropharynx, thereby reducing amount swallowed and absorbed from GI tract, thus limiting systemic effects. MDI, metered-dose inhaler.
PARTICLE SIZE. The size of particles for inhalation is of critical importance in determining the site of deposition in the respiratory tract. The optimum size for particles to settle in the airways is 2-5 μm mass median aerodynamic diameter (MMAD). Larger particles settle out in the upper airways, whereas smaller particles remain suspended and are therefore exhaled. There is increasing interest in delivering drugs to small airways, particularly in COPD and severe asthma. This involves delivering drug particles of ~1 μm MMAD, which is now possible using drugs formulated in hydrofluoroalkane (HFA) propellant.
PHARMACOKINETICS. Of the total drug delivered, only 10-20% enters the lower airways with a conventional pressurized metered-dose inhaler. Drugs are absorbed from the airway lumen and have direct effects on target cells of the airway. Drugs may also be absorbed into the bronchial circulation and then distributed to more peripheral airways. Drugs with higher molecular weights tend to be retained to a greater extent in the airways. Nevertheless, several drugs have greater therapeutic efficacy when given by the inhaled route. More extensive pulmonary distribution of a drug with a smaller MMAD increases alveolar deposition and thus is likely to increase absorption from the lungs into the general circulation resulting in more systemic side effects.
Pressurized Metered-Dose Inhalers (pMDIs). Drugs are propelled from a canister with the aid of a propellant, previously with a chlorofluorocarbon (Freon) but now replaced by an HFA that is “ozone friendly.” These devices are convenient, portable, and typically deliver 100-400 doses of drug.
Spacer Chambers. Large-volume spacer devices between the pMDI and the patient reduce the velocity of particles entering the upper airways and the size of the particles by allowing evaporation of liquid propellant. This reduces the amount of drug that impinges on the oropharynx and gets swallowed, and increases the proportion of drug inhaled into the lower airways. Application of spacer chambers is useful in the reduction of the oropharyngeal deposition of ICS and the consequent reduction in the local and systemic side effects of these drugs. Spacer devices are also useful in delivering inhaled drugs to small children who are not able to use a pMDI.
Dry Powder Inhalers. Drugs may also be delivered as a dry powder using devices that scatter a fine powder dispersed by air turbulence on inhalation. Children <7 years of age find it difficult to use a dry powder inhaler (DPI). DPIs have been developed to deliver peptides and proteins, such as insulin (e.g., EXUBERA, AFRESA), systemically.
Nebulizers. Two types of nebulizer are available. Jet nebulizers are driven by a stream of gas (air or oxygen), whereas ultrasonic nebulizers use a rapidly vibrating piezo-electric crystal and thus do not require a source of compressed gas. The nebulized drug is inspired during tidal breathing, and it is possible to deliver much higher doses of drug compared with pMDI. Nebulizers are useful in treating acute exacerbations of asthma and COPD, for delivering inhaled drugs to infants and small children, and for giving drugs such as antibiotics when relatively high doses must be delivered.
Drugs for treatment of pulmonary diseases may also be given orally. The oral dose is much higher than the inhaled dose required to achieve the same effect (typically by a ratio of ~20:1), so that systemic side effects are more common. When there is a choice of inhaled or oral route for a drug (e.g.,β2 agonist or corticosteroid), the inhaled route is always preferable, and the oral route should be reserved for the few patients unable to use inhalers (e.g., small children, patients with physical problems such as severe arthritis of the hands). Theophylline is ineffective by the inhaled route; it must be given systemically. Corticosteroids may have to be given orally for parenchymal lung diseases (e.g., in interstitial lung diseases).
The intravenous route should be reserved for delivery of drugs in the severely ill patient who is unable to absorb drugs from the GI tract. Side effects are generally frequent due to the high plasma concentrations.
Bronchodilator drugs relax constricted airway smooth muscle in vitro and cause immediate reversal of airway obstruction in asthma in vivo. They also prevent bronchoconstriction (and thereby provide bronchoprotection). Three main classes of bronchodilator are in current clinical use:
• β2 Adrenergic agonists (sympathomimetics)
• Theophylline (a methylxanthine)
• Anticholinergic agents (muscarinic receptor antagonists)
Drugs such as cromolyn sodium, which prevent bronchoconstriction, have no direct bronchodilator action and are ineffective once bronchoconstriction has occurred. Anti-leukotrienes (leukotriene receptor antagonists and 5‼-lipoxygenase inhibitors) have a small bronchodilator effect in some asthmatic patients and appear to prevent bronchoconstriction. Corticosteroids, although gradually improving airway obstruction, have no direct effect on contraction of airway smooth muscle and are not therefore considered to be bronchodilators.
β2 ADRENERGIC AGONISTS
Inhaled β2 agonists are the bronchodilator treatment of choice in asthma because they are the most effective bronchodilators and have minimal side effects when used correctly. The basic pharmacology of these agents (albuterol, terbutaline, salmeterol, formoterol, indacaterol, and related compounds) is presented in Chapters 8 and 12.
MODE OF ACTION
Agonist stimulation of β2 receptors in airway smooth muscle results in the activation of the Gs-adenylyl cyclase-cAMP-PKA pathway and consequent phosphorylative events leading to bronchial smooth muscle relaxation (Figure 36–4), effectively reversing the Ca2+-stimulated events that initiate contraction.
Figure 36–4 Molecular actions of β2 agonists to induce relaxation of airway smooth muscle cells. A rise in [Ca2+]i initiates contraction by activating myosin light-chain kinase (MLCK), thereby enhancing the level of phosphorylation of myosin light chains and increasing the contractile interaction of actin and myosin. Stimulation of β2 receptors activates cyclic AMP-PKA pathway and reverses the contractile process by reducing [Ca2+]i, reducing MLCK activation, and promoting dephosphorylation of light chains. PKA phosphorylates a variety of target substrates, resulting in: opening of Ca2+-activated K+channels (KCa) [which facilitates hyperpolarization], decreased phosphoinositide (PI) hydrolysis, increased Na+/Ca2+ exchange, increased Na+, Ca2+-ATPase activity, decreased MLCK activity, and increased MLC phosphatase activity. β2 Receptors may also couple to KCa via Gs. PDE, cyclic nucleotide phosphodiesterase.
β2 agonists may cause bronchodilation in vivo not only via a direct action on airways smooth muscle, but also indirectly by inhibiting the release of bronchoconstrictor mediators from inflammatory cells and of bronchoconstrictor neurotransmitters from airway nerves. These mechanisms include:
• Prevention of mediator release from isolated human lung mast cells (via β2 receptors)
• Prevention of microvascular leakage and thus the development of bronchial mucosal edema after exposure to mediators, such as histamine and leukotriene D4
• Increase in mucus secretion from submucosal glands and ion transport across airway epithelium (may enhance mucociliary clearance, reversing defective clearance found in asthma)
• Reduction in neurotransmission in human airway cholinergic nerves by an action at presynaptic β2 receptors to inhibit acetylcholine release
β2 agonists do not appear to have a significant inhibitory effect on the chronic inflammation of asthmatic airways, which is suppressed by corticosteroids. This may be related to the fact that effects of β2 agonists on macrophages, eosinophils, and lymphocytes are rapidly desensitized.
SHORT-ACTING β2 AGONISTS. Inhaled short-acting β2 agonists are the most widely used and effective bronchodilators in the treatment of asthma due to their functional antagonism of bronchoconstriction. These agents also are effective in protecting against various challenges, such as exercise, cold air, and allergens. Inhalation is preferable to the oral administration because inhalation may be more effective and systemic side effects are less. Short-acting inhaled β2 agonists, such as albuterol, should be used “as required” by symptoms and not on a regular basis in the treatment of mild asthma; increased use indicates the need for more anti- inflammatory therapy.
Slow-release preparations (e.g., slow-release albuterol and bambuterol) may be indicated in nocturnal asthma; however, these agents have an increased risk of side effects. All short-acting β2 agonists currently available are usable by inhalation and orally, have a similar duration of action (~3-4 h; less in severe asthma), and similar side effects. Drugs in clinical use include albuterol (salbutamol), levalbuterol metaproterenol, terbutaline (in the U.S.), fenoterol, tulobuterol, rimiterol, and pirbuterol (in other countries).
LONG-ACTING INHALED β2 AGONISTS. The long-acting inhaled β2 agonists (LABA) salmeterol, formoterol, and arformoterol have a bronchodilator action of >12 h and protect against bronchoconstriction for a similar period. They improve asthma control (when given twice daily) compared with regular treatment with short-acting β2 agonists (4-6 times daily). Indacaterol is a once-daily “ultra-LABA” approved for treatment of COPD but not asthma; its duration of action exceeds those of salmeterol and formoterol.
In COPD, LABA are effective bronchodilators that may be used alone or in combination with anticholinergics or ICS. LABA improve symptoms and exercise tolerance by reducing both air trapping and exacerbations. In asthma patients, LABA should never be used alone because they do not treat the underlying chronic inflammation; rather, LABA should always be used in combination with ICS (preferably in a fixed-dose combination inhaler). LABA are an effective add-on therapy to ICS and are more effective than increasing the dose of ICS when asthma is not controlled at low doses. Tolerance to the bronchodilator effect of formoterol and the bronchoprotective effects of formoterol and salmeterol has been demonstrated but is of doubtful clinical significance. No significant clinical differences between salmeterol and formoterol have been found in the treatment of patients with severe asthma.
COMBINATION INHALERS. Combination inhalers that contain a LABA and a corticosteroid (e.g., fluticasone/salmeterol [ADVAIR], budesonide/formoterol [SYMBICORT]) are now widely used in the treatment of asthma and COPD. Combining LABA with a corticosteroid offers complementary synergistic actions. The combination inhaler is more convenient for patients, simplifies therapy, and improves compliance. These combination inhalers are also more effective in COPD patients than LABA and ICS alone.
SIDE EFFECTS. Unwanted effects are dose related and due to stimulation of extrapulmonary β receptors (Table 36–1 and Chapter 12). Side effects are not common with inhaled therapy but quite common with oral or intravenous administration, usually only after large systemic doses. Short-acting inhaled β2 agonists should only be used on demand for symptom control, and with an ICS if they are required more than 3 times weekly. LABA should only be used when ICS are also prescribed. All LABA approved in the U.S. carry a black box warning cautioning against overuse. There are less safety concerns with LABA use in COPD.
Side Effects of β Agonists
The methylxanthine, theophylline, is still widely used in developing countries because it is inexpensive. However, the frequency of side effects and the relative low efficacy of theophylline have led to reduced use because inhaled β2 agonists are far more effective as bronchodilators and ICS have a greater anti-inflammatory effect. In patients with severe asthma and COPD, theophylline remains a very useful drug.
MECHANISM OF ACTION. The mechanisms of action of theophylline are still uncertain. In addition to its bronchodilator action, theophylline has many nonbronchodilator effects that may be relevant to its effects in asthma and COPD (Figure 36–5). Several molecular mechanisms of action have been proposed:
Figure 36–5 Theophylline affects multiple cell types in the airway.
• Inhibition of cyclic nucleotide phosphodiesterases. Theophylline is a nonselective PDE inhibitor. PDE inhibition and the concomitant elevation of cellular cyclic AMP and cyclic GMP likely account for the bronchodilator action of theophylline (see Figure 36–4). The PDE isoenzymes recognized in smooth muscle relaxation include PDE3, PDE4, and PDE5.
• Adenosine receptor antagonism. Theophylline antagonizes adenosine receptors at therapeutic concentrations. Adenosine causes bronchoconstriction in airways from asthmatic patients by releasing histamine and leukotrienes. Antagonism of A1 receptors may be responsible for serious side effects, including cardiac arrhythmias and seizures.
• Interleukin-10 release. IL-10 has a broad spectrum of anti-inflammatory effects, and there is evidence that its secretion is reduced in asthma. IL-10 release is increased by theophylline, and this effect may be mediated via inhibition of PDE activities.
• Effects on gene transcription. Theophylline prevents the translocation of the pro-inflammatory transcription factor NF-kB into the nucleus, potentially reducing the expression of inflammatory genes in asthma and COPD. However, these effects are seen at high concentrations and may be mediated by inhibition of PDE.
• Effects on apoptosis. Prolonged survival of granulocytes due to a reduction in apoptosis may be important in perpetuating chronic inflammation in asthma (eosinophils) and COPD (neutrophils). Theophylline promotes apoptosis in eosinophils and neutrophils in vitro. This effect may be mediated by antagonism of adenosine A2A receptors. Theophylline also induces apoptosis in T lymphocytes via PDE inhibition.
• Histone deacetylase activation. Recruitment of histone deacetylase-2 (HDAC2) by glucocorticoid receptors switches off inflammatory genes. Therapeutic concentrations of theophylline activate HDAC, thereby enhancing the anti-inflammatory effects of corticosteroids. This mechanism appears to be mediated by inhibition of PI3-kinase-δ, which is activated by oxidative stress.
NONBRONCHODILATOR EFFECTS. There is increasing evidence that theophylline has anti-inflammatory effects in asthma. For example, chronic oral treatment with theophylline inhibits the late response to inhaled allergen and reduces infiltration of eosinophils and CD4+ lymphocytes into the airways after allergen challenge. In patients with COPD, theophylline reduces the total number and proportion of neutrophils in induced sputum, the concentration of IL-8, and neutrophil chemotactic responses. Theophylline withdrawal in COPD patients results in worsening of disease. In vitro theophylline is able to increase responsiveness to corticosteroids and to reverse corticosteroid resistance in cells from COPD subjects.
PHARMACOKINETICS AND METABOLISM. Theophylline has anti-asthma effects other than bronchodilation below 10 mg/L, so the therapeutic range is now taken as 5-15 mg/L. The dose of theophylline required to give these therapeutic concentrations varies among subjects, largely because of differences in clearance of the drug. In addition, there may be differences in bronchodilator response to theophylline; furthermore, with acute bronchoconstriction, higher concentrations may be required to produce bronchodilation. Theophylline is rapidly and completely absorbed, but there are large interindividual variations in clearance, due to differences in hepatic metabolism. Theophylline is metabolized in the liver, mainly by CYP1A2; myriad factors influence metabolism and clearance of theophylline (Table 36–2). Because of these variations in clearance, individualization of theophylline dosage is required and plasma concentrations should be measured 4 h after the last dose with slow-release preparations when steady state has been achieved.
Factors Affecting Clearance Of Theophylline
PREPARATIONS AND ROUTES OF ADMINISTRATION. Intravenous aminophylline (the ethylenediamine salt of theophylline, with better solubility at neutral pH) is used in the treatment of acute severe asthma, at a recommended dose of 6 mg/kg over 20-30 min, followed by a maintenance dose of 0.5 mg/kg/h. If the patient is already taking theophylline, or has decreased clearance, these doses should be halved and the plasma level checked more frequently. Oral immediate-release theophylline tablets or elixir, which are rapidly absorbed, give wide fluctuations in plasma levels, and are not recommended. Sustained-release preparations provide steady plasma concentrations over a 12- to 24-h period. Both slow-release aminophylline and theophylline are equally effective. For continuous treatment twice daily therapy (~8 mg/kg twice daily) is needed.
CLINICAL USE. In patients with acute asthma, intravenous aminophylline is less effective than nebulized β2 agonists and should therefore be reserved for those patients who fail to respond to, or are intolerant of, β agonists. Addition of low-dose theophylline to either a high or low dose of ICS in patients who are not adequately controlled provides better symptom control and lung function than doubling the dose of inhaled steroid. Although theophylline is less effective than a β2 agonist and corticosteroids, a minority of asthmatic patients appears to derive unexpected benefit; even patients on oral steroids may show a deterioration in lung function when theophylline is withdrawn. Although LABA are more effective as an add-on therapy, theophylline is considerably less expensive when the costs of medication are limiting.
Theophylline is still used as a bronchodilator in COPD, but inhaled anticholinergics and β2 agonists are preferred. Theophylline tends to be added to these inhaled bronchodilators in more severe patients and has been shown to give additional clinical improvement when added to a long-acting β2 agonist.
SIDE EFFECTS. Unwanted effects of theophylline are usually related to plasma concentration and tend to occur at Cp > 15 mg/L. The most common side effects are headache, nausea, and vomiting, abdominal discomfort, and restlessness (Table 36–3). There may also be increased acid secretion and diuresis. Theophylline may lead to behavioral disturbance and learning difficulties in schoolchildren. At high concentrations, cardiac arrhythmias and seizures may occur. Using low doses of theophylline to achieve plasma concentrations of 5-10 mg/L largely avoids side effects and drug interactions.
Side Effects Of Theophylline And Mechanisms
MUSCARINIC CHOLINERGIC ANTAGONISTS
MODE OF ACTION
As competitive antagonists of endogenous ACh at muscarinic receptors, these agents inhibit the direct constrictor effect on bronchial smooth muscle mediated via the M3-Gq-PLC-IP3-Ca2+ pathway (see Chapters 3 and 9). Their efficacy stems from the role of the parasympathetic nervous system in regulating bronchomotor tone. The effects of ACh on the respiratory system include not only bronchoconstriction but also increased tracheobronchial secretion and stimulation of the chemoreceptors of the carotid and aortic bodies. However, the myriad inflammatory mediators involved in the pathogenesis of asthma and COPD may also induce components of muscarinic responsiveness, such as Gαq and rho, and contribute to hyperresponsiveness of the airway. Thus, the contractility of bronchial smooth muscle and antagonism of muscarinic responsiveness could be moving targets in asthma and COPD.
CLINICAL USE. In asthmatic patients, anticholinergic drugs are less effective as bronchodilators than β2 agonists and offer less efficient protection against bronchial challenges. Anticholinergics are currently used as an additional bronchodilator in asthmatic patients not controlled on an LABA. In the acute and chronic treatment of asthma, anticholinergic drugs may have an additive effect with β2agonists and should be considered when control of asthma is not adequate with nebulized β2 agonists. In COPD, anticholinergic drugs may be as effective as or even superior to β2 agonists. Their relatively greater effect in COPD than in asthma may be explained by an inhibitory effect on vagal tone (Figure 36–6).
Figure 36–6 Anticholinergic drugs inhibit vagally mediated airway tone, thereby producing bronchodilation. This effect is small in normal airways but is greater in airways of patients with chronic obstructive pulmonary disease (COPD), which are structurally narrowed and have higher resistance to airflow because airway resistance is inversely related to the fourth power of the radius (r). ACh, acetylcholine.
THERAPEUTIC CHOICES.Ipratropium bromide (ATROVENT, others) is available as a pMDI and nebulized preparation. The onset of bronchodilation is relatively slow and is usually maximal 30-60 min after inhalation, but may persist for 6-8 h. It is usually given by MDI 3 to 4 times daily on a regular basis, rather than intermittently for symptom relief, in view of its slow onset of action. Oxitropium bromide (not available in the U.S.) is a quaternary anticholinergic bronchodilator that is similar to ipratropium bromide. It is available in higher doses by inhalation and may therefore have a more prolonged effect.
Combination inhalers of an anticholinergic and β2 agonist, such as ipratropium/albuterol (COMBIVENT, DUONEB, others), are popular, particularly among patients with COPD. The additive effects of these 2 drugs may provide an advantage over increasing the dose of β2 agonist in patients who have side effects.
Tiotropium bromide is a long-acting anticholinergic drug that is suitable for once-daily dosing as a DPI (SPIRIVA) or via a soft mist mini-nebulizer device (not available in the U.S.). Tiotropium binds to all muscarinic receptor subtypes but dissociates very slowly from M3 and M1 receptors, giving it a degree of kinetic receptor selectivity for these receptors compared with M2 receptors, from which it dissociates more rapidly. Thus, compared with ipratropium, tiotropium is less likely to antagonize M2-mediated inhibition of ACh release. It is an effective bronchodilator in patients with COPD and is more effective than ipratropium 4 times daily without any loss of efficacy over a 1-year treatment period. Over a 4-year period, tiotropium improves lung function and health status and reduces exacerbations and all-cause mortality, although there is no effect on disease progression. As a result, tiotropium is becoming the bronchodilator of choice for COPD patients.
Aclidinium bromide (TUDORZA Pressair) is a long-acting, anticholinergic inhalation powder approved for long-term maintenance treatment of COPD.
ADVERSE EFFECTS. Systemic side effects after ipratropium bromide and tiotropium bromide are uncommon because there is little systemic absorption. A significant unwanted effect is the unpleasantbitter taste of inhaled ipratropium, which may reduce compliance. Nebulized ipratropium bromide may precipitate glaucoma in elderly patients due to a direct effect of the nebulized drug on the eye. This may be prevented by nebulization with a mouthpiece rather than a face mask. Occasionally, bronchoconstriction may occur with ipratropium bromide given by MDI. Tiotropium causes dryness of the mouth in 10-15% of patients, but this usually disappears during continued therapy. Urinary retention is occasionally seen in elderly patients.
The introduction of ICS, has revolutionized the treatment of chronic asthma. Because asthma is a chronic inflammatory disease, ICS are considered as first-line therapy in all but the mildest of patients. In marked contrast, ICS are much less effective in COPD and should only be used in patients with severe disease who have frequent exacerbations. Oral corticosteroids remain the mainstay of treatment of several other pulmonary diseases, such as sarcoidosis, interstitial lung diseases, and pulmonary eosinophilic syndromes (seeChapter 42).
MECHANISM OF ACTION. Probably the most important action of ICS in suppressing asthmatic inflammation is the inhibition of expression of multiple inflammatory genes in airway epithelial cells. Corticosteroids reverse the activating effect of pro-inflammatory transcription factors on histone acetylation by recruiting HDAC2 to inflammatory genes that have been activated through acetylation of associated histones (see molecular details in Figure 36–7). Steroids have inhibitory effects on many inflammatory and structural cells that are activated in asthma and prevent the recruitment of inflammatory cells into the airways (Figure 36–8). Steroids potently inhibit the formation of cytokines (e.g., IL-1, IL-3, IL-4, IL-5, IL-9, IL-13, TNF-α, and granulocyte-macrophage colony-stimulating factor, GM-CSF) that are secreted in asthma by T-lymphocytes, macrophages, and mast cells.
Figure 36–7 Mechanism of anti-inflammatory action of corticosteroids in asthma. Inflammatory stimuli activate the NF-kB pathway, leading to increased histone acetyltransferase (HAT) activity, resulting in acetylation of core histones and increased expression of genes encoding multiple inflammatory proteins. Corticosteroids, acting via cytosolic glucocorticoid receptors (GR), antagonize HAT activity in two ways: directly and, more importantly, by recruiting histone deacetylase-2 (HDAC2), which reverses histone acetylation, leading to the suppression of activated inflammatory genes. CBP, CREB binding protein.
Figure 36–8 Effect of corticosteroids on inflammatory and structural cells in the airways.
Corticosteroids have no direct effect on contractile responses of airway smooth muscle; improvement in lung function after ICS is presumably due to an effect on the chronic airway inflammation and airway hyperresponsiveness. A single dose of ICS has no effect on the early response to allergen (reflecting their lack of effect on mast cell mediator release) but inhibits the late response (which may be due to an effect on macrophages, eosinophils, and airway wall edema) and also inhibits the increase in airway hyperresponsiveness. Corticosteroids suppress inflammation in the airways but do not cure the underlying disease. When steroids are withdrawn, there is a recurrence of the same degree of airway hyperresponsiveness, although in patients with mild asthma it may take several months to return.
RECIPROCAL SYNERGISTIC EFFECTS OF β2 AGONISTS AND CORTICOSTEROIDS. Steroids potentiate the effects of β agonists on bronchial smooth muscle and prevent and reverse β receptor desensitization in airways. At a molecular level, corticosteroids increase the transcription of the β2 receptor gene in human lung in vitro and in the respiratory mucosa in vivo and increase the stability of its messenger RNA. They also prevent or reverse uncoupling of β2 receptors from Gs. In animal systems, corticosteroids prevent downregulation of β2 receptors. β2 Agonists also increase the association of liganded glucocorticoid receptors (GR) with DNA, an effect demonstrated in sputum macrophages of asthmatic patients after an ICS and inhaled LABA, suggesting that β2 agonists and corticosteroids enhance each other’s beneficial effects in asthma therapy.
PHARMACOKINETICS. The pharmacokinetics of oral corticosteroids are described in Chapter 42. The pharmacokinetics of ICS are important in relation to systemic effects. The fraction of steroid that is inhaled into the lungs acts locally on the airway mucosa but may be absorbed from the airway and alveolar surface and reaches the systemic circulation. Furthermore, the fraction of inhaled steroid that is deposited in the oropharynx is swallowed and absorbed from the gut. The absorbed fraction may be metabolized in the liver (first-pass metabolism) before reaching the systemic circulation (see Figure 36–3). The use of a spacer chamber reduces oropharyngeal deposition and therefore reduces systemic absorption of ICS. Beclomethasone dipropionate and ciclesonide are prodrugs that release the active corticosteroid after the ester group is cleaved by esterases in the lung. Ciclesonide is available as an MDI (ALVESCO) for asthma and as a nasal spray for allergic rhinitis (OMNARIS). 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.
ROUTES OF ADMINISTRATION AND DOSING
INHALED CORTICOSTEROIDS IN ASTHMA. Inhaled corticosteroids are recommended as first-line therapy for all patients with persistent asthma. They should be started in any patient who needs to use a β2 agonist inhaler for symptom control more than twice weekly.
Most of the benefit may be obtained from doses <400 <g beclomethasone dipropionate or equivalent. However, some patients (with relative corticosteroid resistance) may benefit from higher doses (up to 2000 <g/day). For most patients, ICS should be used twice daily, a regimen that improves compliance once control of asthma has been achieved (which may require 4-times daily dosing initially or a course of oral steroids if symptoms are severe). Administration once daily of some steroids (e.g., budesonide, mometasone, and ciclesonide) is effective when doses ≤400 <g are needed. If a dose >800 <g daily via pMDI is used, a spacer device should be employed to reduce the risk of oropharyngeal side effects. ICS may be used in children in the same way as in adults.
INHALED CORTICOSTEROIDS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Patients with COPD occasionally respond to steroids, and these patients are likely to have concomitant asthma. Corticosteroids do not appear to have any significant anti-inflammatory effect in COPD; there appears to be an active resistance mechanism, which may be explained by impaired activity of HDAC2 as a result of oxidative stress. Patients with cystic fibrosis, which involves inflammation of the airways, are also resistant to high doses of ICS.
SYSTEMIC STEROIDS. Intravenous steroids are indicated in acute asthma if lung function is <30% predicted and in patients who show no significant improvement with nebulized β2 agonist. Hydrocortisone is the steroid of choice because it has the most rapid onset (5-6 h after administration), compared with 8 h with prednisolone.
It is common to give hydrocortisone 4 mg/kg initially, followed by a maintenance dose of 3 mg/kg every 6 h. Oral prednisolone (40-60 mg) has a similar effect to intravenous hydrocortisone. Prednisolone and prednisone are the most commonly used oral steroids. The usual maintenance dose is ~10-15 mg/day. Oral steroids are usually given as a single dose in the morning because this coincides with the normal diurnal increase in plasma cortisol and produces less adrenal suppression than if given in divided doses or at night.
Adverse Effects. Corticosteroids inhibit ACTH and cortisol secretion by a negative feedback effect on the pituitary gland (see Chapter 42). Hypothalamic-pituitary-adrenal (HPA) axis suppression depends on dose and usually only occurs with doses of prednisone >7.5-10 mg/day. Significant suppression after short courses of corticosteroid therapy is not usually a problem. Steroid doses after prolonged oral therapy must be reduced slowly. Symptoms of “steroid withdrawal syndrome” include lassitude, musculoskeletal pains, and, occasionally, fever. HPA suppression with inhaled steroids is usually seen only when the daily inhaled dose exceeds 2000 <g beclomethasone dipropionate or its equivalent daily.
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. Their frequency tends to increase with age. Very occasionally adverse reactions (such as anaphylaxis) to intravenous hydrocortisone have been described, particularly in aspirin-sensitive asthmatic patients.
ICS may have local side effects due to the deposition of inhaled steroid in the oropharynx. The most common problem is hoarseness and weakness of the voice (dysphonia) due to atrophy of the vocal cords following laryngeal deposition of steroid; it may occur in up to 40% of patients and is noticed particularly by patients who need to use their voices during their work (lecturers, teachers, and singers). Throat irritation and coughing after inhalation are common with MDI and appear to be due to additives since these problems are not usually seen if the patient switches to a DPI. Oropharyngeal candidiasis occurs in ~5% of patients. Growing evidence suggests that high doses of ICS increase the risk of pneumonia in patients with COPD using high doses of fluticasone propionate. The incidence of systemic side effects after ICS is an important consideration, particularly in children (Table 36–4). Adrenal suppression can occur with inhaled doses >1500-2000 <g/day, possibly less. It is important to reduce the likelihood of systemic effects by using the lowest dose of inhaled steroid needed to control the asthma, and by use of a large-volume spacer to reduce oropharyngeal deposition.
Side Effects Of Inhaled Corticosteroids
Therapeutic Choices. Numerous ICS are now available including beclomethasone dipropionate (QVAR), triamcinolone, flunisolide (AEROBID), budesonide (PULMICORT, others), fluticasone hemihydrate(AEROSPAN), fluticasone propionate (FLOVENT), mometasone furoate (ASMANEX), and ciclesonide (ALVESCO). All are equally effective as anti-asthma drugs, but there are differences in their pharmacokinetics: Budesonide, fluticasone, mometasone, and ciclesonide have a lower oral bioavailability than beclomethasone dipropionate because they are subject to greater first-pass hepatic metabolism; this results in reduced systemic absorption and thus reduced adverse effects. Ciclesonide is another choice; it is a prodrug that is converted to the active metabolite by esterases in the lung, giving it a low oral bioavailability and a high therapeutic index.
Cromolyn sodium (sodium cromoglycate) is a derivative of khellin, an Egyptian herbal remedy. A structurally related drug, nedocromil sodium, was subsequently developed. The use of cromolyn has sharply declined with the widespread use of the more effective ICS.
Both H1 antihistamines and antileukptrienes have been applied to airway disease, but their added benefit over β2 agonists and corticosteroids is slight.
ANTIHISTAMINES. Histamine mimics many of the features of asthma and is released from mast cells in acute asthmatic responses, suggesting that antihistamines may be useful in asthma therapy. There is little evidence that histamine H1 receptor antagonists provide any useful clinical benefit, as demonstrated by a meta-analysis. Newer antihistamines, including cetirizine and azelastine, have some beneficial effects, but this may be unrelated to H1 receptor antagonism.
ANTILEUKOTRIENES. There is considerable evidence that cysteinyl-leukotrienes (LTs) are produced in asthma and that they have potent effects on airway function, inducing bronchoconstriction, airway hyperresponsiveness, plasma exudation, mucus secretion, and eosinophilic inflammation (Figure 36–9; also see Chapter 33). These data motivated the development of 5’-lipoxygenase (5-LO) enzyme inhibitors (of which zileuton [ZYFLO] is the only drug marketed) and several antagonists of the cys-LT1 receptor, including montelukast (SINGULAIR), zafirlukast (ACCOLATE), and pranlukast.
Figure 36–9 Effects of cysteinyl-leukotrienes on the airways and their inhibition by antileukotrienes. AS, aspirin sensitive; 5-LO, 5’-lipoxygenase; LT, leukotriene; PAF, platelet-activating factor.
Clinical Studies. In patients with mild to moderate asthma, antileukotrienes cause a significant improvement in lung function and asthma symptoms, with a reduction in the use of rescue inhaled β2 agonists. However, antileukotrienes are considerably less effective than ICS in the treatment of mild asthma and cannot be considered the treatment of first choice. Antileukotrienes are indicated as an add-on therapy in patients who are not well controlled on ICS. The added benefit is small and less effective than adding an LABA.
Antileukotrienes are effective in preventing exercise-induced asthma, with efficacy similar to that of LABA. Antileukotrienes appear to act mainly as antibronchoconstrictor drugs, and they are clearly less broadly effective than β2 agonists because they antagonize only one of several bronchoconstrictor mediators. Cys-LTl receptor antagonists have no role in the therapy of COPD.
Adverse Effects. Zileuton, zafirlukast, and montelukast are all associated with rare cases of hepatic dysfunction; thus, liver-associated enzymes should be monitored. Several cases of Churg-Strauss syndrome have been associated with the use of zafirlukast and montelukast.
Immunosuppressive therapies (e.g., methotrexate, cyclosporine A, gold, intravenous immunoglobulin) have been considered in asthma when other treatments have been unsuccessful or to reduce the dose of oral steroids required. However, immunosuppressive treatments are less effective and have a greater propensity for side effects than oral corticosteroids.
ANTI-IgE RECEPTOR THERAPY
Omalizumab is a humanized monoclonal antibody that blocks the binding of IgE to high-affinity IgE receptors (FcεRI) on mast cells and thus prevents their activation by allergens (Figure 36–10). It also blocks binding on IgE to low-affinity IgE receptors (FcεRII, CD23) on other inflammatory cells, including T and B lymphocytes, macrophages, and possibly eosinophils, to inhibit chronic inflammation. Omalizumab also reduces levels of circulating IgE.
Figure 36–10 Immunoglobulin (Ig) E plays a central role in allergic diseases. Blocking IgE using an antibody, such as omalizumab, is a rational therapeutic approach. IgE may activate high-affinity receptors (FcεRI) on mast cells as well as low-affinity receptors (FcεRII, CD23) on other inflammatory cells. Omalizumab prevents these interactions and the resulting inflammation. cys-LT, cysteinyl-leukotriene; IL, interleukin; PG, prostaglandin.
Clinical Use. Omalizumab is used for the treatment of patients with severe asthma. The antibody is administered by subcutaneous injection every 2-4 weeks, and the dose is determined by the titer of circulating IgE. Omalizumab reduces the requirement for oral and ICS and markedly reduces asthma exacerbations. Because of its very high cost, this treatment is generally used only in patients with very severe asthma who are poorly controlled even on oral corticosteroids and in patients with very severe concomitant allergic rhinitis. The major side effect of omalizumab is an anaphylactic response, which is uncommon (<0.1%).
Mucus hypersecretion occurs in chronic bronchitis, COPD, cystic fibrosis, and asthma. In chronic bronchitis, mucus hypersecretion is related to chronic irritation by cigarette smoke and may involve neural mechanisms and the activation of neutrophils to release enzymes such as neutrophil elastase and proteinase-3 that have powerful stimulatory effects on mucus secretion. Mast cell–derived chymase is also a potent mucus secretagogue. Systemic anticholinergic drugs appear to reduce mucociliary clearance, but this is not observed with either ipratropium bromide or tiotropium bromide, presumably reflecting their poor absorption from the respiratory tract. β2 Agonists increase mucus production and mucociliary clearance. Because inflammation leads to mucus hypersecretion, anti-inflammatory treatments should reduce mucus hypersecretion; ICS are very effective in reducing increased mucus production in asthma.
Sensory nerves and neuropeptides are important in the secretory activities of the submucosal gland and goblet cell (more notable in peripheral airways). Opioids and K+ channel openers inhibit mucus secretion mediated via sensory neuropeptide release; peripherally acting opioids may be developed to control mucus hypersecretion due to irritants in the future.
Whenever possible, treat the underlying cause, not the cough.
Viral infections of the upper respiratory tract are the most common cause of cough; postviral cough is usually self-limiting and commonly patient-medicated. Because cough is a defensive reflex, its suppression may be inappropriate in bacterial lung infection. Before treatment with antitussives, it is important to identify underlying causal mechanisms that may require therapy. Asthma commonly presents as cough, and the cough will usually respond to ICS. A syndrome characterized by cough in association with sputum eosinophilia but no airway hyperresponsiveness and termed eosinophilic bronchitis also responds to ICS. Nonasthmatic cough does not respond to ICS but sometimes responds to anticholinergic therapy. The cough associated with postnasal drip of sinusitis responds to antibiotics (if warranted), nasal decongestants, and intranasal steroids. The cough associated with ACE inhibitors (in ~15% of patients treated) responds to lowering the dose or withdrawal of the drug and substitution of an AT1 receptor antagonist (see Chapter 26). Gastroesophageal reflux is a common cause of cough through a reflex mechanism and occasionally as a result of acid aspiration into the lungs. This cough may respond to suppression of gastric acid with an H2 receptor antagonist or a proton pump inhibitor (see Chapter 45). Some patients have a chronic cough with no obvious cause, and this chronic idiopathic cough may be due to airway sensory neural hyperesthesia.
OPIATES. Opiates have a central mechanism of action on < opioid receptors in the medullary cough center, but there is some evidence that they may have additional peripheral action on cough receptors in the proximal airways. Codeine and pholcodine (not available in the U.S.) are commonly used, but there is little evidence that they are clinically effective, particularly on postviral cough; in addition, they are associated with sedation and constipation. Morphine and methadone are effective but indicated only for intractable cough associated with bronchial carcinoma.
DEXTROMETHORPHAN. Dextromethorphan is a centrally active N-methyl-D-aspartate (NMDA) receptor antagonist. It may also antagonize opioid receptors. Despite the fact that it is in numerous over-the-counter cough suppressants and used commonly to treat cough, it is poorly effective. It can cause hallucinations at higher doses and has significant abuse potential.
BENZONATATE.(TESSALON, others), a local anesthetic, acts peripherally by anesthetizing the stretch receptors located in the respiratory passages, lungs, and pleura. By dampening the activity of these receptors, benzonatate may reduce the cough reflex at its source. The recommended dose is 100 mg, three times daily, and up to 600 mg/day, if needed. Side effects include dizziness and dysphagia. Seizures and cardiac arrest have occurred following an acute ingestion. Severe allergic reactions have been reported in patients allergic to para-aminobenzoic acid, a metabolite of benzonatate.
OTHER DRUGS. Several other drugs reportedly have small benefits in reducing cough in pulmonary diseases. These drugs include moguisteine (not available in the U.S.), which acts peripherally and appears to open ATP-sensitive K+ channels; baclofen, a GABAB-selective agonist; and theobromine, a naturally occurring methylxanthine.
DRUGS FOR DYSPNEA AND VENTILATORY CONTROL
DRUGS FOR DYSPNEA
Bronchodilators should reduce breathlessness in patients with airway obstruction. Chronic oxygen may have a beneficial effect, but in a few patients dyspnea may be extreme. Drugs that reduce breathlessness may also depress ventilation and may therefore be dangerous. Some patients show a beneficial response to dihydrocodeine and diazepam; however, these drugs must be used with great caution because of the risk of ventilatory depression. 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.
Selective respiratory stimulants are indicated if ventilation is impaired as a result of overdose with sedatives, in post-anesthetic respiratory depression, and in idiopathic hypoventilation. Respiratory stimulants are rarely indicated in 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.
DOXAPRAM. (DOPRAM, others). At low doses (0.5 mg/kg IV), doxapram stimulates carotid chemoreceptors; at higher doses it stimulates medullary respiratory centers. Its effect is transient; thus, intravenous infusion (0.3-3 mg/kg/min) is needed for sustained effect. Unwanted effects include nausea, sweating, anxiety, and hallucinations. At higher doses, increased pulmonary and systemic pressures may occur. Both the kidney and the liver participate in the clearance of doxapram, which should be used with caution if hepatic or renal function is impaired. In COPD, the infusion of doxapram is restricted to 2 h. The use of doxapram to treat ventilatory failure in COPD has now largely been replaced by noninvasive ventilation.
ALMITRINE. Almitrine bismesylate is a piperazine derivative that appears to selectively stimulate peripheral chemoreceptors and is without central actions. Almitrine stimulates ventilation only when there is hypoxia. Long-term use of almitrine is associated with peripheral neuropathy, limiting its availability in most countries.
ACETAZOLAMIDE. The carbonic anhydrase inhibitor acetazolamide (see Chapter 25) 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 proved useful in prevention of high altitude sickness.
NALOXONE. Naloxone is a competitive opioid antagonist that is indicated only if ventilatory depression is due to overdose of opioids.
FLUMAZENIL. Flumazenil is a benzodiazepine receptor antagonist that can reverse respiratory depression due to overdose of benzodiazepines.
PHARMACOTHERAPY OF PULMONARY ARTERIAL HYPERTENSION
Pulmonary arterial hypertension (PAH) is characterized by vascular proliferation and remodeling of small pulmonary arteries, resulting in a progressive increase in pulmonary vascular resistance that may lead to right heart failure and death. PAH involves dysfunction of pulmonary vascular endothelial and smooth muscle cells and their interplay and results from an imbalance in vasoconstrictor and vasodilator mediators. Vasodilators are the mainstay of drug therapy for PAH. However, the vasodilators used to treat systemic hypertension lower systemic blood pressure, which may result in reduced pulmonary perfusion. Calcium channel blockers, such as nifedipine, are poorly effective, but a few patients may benefit. In PAH, there is an increase in the vasoconstrictor mediators ET-1, TxA2, and 5HT, and a decrease in the vasodilating mediators prostacyclin (PGI2), NO, and VIP. Therapies aim at antagonizing the vasoconstrictive mediators and enhancing vasodilation (Figure 36–11).
Figure 36–11 Interactions of endothelium and vascular smooth muscle in pulmonary artery hypertension (PAH). A. In normal pulmonary artery, there is a balance between constrictor and relaxant influences that may be viewed as competition between Ca2+ signaling pathways and cyclic nucleotide signaling pathways in vascular smooth muscle (VSM). Endothelin (ET-1) binds to the ETA receptor on VSM cells and activates the Gq-PLC-IP3 pathway to increase cytosolic Ca2+; ET-1 may also couple to Gi to inhibit cyclic AMP (cAMP) production. In depolarizing VSM cells, Ca2+ may enter via the L-type Ca2+ channel (Cav1.2). Endothelial cells also produce relaxant factors, prostacyclin (PGI2) and NO. NO stimulates the soluble guanylyl cyclase (cGC), causing accumulation of cyclic GMP (cGMP) in VSM cells; PGI2 binds to the IP receptor and stimulates cAMP production; elevation of these cyclic nucleotides promotes VSM relaxation (see Figures 36–4 and 3–11). B. In PAH, ET-1 production is enhanced, production of PGI2 and NO is reduced, and the balance is shifted toward constriction and proliferation of vascular smooth muscle. C. In treating PAH, ETA receptor antagonists can reduce the constrictor effects of ET-1, and Ca2+ channel antagonists can further reduce Ca2+-dependent contraction. Exogenous PGI2 and NO can be supplied to promote vasodilation (relaxation of VSM); inhibition of PDE5 can enhance the relaxant effect of NO by inhibiting the degradation of cGMP. Thus, these drugs can reduce Ca2+ signaling and enhance cyclic nucleotide signaling, restoring the balance between the forces of contraction/proliferation and relaxation/antiproliferation. Remodeling and deposition of extracellular matrix by adjacent fibroblasts is influenced positively and negatively by the same contractile and relaxant signaling pathways, respectively.
Most cases of pulmonary hypertension are associated with connective tissue disorders, such as systemic sclerosis, or they are secondary to hypoxic lung diseases, such as interstitial lung disease and COPD, where chronic hypoxia leads to hypoxic pulmonary vasoconstriction. In secondary pulmonary hypertension due to chronic hypoxia, the initial treatment is correction of hypoxia using supplementary O2therapy. Right heart failure is treated initially with diuretics. Anticoagulants are indicated for the treatment of pulmonary hypertension secondary to chronic thromboembolic disease, but they may also be indicated for patients with severe pulmonary hypertension who have an increased risk of venous thrombosis.
Prostacyclin (PGI2; epoprostenol) is produced by endothelial cells in the pulmonary circulation and directly relaxes pulmonary vascular smooth muscle cells by increasing intracellular cyclic AMP concentrations (see Chapter 33). Reduced prostacyclin production in PAH has led to the therapeutic use of epoprostenol and other stable prostacyclin derivatives. Functionally, PGI2 opposes the effects of TXA2.
Intravenous epoprostenol (FLOLAN, others) is effective in lowering pulmonary arterial pressures, improving exercise performance, and prolonging survival in primary PAH (PPAH). Because of its short plasma t1/2, prostacyclin must be administered by continuous intravenous infusion using an infusion pump. Common side effects are headache, flushing, diarrhea, nausea, and jaw pain. Continuous intravenous infusion is inconvenient and very expensive. This has led to the development of more stable prostacyclin analogs. Treprostinil (REMODULIN) is given by continuous subcutaneous infusion or as an inhalation (TYVASO), consisting of 4 daily treatment sessions with 9 breaths per session. Iloprost (VENTAVIS) is a stable analog that is given by inhalation, but it needs to be given by nebulizer 6 to 9 times daily. It is associated with the vasodilator side effects of prostacyclin, including syncope. It may also cause cough and bronchoconstriction because it sensitizes airway sensory nerves.
ENDOTHELIN RECEPTOR ANTAGONISTS
Endothelin-1 (ET-1) is a potent pulmonary vasoconstrictor that is produced in increased amounts in PAH. ET-1 contracts vascular smooth muscle cells and causes proliferation mainly via ETA receptors. ETB receptors mediate the release of prostacyclin and NO from endothelial cells. Several endothelin antagonists are now on the market for the treatment of PPAH.
Bosentan (TRACLEER) is an ETA/ETB receptor antagonist. Bosentan is effective in reducing symptoms and improving mortality in PPAH. Starting dose is 62.5 mg twice daily for 4 weeks, and maintenance dose is 125 mg twice daily. The drug is generally well tolerated. Adverse effects include abnormal liver function tests, anemia, headaches, peripheral edema, and nasal congestion. Liver aminotransferases should be monitored monthly. A class effect is a risk of testicular atrophy and infertility; bosentan is potentially teratogenic.
Ambrisentan (LETAIRIS) is a selective ETA receptor antagonist. It is given orally once daily at a dose of 5-10 mg with clinical efficacy and adverse effects similar to that of bosentan. Use of ambrisentan also requires monthly monitoring of liver aminotransferases. Sitaxsentan (THELIN, not available in the U.S.) is a selective ETA receptor antagonist that was withdrawn from the market because of post-marketing reports of fatal liver complications in patients with PAH related to its use.
Nitric oxide activates soluble guanylate cyclase to increase cyclic GMP, which is hydrolyzed to 5′GMP by PDE5 (see Chapter 27). Elevation of cGMP in smooth muscle causes relaxation (see Chapter 3), which the inhibition of PDE5 prolongs and accentuates. In the pulmonary bed, inhibition of PDE5 induces vasodilation.
SILDENAFIL. Sildenafil (REVATIO) is a selective PDE5 inhibitor that is given at a dose (20 mg 3 time daily orally) that is lower than used for erectile dysfunction (100 mg; see Chapter 27). It is effective in lowering pulmonary resistance and improving exercise tolerance in patients with PAH. Side effects include headache, flushing, dyspepsia, and visual disturbances.
TADALAFIL. Tadalafil (ADCIRCA) has a longer duration of action than sildenafil so may be suitable for once-daily dosing.
Roflumilast. Roflumilast (DALIRESP) and its active metabolite (roflumilast N-oxide) selectively inhibit PDE4, have anti-inflammtory effects, and are used to decrease exacerbations of severe COPD. Roflumilast is metabolized by CYPs to roflumilast N-oxide and then to conjugates that are mostly excreted in urine. Adverse effects include diarrhea, weight loss, nausea, headache, and can be dose-limiting. Some patients may experience anxiety, depression, and suicidal thoughts.