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These agents are prodrugs that are sources of nitric oxide (NO). NO activates the soluble isoform of guanylyl cyclase, thereby increasing intracellular levels of cyclic GMP. In turn, cyclic GMP promotes the dephosphorylation of the myosin light chain and the reduction of cystolic Ca2+ and leads to the relaxation of smooth muscle cells in a broad range of tissues. The NO-dependent relaxation of vascular smooth muscle leads to vasodilation; NO-mediated guanylyl cyclase activation inhibits platelet aggregation and relaxes smooth muscle in the bronchi and GI tract (Murad, 1996).
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The broad biological response to nitrovasodilators reflects the existence of endogenous NO-modulated regulatory pathways. The endogenous synthesis of NO in humans is catalyzed by a family of NO synthases that oxidize the amino acid l-arginine to form NO, plus l-citrulline as a co-product. There are three distinct mammalian NO synthase isoforms termed nNOS, eNOS, and iNOS (see Chapter 3), and they are involved in processes as diverse as neurotransmission, vasomotion, and immunomodulation. In several vascular disease states, pathways of endogenous NO-dependent regulation appear to be deranged (reviewed in Dudzinski et al., 2006).
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History. Nitroglycerin was first synthesized in 1846 by Sobrero, who observed that a small quantity placed on the tongue elicited a severe headache. The explosive properties of nitroglycerin also were soon noted, and control of this unstable compound for military and industrial use was not realized until Alfred Nobel devised a process to stabilize the nitroglycerin and patented a specialized detonator in 1863. The vast fortune that Nobel accrued from the nitroglycerin detonator patent provided the funds later used to establish the Nobel prizes. In 1857, T. Lauder Brunton of Edinburgh administered amyl nitrite, a known vasodepressor, by inhalation and noted that anginal pain was relieved within 30- 60 seconds. The action of amyl nitrite was transitory, however, and the dosage was difficult to adjust. Subsequently, William Murrell surmised that the action of nitroglycerin mimicked that of amyl nitrite and established the use of sublingual nitroglycerin for relief of the acute anginal attack and as a prophylactic agent to be taken prior to exertion. The empirical observation that organic nitrates could dramatically and safely alleviate the symptoms of angina pectoris led to their widespread acceptance by the medical profession. Indeed, Alfred Nobel himself was prescribed nitroglycerin by his physicians when he developed angina in 1890. Basic investigations defined the role of NO in both the vasodilation produced by nitrates and endogenous vasodilation. The importance of NO as a signaling molecule in the cardiovascular system and elsewhere was recognized by the awarding of the 1998 Nobel Prize in medicine/physiology to the pharmacologists Robert Furchgott, Louis Ignarro, and Ferid Murad.
Chemistry. Organic nitrates are polyol esters of nitric acid, whereas organic nitrites are esters of nitrous acid (Table 27–1). Nitrate esters (—C—O—NO2) and nitrite esters (—C—O—NO) are characterized by a sequence of carbon–oxygen–nitrogen, whereas nitro compounds possess carbon–nitrogen bonds (C—NO2). Thus glyceryl trinitrate is not a nitro compound, and it is erroneously called nitroglycerin; however, this nomenclature is both widespread and official. Amyl nitrite is a highly volatile liquid that must be administered by inhalation and is of limited therapeutic utility. Organic nitrates of low molecular mass (such as nitroglycerin) are moderately volatile, oily liquids, whereas the high-molecular-mass nitrate esters (e.g., erythrityl tetranitrate, isosorbide dinitrate, and isosorbide mononitrate) are solids. In the pure form (without an inert carrier such as lactose), nitroglycerin is explosive. The organic nitrates and nitrites, collectively termed nitrovasodilators, must be metabolized (reduced) to produce gaseous NO, which appears to be the active principle of this class of compounds. Nitric oxide gas also can be directly administered by inhalation (Bloch et al., 2007).
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Pharmacological Properties
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Mechanism of Action. Nitrites, organic nitrates, nitroso compounds, and a variety of other nitrogen oxide–containing substances (including nitroprusside; see later in the chapter) lead to the formation of the reactive gaseous free radical NO and related NO-containing compounds. Nitric oxide gas also may be administered by inhalation. The exact mechanism(s) of denitration of the organic nitrates to liberate NO remains an active area of investigation (Chen et al., 2002).
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Phosphorylation of the myosin light chain regulates the maintenance of the contractile state in smooth muscle. NO can activate guanylyl cyclase, increase the cellular level of cyclic GMP, activate PKG, and modulate the activities of cyclic nucleotide phosphodiesterases (PDEs 2, 3, and 5) in a variety of cell types. In smooth muscle, the net result is reduced phosphorylation of myosin light chain, reduced Ca2+ concentration in the cytosol, and relaxation. One important consequence of the NO-mediated increase in intracellular cyclic GMP is the activation of PKG, which catalyzes the phosphorylation of various proteins in smooth muscle. Another important target of this kinase is the myosin light-chain phosphatase, which is activated on binding PKG and leads to dephosphorylation of the myosin light chain and thereby promotes vasorelaxation and smooth muscle relaxation in many other tissues.
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The pharmacological and biochemical effects of the nitrovasodilators appear to be identical to those of an endothelium-derived relaxing factor now known to be NO. Although the soluble isoform of guanylyl cyclase remains the most extensively characterized molecular "receptor" for NO, it is increasingly clear that NO also forms specific adducts with thiol groups in proteins and with reduced glutathione to form nitrosothiol compounds with distinctive biological properties (Stamler et al., 2001). Mitochondrial aldehyde dehydrogenase has been shown to catalyze the reduction of nitroglycerin to yield bioactive NO metabolites (Chen et al., 2002), providing a potentially important clue to the biotransformation of organic nitrates in intact tissues. The regulation and pharmacology of eNOS have been reviewed (Dudzinski et al., 2006).
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Cardiovascular Effects Hemodynamic Effects. The nitrovasodilators promote relaxation of vascular smooth muscle. Low concentrations of nitroglycerin preferentially dilate veins more than arterioles. This venodilation decreases venous return, leading to a fall in left and right ventricular chamber size and end-diastolic pressures, but usually results in little change in systemic vascular resistance. Systemic arterial pressure may fall slightly, and heart rate is unchanged or may increase slightly in response to a decrease in blood pressure. Pulmonary vascular resistance and cardiac output are slightly reduced. Doses of nitroglycerin that do not alter systemic arterial pressure may still produce arteriolar dilation in the face and neck, resulting in a facial flush, or dilation of meningeal arterial vessels, causing headache. The molecular basis for the differential response of arterial versus venous tissues to nitroglycerin remains incompletely understood.
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Higher doses of organic nitrates cause further venous pooling and may decrease arteriolar resistance as well, thereby decreasing systolic and diastolic blood pressure and cardiac output and causing pallor, weakness, dizziness, and activation of compensatory sympathetic reflexes. The reflex tachycardia and peripheral arteriolar vasoconstriction tend to restore systemic vascular resistance; this is superimposed on sustained venous pooling. Coronary blood flow may increase transiently as a result of coronary vasodilation but may decrease subsequently if cardiac output and blood pressure decrease sufficiently.
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In patients with autonomic dysfunction and an inability to increase sympathetic outflow (multiple-system atrophy and pure autonomic failure are the most common forms, much less commonly seen in the autonomic dysfunction associated with diabetes), the fall in blood pressure consequent to the venodilation produced by nitrates cannot be compensated. In these clinical contexts, nitrates may reduce arterial pressure and coronary perfusion pressure significantly, producing potentially life-threatening hypotension and even aggravating angina. The appropriate therapy in patients with orthostatic angina and normal coronary arteries is to correct the orthostatic hypotension by expanding volume (fludrocortisone and a high-sodium diet), to prevent venous pooling with fitted support garments, and to carefully titrate use of oral vasopressors. Because patients with autonomic dysfunction occasionally may have coexisting coronary artery disease, the coronary anatomy should be defined before therapy is undertaken.
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Effects on Total and Regional Coronary Blood Flow. Myocardial ischemia is a powerful stimulus to coronary vasodilation, and regional blood flow is adjusted by autoregulatory mechanisms. In the presence of atherosclerotic coronary artery narrowing, ischemia distal to the lesion stimulates vasodilation; if the stenosis is severe, much of the capacity to dilate is used to maintain resting blood flow. When demand increases, further dilation may not be possible. After demonstration of direct coronary artery vasodilation in experimental animals, it became generally accepted that nitrates relieved anginal pain by dilating coronary arteries and thereby increasing coronary blood flow. In the presence of significant coronary stenoses, there is a disproportionate reduction in blood flow to the subendocardial regions of the heart, which are subjected to the greatest extravascular compression during systole; organic nitrates tend to restore blood flow in these regions toward normal.
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The hemodynamic mechanisms responsible for these effects are not entirely clear. Most hypotheses have focused on the ability of organic nitrates to cause dilation and prevent vasoconstriction of large epicardial vessels without impairing autoregulation in the small vessels, which are responsible for ~90% of the overall coronary vascular resistance. The vessel diameter is an important determinant of the response to nitroglycerin; vessels >200 μm in diameter are highly responsive, whereas those >100 μm respond minimally. Experimental evidence in patients undergoing coronary bypass surgery indicates that nitrates do have a relaxant effect on large coronary vessels. Collateral flow to ischemic regions also is increased. Moreover, analyses of coronary angiograms in humans have shown that sublingual nitroglycerin can dilate epicardial stenoses and reduce the resistance to flow through such areas (Brown et al., 1981; Feldman et al., 1981). The resulting increase in blood flow would be distributed preferentially to ischemic myocardial regions as a consequence of vasodilation induced by autoregulation. An important indirect mechanism for a preferential increase in subendocardial blood flow is the nitroglycerin-induced reduction in intracavitary systolic and diastolic pressures that oppose blood flow to the subendocardium (see below). To the extent that organic nitrates decrease myocardial requirements for O2 (see the next section), the increased blood flow in ischemic regions could be balanced by decreased flow in nonischemic areas, and an overall increase in coronary artery blood flow need not occur. Dilation of cardiac veins may improve the perfusion of the coronary microcirculation. Such redistribution of blood flow to subendocardial tissue is not typical of all vasodilators. Dipyridamole, e.g., dilates resistance vessels nonselectively by distorting autoregulation and is ineffective in patients with typical angina.
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In patients with angina owing to coronary artery spasm, the ability of organic nitrates to dilate epicardial coronary arteries, and particularly regions affected by spasm, may be the primary mechanism by which they are of benefit.
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Effects on Myocardial O2 Requirements. By their effects on the systemic circulation, the organic nitrates also can reduce myocardial O2 demand. The major determinants of myocardial O2 consumption include left ventricular wall tension, heart rate, and myocardial contractility. Ventricular wall tension is affected by a number of factors that may be considered under the categories of preload and afterload. Preload is determined by the diastolic pressure that distends the ventricle (ventricular end-diastolic pressure). Increasing end-diastolic volume augments the ventricular wall tension (by the law of Laplace, tension is proportional to pressure times radius). Increasing venous capacitance with nitrates decreases venous return to the heart, decreases ventricular end-diastolic volume, and thereby decreases O2 consumption. An additional benefit of reducing preload is that it increases the pressure gradient for perfusion across the ventricular wall, which favors subendocardial perfusion. Afterload is the impedance against which the ventricle must eject. In the absence of aortic valvular disease, afterload is related to peripheral resistance. Decreasing peripheral arteriolar resistance reduces afterload and thus myocardial work and O2 consumption.
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Organic nitrates decrease both preload and afterload as a result of respective dilation of venous capacitance and arteriolar resistance vessels. Organic nitrates do not appear to significantly alter the inotropic or chronotropic state of the heart, although NO synthesized by cardiac myocytes and fibroblasts may play a role in the modulation of cyclic nucleotide metabolism and may thereby alter autonomic responses (Gustafsson and Brunton, 2002). Because nitrates affect several of the primary determinants of myocardial O2 demand, their net effect usually is to decrease myocardial O2 consumption. In addition, an improvement in the lusitropic state of the heart may be seen with more rapid early diastolic filling. This may be secondary to the relief of ischemia rather than primary, or it may be due to a reflex increase in sympathetic activity. Nitrovasodilators also increase cyclic GMP in platelets, with consequent inhibition of platelet function (Loscalzo, 2001) and decreased deposition of platelets in animal models of arterial wall injury (Lam et al., 1988). While this may contribute to their anti-anginal efficacy, the effect appears to be modest and in some settings may be confounded by the potential of nitrates to alter the pharmacokinetics of heparin, reducing its anti-thrombotic effect.
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When nitroglycerin is injected or infused directly into the coronary circulation of patients with coronary artery disease, anginal attacks (induced by electrical pacing) are not aborted even when coronary blood flow is increased. However, sublingual administration of nitroglycerin does relieve anginal pain in the same patients. Furthermore, venous phlebotomy that is sufficient to reduce left ventricular end-diastolic pressure can mimic the beneficial effect of nitroglycerin.
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Patients can exercise for considerably longer periods after the administration of nitroglycerin. Nevertheless, with or without nitroglycerin, angina occurs at the same value of the triple product (aortic pressure × heart rate × ejection time, which is roughly proportional to myocardial consumption of O2). The observation that angina occurs at the same level of myocardial O2 consumption suggests that the beneficial effects of nitroglycerin result from reduced cardiac O2 demand rather than an increase in the delivery of O2 to ischemic regions of myocardium. However, these results do not preclude the possibility that a favorable redistribution of blood flow to ischemic subendocardial myocardium may contribute to relief of pain in a typical anginal attack, nor do they preclude the possibility that direct coronary vasodilation may be the major effect of nitroglycerin in situations where vasospasm compromises myocardial blood flow.
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Mechanism of Relief of Symptoms of Angina Pectoris. The ability of nitrates to dilate epicardial coronary arteries, even in areas of atherosclerotic stenosis, is modest, and the preponderance of evidence continues to favor a reduction in myocardial work, and thus in myocardial O2 demand, as their primary effect in chronic stable angina.
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Paradoxically, high doses of organic nitrates may reduce blood pressure to such an extent that coronary flow is compromised; reflex tachycardia and adrenergic enhancement of contractility also occur. These effects may override the beneficial action of the drugs on myocardial O2 demand and can aggravate ischemia. Additionally, sublingual nitroglycerin administration may produce bradycardia and hypotension, probably owing to activation of the Bezold-Jarisch reflex.
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Other Effects. The nitrovasodilators act on almost all smooth muscle tissues. Bronchial smooth muscle is relaxed irrespective of the preexisting tone. The muscles of the biliary tract, including those of the gallbladder, biliary ducts, and sphincter of Oddi, are effectively relaxed. Smooth muscle of the GI tract, including that of the esophagus, can be relaxed and its spontaneous motility decreased by nitrates both in vivo and in vitro. The effect may be transient and incomplete in vivo, but abnormal "spasm" frequently is reduced. Indeed, many incidences of atypical chest pain and "angina" are due to biliary or esophageal spasm, and these too can be relieved by nitrates. Similarly, nitrates can relax ureteral and uterine smooth muscle, but these responses are of uncertain clinical significance.
Absorption, Fate, and Excretion. More than a century after the first use of organic nitrates to treat angina pectoris, their biotransformation remains the subject of active investigation. Studies in the 1970s suggested that nitroglycerin is reductively hydrolyzed by hepatic glutathione–organic nitrate reductase. More recent studies have implicated a mitochondrial aldehyde dehydrogenase enzyme in the biotransformation of nitroglycerin (Chen et al., 2002). Other enzymatic and nonenzymatic pathways also may contribute to the biotransformation of nitrovasodilators. Despite uncertainties about the quantitative importance of the various pathways involved in nitrovasodilator metabolism, the pharmacokinetic properties of nitroglycerin and isosorbide dinitrate have been studied in some detail (Parker and Parker, 1998).
Preparations
Nitroglycerin. In humans, peak concentrations of nitroglycerin are found in plasma within 4 minutes of sublingual administration; the drug has a t1/2 of 1-3 minutes. The onset of action of nitroglycerin may be even more rapid if it is delivered as a sublingual spray rather than as a sublingual tablet. Glyceryl dinitrate metabolites, which have about one-tenth the vasodilator potency, appear to have half-lives of ~40 minutes.
Isosorbide Dinitrate. The major route of metabolism of isosorbide dinitrate in humans appears to be by enzymatic denitration followed by glucuronide conjugation. Sublingual administration produces maximal plasma concentrations of the drug by 6 minutes, and the fall in concentration is rapid (t1/2 of ~45 minutes). The primary initial metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate, have longer half-lives (3-6 hours) and are presumed to contribute to the therapeutic efficacy of the drug.
Isosorbide-5-Mononitrate. This agent is available in tablet form. It does not undergo significant first-pass metabolism and so has excellent bioavailability after oral administration. The mononitrate has a significantly longer t1/2 than does isosorbide dinitrate and has been formulated as a plain tablet and as a sustained-release preparation; both have longer durations of action than the corresponding dosage forms of isosorbide dinitrate.
Inhaled NO. Nitric oxide gas administered by inhalation appears to exert most of its therapeutic effects on the pulmonary vasculature because of the rapid inactivation of NO by hemoglobin in the blood. The selective pulmonary vasodilation observed when NO is administered by inhalation has formed the basis for the widespread use of inhaled NO to treat pulmonary hypertension in hypoxemic neonates, where inhaled NO has been shown to significantly reduce morbidity and mortality (Bloch et al., 2007). The efficacy of inhaled NO in adults for other clinical situations that are characterized by elevated pulmonary vascular pressures (acute lung injury and primary pulmonary hypertension, among other disease states) has not yet been established, and therapies using inhaled NO remain under active investigation.
Correlation of Plasma Concentrations of Drug and Biological Activity. Intravenous administration of nitroglycerin or long-acting organic nitrates in anesthetized animals produces the same transient (1-4 minutes) decrease in blood pressure. Because denitration markedly reduces the activity of the organic nitrates, their rapid clearance from blood indicates that the transient duration of action under these conditions correlates with the concentrations of the parent compounds. The rate of hepatic denitration is characteristic of each nitrate and is influenced by hepatic blood flow or the presence of hepatic disease. In experimental animals, injection of moderate amounts of organic nitrates into the portal vein results in little or no vasodepressor activity, indicating that a substantial fraction of drug can be inactivated by first-pass metabolism in the liver (isosorbide mononitrate is an exception).
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Sublingual organic nitrates should be taken at the time of an anginal attack or in anticipation of exercise or stress. Such intermittent treatment provides reproducible cardiovascular effects. However, frequently repeated or continuous exposure to high doses of organic nitrates leads to a marked attenuation in the magnitude of most of their pharmacological effects. The magnitude of tolerance is a function of dosage and frequency of use.
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Tolerance may result from a reduced capacity of the vascular smooth muscle to convert nitroglycerin to NO, true vascular tolerance, or to the activation of mechanisms extraneous to the vessel wall, pseudotolerance (Münzel et al., 1995). Multiple mechanisms have been proposed to account for nitrate tolerance, including volume expansion, neurohumoral activation, cellular depletion of sulfhydryl groups, and the generation of free radicals (Parker and Parker, 1998). Inactivation of mitochondrial aldehyde dehydrogenase, an enzyme implicated in biotransformation of nitroglycerin, is seen in models of nitrate tolerance (Sydow et al., 2004), potentially associated with oxidative stress (Parker, 2004). A reactive intermediate formed during the generation of NO from organic nitrates may itself damage and inactivate the enzymes of the activation pathway; tolerance could involve endothelium-derived reactive oxygen species (Münzel et al., 1995; Parker 2004). Clinical data relating to the ability of agents that modify the renin–angiotensin–aldosterone system to prevent nitrate tolerance are contradictory (Parker and Parker, 1998). Important to the interpretation of clinical trials, factors that may influence the ability of such modification to prevent nitrate tolerance include the dose, whether the ACE inhibitors or angiotensin receptor antagonists were administered prior to the initiation of nitrates, and the tissue specificity of the agent. Despite experimental evidence that depletion of sulfhydryl groups may lead to impaired biotransformation of nitrates to NO and thereby result in nitrate tolerance, experimental results to date with sulfhydryl donors have been disappointing. Other changes that are observed in the setting of nitroglycerin tolerance include an enhanced response to vasoconstrictors such as angiotensin II (AngII), serotonin, and phenylephrine. Administration of nitroglycerin is associated with plasma volume expansion, which may be reflected by a decrease in hematocrit. Although diuretic therapy with hydrochlorothiazide can improve a patient's exercise duration, appropriately designed crossover trials have failed to demonstrate an effect of diuretics on nitrate tolerance (Parker et al., 1996).
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A more effective approach to restoring responsiveness is to interrupt therapy for 8-12 hours each day, which allows the return of efficacy. It is usually most convenient to omit dosing at night in patients with exertional angina either by adjusting dosing intervals of oral or buccal preparations or by removing cutaneous nitroglycerin. However, patients whose anginal pattern suggests its precipitation by increased left ventricular filling pressures (i.e., occurring in association with orthopnea or paroxysmal nocturnal dyspnea) may benefit from continuing nitrates at night and omitting them during a quiet period of the day. Tolerance also has been seen with isosorbide-5-mononitrate; an eccentric twice-daily dosing schedule appears to maintain efficacy (Parker and Parker, 1998).
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While these approaches appear to be effective, some patients develop an increased frequency of nocturnal angina when a nitrate-free interval is employed using nitroglycerin patches; such patients may require another class of anti-anginal agent during this period. Tolerance is not universal, and some patients develop only partial tolerance. The problem of anginal rebound during nitrate-free intervals is especially problematic in the treatment of unstable angina with intravenous nitroglycerin. As tolerance develops, increasing doses are required to achieve the same therapeutic effects; eventually, despite dose escalation, the drug loses efficacy.
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A special form of nitroglycerin tolerance is observed in individuals exposed to nitroglycerin in the manufacture of explosives. If protection is inadequate, workers may experience severe headaches, dizziness, and postural weakness during the first several days of employment. Tolerance then develops, but headache and other symptoms may reappear after a few days away from the job—the "Monday disease." The most serious effect of chronic exposure is a form of organic nitrate dependence. Workers without demonstrable organic vascular disease have been reported to have an increase in the incidence of acute coronary syndromes during the 24-72-hour periods away from the work environment (Parker et al., 1995). Coronary and digital arteriospasm during withdrawal and its relaxation by nitroglycerin also have been demonstrated radiographically. Because of the potential problem of nitrate dependence, it seems prudent not to withdraw nitrates abruptly from a patient who has received such therapy chronically.
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Toxicity and Untoward Responses
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Untoward responses to the therapeutic use of organic nitrates are almost all secondary to actions on the cardiovascular system. Headache is common and can be severe. It usually decreases over a few days if treatment is continued and often can be controlled by decreasing the dose. Transient episodes of dizziness, weakness, and other manifestations associated with postural hypotension may develop, particularly if the patient is standing immobile, and may progress occasionally to loss of consciousness, a reaction that appears to be accentuated by alcohol. It also may be seen with very low doses of nitrates in patients with autonomic dysfunction. Even in severe nitrate syncope, positioning and other measures that facilitate venous return are the only therapeutic measures required. All the organic nitrates occasionally can produce drug rash.
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Interaction of Nitrates with PDE5 Inhibitors. Erectile dysfunction is a frequently encountered problem whose risk factors parallel those of coronary artery disease. Thus many men desiring therapy for erectile dysfunction already may be receiving (or may require, especially if they increase physical activity) anti-anginal therapy. The combination of sildenafil and other phosphodiesterase 5 (PDE5) inhibitors with organic nitrate vasodilators can cause extreme hypotension.
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Cells in the corpus cavernosum produce NO during sexual arousal in response to nonadrenergic, noncholinergic neurotransmission (Burnett et al., 1992). NO stimulates the formation of cyclic GMP, which leads to relaxation of smooth muscle of the corpus cavernosum and penile arteries, engorgement of the corpus cavernosum, and erection. The accumulation of cyclic GMP can be enhanced by inhibition of the cyclic GMP–specific PDE5 family. Sildenafil (viagra, revatio) and congeners inhibit PDE5 and have been demonstrated to improve erectile function in patients with erectile dysfunction. Not surprisingly, PDE5 inhibitors have assumed the status of widely used recreational drugs. Since the introduction of sildenafil, two additional PDE5 inhibitors have been developed for use in therapy of erectile dysfunction. Tadalafil (cialis, adcirca) and vardenafil (levitra) share similar therapeutic efficacy and side-effect profiles with sildenafil; tadalafil has a longer time to onset of action and a longer therapeutic t1/2 than the other PDE5 inhibitors. Sildenafil has been the most thoroughly characterized of these compounds, but all three PDE5 inhibitors are contraindicated for patients taking organic nitrate vasodilators, and the PDE5 inhibitors should be used with caution in patients taking α or β adrenergic receptor antagonists (see Chapter 12).
The side effects of sildenafil and other PDE5 inhibitors are largely predictable on the basis of their effects on PDE5. Headache, flushing, and rhinitis may be observed, as well as dyspepsia owing to relaxation of the lower esophageal sphincter. Sildenafil and vardenafil also weakly inhibit PDE6, the enzyme involved in photoreceptor signal transduction (Chapters 3 and 64), and can produce visual disturbances, most notably changes in the perception of color hue or brightness. In addition to visual disturbances, sudden one-sided hearing loss has also been reported. Tadalafil inhibits PDE11, a widely distributed PDE isoform, but the clinical importance of this effect is not clear. The most important toxicity of all these PDE5 inhibitors is hemodynamic. When given alone to men with severe coronary artery disease, these drugs have modest effects on blood pressure, producing >10% fall in systolic, diastolic, and mean systemic pressures and in pulmonary artery systolic and mean pressures (Herrmann et al., 2000). However, sildenafil, tadalafil, and vardenafil all have a significant and potentially dangerous interaction with organic nitrates, the therapeutic actions of which are mediated via their conversion to NO with resulting increases in cyclic GMP. In the presence of a PDE5 inhibitor, nitrates cause profound increases in cyclic GMP and can produce dramatic reductions in blood pressure. Compared with controls, healthy male subjects pretreated with sildenafil or the other PDE5 inhibitors exhibit a much greater decrease in systolic blood pressure when treated with sublingual glyceryl trinitrate, and in many subjects a fall of more than 25 mm Hg was detected. This drug class toxicity is the basis for the warning that PDE5 inhibitors should not be prescribed to patients receiving any form of nitrate (Cheitlin et al., 1999) and dictates that patients should be questioned about the use of PDE5 inhibitors within 24 hours before nitrates are administered. A period of longer than 24 hours may be needed following administration of a PDE5 inhibitor for safe use of nitrates, especially with tadalafil because of its prolonged t1/2. In the event that patients develop significant hypotension following combined administration of sildenafil and a nitrate, fluids and α-adrenergic receptor agonists, if needed, should be used for support (Cheitlin et al., 1999). These same hemodynamic responses to PDE5 inhibition also may underlie the efficacy of sildenafil in the treatment of patients with primary pulmonary hypertension, in whom chronic treatment with the drug appears to result in enhanced exercise capacity associated with a decrease in pulmonary vascular resistance (Tsai and Kass, 2009). PDE5 inhibitors also are being studied in patients with congestive heart failure and cardiac hypertrophy (see Chapter 28).
Sildenafil, tadalafil, and vardenafil are metabolized via CYP3A4, and their toxicity may be enhanced in patients who receive other substrates of this enzyme, including macrolide and imidazole antibiotics, some statins, and antiretroviral agents (see individual chapters and Chapter 6). PDE5 inhibitors also may prolong cardiac repolarization by blocking the IKr. Although these interactions and effects are important clinically, the overall incidence and profile of adverse events observed with PDE5 inhibitors, when used without nitrates, are consistent with the expected background frequency of the same events in the treated population. In patients with coronary artery disease whose exercise capacity indicates that sexual activity is unlikely to precipitate angina and who are not currently taking nitrates, the use of PDE5 inhibitors can be considered. Such therapy needs to be individualized, and appropriate warnings must be given about the risk of toxicity if nitrates are taken subsequently for angina; this drug interaction may persist for approximately 24 hours for sildenafil and vardenafil and for considerably longer with tadalafil. Alternative nonnitrate anti-anginal therapy, such as β adrenergic receptor antagonists, should be used during these time periods (Cheitlin et al., 1999).
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Angina. Diseases that predispose to angina should be treated as part of a comprehensive therapeutic program with the primary goal being to prolong life. Conditions such as hypertension, anemia, thyrotoxicosis, obesity, heart failure, cardiac arrhythmias, and acute anxiety can precipitate anginal symptoms in many patients. Patients should be counseled to stop smoking, lose weight, and maintain a low-fat, high-fiber diet; hypertension and hyperlipidemia should be corrected; and daily aspirin (or clopidogrel if aspirin is not tolerated) (see Chapter 30) should be prescribed. Exposure to sympathomimetic agents (e.g., those in nasal decongestants and other sources) probably should be avoided. The use of drugs that modify the perception of pain is a poor approach to the treatment of angina because the underlying myocardial ischemia is not relieved.
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Table 27–1 lists the preparations and dosages of the nitrites and organic nitrates. The rapidity of onset, the duration of action, and the likelihood of developing tolerance are related to the method of administration.
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Sublingual Administration. Because of its rapid action, long-established efficacy, and low cost, nitroglycerin is the most useful drug of the organic nitrates given sublingually. The onset of action is within 1-2 minutes, but the effects are undetectable by 1 hour after administration. An initial dose of 0.3 mg nitroglycerin often relieves pain within 3 minutes. Absorption may be limited in patients with dentures or with dry mouths. Nitroglycerin tablets are stable but should be dispensed in glass containers and protected from moisture, light, and extremes of temperature. Active tablets usually produce a burning sensation under the tongue, but the absence of this sensation does not reliably predict loss of activity; elderly patients especially may be unable to detect the burning sensation. Anginal pain may be prevented when the drug is used prophylactically immediately prior to exercise or stress. The smallest effective dose should be prescribed. Patients should be instructed to seek medical attention immediately if three tablets taken over a 15-minute period do not relieve a sustained attack because this situation may be indicative of myocardial infarction (MI), unstable angina, or another cause of the pain. Patients also should be advised that there is no virtue in trying to avoid taking sublingual nitroglycerin for anginal pain. Other nitrates that can be taken sublingually do not appear to be longer acting than nitroglycerin because their half-lives depend only on the rate at which they are delivered to the liver. They are no more effective than nitroglycerin and often are more expensive.
Oral Administration. Oral nitrates often are used to provide prophylaxis against anginal episodes in patients who have more than occasional angina. They must be given in sufficient dosage to provide effective plasma levels after first-pass hepatic degradation. Low doses (e.g., 5-10 mg isosorbide dinitrate) are no more effective than placebo in decreasing the frequency of anginal attacks or increasing exercise tolerance. Higher doses of either isosorbide dinitrate (e.g., 20 mg or more orally every 4 hours) or sustained-release preparations of nitroglycerin decrease the frequency of anginal attacks and improve exercise tolerance. Effects peak at 60-90 minutes and last for 3-6 hours. Under these circumstances, the activities of less potent metabolites also may contribute to the therapeutic effect. Chronic oral administration of isosorbide dinitrate (120-720 mg daily) results in persistence of the parent compound and higher plasma concentrations of metabolites. However, these doses are more likely to cause troublesome side effects and lead to tolerance. Administration of isosorbide mononitrate (typically starting at 20 mg) once or twice daily (in the latter case, with the doses administered 7 hours apart) is efficacious in the treatment of chronic angina, and once-daily dosing or an eccentric twice-daily dosing schedule can minimize the development of tolerance.
Cutaneous Administration. Application of nitroglycerin ointment can relieve angina, prolong exercise capacity, and reduce ischemic ST-segment depression with exercise for 4 hours or more. Nitroglycerin ointment (2%) is applied to the skin (2.5-5 cm) as it is squeezed from the tube and then spread in a uniform layer; the dosage must be adjusted for each patient. Effects are apparent within 30-60 minutes (although absorption is variable) and last for 4-6 hours. The ointment is particularly useful for controlling nocturnal angina, which commonly develops within 3 hours after the patient goes to sleep. Transdermal nitroglycerin disks use a nitroglycerin-impregnated polymer (bonded to an adhesive bandage) that permits gradual absorption and a continuous plasma nitrate concentration over 24 hours. The onset of action is slow, with peak effects occurring at 1-2 hours. To avoid tolerance, therapy should be interrupted for at least 8 hours each day. With this regimen, long-term prophylaxis of ischemic episodes often can be attained.
Transmucosal or Buccal Nitroglycerin. This formulation is inserted under the upper lip above the incisors, where it adheres to the gingiva and dissolves gradually in a uniform manner. Hemodynamic effects are seen within 2-5 minutes, and it is therefore useful for short-term prophylaxis of angina. Nitroglycerin continues to be released into the circulation for a prolonged period, and exercise tolerance may be enhanced for up to 5 hours.
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Congestive Heart Failure. The utility of nitrovasodilators to relieve pulmonary congestion and to increase cardiac output in congestive heart failure is addressed in Chapter 28.
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Unstable Angina Pectoris and Non-ST-Segment– Elevation Myocardial Infarction. The term unstable angina pectoris has been used to describe a broad spectrum of clinical entities characterized by an acute or subacute worsening in a patient's anginal symptoms. The variable prognosis of unstable angina no doubt reflects the broad range of clinical entities subsumed by the term. More recently, efforts have been directed toward identifying patients with unstable angina on the basis of their risks for subsequent adverse outcomes such as MI or death. The term acute coronary syndrome has been useful in this context: Common to most clinical presentations of acute coronary syndrome is disruption of a coronary plaque, leading to local platelet aggregation and thrombosis at the arterial wall, with subsequent partial or total occlusion of the vessel. There is some variability in the pathogenesis of unstable angina, with gradually progressive atherosclerosis accounting for some cases of new-onset exertional angina. Less commonly, vasospasm in minimally atherosclerotic coronary vessels may account for some cases where rest angina has not been preceded by symptoms of exertional angina. For the most part, the pathophysiological principles that underlie therapy for exertional angina—which are directed at decreasing myocardial oxygen demand—have limited efficacy in the treatment of acute coronary syndromes characterized by an insufficiency of myocardial oxygen (blood) supply.
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Notably, the degree of coronary stenosis correlates poorly with the likelihood of plaque rupture. Drugs that reduce myocardial O2 consumption by reducing ventricular preload (nitrates) or by reducing heart rate and ventricular contractility (using β adrenergic receptor antagonists) are efficacious, but additional therapies are directed at the atherosclerotic plaque itself and the consequences (or prevention) of its rupture. As discussed later, these therapies include combinations of:
anti-platelet agents, including aspirin and thioenopyridines such as clopidogrel or prasugrel
anti-thrombin agents such as heparin and the thrombolytics
anti-integrin therapies that directly inhibit platelet aggregation mediated by glycoprotein (GP)IIb/IIIa
mechano-pharmacological approaches with percutaneously deployed intracoronary stents
coronary bypass surgery for selected patients
Along with nitrates and β adrenergic receptor antagonists, antiplatelet agents represent the cornerstone of therapy for acute coronary syndrome (Hillis and Lange, 2009). Aspirin (see later in the chapter) inhibits platelet aggregation and improves survival (Yeghiazarians et al., 2000). Heparin (either unfractionated or low-molecular-weight) also appears to reduce angina and prevent infarction. These and related agents are discussed in detail in Chapters 34 and 30. Anti-integrin agents directed against the platelet integrin GPIIb/IIIa (including abciximab, tirofiban, and eptifibatide) are effective in combination with heparin, as discussed later. Nitrates are useful both in reducing vasospasm and in reducing myocardial O2 consumption by decreasing ventricular wall stress. Intravenous administration of nitroglycerin allows high concentrations of drug to be attained rapidly. Because nitroglycerin is degraded rapidly, the dose can be titrated quickly and safely using intravenous administration. If coronary vasospasm is present, intravenous nitroglycerin is likely to be effective, although the addition of a Ca2+ channel blocker may be required to achieve complete control in some patients. Because of the potential risk of profound hypotension, nitrates should be withheld and alternate anti-anginal therapy administered if patients have consumed a PDE5 inhibitor within 24 hours (discussed earlier).
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Acute Myocardial Infarction. Therapeutic maneuvers in MI are directed at reducing the size of the infarct, preserving or retrieving viable tissue by reducing the O2 demand of the myocardium, and preventing ventricular remodeling that could lead to heart failure.
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Nitroglycerin is commonly administered to relieve ischemic pain in patients presenting with MI, but evidence that nitrates improve mortality in MI is sparse. Because they reduce ventricular preload through vasodilation, nitrates are effective in relief of pulmonary congestion. A decreased ventricular preload should be avoided in patients with right ventricular infarction because higher right-sided heart filling pressures are needed in this clinical context. Nitrates are relatively contraindicated in patients with systemic hypotension. According to the American Heart Association/American College of Cardiology (AHA/ACC) guidelines, "nitrates should not be used if hypotension limits the administration of β blockers, which have more powerful salutary effects" (Antman et al., 2004).
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Because the proximate cause of MI is intracoronary thrombosis, reperfusion therapies are critically important, employing, when possible, direct percutaneous coronary interventions (PCIs) for acute MI, usually using drug-eluting intracoronary stents (Antman et al., 2004). Thrombolytic agents are administered at hospitals where emergency PCI is not performed, but outcomes are better with direct PCI than with thrombolytic therapy (Antman et al., 2004) (see discussion of thrombolytic and antiplatelet therapies in Chapter 30).
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Variant (Prinzmetal) Angina. The large coronary arteries normally contribute little to coronary resistance. However, in variant angina, coronary constriction results in reduced blood flow and ischemic pain. Multiple mechanisms have been proposed to initiate vasospasm, including endothelial cell injury. Whereas long-acting nitrates alone are occasionally efficacious in abolishing episodes of variant angina, additional therapy with Ca2+ channel blockers usually is required. Ca2+ channel blockers, but not nitrates, have been shown to influence mortality and the incidence of MI favorably in variant angina; they should generally be included in therapy.