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Pharmacology_Katzung. Norel X et al: Prostanoid receptors. IUPHAR/BPS Guide to Pharmacology. http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?famil yId=58. Accessed on June 7, 2016. Perrin S et al: New pharmacotherapy options for pulmonary arterial hypertension. Exp Opin Pharmacother 2015;16:2113. Rao CV et al: Simultaneous targeting of 5-LOX-COX and EGFR blocks progression of pancreatic ductal adenocarcinoma. Oncotarget 2015;6:33290. Smith WL, Urade Y, Jakobsson PJ: Enzymes of the cyclooxygenase pathways of prostanoid biosynthesis. Chem Rev 2011;111:5821. Smyth EM et al: Prostanoids in health and disease. J Lipid Res 2009;50:S423. Stitham J, Hwa J: Prostacyclin, atherothrombosis and diabetes mellitus: Physiologic and clinical considerations. Curr Mol Med 2016:16:328. Varnavas DM, Dennis EA: Membrane and inhibitor interactions of intracellular phospholipase A2. Adv Biol Regul 2016;61:17. Wang D, Dubois RN: Eicosanoids and cancer. Nat Rev Cancer 2010;10:181.


Pharmacology_Katzung

Pharmacology_Katzung. Varnavas DM, Dennis EA: Membrane and inhibitor interactions of intracellular phospholipase A2. Adv Biol Regul 2016;61:17. Wang D, Dubois RN: Eicosanoids and cancer. Nat Rev Cancer 2010;10:181. Woodward DF, Jones RL Narumiya S: International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of prostanoid receptors, updating 15 years of progress. Pharmacol Rev 2011;63:471. Prostacyclin analogs have been shown to be effective in the treatment of pulmonary hypertension. Multiple for-mulations are now available including intravenous, inha-lational, and more recently, oral. These agents activate the G protein-coupled IP receptor, leading to elevated cAMP. The result is reduced proliferation of vascular smooth mus-cle cells and vasodilation, key strategies in the treatment of pulmonary hypertension. Samie R. Jaffrey, MD, PhD


Pharmacology_Katzung

Pharmacology_Katzung. Samie R. Jaffrey, MD, PhD Nitric oxide (NO) is a gaseous signaling molecule that readily diffuses across cell membranes and regulates a wide range of physiologic and pathophysiologic processes including cardiovascular, inflammatory, and neuronal functions. Nitric oxide should not be confused with nitrous oxide (N2O), an anesthetic gas, or with nitrogen dioxide (NO2), a toxic pulmonary irritant gas. The understanding that NO is an endogenously synthesized signaling molecule came from a series of discoveries that began with Italian chemist Ascanio Sobrero, who synthesized nitroglycerin in 1846 and found it to be unstable and explosive. Nevertheless, upon tasting the chemical, which was not an unusual practice at the time, he noted profound headache, which was soon understood to be caused by cerebral vasodilation. Based on this early observation, nitroglycerin was used to treat angina and hypertension within 20 years.


Pharmacology_Katzung

Pharmacology_Katzung. These and other early studies demonstrated that human cells have the capacity to detect and respond to nitroglycerin, as well as its metabolite, NO. However, the first indication that there may be an endogenous source of NO came from studies of cultured macrophages, which release byproducts of NO breakdown, including nitrate and nitrite, after treatment with inflammatory mediators such as bacterial endotoxin. Similarly, injection of endotoxin in animals elevated urinary nitrite and nitrate.


Pharmacology_Katzung

Pharmacology_Katzung. The second indication came from studies of vascular tissue, the well-known target of nitroglycerin. Several molecules, such as acetylcholine, were known to cause relaxation of blood vessels. This effect occurred only when the vessels were prepared so that the luminal endothelial cells covering the smooth muscle of the vessel wall were retained (see Figure 7–5). Subsequent studies showed that these endothelial cells respond to vasorelaxants by releasing a soluble endothelial-derived relaxing factor (EDRF). EDRF acts on vascular muscle to elicit relaxation. These findings prompted an intense search for the identity of EDRF.


Pharmacology_Katzung

Pharmacology_Katzung. NO was suspected to be EDRF because they have similar vasorelaxation effects. Systematic comparison of the biochemical and pharmacologic properties of EDRF and NO provided initial evidence that NO is the major bioactive component of EDRF. These findings also made it clear that exogenously applied NO and NO-releasing compounds (nitrates, nitrites, nitroprusside; see Chapters 11 and 12) elicit their effects by recruiting physiologic signaling pathways that normally mediate the actions of endogenously generated NO. ■ NITRIC OXIDE SYNTHESIS, SIGNALING MECHANISMS, & INACTIVATION


Pharmacology_Katzung

Pharmacology_Katzung. ■ NITRIC OXIDE SYNTHESIS, SIGNALING MECHANISMS, & INACTIVATION NO, written as NO• to indicate an unpaired electron in its chemical structure, or simply NO, is a highly reactive signaling molecule that is synthesized in cells by any of three closely related NO synthase (NOS, EC 1.14.13.49) isoenzymes, each of which is encoded by a separate gene and named for the initial cell type from which it was isolated (Table 19–1). These enzymes, neuronal NOS (nNOS or NOS-1), macrophage or inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3), despite their names, are each expressed in a wide variety of cell types, often with an overlapping distribution.


Pharmacology_Katzung

Pharmacology_Katzung. These NOS isoforms generate NO from the amino acid l-arginine in an O2-and NADPH-dependent reaction (Figure 19–1). This enzymatic reaction involves enzyme-bound cofactors, including heme, tetrahydrobiopterin, and flavin adenine dinucleotide (FAD). In the case of nNOS and eNOS, NO synthesis is triggered by agents and signaling events that increase cytosolic calcium concentrations. Cytosolic calcium forms complexes with calmodulin, an abundant calcium-binding protein, which then binds and activates eNOS and nNOS. On the other hand, iNOS is not regulated by calcium, but after synthesis is constitutively active. In macrophages and several other cell types, iNOS is normally not readily detectable until inflammatory mediators induce TABLE 19–1 Properties of the three isoforms of nitric oxide synthase (NOS). the transcription of the iNOS gene, resulting in accumulation of iNOS and synthesis of large quantities of NO.


Pharmacology_Katzung

Pharmacology_Katzung. NO mediates its effects by covalent modification of proteins. There are three major targets of NO (Figure 19–1): 1. Metalloproteins—NO interacts with metals, especially iron in heme, a prosthetic group in certain proteins. The major heme-containing target of NO is soluble guanylyl cyclase (sGC), an enzyme that generates cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). When NO binds the heme in sGC, the enzyme is activated, resulting in an elevation in intracellular cGMP levels. cGMP activates protein kinase G (PKG), which phosphorylates specific proteins. In blood vessels, NO is released from endothelial cells to increase cGMP and PKG activity in vascular smooth muscle cells. The elevated PKG activity results in the phosphorylation of proteins that lead to reduced cytosolic calcium levels. Since calcium triggers contraction of smooth muscle, the NO-mediated reduction in cytosolic calcium leads to vasorelaxation.


Pharmacology_Katzung

Pharmacology_Katzung. NO also has cytotoxic effects, especially when it is produced at high levels, eg, in activated macrophages. Excessive NO production results in NO complexing with metals in metalloproteins involved in cellular respiration, including the citric acid cycle enzyme aconitase and the electron transport chain protein cytochrome oxidase. Additionally, inhibition of heme-containing cytochrome P450 enzymes by NO is a major pathogenic mechanism in inflammatory liver disease. 2. Thiols—Although the primary target of NO, especially in the context of vasorelaxation, is sGC, some of the effects of NO+NADPH, O2 Superoxide Activation of guanylyl cyclase Heme iron in Guanylyl cyclase NOSL-NMMA Arginine Citrulline O2, metals +H3N NH2 NH O +H3N NH2 NH +H3N +H3N COO– COO– COO– COO– OH S N O


Pharmacology_Katzung

Pharmacology_Katzung. NO+NADPH, O2 Superoxide Activation of guanylyl cyclase Heme iron in Guanylyl cyclase NOSL-NMMA Arginine Citrulline O2, metals +H3N NH2 NH O +H3N NH2 NH +H3N +H3N COO– COO– COO– COO– OH S N O FIGURE 19–1 Synthesis and reactions of nitric oxide (NO). L-NMMA (see Table 19–3) inhibits nitric oxide synthase (NOS). NO binds to the iron in hemoproteins (eg, guanylyl cyclase), resulting in the activation of cyclic guanosine monophosphate (cGMP) synthesis and cGMP target proteins such as protein kinase G. Under conditions of oxidative stress, NO can react with superoxide to nitrate tyrosine. GTP, guanosine triphosphate.


Pharmacology_Katzung

Pharmacology_Katzung. NO may involve metal-independent interactions with other cellular proteins. NO reacts with thiols (compounds containing the –SH group) to form nitrosothiols. In proteins, the thiol moiety is found in the amino acid cysteine. This posttranslational modification, termed S-nitrosylation or S-nitrosation, requires either metals or O2 to catalyze the formation of the nitrosothiol adduct. S-nitrosylation is highly specific, with only certain cysteine residues in proteins becoming S-nitrosylated. S-nitrosylation can alter the function, stability, or localization of target proteins. Major targets of S-nitrosylation include H-ras, a regulator of cell proliferation that is activated by S-nitrosylation, and the metabolic enzyme glyceraldehyde-3-phosphate dehydrogenase, which is inhibited when it is S-nitrosylated. Denitrosylation of proteins is poorly understood but may involve enzymes, such as thioredoxin, or chemical reduction by intracellular reducing agents such as glutathione, an abundant


Pharmacology_Katzung

Pharmacology_Katzung. S-nitrosylated. Denitrosylation of proteins is poorly understood but may involve enzymes, such as thioredoxin, or chemical reduction by intracellular reducing agents such as glutathione, an abundant intracellular sulfhydryl-containing compound. Glutathione can also be S-nitrosylated under physiologic conditions to generate S-nitrosoglutathione. S-nitrosoglutathione may serve as an endogenous stabilized form of NO or as a carrier of NO. Vascular glutathione is decreased in diabetes mellitus and atherosclerosis, and the resulting deficiency of S-nitrosoglutathione may account for the increased incidence of cardiovascular complications in these conditions.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Tyrosine Nitration—Additional reactions of NO are seen, especially in immune system cells producing large amounts of NO. NO undergoes both oxidative and reductive reactions, which allow it to nitrosylate thiols and add nitrate to tyrosines (described below) or lead to stable oxidation products (Table 19–2). NO reacts very efficiently with superoxide to form peroxynitrite (ONOO–), a highly reactive oxidant that leads to DNA damage, nitration of tyrosine, and oxidation of cysteine to disulfides or to various sulfur oxides (SOx). Several cellular enzymes synthesize superoxide, and these enzymes are elevated in concert with NO synthase in numerous inflammatory and degenerative diseases, resulting in an increase in peroxynitrite levels. Numerous proteins TABLE 19–2 Oxides of nitrogen.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 19–2 Oxides of nitrogen. are susceptible to peroxynitrite-catalyzed tyrosine nitration, and this irreversible modification can be associated with either activation or inhibition of protein function. Detection of tyrosine nitration in tissue is often used as a marker of excessive NO production, although a direct causal role of tyrosine nitration in the pathogenesis of any disease has not been definitively established. Peroxynitrite-mediated protein modification is mitigated by intracellular levels of glutathione, which can protect against tissue damage by scavenging peroxynitrite. Factors that regulate the biosynthesis and decomposition of glutathione may be important modulators of the toxicity of NO.


Pharmacology_Katzung

Pharmacology_Katzung. NO is highly labile due to its rapid reaction with metals, O2, and reactive oxygen species. NO can react with heme and hemoproteins, including oxyhemoglobin, which oxidizes NO to nitrate. The reaction of NO with hemoglobin may also lead to S-nitrosylation of hemoglobin, resulting in transport of NO throughout the vasculature. NO is also inactivated by reaction with O2 to form nitrogen dioxide. As noted, NO reacts with superoxide, which results in the formation of the highly reactive oxidizing species, peroxynitrite. Scavengers of superoxide anion such as superoxide dismutase may protect NO, enhancing its potency and prolonging its duration of action. Inhibitors of Nitric Oxide Synthesis NOS enzyme inhibitors are currently being evaluated for efficacy in diseases associated with elevated NO production, such as inflammatory conditions, sepsis, and neurodegenerative diseases. The majority of these inhibitors are arginine analogs that bind to the NOS


Pharmacology_Katzung

Pharmacology_Katzung. O−Nitric oxide (NO) Vasodilator, platelet inhibitor, immune regulator, neurotransmitter Oxidant and nitrating agent Can form from nonspecific donation of an electron from metals to NO Exhibits NO-like effects, possibly by first being oxidized to NO Anesthetic Auto-oxidation product of NO that can nitrosylate protein thiols Stable oxidation product of NO Slowly metabolized to nitrosothiols, and decomposes to NO at acidic pH Stable oxidation product of NO N=O•O=N−O−O−N−=O N−=N+=O O=N=O−Peroxynitrite (NO3 −) Nitrite (NO2 −) Nitrate (NO3 −) Nitroxyl anion (NO−) Nitrous oxide (N2O) Dinitrogen trioxide (N2O3) O=N−N+=O O=N+−O−O− arginine-binding site. Since each of the NOS isoforms has high structural similarity, most of these inhibitors do not exhibit selectivity for individual NOS isoforms. In inflammatory disorders and sepsis (see below), inhibition of the iNOS isoform is potentially beneficial, whereas in neurodegenerative conditions, nNOS-specific inhibitors may be useful. However,


Pharmacology_Katzung

Pharmacology_Katzung. In inflammatory disorders and sepsis (see below), inhibition of the iNOS isoform is potentially beneficial, whereas in neurodegenerative conditions, nNOS-specific inhibitors may be useful. However, administration of nonselective NOS inhibitors leads to concurrent inhibition of eNOS, which impairs its homeostatic signaling and also results in vasoconstriction and potential ischemic damage. Thus, NOS isoform-selective inhibitors are being designed that exploit subtle differences in substrate binding sites between the isoforms, as well as newer isoform-selective inhibitors that prevent NOS dimerization, the conformation required for enzymatic activity. The efficacy of NOS isoform-selective inhibitors in medical conditions is under investigation.


Pharmacology_Katzung

Pharmacology_Katzung. NO donors, which release NO or related NO species, are used clinically to elicit smooth muscle relaxation. Different classes of NO donors have differing biologic properties, depending on the nature of the NO species released and the mechanism that is responsible for its release. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Organic Nitrates—Nitroglycerin, which dilates veins and coronary arteries, is metabolized to NO by mitochondrial aldehyde reductase, an enzyme enriched in venous smooth muscle, accounting for the potent venodilating activity of this molecule. Venous dilation decreases cardiac preload, which along with coronary artery dilation accounts for the antianginal effects of nitroglycerin. Other organic nitrates, such as isosorbide dinitrate, are metabolized to an NO-releasing species through a poorly understood enzymatic pathway. Unlike NO, organic nitrates have less significant effects on aggregation of platelets, which appear to lack the enzymatic pathways necessary for rapid metabolic activation. Patients taking organic nitrates exhibit rapid tolerance during continuous administration. This nitrate tolerance may derive from the generation of reactive oxygen species that inhibit mitochondrial aldehyde reductase, endogenous NO synthesis, and other pathways (see Chapter 12). 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Organic Nitrites—Organic nitrites, such as the antianginal inhalant amyl nitrite, also require metabolic activation to elicit vasorelaxation, although the responsible enzyme has not been identified. Nitrites are arterial vasodilators and do not exhibit the rapid tolerance seen with nitrates. Amyl nitrite is abused for euphoric effects, and combining it with phosphodiesterase inhibitors, such as sildenafil, can cause lethal hypotension. In clinical medicine, amyl nitrite has been largely replaced by nitrates, such as nitroglycerin, which are more easily administered. 3. Sodium Nitroprusside—Sodium nitroprusside, which dilates arterioles and venules, is used for rapid pressure reduction in arterial hypertension. In response to light as well as chemical or enzymatic mechanisms in cell membranes, sodium nitroprusside breaks down to generate five cyanide molecules and a single NO. See Chapter 11 for additional details. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. NO Gas Inhalation—NO itself can be used therapeutically. Inhalation of NO results in reduced pulmonary artery pressure and improved perfusion of ventilated areas of the lung. Inhaled NO is used for pulmonary hypertension, acute hypoxemia, and cardiopulmonary resuscitation, and there is evidence of short-term improvements in pulmonary function. NO for inhalation is stored as a compressed gas mixture with nitrogen, which does not readily react with NO, and further diluted to the desired concentration upon administration. NO can react with O2 to form nitrogen dioxide, a pulmonary irritant that can cause deterioration of lung function (see Chapter 56). Additionally, NO can induce the formation of methemoglobin, a form of hemoglobin containing Fe3+ rather than Fe2+, which does not bind O2 (see also Chapter 12). Therefore, nitrogen dioxide and methemoglobin levels are monitored during inhaled NO treatment. 5.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Alternate Strategies—Another mechanism to potentiate the actions of NO is to inhibit the phosphodiesterase enzymes that degrade cGMP. Inhibitors of type 5 phosphodiesterase such as sildenafil allow NO-induced cGMP elevations to achieve higher cytosolic levels and result in prolongation of the duration of the cGMP elevations in a variety of tissues (see Chapter 12). This can allow otherwise insufficient NO production to have more pronounced physiologic effects. NO has a significant effect on vascular smooth muscle tone and blood pressure. Numerous endothelium-dependent vasodilators, such as acetylcholine and bradykinin, act by increasing intracellular calcium levels in endothelial cells, leading to the synthesis of NO. NO diffuses to vascular smooth muscle, leading to vasorelaxation (Figure 19–2). Mice with a knockout mutation in the eNOS gene display increased vascular tone and elevated mean arterial pressure, indicating that eNOS is a fundamental regulator of blood pressure.


Pharmacology_Katzung

Pharmacology_Katzung. Apart from being a vasodilator and regulating blood pressure, NO also has antithrombotic effects. Both endothelial cells and platelets contain eNOS, which acts via an NO-cGMP pathway to inhibit platelet activation, an initiator of thrombus formation. In diseases such as diabetes, endothelial cells are dysfunctional and produce reduced levels of NO, resulting in an increased propensity for abnormal platelet function and thrombosis. NO may have an additional inhibitory effect on blood coagulation by enhancing fibrinolysis via an effect on plasminogen. NO also protects against atherogenesis. A major antiatherogenic mechanism of NO involves the inhibition of proliferation and migration of vascular smooth muscle cells. In animal models, myointimal proliferation following angioplasty can be blocked by NO donors, by NOS gene transfer, and by NO inhalation. NO reduces the ability of monocytes and leukocytes to adhere to endothelial cells, which is an early step in the development of


Pharmacology_Katzung

Pharmacology_Katzung. Acetylcholine,bradykininEndothelial cellEndoplasmicreticulumArginineNOeNOSCa2+Ca2+Ca2+•CaMCaMPKGcGMPGTPGMPPhosphodiesteraseVascular smooth muscle cell ContractionLumen of blood vessel Solubleguanylylcyclase--


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 19–2 Regulation of vasorelaxation by endothelial-derived nitric oxide (NO). Endogenous vasodilators, eg, acetylcholine and bradykinin, cause calcium (Ca2+) efflux from the endoplasmic reticulum in the luminal endothelial cells into the cytoplasm. Calcium binds to calmodulin (CaM), which activates endothelial NO synthase (eNOS), resulting in NO synthesis from L-arginine. NO diffuses into smooth muscle cells, where it activates soluble guanylyl cyclase and cyclic guanosine monophosphate (cGMP) synthesis from guanosine triphosphate (GTP). cGMP binds and activates protein kinase G (PKG), resulting in an overall reduction in calcium influx, and inhibition of calcium-dependent muscle contraction. PKG can also block other pathways that lead to muscle contraction. cGMP signaling is terminated by phosphodiesterases, which convert cGMP to GMP.


Pharmacology_Katzung

Pharmacology_Katzung. atheromatous plaques. This effect is due to the inhibitory effect of NO on the expression of adhesion molecules on the endothelial cell surface. The antiatherogenic effect of NO may also involve an antioxidant effect, blocking the oxidation of low-density lipoproteins and thus preventing or reducing the formation of foam cells in the vascular wall. Plaque formation is also reduced by NO-dependent reduction of endothelial cell permeability to lipoproteins. The importance of eNOS in cardiovascular disease is supported by experiments showing increased atherosclerosis in animals treated with eNOS inhibitors. Atherosclerosis risk factors, such as smoking, hyperlipidemia, diabetes, and hypertension, are associated with decreased endothelial NO production, and thus with a loss of the diverse antiatherogenic effects of NO.


Pharmacology_Katzung

Pharmacology_Katzung. Sepsis is a systemic inflammatory response caused by infection. Endotoxin components from the bacterial wall along with endogenously generated tumor necrosis factor-α and other cytokines induce synthesis of iNOS in macrophages, neutrophils, and T cells, as well as hepatocytes, smooth muscle cells, endothelial cells, and fibroblasts. This widespread generation of NO results in exaggerated hypotension, shock, and, in some cases, death. This hypotension is reduced or reversed by NOS inhibitors in humans as well as in animal models (Table 19–3). A similar reversal of hypotension is produced by compounds that prevent the action of NO, such as the sGC inhibitor methylene blue. Furthermore, knockout mice lacking a functional iNOS gene are more resistant to endotoxin than wild-type mice. However, despite the ability of NOS inhibitors to ameliorate hypotension in sepsis, there is no overall improvement in survival in patients with gram-negative sepsis treated with NOS inhibitors. The absence


Pharmacology_Katzung

Pharmacology_Katzung. despite the ability of NOS inhibitors to ameliorate hypotension in sepsis, there is no overall improvement in survival in patients with gram-negative sepsis treated with NOS inhibitors. The absence of benefit may reflect the inability of


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 19–3 Some inhibitors of nitric oxide synthesis or action. BBS-2, a pyrimide imidazole; NOS, nitric oxide synthase. the NOS inhibitors used in these trials to differentiate between NOS isoforms, or may reflect concurrent inhibition of beneficial aspects of iNOS signaling.


Pharmacology_Katzung

Pharmacology_Katzung. The generation of NO has both beneficial and detrimental roles in the host immune response and in inflammation. The host response to infection or injury involves the recruitment of leukocytes and the release of inflammatory mediators, such as tumor necrosis factor and interleukin-1. This leads to a marked increase in iNOS levels and activity in leukocytes, fibroblasts, and other cell types. The NO that is produced, along with peroxynitrite that forms from its interaction with superoxide, is an important microbicide. NO also appears to play an important protective role in the body via immune cell function. When challenged with foreign antigens, Th1 cells (see Chapter 55) respond by synthesizing NO, which has roles in Th1 cells. The importance of NO in Th1 cell function is demonstrated by the impaired protective response to injected parasites in animal models after inhibition of iNOS. NO also stimulates the synthesis of inflammatory prostaglandins by activating cyclooxygenase isoenzyme


Pharmacology_Katzung

Pharmacology_Katzung. impaired protective response to injected parasites in animal models after inhibition of iNOS. NO also stimulates the synthesis of inflammatory prostaglandins by activating cyclooxygenase isoenzyme 2 (COX-2). Through its effects on COX-2, its direct vasodilatory effects, and other mechanisms, NO generated during inflammation contributes to the erythema, vascular permeability, and subsequent edema associated with acute inflammation.


Pharmacology_Katzung

Pharmacology_Katzung. However, in both acute and chronic inflammatory conditions, prolonged or excessive NO production may exacerbate tissue injury. Indeed, psoriasis lesions, airway epithelium in asthma, and inflammatory bowel lesions in humans all demonstrate elevated levels of NO and iNOS, suggesting that persistent iNOS induction may contribute to disease pathogenesis. Moreover, these tissues also exhibit increased levels of nitrotyrosine, indicating excessive formation of peroxynitrite. In several animal models of arthritis, increasing NO production by dietary l-arginine supplementation exacerbates arthritis, whereas protection is seen with iNOS inhibitors. Thus, inhibition of the NO pathway may have a beneficial effect on a variety of acute and chronic inflammatory diseases.


Pharmacology_Katzung

Pharmacology_Katzung. NO has an important role in the central nervous system as a neurotransmitter (see Chapter 21). Unlike classic transmitters such as glutamate or dopamine, which are stored in synaptic vesicles and released in the synaptic cleft upon vesicle fusion, NO is not stored, but rather is synthesized on demand and immediately diffuses to neighboring cells. NO synthesis is induced at postsynaptic sites in neurons, most commonly upon activation of the NMDA subtype of glutamate receptor, which results in calcium influx and activation of nNOS. In several neuronal subtypes, eNOS is also present and activated by neurotransmitter pathways that lead to calcium influx. NO synthesized postsynaptically may function as a retrograde messenger and diffuse to the presynaptic terminal to enhance the efficiency of neurotransmitter release, thereby regulating synaptic plasticity, the process of synapse strengthening that underlies learning and memory. Because aberrant NMDA receptor activation and excessive NO


Pharmacology_Katzung

Pharmacology_Katzung. neurotransmitter release, thereby regulating synaptic plasticity, the process of synapse strengthening that underlies learning and memory. Because aberrant NMDA receptor activation and excessive NO synthesis is linked to excitotoxic neuronal death in several neurologic diseases, including stroke, amyotrophic lateral sclerosis, and Parkinson’s disease, therapy with NOS inhibitors may reduce neuronal damage in these conditions. However, clinical trials have not clearly supported any benefit of NOS inhibition, which may reflect nonselectivity of the inhibitors, resulting in inhibition of the beneficial effects of eNOS.


Pharmacology_Katzung

Pharmacology_Katzung. Nonadrenergic, noncholinergic (NANC) neurons are widely distributed in peripheral tissues, especially the gastrointestinal and reproductive tracts (see Chapter 6). Considerable evidence implicates NO as a mediator of certain NANC actions, and some NANC neurons appear to release NO. Penile erection is thought to be caused by the release of NO from NANC neurons; NO promotes relaxation of the smooth muscle in the corpora cavernosa—the initiating factor in penile erection—and inhibitors of NOS have been shown to prevent erection caused by pelvic nerve stimulation in the rat. An established approach in treating erectile dysfunction is to enhance the effect of NO signaling by inhibiting the breakdown of cGMP by the phosphodiesterase (PDE isoform 5) present in the smooth muscle of the corpora cavernosa with drugs such as sildenafil, tadalafil, and vardenafil (see Chapter 12).


Pharmacology_Katzung

Pharmacology_Katzung. NO is administered by inhalation to newborns with hypoxic respiratory failure associated with pulmonary hypertension. The current treatment for severely defective gas exchange in the newborn is with extracorporeal membrane oxygenation (ECMO), which does not directly affect pulmonary vascular pressures. NO inhalation dilates pulmonary vessels, resulting in decreased pulmonary vascular resistance and reduced pulmonary artery pressure. Inhaled NO also improves oxygenation by reducing mismatch of ventilation and perfusion in the lung. Inhalation of NO results in dilation of pulmonary vessels in areas of the lung with better ventilation, thereby redistributing pulmonary blood flow away from poorly ventilated areas. NO inhalation does not typically exert pronounced effects on the systemic circulation. Inhaled NO has also been shown to improve cardiopulmonary function in adult patients with pulmonary artery hypertension.


Pharmacology_Katzung

Pharmacology_Katzung. An additional approach for treating pulmonary hypertension is to potentiate the actions of NO in pulmonary vascular beds. Due to the enrichment of PDE-5 in pulmonary vascular beds, PDE-5 inhibitors such as sildenafil and tadalafil induce vasodilation and marked reductions in pulmonary hypertension (see also Chapters 12 and 17). Chen Z, Stamler JS: Bioactivation of nitroglycerin by the mitochondrial aldehyde dehydrogenase. Trends Cardiovasc Med 2006;16:259. Griffiths MJ, Evans TW: Inhaled nitric oxide therapy in adults. N Engl J Med 2005;353:2683. Guix FX et al: The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 2005;76:126. McMillan K et al: Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. Proc Nat Acad Sci USA 2000;97:1506. Moncada S, Higgs EA: The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol 2006;147:S193.


Pharmacology_Katzung

Pharmacology_Katzung. Moncada S, Higgs EA: The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol 2006;147:S193. Napoli C, Ignarro LJ: Nitric oxide-releasing drugs. Annu Rev Pharmacol Toxicol 2003;43:97. Paige JS, Jaffrey, SR: Pharmacologic manipulation of nitric oxide signaling: Targeting NOS dimerization and protein-protein interactions. Curr Topics Med Chem 2007;7:97. Wimalawansa SJ: Nitric oxide: New evidence for novel therapeutic indications. Expert Opin Pharmacother 2008;9:1935.


Pharmacology_Katzung

Pharmacology_Katzung. Joshua M. Galanter, MD, & Homer A. Boushey, MD and respirations are 32/min. Her mother states that she has used her albuterol inhaler several times a day for the past 3 days and twice during the previous night. She took an additional two puffs on her way to the emergency department, but her mother states that “the inhaler didn’t seem to be helping so I told her not to take any more.” What emergency measures are indicated? How should her long-term management be altered? A 14-year-old girl with a history of asthma requiring daily inhaled corticosteroid therapy and allergies to house dust mites, cats, grasses, and ragweed presents to the emergency department in mid-September, reporting a recent “cold” com-plicated by worsening shortness of breath and audible inspi-ratory and expiratory wheezing. She appears frightened and refuses to lie down but is not cyanotic. Her pulse is 120 bpm,


Pharmacology_Katzung

Pharmacology_Katzung. A consistent increase in the prevalence of asthma over the past 60 years has made it an extraordinarily common disease. The reasons for this increase—most striking in people under 18 years of age and shared across all modern, “Westernized” societies—are poorly understood. The global estimate of the number of affected individuals is 300 million. In the United States alone, 17.7 million adults (7.4% of the population) and 6.3 million children (8.6% of the population) have asthma. The condition accounts for 10.5 million outpatient visits, 1.8 million emergency department visits, and 439,000 hospitalizations each year. Considering the disease’s prevalence, the annual mortality in the USA is low— around 3500 deaths—but many of these deaths are considered preventable, and the number has not changed much despite improvements in treatment.


Pharmacology_Katzung

Pharmacology_Katzung. The clinical features of asthma are recurrent episodes of shortness of breath, chest tightness, and wheezing, often associated with coughing. Its hallmark pathophysiologic features are widespread, reversible narrowing of the bronchial airways and a marked increase in bronchial responsiveness to inhaled stimuli. Its pathologic features are lymphocytic, eosinophilic inflammation of the bronchial mucosa. These changes are accompanied by “remodeling” of the bronchial wall, with thickening of the lamina reticularis beneath the epithelium and hyperplasia of the bronchial vasculature, smooth muscle, secretory glands, and goblet cells.


Pharmacology_Katzung

Pharmacology_Katzung. In mild asthma, symptoms occur only intermittently, as on exposure to allergens or airway irritants such as air pollution or tobacco smoke, on exercise, or after viral upper respiratory infection. More severe forms of asthma are associated with more frequent and severe symptoms, especially at night. Chronic airway constriction causes persistent respiratory impairment, punctuated by periodic asthma exacerbations marked by acute worsening of symptoms. These attacks are most often associated with viral respiratory infections and are characterized by severe airflow obstruction from intense contraction of airway smooth muscle, inspissation of mucus plugs in the airway lumen, and thickening of the bronchial mucosa from edema and inflammatory cell infiltration. The spectrum of asthma’s severity is wide, and patients are classified based on two domains: impairment and risk. Measures of impairment are based on the frequency and severity of symptoms, the severity of airflow obstruction on


Pharmacology_Katzung

Pharmacology_Katzung. is wide, and patients are classified based on two domains: impairment and risk. Measures of impairment are based on the frequency and severity of symptoms, the severity of airflow obstruction on pulmonary function testing, and the intensity of therapy required for maintenance of asthma control. Measures of risk are based on susceptibility to asthma exacerbations. Based on measures of impairment, patients may be classified as having “mild intermittent,” “mild persistent,” “moderate persistent,” or “severe persistent” asthma, but will be classified in a more severe category if their history indicates they are prone to frequent or severe exacerbations (“exacerbationprone” versus “exacerbation-resistant”).


Pharmacology_Katzung

Pharmacology_Katzung. Until recently, the entire range of asthma severity was regarded as eminently treatable, because treatments for quick relief of symptoms of acute bronchoconstriction (“short-term relievers”) and treatments for reduction in symptoms and prevention of attacks, especially using inhaled corticosteroids (“long-term controllers”), had been shown to be effective in many large, well-designed randomized clinical trials, pragmatic clinical trials, observational studies, and evidence-based reviews. The persistence of high medical costs for asthma, driven largely by the costs of emergency department and hospital treatment of asthma exacerbations, was thus believed to reflect underutilization of the treatments available. Reconsideration of this view was driven by recognition that the term “asthma” is applied to a variety of different disorders sharing common clinical features but fundamentally different pathophysiologic mechanisms. Attention has thus turned to the possibility that there are


Pharmacology_Katzung

Pharmacology_Katzung. is applied to a variety of different disorders sharing common clinical features but fundamentally different pathophysiologic mechanisms. Attention has thus turned to the possibility that there are different asthma phenotypes, some of which are less responsive to the current mainstays of asthma controller therapy. The current view of asthma treatment may be summarized as follows: that the treatments commonly used at present are indeed effective for the most common form of the disease, as it presents in children and young adults with allergic asthma, but that there are other phenotypes of asthma for which these therapies are less effective, and that represent an unmet medical need. Accordingly, this chapter first reviews the pathophysiology of the most common form of asthma (classic allergic asthma) and the basic pharmacology of the agents used in its treatment. This is followed by a discussion of different forms or phenotypes of asthma and the efforts to develop effective therapies for


Pharmacology_Katzung

Pharmacology_Katzung. asthma) and the basic pharmacology of the agents used in its treatment. This is followed by a discussion of different forms or phenotypes of asthma and the efforts to develop effective therapies for them.


Pharmacology_Katzung

Pharmacology_Katzung. Classic allergic asthma is regarded as mediated by immune globulin (IgE), produced in response to exposure to foreign proteins, like those from house dust mite, cockroach, animal danders, molds, and pollens. These qualify as allergens on the basis of their induction of IgE antibody production in people exposed to them. The tendency to produce IgE is at least in part genetically determined, and asthma clusters with other allergic diseases (allergic rhinitis, eczema, food allergy) in family groups. Once produced, IgE binds to high-affinity receptors (FCεR-1) on mast cells in the airway mucosa (Figure 20–1), so that re-exposure to the allergen triggers the release of mediators stored in the mast cells’ granules and the synthesis and release of other mediators. The histamine, tryptase, leukotrienes C4 and D4, and prostaglandin D2 released cause the smooth muscle contraction and vascular leakage responsible for the acute bronchoconstriction of the “early asthmatic response.” This response


Pharmacology_Katzung

Pharmacology_Katzung. C4 and D4, and prostaglandin D2 released cause the smooth muscle contraction and vascular leakage responsible for the acute bronchoconstriction of the “early asthmatic response.” This response is often followed in 3–6 hours by a second, more sustained phase of bronchoconstriction, the “late asthmatic response,” associated with an influx of inflammatory cells into the bronchial mucosa and with an increase in bronchial reactivity. This late response is thought to be due to cytokines characteristically produced by T2 lymphocytes, especially interleukins (IL) 5, 9, and 13. These cytokines are thought to attract and activate eosinophils, stimulate IgE production by B lymphocytes, and stimulate mucus production by bronchial epithelial cells. It is not clear whether lymphocytes or mast cells in the airway mucosa are the primary source of the mediators responsible for the late inflammatory response, but the benefits of corticosteroid therapy are attributed to their inhibition of the


Pharmacology_Katzung

Pharmacology_Katzung. cells in the airway mucosa are the primary source of the mediators responsible for the late inflammatory response, but the benefits of corticosteroid therapy are attributed to their inhibition of the production of proinflammatory cytokines in the airways and of the response of airway epithelial cells to them.


Pharmacology_Katzung

Pharmacology_Katzung. A major limitation to this classic conception of asthma as an allergic disease is that it applies only to a subgroup of patients with asthma, those with evidence of allergy. Allergic asthma accounts for a great proportion of asthma that develops in childhood, but a smaller proportion of adult-onset asthma. This is implied by the use of modifying terms to describe asthma in different patients, such as “extrinsic” versus “intrinsic,” “aspirin-sensitive,” “adult-onset,” “postviral,” and “obesity-related.” The allergen challenge model fails to account for all the features of the condition even in allergic asthmatics. Many pathways and mechanisms other than production of IgE and activation of mast cell degranulation are involved in asthma’s pathogenesis (Figure 20–2), and most asthma attacks are not triggered by inhalation of allergens, but instead by viral respiratory infections. Asthmatic bronchospasm can also be provoked by nonallergenic stimuli such as distilled water aerosol,


Pharmacology_Katzung

Pharmacology_Katzung. are not triggered by inhalation of allergens, but instead by viral respiratory infections. Asthmatic bronchospasm can also be provoked by nonallergenic stimuli such as distilled water aerosol, exercise, cold air, cigarette smoke, and sulfur dioxide. This tendency to develop bronchospasm on encountering nonallergenic stimuli—assessed by measuring the fall in maximal expiratory flow provoked by inhaling serially increasing concentrations of the aerosolized cholinergic agonist methacholine—is described as “bronchial hyperreactivity.” It is considered fundamental to asthma’s pathogenesis because it is nearly ubiquitous in patients with asthma, and its degree roughly correlates with the clinical severity of the disease.


Pharmacology_Katzung

Pharmacology_Katzung. The mechanisms underlying bronchial hyperreactivity are incompletely understood but appear to be related to inflammation of the airway mucosa. The anti-inflammatory activity of inhaled corticosteroid (ICS) treatment is credited with preventing the increase in bronchial reactivity associated with the late asthmatic response (Figure 20–1). Whatever the mechanisms responsible for bronchial hyperreactivity, bronchoconstriction itself results not simply from the direct effect of the released mediators but also from their activation of neural pathways. This is suggested by the effectiveness of muscarinic receptor antagonists, which have no direct effect on smooth muscle contractility, in inhibiting the bronchoconstriction caused by inhalation of allergens and airway irritants.


Pharmacology_Katzung

Pharmacology_Katzung. The hypothesis suggested by this conceptual model—that asthmatic bronchospasm results from a combination of release of mediators and an exaggeration of responsiveness to their effects— predicts that drugs with different modes of action may effectively treat asthma. The bronchospasm provoked by exposure to allergens might be reversed or prevented, for example, by drugs that reduce the amount of IgE bound to mast cells (anti-IgE antibody), reduce the number and activity of eosinophils in the airway mucosa (antiIL-5 antibody), block the receptor for IL-4 and IL-13 (anti-IL-4α receptor antibody), prevent mast cell degranulation (cromolyn or nedocromil, sympathomimetic agents, calcium channel blockers), block the action of the products released (antihistamines and


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 20–1 Conceptual model for the immunopathogenesis of asthma. Exposure to allergen causes synthesis of IgE, which binds to mast cells in the airway mucosa. On re-exposure to allergen, antigen-antibody interaction on mast cell surfaces triggers release of mediators of anaphylaxis: histamine, tryptase, prostaglandin D2 (PGD2), leukotriene (LT) C4, and platelet-activating factor (PAF). These agents provoke contraction of airway smooth muscle, causing the immediate fall in forced expiratory volume in 1 second (FEV1). Re-exposure to allergen also causes the synthesis and release of a variety of cytokines: interleukins (IL) 4 and 5, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF), and tissue growth factor (TGF) from T cells and mast cells. These cytokines in turn attract and activate eosinophils and neutrophils, whose products include eosinophil cationic protein (ECP), major basic protein (MBP), proteases, and platelet-activating factor. These


Pharmacology_Katzung

Pharmacology_Katzung. in turn attract and activate eosinophils and neutrophils, whose products include eosinophil cationic protein (ECP), major basic protein (MBP), proteases, and platelet-activating factor. These mediators cause the edema, mucus hypersecretion, smooth muscle contraction, and increase in bronchial reactivity associated with the late asthmatic response, indicated by a second fall in FEV1 3–6 hours after the exposure.


Pharmacology_Katzung

Pharmacology_Katzung. leukotriene receptor antagonists), or interfere with the action of inflammatory cytokines (anti-IL-5 and anti-IL-13 monoclonal antibodies). Other drugs that might be expected to be effective in all forms of asthma are those that relax airway smooth muscle (sympathomimetic agents, phosphodiesterase inhibitors) or inhibit the effect of acetylcholine released from vagal motor nerves (muscarinic antagonists, also described as anticholinergic agents). Another approach to asthma treatment is aimed at reducing the level of bronchial responsiveness. Because increased responsiveness appears to be linked to airway inflammation and because airway inflammation is a feature of late asthmatic responses, this strategy is implemented both by reducing exposure to the allergens that provoke inflammation and by prolonged therapy with anti-inflammatory agents, especially inhaled corticosteroids (ICS).


Pharmacology_Katzung

Pharmacology_Katzung. This therapy, once expected to be effective for all forms of asthma, is now recognized to be more effective for allergic than nonallergic asthma (see Future Directions of Asthma Therapy below). The drugs most used for asthma management are adrenoceptor agonists or sympathomimetic agents (used as “relievers” or bronchodilators) and inhaled corticosteroids (used as “controllers” or anti-inflammatory agents). Their basic pharmacology is presented (such as oxidant, Goblet cell mucus TSLP, IL-25 eosinophils, mast cellsexpression DC migration to draining lymph node IL-5 and IL-13 production in the airway epithelium and subepithelial mucosa IgE ‘arming’ of mast Pathological cells and basophils changes in the airway predispose to


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 20–2 Inflammatory mechanism of asthma. Airway epithelial cells exposed to activation stimuli, including allergens, viruses, and irritants, release cytokines that promote dendritic cell (DC) mobilization to draining lymph nodes, where they present antigens and thereby activate naive CD4 T cells. These T cells then induce B-cell class switching and maturation into plasma cells, which produce IgE. TH2 cells also migrate into the airway subepithelial mucosa, where they release inflammatory cytokines such as IL-5 and IL-13, which induce goblet cell metaplasia and mucus production, and act as a chemokine for eosinophils, mast cells, and basophils. Unbound IgE secreted by plasma cells binds the FcεRI receptor on submucosal mast cells and basophils and, when crosslinked by an antigen, induces the release of preformed mediators such as histamine and leukotrienes, as well as the release of inflammatory cytokines. (Modified and reproduced, with permission, from Fahy JV: Type 2


Pharmacology_Katzung

Pharmacology_Katzung. induces the release of preformed mediators such as histamine and leukotrienes, as well as the release of inflammatory cytokines. (Modified and reproduced, with permission, from Fahy JV: Type 2 inflammation in asthma: Present in most, absent in many. Nat Rev Immunol 2015;15:57.) elsewhere (see Chapters 9 and 39). In this chapter, we review their pharmacology relevant to asthma.


Pharmacology_Katzung

Pharmacology_Katzung. Adrenoceptor agonists are mainstays in the treatment of asthma. Their binding to β-adrenergic receptors—abundant on airway smooth muscle cells—stimulates adenylyl cyclase and increases the formation of intracellular cAMP (Figure 20–3), thereby relaxing airway smooth muscle and inhibiting release of bronchoconstricting mediators from mast cells. They may also inhibit microvascular leakage and increase mucociliary transport. Adverse effects, especially of adrenoceptor agonists that activate β1 as well as β2 receptors, include tachycardia, skeletal muscle tremor, and decreases in serum potassium levels. Sympathomimetic agents now widely used in the treatment of asthma include albuterol and other β2-selective agents (Figure 20–4). The place of epinephrine and isoproterenol has markedly diminished because of their effects on the rate and force of cardiac contraction (mediated mainly by β1 receptors).


Pharmacology_Katzung

Pharmacology_Katzung. In general, β-adrenoceptor agonists are best delivered by inhalation. This results in the greatest local effect on airway smooth muscle with the least systemic toxicity. Aerosol deposition depends on the particle size, the pattern of breathing, and the geometry of the airways. Even with particles in the optimal size range of 2–5 μm, 80–90% of the total dose of aerosol is deposited in the mouth or pharynx. Particles under 1–2 μm remain suspended and may be exhaled. Bronchial deposition of an aerosol is increased by FIGURE 20–3 Bronchodilation is promoted by cAMP. Intracellular levels of cAMP can be increased by β-adrenoceptor agonists, which increase the rate of its synthesis by adenylyl cyclase (AC), or by phosphodiesterase (PDE) inhibitors such as theophylline, which slow the rate of its degradation. Bronchoconstriction can be inhibited by muscarinic antagonists and possibly by adenosine antagonists.


Pharmacology_Katzung

Pharmacology_Katzung. slow inhalation of a nearly full breath and by 5 or more seconds of breath-holding at the end of inspiration. Epinephrine is an effective, rapidly acting bronchodilator when injected subcutaneously (0.4 mL of 1:1000 solution) or inhaled as a microaerosol from a pressurized canister (320 mcg per puff). Maximal bronchodilation is achieved within 15 minutes after inhalation and lasts 60–90 minutes. Because epinephrine stimulates α and β1 as well as β2 receptors, tachycardia, arrhythmias, and worsening of angina pectoris are potentially serious adverse effects. Its current use is thus largely for treatment of the acute vasodilation and bronchospasm of anaphylaxis. Aerosol delivery of other, more β-selective agents has largely displaced its use in asthma (see below).


Pharmacology_Katzung

Pharmacology_Katzung. Ephedrine was used in China for more than 2000 years before its introduction into Western medicine in 1924. Compared with epinephrine, ephedrine has a longer duration, oral activity, more pronounced central effects, and much lower potency. Because of the development of more efficacious and FIGURE 20–4 Structures of isoproterenol and several β2-selective analogs. β2-selective agonists, ephedrine is now used infrequently in treating asthma. Isoproterenol is a potent nonselective β1 and β2 bronchodilator. When inhaled as a microaerosol from a pressurized canister, 80–120 mcg isoproterenol causes maximal bronchodilation within 5 minutes and has a 60to 90-minute duration of action. An increase in asthma mortality in the United Kingdom in the mid-1960s was attributed to cardiac arrhythmias resulting from the use of high doses of inhaled isoproterenol. As a result of the availability and efficacy of β2-selective agonists, these have displaced the use of isoproterenol for asthma.


Pharmacology_Katzung

Pharmacology_Katzung. The β2-selective adrenoceptor agonist drugs, particularly albuterol, are now the most widely used sympathomimetics for the treatment of acute bronchoconstriction (Figure 20–4). These agents differ structurally from epinephrine in having a larger substitution on the amino group and in the position of the hydroxyl groups on the aromatic ring. They are effective after inhaled or oral administration and have a longer duration of action than epinephrine or isoproterenol.


Pharmacology_Katzung

Pharmacology_Katzung. Albuterol, terbutaline, metaproterenol, and pirbuterol are available as metered-dose inhalers. Given by inhalation, these agents cause bronchodilation equivalent to that produced by isoproterenol. Bronchodilation is maximal within 15 minutes and persists for 3–4 hours. All can be diluted in saline for administration from a hand-held nebulizer. Because the particles generated by a nebulizer are much larger than those from a metered-dose inhaler, much higher doses must be given (2.5–5.0 mg vs 100– 400 mcg) but are no more effective. Nebulized therapy should thus be reserved for patients unable to coordinate inhalation from a metered-dose inhaler.


Pharmacology_Katzung

Pharmacology_Katzung. Most preparations of β2-selective drugs are a mixture of R (levo) and S (dextro) isomers. Only the R isomer activates the β-agonist receptor. Reasoning that the S isomer may promote inflammation, a purified preparation of the R isomer of albuterol has been developed (levalbuterol). Although this purified isomer is often used in children with asthma, meta-analyses of clinical trials have not shown it to have greater efficacy or lower toxicity than the standard and less expensive racemic mixture of Rand S-albuterol in treating exacerbations of asthma or chronic obstructive pulmonary disease (COPD). Albuterol and terbutaline are also available in oral form. One tablet two or three times daily is the usual regimen; the principal adverse effects are skeletal muscle tremor, nervousness, and occasional weakness. This route of administration presents no advantage over inhaled treatment and produces more pronounced adverse effects and is thus rarely prescribed.


Pharmacology_Katzung

Pharmacology_Katzung. Of these agents, only terbutaline is available for subcutaneous injection (0.25 mg). The indications for this route are similar to those for subcutaneous epinephrine—severe asthma requiring emergency treatment when aerosolized therapy is not available or has been ineffective—but it should be remembered that terbutaline’s longer duration of action means that cumulative effects may be seen after repeated injections. Large doses of parenteral terbutaline are sometimes used to inhibit the uterine contractions associated with premature labor.


Pharmacology_Katzung

Pharmacology_Katzung. Long-acting β2-selective agonists (LABA), with 12-hour durations of action, such as salmeterol and formoterol, were developed to facilitate asthma management. These drugs generally achieve their long duration of bronchodilating action as a result of high lipid solubility. This permits them to dissolve in the smooth muscle cell membrane in high concentrations or, possibly, attach to “mooring” molecules in the vicinity of the adrenoceptor. These drugs appear to interact with inhaled corticosteroids to improve asthma control. Because they have no anti-inflammatory action, they should not be used as monotherapy for asthma. Ultra-long-acting β agonists, such as indacaterol, olodaterol, vilanterol, and bambuterol, need to be taken only once a day, but because their prolonged bronchodilation masks symptoms of bronchial inflammation, they should be used only in combination with an ICS for asthma. However, they may be used as mono-therapy for treatment of COPD.


Pharmacology_Katzung

Pharmacology_Katzung. Concerns over the potential toxicities of acute treatment of asthma with inhaled sympathomimetic agents—worsened hypoxemia and cardiac arrhythmia—have been largely put to rest. Although the vasodilating action of β2-agonist treatment may increase perfusion of poorly ventilated lung units, transiently decreasing arterial oxygen tension (PaO2), this effect is small, is easily overcome by the routine administration of supplemental oxygen, and is made irrelevant after a short period of time by the increase in oxygen tension that follows β-agonist-induced bronchodilation. The other concern, precipitation of cardiac arrhythmias, appears unsubstantiated. In patients presenting for emergency treatment of severe asthma, irregularities in cardiac rhythm improve with the improvements in gas exchange effected by bronchodilator treatment and oxygen administration.


Pharmacology_Katzung

Pharmacology_Katzung. Another concern about the administration of β-agonists is their induction of tachyphylaxis. A reduction in the bronchodilator response to low-dose β-agonist treatment can be shown after several days of regular β-agonist use, but maximal bronchodilation is still achieved well within the range of doses usually given. Tachyphylaxis is more clearly reflected by a loss of the protection afforded by acute treatment with a β agonist against a later challenge by exercise or inhalation of allergen or an airway irritant. It remains to be demonstrated in a clinical trial, however, whether this loss of bronchoprotective efficacy is associated with adverse outcomes.


Pharmacology_Katzung

Pharmacology_Katzung. The demonstration of genetic variations in the β receptor raised the possibility that the risks of adverse effects might not be uniformly distributed among asthmatic patients. Attention first focused on a single nucleotide polymorphism (SNP) that changes the amino acid code at position 16 from glycine to arginine (Gly16Arg). Retrospective analyses of studies of regular β-agonist treatment suggested that asthma control deteriorated among patients homozygous for arginine at this locus, prompting speculation that a genetic variant may underlie the controversial reports of increased asthma mortality in studies of very large numbers of patients treated with an LABA (see below). Studies of LABA treatment have since shown, however, that differences in multiple measures of asthma control are negligible in patient groups with different genotypes at that locus. Nonetheless, it is certain that pharmacogenetic studies of asthma treatment will continue to be an active focus of research, as an


Pharmacology_Katzung

Pharmacology_Katzung. negligible in patient groups with different genotypes at that locus. Nonetheless, it is certain that pharmacogenetic studies of asthma treatment will continue to be an active focus of research, as an approach to the development of “personalized therapy.”


Pharmacology_Katzung

Pharmacology_Katzung. The three important methylxanthines are theophylline, theobromine, and caffeine. Their major source is beverages (tea, cocoa, and coffee, respectively). The use of theophylline, once a mainstay of asthma treatment, has almost ceased with demonstration of the greater efficacy of inhaled adrenoceptor agonists for acute asthma and of inhaled anti-inflammatory agents for chronic asthma. Accelerating this decline in theophylline’s use are its toxicities (nausea, vomiting, tremulousness, arrhythmias) and the requirement for monitoring serum levels because of its narrow therapeutic index. This monitoring is made all the more necessary by individual differences in theophylline metabolism and frequent drug-drug interactions. Despite these disadvantages of theophylline, it is still used in some countries because of its low cost.


Pharmacology_Katzung

Pharmacology_Katzung. As shown below (Figure 20–5), theophylline is 1,3-dimethylxanthine; theobromine is 3,7-dimethylxanthine; and caffeine is 1,3,7-trimethylxanthine. A theophylline preparation commonly used for therapeutic purposes is aminophylline, a theophyllineethylenediamine complex. The pharmacokinetics of theophylline are discussed below (see Clinical Uses of Methylxanthines). Its metabolic products, partially demethylated xanthines (not uric acid), are excreted in the urine. FIGURE 20–5 Structures of theophylline and other methylxanthines. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 20–5 Structures of theophylline and other methylxanthines. Mechanism of Action Several mechanisms have been proposed for the actions of methylxanthines, but none has been firmly established. At high concentrations, they can be shown to inhibit several members of the phosphodiesterase (PDE) enzyme family in vitro, thereby increasing concentrations of intracellular cAMP and, in some tissues, cGMP (Figure 20–3). Cyclic AMP regulates many cellular functions including, but not limited to, stimulation of cardiac function, relaxation of smooth muscle, and reduction in the immune and inflammatory activity of specific cells.


Pharmacology_Katzung

Pharmacology_Katzung. Another proposed mechanism for the bronchodilating action of this class of drugs is inhibition of cell surface receptors for adenosine. Adenosine has been shown to provoke contraction of isolated airway smooth muscle and release of histamine from airway mast cells. It has been shown, however, that xanthine derivatives devoid of adenosine antagonism (eg, enprofylline) can inhibit bronchoconstriction in asthmatic subjects.


Pharmacology_Katzung

Pharmacology_Katzung. A third proposed mechanism of action for theophylline’s efficacy is enhancement of histone deacetylation. Acetylation of core histones is necessary for activation of inflammatory gene transcription. Corticosteroids act, at least in part, by recruiting histone deacetylactylases to the site of inflammatory gene transcription, an action enhanced by low-dose theophylline. This interaction should predict that low-dose theophylline treatment would enhance the effectiveness of corticosteroid treatment, but this approach to treating patients with asthma or COPD uncontrolled by ICS plus LABA therapy has not been widely adopted. Of the various isoforms of PDE identified, inhibition of PDE3 appears to be the most involved in relaxing airway smooth muscle and inhibition of PDE4 in inhibiting release of cytokines and chemokines, thus decreasing immune cell migration and activation. This anti-inflammatory effect is achieved at doses lower than those necessary for bronchodilation.


Pharmacology_Katzung

Pharmacology_Katzung. In an effort to reduce toxicity while maintaining therapeutic efficacy, selective inhibitors of PDE4 have been developed. Many were abandoned after clinical trials showed that they induced unacceptably frequent side effects of nausea, headache, and diarrhea. However, one, roflumilast, has been shown to be effective for reducing the frequency of exacerbations of COPD and is approved by the US Food and Drug Administration (FDA) as a treatment for COPD, although not for asthma. The methylxanthines have effects on the central nervous system, kidney, and cardiac and skeletal muscle as well as smooth muscle. Of the three agents, theophylline is most selective in its smooth muscle effects, whereas caffeine has the most marked central nervous system effects. A. Central Nervous System Effects


Pharmacology_Katzung

Pharmacology_Katzung. A. Central Nervous System Effects All methylxanthines, particularly caffeine, cause mild cortical arousal with increased alertness and deferral of fatigue. The caffeine contained in beverages, approximately 100 mg in a cup of coffee, is sufficient to cause nervousness and insomnia in sensitive individuals and slight bronchodilation in patients with asthma. The larger doses necessary for more effective bronchodilation cause nervousness and tremor. Very high doses, from accidental or suicidal overdose, can cause medullary stimulation, convulsions, and even death. B. Cardiovascular Effects


Pharmacology_Katzung

Pharmacology_Katzung. B. Cardiovascular Effects Methylxanthines have positive chronotropic and inotropic effects on the heart. At low concentrations, these effects result from inhibition of presynaptic adenosine receptors in sympathetic nerves, increasing catecholamine release at nerve endings. The higher concentrations (>10 μmol/L, 2 mg/L) associated with inhibition of phosphodiesterase and increases in cAMP may result in increased influx of calcium. At much higher concentrations (>100 μmol/L), sequestration of calcium by the sarcoplasmic reticulum is impaired.


Pharmacology_Katzung

Pharmacology_Katzung. The clinical expression of these effects on cardiovascular function varies among individuals. Ordinary consumption of methylxanthine-containing beverages usually produces slight tachycardia, an increase in cardiac output, and an increase in peripheral resistance, potentially raising blood pressure slightly. In sensitive individuals, consumption of a few cups of coffee may result in arrhythmias. High doses of these agents relax vascular smooth muscle except in cerebral blood vessels, where they cause contraction. Methylxanthines decrease blood viscosity and may improve blood flow under certain conditions. The mechanism of this action is not well defined, but the effect is exploited in the treatment of intermittent claudication with pentoxifylline, a dimethylxanthine agent. C. Effects on Gastrointestinal Tract


Pharmacology_Katzung

Pharmacology_Katzung. C. Effects on Gastrointestinal Tract The methylxanthines stimulate secretion of both gastric acid and digestive enzymes. However, even decaffeinated coffee has a potent stimulant effect on secretion, which means that the primary secretagogue in coffee is not caffeine. D. Effects on Kidney The methylxanthines—especially theophylline—are weak diuretics. This effect may involve both increased glomerular filtration and reduced tubular sodium reabsorption. The diuresis is not of sufficient magnitude to be therapeutically useful, although it does counteract some of the cardiovascular effects and limits the degree of hypertension produced. E. Effects on Smooth Muscle


Pharmacology_Katzung

Pharmacology_Katzung. E. Effects on Smooth Muscle The bronchodilation produced by the methylxanthines is the major therapeutic action in asthma. Tolerance does not develop, but adverse effects, especially in the central nervous system, limit the dose (see below). In addition to their effect on airway smooth muscle, these agents—in sufficient concentration—inhibit antigen-induced release of histamine from lung tissue. F. Effects on Skeletal Muscle The respiratory actions of methylxanthines are not confined to the airways; they also improve contractility of skeletal muscle and reverse fatigue of the diaphragm in patients with COPD. This effect—rather than an effect on the respiratory center—may account for theophylline’s ability to improve the ventilatory response to hypoxia and to diminish dyspnea even in patients with irreversible airflow obstruction.


Pharmacology_Katzung

Pharmacology_Katzung. Of the xanthines, theophylline is the most effective bronchodilator. It relieves airflow obstruction in acute asthma and reduces the severity of symptoms in patients with chronic asthma. However, the efficacy and safety of other drugs, especially inhaled β2agonists and inhaled corticosteroids, and the toxicities and need for monitoring of blood concentration of theophylline have made it almost obsolete in asthma treatment.


Pharmacology_Katzung

Pharmacology_Katzung. Observation of the use of leaves from Datura stramonium for asthma treatment in India led to the discovery of atropine, a potent competitive inhibitor of acetylcholine at postganglionic muscarinic receptors, as a bronchodilator. Interest in the potential value of antimuscarinic agents increased with demonstration of the importance of the vagus nerves in bronchospastic responses of laboratory animals and with the development of ipratropium, a potent atropine analog that is poorly absorbed after aerosol administration and is therefore relatively free of systemic atropine-like effects. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Muscarinic antagonists competitively inhibit the action of acetylcholine at muscarinic receptors and are therefore sometimes referred to as “anticholinergic agents” (see Chapter 8). In the airways, acetylcholine is released from efferent endings of the vagus nerve, and muscarinic antagonists block the contraction of airway smooth muscle and the increase in secretion of mucus that occurs in response to vagal activity (Figure 20–6). This selectivity of muscarinic antagonists accounts for their usefulness as investigative tools to examine the role of parasympathetic reflex pathways in bronchomotor responses but limits their usefulness in preventing bronchospasm. In the doses given, antimuscarinic agents inhibit only that portion of the response mediated by muscarinic receptors, which varies by stimulus and which further appears to vary among individual responses to the same stimulus.


Pharmacology_Katzung

Pharmacology_Katzung. Antimuscarinic agents are effective bronchodilators. Even when administered by aerosol, the bronchodilation achievable with atropine, the prototypic muscarinic antagonist, is limited by absorption into the circulation and across the blood-brain barrier. Greater bronchodilation, with less toxicity from systemic absorption, is achieved with a selective quaternary ammonium derivative of atropine, ipratropium bromide, which can be inhaled in high doses because of its poor absorption into the circulation and poor


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 20–6 Mechanisms of response to inhaled irritants. The airway is represented microscopically by a cross-section of the wall with branching vagal sensory endings lying adjacent to the lumen. Afferent pathways in the vagus nerves travel to the central nervous system; efferent pathways from the central nervous system travel to efferent ganglia. Postganglionic fibers release acetylcholine (ACh), which binds to muscarinic receptors on airway smooth muscle. Inhaled materials may provoke bronchoconstriction by several possible mechanisms. First, they may trigger the release of chemical mediators from mast cells. Second, they may stimulate afferent receptors to initiate reflex bronchoconstriction or to release tachykinins (eg, substance P) that directly stimulate smooth muscle contraction.


Pharmacology_Katzung

Pharmacology_Katzung. entry into the central nervous system. Studies with this agent have shown that the degree of involvement of parasympathetic pathways in bronchomotor responses varies among subjects. This variation indicates that other mechanisms in addition to parasympathetic reflex pathways must be involved. Even though the bronchodilation and inhibition of provoked bronchoconstriction afforded by antimuscarinic agents are incomplete, their use is of clinical value, especially for patients intolerant of inhaled β agonists.


Pharmacology_Katzung

Pharmacology_Katzung. Ipratropium appears to be as effective as albuterol in patients with COPD who have at least partially reversible obstruction. Longer-acting antimuscarinic agents, including tiotropium, aclidinium, and umeclidinium, are approved for maintenance therapy of COPD. These drugs bind to M1, M2, and M3 receptors with equal affinity, but dissociate most rapidly from M2 receptors, expressed on the efferent nerve ending. This means that they do not inhibit the M2-receptor-mediated inhibition of acetylcholine release and thus benefit from a degree of receptor selectivity. They are taken by inhalation. A single dose of 18 mcg of tiotropium or 62.5 mcg of umeclidinium has a 24-hour duration of action, whereas inhalation of 400 mcg of aclidinium has a 12-hour duration of action and is thus taken twice daily. Daily inhalation of tiotropium has been shown not only to improve functional capacity of patients with COPD, but also to reduce the frequency of exacerbations of their condition. These drugs


Pharmacology_Katzung

Pharmacology_Katzung. daily. Daily inhalation of tiotropium has been shown not only to improve functional capacity of patients with COPD, but also to reduce the frequency of exacerbations of their condition. These drugs have not yet been approved as maintenance treatment for asthma, but the addition of tiotropium is no less effective than addition of an LABA in asthmatic patients insufficiently controlled by ICS therapy alone.


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Corticosteroids (specifically, glucocorticoids) have long been used in the treatment of asthma and are presumed to act by their broad anti-inflammatory efficacy, mediated in part by inhibition of production of inflammatory cytokines (see Chapter 39).


Pharmacology_Katzung

Pharmacology_Katzung. They do not relax airway smooth muscle directly but reduce bronchial hyperreactivity and reduce the frequency of asthma exacerbations if taken regularly. Their effect on airway obstruction is due in part to their contraction of engorged vessels in the bronchial mucosa and their potentiation of the effects of β-receptor agonists, but their most important action is inhibition of the infiltration of asthmatic airways by lymphocytes, eosinophils, and mast cells. The remarkable benefits of systemic glucocorticoid treatment for patients with severe asthma have been noted since the 1950s. So too have been its numerous and severe toxicities, especially when given repeatedly, as is necessary for a chronic disease like asthma. The development of beclomethasone in the 1970s as a topically active glucocorticoid preparation that could be taken by inhalation enabled delivery of high doses of a glucocorticoid to the target tissue—the bronchial mucosa—with little absorption into the systemic


Pharmacology_Katzung

Pharmacology_Katzung. glucocorticoid preparation that could be taken by inhalation enabled delivery of high doses of a glucocorticoid to the target tissue—the bronchial mucosa—with little absorption into the systemic circulation. The development of ICS has transformed the treatment of all but mild, intermittent asthma, which can be treated with “as-needed” use of albuterol alone.


Pharmacology_Katzung

Pharmacology_Katzung. Clinical studies of corticosteroids consistently show them to be effective in improving all indices of asthma control: severity of symptoms, tests of airway caliber and bronchial reactivity, frequency of exacerbations, and quality of life. Because of severe adverse effects when given chronically, oral and parenteral corticosteroids are reserved for patients who require urgent treatment, ie, those who have not improved adequately with bronchodilators or who experience worsening symptoms despite high-dose maintenance therapy. For severe asthma exacerbations, urgent treatment is often begun with an oral dose of 30–60 mg prednisone per day or an intravenous dose of 0.5–1 mg/kg methylprednisolone every 6–12 hours; the dose is decreased after airway obstruction has improved. In most patients, systemic corticosteroid therapy can be discontinued in 5–10 days, but symptoms may worsen in other patients as the dose is decreased to lower levels.


Pharmacology_Katzung

Pharmacology_Katzung. Inhalational treatment is the most effective way to avoid the systemic adverse effects of corticosteroid therapy. The introduction of ICS such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone, and triamcinolone has made it possible to deliver corticosteroids to the airways with minimal systemic absorption. An average daily dose of 800 mcg of inhaled beclomethasone is equivalent to about 10–15 mg/d of oral prednisone for the control of asthma, with far fewer systemic effects. Indeed, one of the cautions in switching patients from chronic oral to ICS therapy is to taper oral therapy slowly to avoid precipitation of adrenal insufficiency. In patients requiring continued prednisone treatment despite standard doses of an ICS, higher inhaled doses are often effective and enable tapering and discontinuing prednisone treatment. Although these high doses of inhaled steroids may cause mild adrenal suppression, the risks of systemic toxicity from their chronic use


Pharmacology_Katzung

Pharmacology_Katzung. and enable tapering and discontinuing prednisone treatment. Although these high doses of inhaled steroids may cause mild adrenal suppression, the risks of systemic toxicity from their chronic use are negligible compared with those of the oral corticosteroid therapy they replace.


Pharmacology_Katzung

Pharmacology_Katzung. A special problem caused by inhaled topical corticosteroids is the occurrence of oropharyngeal candidiasis. This is easily treated with topical clotrimazole, and the risk of this complication can be reduced by having patients gargle water and expectorate after each inhaled treatment. Ciclesonide, a prodrug activated by bronchial esterases, is comparably effective to other inhaled corticosteroids and is associated with less frequent candidiasis. Hoarseness can also result from a direct local effect of ICS on the vocal cords. Although a majority of the inhaled dose is deposited in the oropharynx and swallowed, inhaled corticosteroids are subject to first-pass metabolism in the liver and thus are remarkably free of other short-term complications in adults. Nonetheless, chronic use may increase the risks of osteoporosis and cataracts. In children, ICS therapy has been shown to slow the rate of growth by about 1 cm over the first year of treatment, but not the rate of growth thereafter, so


Pharmacology_Katzung

Pharmacology_Katzung. the risks of osteoporosis and cataracts. In children, ICS therapy has been shown to slow the rate of growth by about 1 cm over the first year of treatment, but not the rate of growth thereafter, so that the effect on adult height is minimal.


Pharmacology_Katzung

Pharmacology_Katzung. Because of the efficacy and safety of inhaled corticosteroids, national and international guidelines for asthma management recommend their prescription for patients with persistent asthma who require more than occasional inhalations of a β agonist for relief of symptoms. This therapy is continued for 10–12 weeks and then withdrawn to determine whether more prolonged therapy is needed; inhaled corticosteroids are not curative. In most patients, the manifestations of asthma return within a few weeks after stopping therapy even if they have been taken in high doses for 2 or more years. A prospective, placebo-controlled study of the early, sustained use of inhaled corticosteroids in young children with asthma showed significantly greater improvement in asthma symptoms, pulmonary function, and frequency of asthma exacerbations over the 2 years of treatment, but no difference in overall asthma control 3 months after the end of the trial. inhaled corticosteroids are thus properly labeled as


Pharmacology_Katzung

Pharmacology_Katzung. frequency of asthma exacerbations over the 2 years of treatment, but no difference in overall asthma control 3 months after the end of the trial. inhaled corticosteroids are thus properly labeled as “controllers.” They are effective only so long as they are taken.


Pharmacology_Katzung

Pharmacology_Katzung. Another approach to reducing the risk of long-term, twice-daily use of ICS is to administer them only intermittently, when symptoms of asthma flare. Taking a single inhalation of an ICS with each inhalation of a short-acting β-agonist reliever (eg, an inhalation of beclomethasone for each inhalation of albuterol) or taking a 5to 10-day course of twice-daily high-dose budesonide or beclomethasone when asthma symptoms worsen has been found to be nearly as effective as regular daily therapy in adults and children with mild to moderate asthma, although these approaches to treatment are neither endorsed by guidelines for asthma management nor approved by the FDA.


Pharmacology_Katzung

Pharmacology_Katzung. Cromolyn sodium (disodium cromoglycate) and nedocromil sodium were once widely used for asthma management, especially in children, but have now been supplanted so completely by other therapies that they are mostly of historic interest as asthma treatments. These drugs are thought to act by inhibiting mast cell degranulation and, as such, have no direct bronchodilator action, but inhibit both antigenand exercise-induced bronchospasm in asthmatic patients. When taken regularly (2–4 puffs 2–4 times daily), these agents modestly but significantly reduce symptomatic severity and the need for bronchodilator medications, particularly in young patients with allergic asthma. These drugs are poorly absorbed into the systemic circulation and have little toxicity, but are not as FIGURE 20–7 Structures of leukotriene receptor antagonists potent or as predictably effective as ICS. (montelukast, zafirlukast) and of the 5-lipoxygenase inhibitor


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 20–7 Structures of leukotriene receptor antagonists potent or as predictably effective as ICS. (montelukast, zafirlukast) and of the 5-lipoxygenase inhibitor The main indication for current use of cromolyn is for reducing symptoms of allergic rhinoconjunctivitis. Applying cromolyn solution by eye drops twice a day is effective in about 75% of patients, even during the peak pollen season. Another indication is the rare disease of systemic mastocytosis for which an oral dose of a solution of 200 mg of cromolyn in water (Gastrocrom) taken four times per day helps control the abdominal cramping and diarrhea caused by activation of overabundant mast cells in the gastrointestinal mucosa.


Pharmacology_Katzung

Pharmacology_Katzung. The involvement of leukotrienes in many inflammatory diseases (see Chapter 18) and in anaphylaxis prompted the development of drugs that block their synthesis or interaction with their receptors. Leukotrienes result from the action of 5-lipoxygenase on arachidonic acid and are synthesized by a variety of inflammatory cells in the airways, including eosinophils, mast cells, macrophages, and basophils. Leukotriene B4 (LTB4) is a potent neutrophil chemoattractant, and LTC4 and LTD4 exert many effects known to occur in asthma, including bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion.


Pharmacology_Katzung

Pharmacology_Katzung. Two approaches to interrupting the leukotriene pathway have been pursued: inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis; and inhibition of the binding of LTD4 to its receptor on target tissues, thereby preventing its action. Efficacy in blocking airway responses to exercise and to antigen challenge has been shown for drugs in both categories: zileuton, a 5-lipoxygenase inhibitor, and zafirlukast and montelukast, LTD4-receptor antagonists (Figure 20–7). All three drugs have been shown to improve asthma control and to reduce the (zileuton).


Pharmacology_Katzung

Pharmacology_Katzung. frequency of asthma exacerbations in clinical trials. They are not as effective as even low-dose ICS therapy in inducing and maintaining asthma control, but are preferred by many patients, especially by the parents of asthmatic children, because of often exaggerated concerns over the toxicities of corticosteroids. They have the additional advantage of being effective when taken orally, which is an easier route of administration than aerosol inhalation in young children, and montelukast is approved for children as young as 12 months of age.


Pharmacology_Katzung

Pharmacology_Katzung. Some patients appear to have particularly favorable responses, but apart from the subclass of patients with aspirin-exacerbated respiratory disease (described below), no clinical features allow identification of “responders” before a trial of therapy. In the USA, zileuton is approved for use in an oral dosage of 1200 mg of the sustained-release form twice daily; zafirlukast, 20 mg twice daily; and montelukast, 10 mg (for adults) or 4 mg (for children) once daily.


Pharmacology_Katzung

Pharmacology_Katzung. Trials with leukotriene inhibitors have demonstrated an important role for leukotrienes in aspirin-exacerbated respiratory disease (AERD), a disease that combines the features of asthma, chronic rhinosinusitis with nasal polyposis, and reactions to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase-1 (COX-1). Aspirin-exacerbated respiratory disease occurs in approximately 5–10% of patients with asthma. In these patients, ingestion of even a very small dose of aspirin causes profound bronchoconstriction, nasal congestion, and symptoms of systemic release of histamine, such as flushing and abdominal cramping. Because this reaction to aspirin is not associated with any evidence of allergic sensitization to aspirin or its metabolites and because it is produced by any of the NSAIDs that target COX-1, AERD is thought to result from inhibition of prostaglandin synthetase (cyclooxygenase), shifting arachidonic acid metabolism from the prostaglandin to


Pharmacology_Katzung

Pharmacology_Katzung. produced by any of the NSAIDs that target COX-1, AERD is thought to result from inhibition of prostaglandin synthetase (cyclooxygenase), shifting arachidonic acid metabolism from the prostaglandin to the leukotriene pathway, especially in platelets adherent to circulating neutrophils. Support for this idea was provided by the demonstration that leukotriene pathway inhibitors impressively reduce the response to aspirin challenge and improve overall control of asthma on a day-to-day basis.


Pharmacology_Katzung

Pharmacology_Katzung. Of these agents, montelukast is by far the most prescribed, because it may be taken without regard to meals, is taken once daily, and does not require periodic monitoring of liver function, as zileuton does. Although not considered first-line therapy, the leukotriene-modifying agents are sometimes given in lieu of inhaled corticosteroids for mild asthma when prescription of an ICS meets patient resistance. The receptor antagonists have little toxicity. Early reports of Churg-Strauss syndrome (a systemic vasculitis accompanied by worsening asthma, pulmonary infiltrates, and eosinophilia) appear to have been coincidental, with the syndrome unmasked by the reduction in prednisone dosage made possible by the addition of zafirlukast or montelukast.


Pharmacology_Katzung

Pharmacology_Katzung. As the pathophysiologic mechanisms responsible for asthma have become better understood, anti-inflammatory therapy targeting specific inflammatory pathways has been developed. Specifically, monoclonal antibodies targeting IgE and IL-5 have been brought to market, and an antibody targeting the receptor for IL-4 and IL-13 is under development (Table 20–1). The monoclonal antibody omalizumab was raised in mice and then humanized, making it less likely to cause sensitization when given to human subjects (see Chapter 55). Because its specific target is the portion of IgE that binds to its receptors (Fcε-R1 and TABLE 20–1 Monoclonal antibodies for use in asthma.1 1Approved or in phase 2 or 3 clinical trials. Fcε-R2 receptors) on dendritic cells, basophils, mast cells, and other inflammatory cells, omalizumab inhibits the binding of IgE but does not activate IgE already bound to its receptor and thus does not provoke mast cell degranulation.


Pharmacology_Katzung

Pharmacology_Katzung. Omalizumab’s use is restricted to patients with severe asthma and evidence of allergic sensitization, and the dose administered is adjusted for total IgE level and body weight. Administered by subcutaneous injection every 2–4 weeks to asthmatic patients, it lowers free plasma IgE to undetectable levels and significantly reduces the magnitude of both early and late bronchospastic responses to antigen challenge. Omalizumab’s most important clinical effect is reduction in the frequency and severity of asthma exacerbations, while enabling a reduction in corticosteroid requirements. Combined analysis of several clinical trials has shown that the patients most likely to respond are those with a history of repeated exacerbations, a high requirement for corticosteroid treatment, and poor pulmonary function. Similarly, the exacerbations most often prevented are the most severe; omalizumab treatment reduced exacerbations requiring hospitalization by 88%. Because exacerbations drive so much of


Pharmacology_Katzung

Pharmacology_Katzung. function. Similarly, the exacerbations most often prevented are the most severe; omalizumab treatment reduced exacerbations requiring hospitalization by 88%. Because exacerbations drive so much of the direct and indirect costs of asthma, these benefits can justify omalizumab’s high cost.


Pharmacology_Katzung

Pharmacology_Katzung. The addition of omalizumab to standard, guideline-based therapy for asthmatic inner-city children and adolescents in early summer significantly improved overall asthma control, reduced the need for other medications, and nearly eliminated the autumnal peak in exacerbations. Omalizumab has also been proven effective as a treatment for chronic recurrent urticaria (for which the drug is now approved) and for peanut allergy.


Pharmacology_Katzung

Pharmacology_Katzung. T2 cells secrete IL-5 as a pro-eosinophilic cytokine that results in eosinophilic airway inflammation. Although not central to the mechanisms of asthma in all patients, a substantial proportion of patients with severe asthma have airway and peripheral eosinophilia driven by up-regulation of IL-5-secreting T2 lymphocytes. Two humanized monoclonal antibodies targeting IL-5, mepolizumab and reslizumab, and another targeting the IL-5 receptor, benralizumab, have recently been developed for the treatment of eosinophilic asthma. Clinical trials with these drugs have shown them to be effective in preventing exacerbations in asthmatic patients with peripheral eosinophilia, leading to their approval as add-on, maintenance therapy of severe asthma in patients with an eosinophilic phenotype.


Pharmacology_Katzung

Pharmacology_Katzung. Like omalizumab, reslizumab carries a small (0.3%) risk of anaphylaxis, and a period of observation following infusion is recommended. Mepolizumab, although not associated with anaphylaxis, has resulted in reports of hypersensitivity. In addition, reactivation of herpes zoster has been reported in some patients who received mepolizumab. Clinical trials of dupilumab (an antibody directed against the IL-4α co-receptor for both IL-4 and IL-13; not yet approved) have shown it to reduce exacerbation frequency and improve measures of asthma control in patients with and without systemic eosinophilia and, further, to markedly reduce the severity of allergic dermatitis.


Pharmacology_Katzung

Pharmacology_Katzung. Ironically, the effectiveness of ICS as a treatment for most patients with asthma, especially young adults with allergic asthma, may have retarded recognition that the term “asthma” encompasses a heterogeneous collection of disorders, many of which are poorly responsive to corticosteroid treatment. The existence of different forms or subtypes of asthma has actually long been recognized, as implied by the use of modifying terms such as “extrinsic,” “intrinsic,” “aspirin-sensitive,” “adult-onset,” “steroid-dependent,” “exacerbation-prone,” “seasonal,” “postviral,” and “obesity-related” to describe asthma in particular patients. More rigorous description of asthma phenotypes, based on cluster analysis of multiple clinical, physiologic, and laboratory features, including analysis of blood and sputum inflammatory cell assessments, has identified as many as five different asthma phenotypes. The key question raised by this approach is whether the phenotypes respond differently to available


Pharmacology_Katzung

Pharmacology_Katzung. sputum inflammatory cell assessments, has identified as many as five different asthma phenotypes. The key question raised by this approach is whether the phenotypes respond differently to available asthma treatments.


Pharmacology_Katzung

Pharmacology_Katzung. Persuasive evidence of the existence of different asthma phenotypes requiring different approaches to therapy is the demonstration of differences in the pattern of gene expression in the airway epithelium of asthmatic and healthy subjects. Compared with healthy controls, half of the asthmatic participants overexpressed genes for periostin, CLCA1, and serpinB2, genes known to be up-regulated in airway epithelial cells by IL-13, a signature cytokine of T2 lymphocytes. The other half of the asthmatic participants did not. These findings suggest that fundamentally different pathophysiologic mechanisms exist even among patients with mild asthma. The participants with overexpression of genes up-regulated by IL-13 are referred to as having a “T2-high molecular phenotype” of asthma. The other subjects, who did not overexpress these genes, are described as having a “non-T2”or “T2-low” molecular phenotype. The T2-high asthmatic subjects on average tended to have more sputum eosinophilia and


Pharmacology_Katzung

Pharmacology_Katzung. subjects, who did not overexpress these genes, are described as having a “non-T2”or “T2-low” molecular phenotype. The T2-high asthmatic subjects on average tended to have more sputum eosinophilia and blood eosinophilia, positive skin test results, higher levels of IgE, and greater expression of certain mucin genes. The response to ICS treatment of these two groups was quite different. Six weeks of treatment with an ICS improved forced expiratory volume in 1 second (FEV1) only in the T2-high subjects. The implications of these findings are far reaching because they indicate that perhaps as many as half of patients with mild to moderate asthma do not respond to ICS therapy. The proportion of non-ICS responders among patients with severe “steroid-resistant” asthma could be much higher.


Pharmacology_Katzung

Pharmacology_Katzung. Current research focuses on further exploring molecular phenotypes in asthma and in finding effective treatments for each group. An investigational IL-13 receptor antagonist, lebrikizumab, for example, has been shown to be more effective in asthmatic subjects with elevated serum levels of periostin (one of the genes up-regulated in the “T2-high molecular phenotype”). To examine whether tiotropium might be an alternative to ICS therapy for “T2-low” asthma, a NIH–sponsored multicenter trial is embarking on a prospective, double-blind, placebo-controlled trial of ICS versus tiotropium in asthmatic subjects characterized as T2-high or non-T2-high by analysis of their induced sputum samples for eosinophil number and for expression of T2-dependent genes (https://clinicaltrials.gov/ct2/ show/NCT02066298).


Pharmacology_Katzung

Pharmacology_Katzung. The pace of advance in the scientific description of the immunopathogenesis of asthma has spurred the development of many new therapies that target different sites in the immune cascade. Beyond the monoclonal antibodies directed against cytokines (IL-4, IL-5, IL-13) already reviewed (Table 20–1), these include antagonists of cell adhesion molecules, protease inhibitors, and immunomodulators aimed at shifting CD4 lymphocytes from the Th2 to the Th1 subtype or at selective inhibition of the subset of Th2 lymphocytes directed against particular antigens. As these new therapies are developed, it will become increasingly important to identify biomarkers of specific phenotypes of asthma that are most likely to benefit from specific therapies. This will enable truly personalized asthma therapy.


Pharmacology_Katzung

Pharmacology_Katzung. National and international guidelines for asthma emphasize the need for adjusting the intensity of asthma therapy to the underlying severity of the disease and the level of control achieved by the patient’s current treatment (https://www.nhlbi.nih.gov/ health-pro/guidelines/current/asthma-guidelines; ginasthma.org). An underlying principle common to these guidelines is that asthma should be considered in two time domains. In the present domain, asthma is important for the symptoms and impairments it causes—cough, nocturnal awakenings, and shortness of breath that interfere with the ability to exercise or to pursue desired activities. For mild asthma, occasional inhalation of a bronchodilator may be all that is needed to control these symptoms. For more severe asthma, treatment with a long-term controller, like an ICS, is necessary to relieve symptoms and restore function. The second domain of asthma is the risk it presents of future events, such as exacerbations or progressive loss of


Pharmacology_Katzung

Pharmacology_Katzung. controller, like an ICS, is necessary to relieve symptoms and restore function. The second domain of asthma is the risk it presents of future events, such as exacerbations or progressive loss of pulmonary function. Satisfaction with the ability to control symptoms and maintain function by frequent use of an inhaled β2 agonist does not mean that the risk of future events is also controlled. In fact, use of two or more canisters of an inhaled β agonist per month is a marker for increased risk of asthma fatality.


Pharmacology_Katzung

Pharmacology_Katzung. The challenges of assessing severity and adjusting therapy for these two domains of asthma are different. For relief of distress in the present domain, the key information is obtained by asking specific questions about the frequency and severity of symptoms, the frequency of rescue use of an inhaled β agonist, the frequency of nocturnal awakenings, and the ability to exercise, and by measuring lung function with spirometry. The best predictor of the risk for future exacerbations is the frequency and severity of their occurrence in the past. Without such a history, estimation of risk is more difficult. In general, patients with poorly controlled symptoms have a heightened risk of exacerbations in the future, but some patients seem unaware of the severity of their airflow obstruction (sometimes described as “poor perceivers”) and can be identified only by measurement of pulmonary function. Reductions in the FEV1 correlate with heightened risk of future attacks of asthma. Other possible


Pharmacology_Katzung

Pharmacology_Katzung. described as “poor perceivers”) and can be identified only by measurement of pulmonary function. Reductions in the FEV1 correlate with heightened risk of future attacks of asthma. Other possible markers of heightened risk are unstable pulmonary function (large variations in FEV1 from visit to visit, large change with bronchodilator treatment), extreme bronchial reactivity, high numbers of eosinophils in blood or sputum, and high levels of nitric oxide in exhaled air. Assessment of these features may identify patients who need increases in therapy for protection against future exacerbations.