English Reading Materials Chapter 21:Vasodilators the Treatment of Angina Pectoris INTRODUCTION Angina pectoris is the most common condition involving tissue ischemia in which vasodilator drugs are used.The name denotes chest pain caused by accumulation of metabolites resulting from myocardial ischemia.The organic nitrates,eg, nitroglycerin,are the mainstay of therapy for the immediate relief of angina.Another group of vasodilators,the calcium channel blockers,is also important,especially for prophylaxis,and the blockers,which are not vasodilators,are also useful in prophylaxis.New groups of drugs under investigation include fatty acid oxidation inhibitors and selective cardiac rate inhibitors. Ischemic heart disease is the most common serious health problem in many Western societies.By far the most frequent cause of angina is atheromatous obstruction of the large coronary vessels (atherosclerotic angina,classic angina).However,transient spasm of localized portions of these vessels,which is usually associated with underlying atheromas,can also cause significant myocardial ischemia and pain (vasospastic or variant angina). The primary cause of angina pectoris is an imbalance between the oxygen requirement of the heart and the oxygen supplied to it via the coronary vessels.In classic angina,the imbalance occurs when the myocardial oxygen requirement increases,as during exercise,and coronary blood flow does not increase proportionately.The resulting ischemia usually leads to pain.Classic angina is therefore "angina of effort."(In some individuals,the ischemia is not always accompanied by pain,resulting in "silent"or "ambulatory"ischemia.)In variant angina,oxygen delivery decreases as a result of reversible coronary vasospasm. Variant angina is also called Prinzmetal's angina. In theory,the imbalance between oxygen delivery and myocardial oxygen demand can be corrected by decreasing oxygen demand or by increasing delivery (by increasing coronary flow).In effort angina,oxygen demand can be reduced by decreasing cardiac work or,according to recent studies,by shifting myocardial metabolism to substrates that require less oxygen per unit of ATP produced.In variant angina,on the other hand,spasm of coronary vessels can be reversed by nitrates or calcium channel blockers.Lipid-lowering drugs,especially the "statins,"have become extremely important in the long-term treatment of atherosclerotic disease. 1
1 English Reading Materials Chapter 21: Vasodilators the Treatment of Angina Pectoris INTRODUCTION Angina pectoris is the most common condition involving tissue ischemia in which vasodilator drugs are used. The name denotes chest pain caused by accumulation of metabolites resulting from myocardial ischemia. The organic nitrates, eg, nitroglycerin, are the mainstay of therapy for the immediate relief of angina. Another group of vasodilators, the calcium channel blockers, is also important, especially for prophylaxis, and the blockers, which are not vasodilators, are also useful in prophylaxis. New groups of drugs under investigation include fatty acid oxidation inhibitors and selective cardiac rate inhibitors. Ischemic heart disease is the most common serious health problem in many Western societies. By far the most frequent cause of angina is atheromatous obstruction of the large coronary vessels (atherosclerotic angina, classic angina). However, transient spasm of localized portions of these vessels, which is usually associated with underlying atheromas, can also cause significant myocardial ischemia and pain (vasospastic or variant angina). The primary cause of angina pectoris is an imbalance between the oxygen requirement of the heart and the oxygen supplied to it via the coronary vessels. In classic angina, the imbalance occurs when the myocardial oxygen requirement increases, as during exercise, and coronary blood flow does not increase proportionately. The resulting ischemia usually leads to pain. Classic angina is therefore "angina of effort." (In some individuals, the ischemia is not always accompanied by pain, resulting in "silent" or "ambulatory" ischemia.) In variant angina, oxygen delivery decreases as a result of reversible coronary vasospasm. Variant angina is also called Prinzmetal's angina. In theory, the imbalance between oxygen delivery and myocardial oxygen demand can be corrected by decreasing oxygen demand or by increasing delivery (by increasing coronary flow). In effort angina, oxygen demand can be reduced by decreasing cardiac work or, according to recent studies, by shifting myocardial metabolism to substrates that require less oxygen per unit of ATP produced. In variant angina, on the other hand, spasm of coronary vessels can be reversed by nitrates or calcium channel blockers. Lipid-lowering drugs, especially the "statins," have become extremely important in the long-term treatment of atherosclerotic disease
Unstable angina,an acute coronary syndrome,is said to be present when there are episodes of angina at rest and when there is a change in the character,frequency,and duration of chest pain as well as precipitating factors in patients with previously stable angina.Unstable angina is caused by episodes of increased epicardial coronary artery tone or small platelet clots occurring in the vicinity of an atherosclerotic plaque.In most cases,formation of labile nonocclusive thrombi at the site of a fissured or ulcerated plaque is the mechanism for reduction in flow.The course and the prognosis of unstable angina are variable,but this subset of acute coronary syndrome is associated with a high risk of myocardial infarction and death. PATHOPHYSIOLOGY OF ANGINA Determinants of Myocardial Oxygen Demand As a consequence of its continuous activity,the heart's oxygen needs are relatively high,and it extracts approximately 75%of the available oxygen even in the absence of stress.The myocardial oxygen requirement increases when there is an increase in heart rate,contractility,arterial pressure,or ventricular volume.These hemodynamic alterations frequently occur during physical exercise and sympathetic discharge, which often precipitate angina in patients with obstructive coronary artery disease. The heart favors fatty acids as a substrate for energy production.However,oxidation of fatty acids requires more oxygen per unit of ATP generated than oxidation of carbohydrates.Therefore,drugs that shift myocardial metabolism toward greater use of glucose(fatty acid oxidation inhibitors)have the potential of reducing the oxygen demand without altering hemodynamics. Determinants of Coronary Blood Flow Myocardial Oxygen Supply Increased myocardial demands for oxygen in the normal heart are met by augmenting coronary blood flow.Coronary blood flow is directly related to the perfusion pressure (aortic diastolic pressure)and the duration of diastole.Because coronary flow drops to negligible values during systole,the duration of diastole becomes a limiting factor for myocardial perfusion during tachycardia.Coronary blood flow is inversely proportional to coronary vascular bed resistance.Resistance is determined mainly by intrinsic factors including metabolic products and autonomic activity and by various pharmacologic agents.Damage to the endothelium of coronary vessels has been shown to alter their ability to dilate and to increase coronary vascular resistance. Determinants of Vascular Tone Arteriolar and venous tone (smooth muscle tension)both play a role in determining myocardial wall stress.Arteriolar tone directly controls peripheral vascular resistance and thus arterial blood pressure.In systole,intraventricular pressure must exceed 2
2 Unstable angina, an acute coronary syndrome, is said to be present when there are episodes of angina at rest and when there is a change in the character, frequency, and duration of chest pain as well as precipitating factors in patients with previously stable angina. Unstable angina is caused by episodes of increased epicardial coronary artery tone or small platelet clots occurring in the vicinity of an atherosclerotic plaque. In most cases, formation of labile nonocclusive thrombi at the site of a fissured or ulcerated plaque is the mechanism for reduction in flow. The course and the prognosis of unstable angina are variable, but this subset of acute coronary syndrome is associated with a high risk of myocardial infarction and death. PATHOPHYSIOLOGY OF ANGINA Determinants of Myocardial Oxygen Demand As a consequence of its continuous activity, the heart's oxygen needs are relatively high, and it extracts approximately 75% of the available oxygen even in the absence of stress. The myocardial oxygen requirement increases when there is an increase in heart rate, contractility, arterial pressure, or ventricular volume. These hemodynamic alterations frequently occur during physical exercise and sympathetic discharge, which often precipitate angina in patients with obstructive coronary artery disease. The heart favors fatty acids as a substrate for energy production. However, oxidation of fatty acids requires more oxygen per unit of ATP generated than oxidation of carbohydrates. Therefore, drugs that shift myocardial metabolism toward greater use of glucose (fatty acid oxidation inhibitors) have the potential of reducing the oxygen demand without altering hemodynamics. Determinants of Coronary Blood Flow Myocardial Oxygen Supply Increased myocardial demands for oxygen in the normal heart are met by augmenting coronary blood flow. Coronary blood flow is directly related to the perfusion pressure (aortic diastolic pressure) and the duration of diastole. Because coronary flow drops to negligible values during systole, the duration of diastole becomes a limiting factor for myocardial perfusion during tachycardia. Coronary blood flow is inversely proportional to coronary vascular bed resistance. Resistance is determined mainly by intrinsic factors including metabolic products and autonomic activity and by various pharmacologic agents. Damage to the endothelium of coronary vessels has been shown to alter their ability to dilate and to increase coronary vascular resistance. Determinants of Vascular Tone Arteriolar and venous tone (smooth muscle tension) both play a role in determining myocardial wall stress. Arteriolar tone directly controls peripheral vascular resistance and thus arterial blood pressure. In systole, intraventricular pressure must exceed
aortic pressure to eject blood;arterial blood pressure thus determines the systolic wall stress in an important way.Venous tone determines the capacity of the venous circulation and controls the amount of blood sequestered in the venous system versus the amount returned to the heart.Venous tone thereby determines the diastolic wall stress. The regulation of smooth muscle contraction and relaxation is shown schematically in Figure 1.As shown in Figures 1 and 2,drugs may relax vascular smooth muscle in several ways: (1)Increasing cGMP:As indicated in Figure 2,cGMP facilitates the dephosphorylation of myosin light chains,preventing the interaction of myosin with actin.Nitric oxide is an effective activator of soluble guanylyl cyclase and acts mainly through this mechanism.Important molecular donors of nitric oxide include nitroprusside and the organic nitrates used in angina. (2)Decreasing intracellular Ca:Calcium channel blockers predictably cause vasodilation because they reduce intracellular Ca2,a major modulator of the activation of myosin light chain kinase.(Beta blockers and calcium channel blockers reduce Ca2 influx in cardiac muscle,thereby reducing rate,contractility,and oxygen requirement unless reversed by compensatory responses.) (3)Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane:The membrane potential of excitable cells is stabilized near the resting potential by increasing potassium permeability.Potassium channel openers,such as minoxidil sulfate,increase the permeability of K channels,probably ATP-dependent K*channels.Certain newer agents under investigation for use in angina (eg, nicorandil)may act,in part,by this mechanism. (4)Increasing cAMP in vascular smooth muscle cells:As shown in Figure 1,an increase in cAMP increases the rate of inactivation of myosin light chain kinase,the enzyme responsible for triggering the interaction of actin with myosin in these cells. This appears to be the mechanism of vasodilation caused by 2 agonists,drugs that are not used in angina. 3
3 aortic pressure to eject blood; arterial blood pressure thus determines the systolic wall stress in an important way. Venous tone determines the capacity of the venous circulation and controls the amount of blood sequestered in the venous system versus the amount returned to the heart. Venous tone thereby determines the diastolic wall stress. The regulation of smooth muscle contraction and relaxation is shown schematically in Figure 1. As shown in Figures 1 and 2, drugs may relax vascular smooth muscle in several ways: (1) Increasing cGMP: As indicated in Figure 2, cGMP facilitates the dephosphorylation of myosin light chains, preventing the interaction of myosin with actin. Nitric oxide is an effective activator of soluble guanylyl cyclase and acts mainly through this mechanism. Important molecular donors of nitric oxide include nitroprusside and the organic nitrates used in angina. (2) Decreasing intracellular Ca2+: Calcium channel blockers predictably cause vasodilation because they reduce intracellular Ca2+, a major modulator of the activation of myosin light chain kinase. (Beta blockers and calcium channel blockers reduce Ca2+ influx in cardiac muscle, thereby reducing rate, contractility, and oxygen requirement unless reversed by compensatory responses.) (3) Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane: The membrane potential of excitable cells is stabilized near the resting potential by increasing potassium permeability. Potassium channel openers, such as minoxidil sulfate, increase the permeability of K+ channels, probably ATP-dependent K+ channels. Certain newer agents under investigation for use in angina (eg, nicorandil) may act, in part, by this mechanism. (4) Increasing cAMP in vascular smooth muscle cells: As shown in Figure 1, an increase in cAMP increases the rate of inactivation of myosin light chain kinase, the enzyme responsible for triggering the interaction of actin with myosin in these cells. This appears to be the mechanism of vasodilation caused by 2 agonists, drugs that are not used in angina
Ca2+channels ca2+-O→ channel blockers ATP Ca2+(intracellular) Calmodulin +-2 agonists Ca2+-calmodulin complex cAMP MLCK*Myosin-LC kinase MLCK- (+ (MLCK) (PO42 Myosin light chain- (myosin-LC) Myosin-LC-PO4Myosin-LC Actin- Contraction Relaxation Figure 1.Control of smooth muscle contraction and site of action of calcium channel-blocking drugs.Contraction is triggered by influx of calcium (which can be blocked by calcium channel blockers)through transmembrane calcium channels.The calcium combines with calmodulin to form a complex that converts the enzyme myosin light chain kinase to its active form (MLCK*).The latter phosphorylates the myosin light chains,thereby initiating the interaction of myosin with actin.Betaz agonists (and other substances that increase cAMP)may cause relaxation in smooth muscle by accelerating the inactivation of MLCK (heavy arrows)and by facilitating the expulsion of calcium from the cell(not shown). Nitrates Endothelial cells NO Guanylyl cyclase* Guanylyl cyclase PDE Sildenafil GTP cGMP GMP MLCK* Myosin-LC Myosin-LC-PO4- Myosin-LC Actin- Contraction Relaxation
4 Figure 1. Control of smooth muscle contraction and site of action of calcium channel-blocking drugs. Contraction is triggered by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The calcium combines with calmodulin to form a complex that converts the enzyme myosin light chain kinase to its active form (MLCK*). The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle by accelerating the inactivation of MLCK (heavy arrows) and by facilitating the expulsion of calcium from the cell (not shown)
Figure 2.Mechanism of action of nitrates,nitrites,and other substances that increase the concentration of nitric oxide (NO)in smooth muscle cells.(MLCK*,activated myosin light chain kinase [see Figure 1];guanylyl cyclase*,activated guanylyl cyclase;?unknown intermediate steps.Steps leading to relaxation are shown with heavy arrows. I.BASIC PHARMACOLOGY OF DRUGS USED TO TREAT ANGINA Drug Action in Angina Three of the four drug groups currently approved for use in angina(organic nitrates, calcium channel blockers,and blockers)decrease myocardial oxygen requirement by decreasing the determinants of oxygen demand (heart rate,ventricular volume, blood pressure,and contractility).In some patients,a redistribution of coronary flow may increase oxygen delivery to ischemic tissue.In variant angina,the nitrates and the calcium channel blockers may also increase myocardial oxygen delivery by reversing coronary arterial spasm.The fourth group,represented by ranolazine,is discussed later. NITRATES NITRITES Chemistry These agents are simple nitric and nitrous acid esters of polyalcohols.Nitroglycerin may be considered the prototype of the group.Although nitroglycerin is used in the manufacture of dynamite,the formulations used in medicine are not explosive.The conventional sublingual tablet form of nitroglycerin may lose potency when stored as a result of volatilization and adsorption to plastic surfaces.Therefore,it should be kept in tightly closed glass containers.It is not sensitive to light. All therapeutically active agents in the nitrate group have identical mechanisms of action and similar toxicities.Therefore,pharmacokinetic factors govern the choice of agent and mode of therapy when using the nitrates. Pharmacokinetics The liver contains a high-capacity organic nitrate reductase that removes nitrate groups in a stepwise fashion from the parent molecule and ultimately inactivates the drug.Therefore,oral bioavailability of the traditional organic nitrates (eg, nitroglycerin and isosorbide dinitrate)is very low (typically 10-20%).For this 5
5 Figure 2. Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in smooth muscle cells. (MLCK*, activated myosin light chain kinase [see Figure 1]; guanylyl cyclase*, activated guanylyl cyclase; ?, unknown intermediate steps. Steps leading to relaxation are shown with heavy arrows.) I. BASIC PHARMACOLOGY OF DRUGS USED TO TREAT ANGINA Drug Action in Angina Three of the four drug groups currently approved for use in angina (organic nitrates, calcium channel blockers, and blockers) decrease myocardial oxygen requirement by decreasing the determinants of oxygen demand (heart rate, ventricular volume, blood pressure, and contractility). In some patients, a redistribution of coronary flow may increase oxygen delivery to ischemic tissue. In variant angina, the nitrates and the calcium channel blockers may also increase myocardial oxygen delivery by reversing coronary arterial spasm. The fourth group, represented by ranolazine, is discussed later. NITRATES NITRITES Chemistry These agents are simple nitric and nitrous acid esters of polyalcohols. Nitroglycerin may be considered the prototype of the group. Although nitroglycerin is used in the manufacture of dynamite, the formulations used in medicine are not explosive. The conventional sublingual tablet form of nitroglycerin may lose potency when stored as a result of volatilization and adsorption to plastic surfaces. Therefore, it should be kept in tightly closed glass containers. It is not sensitive to light. All therapeutically active agents in the nitrate group have identical mechanisms of action and similar toxicities. Therefore, pharmacokinetic factors govern the choice of agent and mode of therapy when using the nitrates. Pharmacokinetics The liver contains a high-capacity organic nitrate reductase that removes nitrate groups in a stepwise fashion from the parent molecule and ultimately inactivates the drug. Therefore, oral bioavailability of the traditional organic nitrates (eg, nitroglycerin and isosorbide dinitrate) is very low (typically 10-20%). For this
reason,the sublingual route,which avoids the first-pass effect,is preferred for achieving a therapeutic blood level rapidly.Nitroglycerin and isosorbide dinitrate are both absorbed efficiently by this route and reach therapeutic blood levels within a few minutes.However,the total dose administered by this route must be limited to avoid excessive effect;therefore,the total duration of effect is brief(15-30 minutes).When much longer duration of action is needed,oral preparations can be given that contain an amount of drug sufficient to result in sustained systemic blood levels of the parent drug plus active metabolites.Other routes of administration available for nitroglycerin include transdermal and buccal absorption from slow-release preparations;these are described below. Amyl nitrite and related nitrites are highly volatile liquids.Amyl nitrite is available in fragile glass ampules packaged in a protective cloth covering.The ampule can be crushed with the fingers,resulting in rapid release of inhalable vapors through the cloth covering.The inhalation route provides very rapid absorption and,like the sublingual route,avoids the hepatic first-pass effect.Because of its unpleasant odor and short duration of action,amyl nitrite is now obsolete for angina. Once absorbed,the unchanged nitrate compounds have half-lives of only 2-8 minutes. The partially denitrated metabolites have much longer half-lives(up to 3 hours).Of the nitroglycerin metabolites (two dinitroglycerins and two mononitro forms),the dinitro derivatives have significant vasodilator efficacy;they probably provide most of the therapeutic effect of orally administered nitroglycerin.The 5-mononitrate metabolite of isosorbide dinitrate is an active metabolite of the latter drug and is available for clinical use as isosorbide mononitrate.It has a bioavailability of 100%. Excretion,primarily in the form of glucuronide derivatives of the denitrated metabolites,is largely by way of the kidney. Pharmacodynamics A.MECHANISM OF ACTION IN SMOOTH MUSCLE Nitroglycerin is denitrated by glutathione S-transferase.Free nitrite ion is released, which is then converted to nitric oxide.A different unknown enzymatic reaction releases nitric oxide directly from the parent drug molecule.As shown in Figure 2, nitric oxide (or an S-nitrosothiol derivative)causes activation of guanylyl cyclase and an increase in cGMP,which are the first steps toward smooth muscle relaxation.The production of prostaglandin E or prostacyclin(PGI2)and membrane hyperpolarization may also be involved.There is no evidence that autonomic receptors are involved in the primary nitrate response (although autonomic reflex responses are evoked when hypotensive doses are given). As described below,tolerance is an important consideration in the use of nitrates. While tolerance may be caused in part by a decrease in tissue sulfhydryl groups,it can 6
6 reason, the sublingual route, which avoids the first-pass effect, is preferred for achieving a therapeutic blood level rapidly. Nitroglycerin and isosorbide dinitrate are both absorbed efficiently by this route and reach therapeutic blood levels within a few minutes. However, the total dose administered by this route must be limited to avoid excessive effect; therefore, the total duration of effect is brief (15-30 minutes). When much longer duration of action is needed, oral preparations can be given that contain an amount of drug sufficient to result in sustained systemic blood levels of the parent drug plus active metabolites. Other routes of administration available for nitroglycerin include transdermal and buccal absorption from slow-release preparations; these are described below. Amyl nitrite and related nitrites are highly volatile liquids. Amyl nitrite is available in fragile glass ampules packaged in a protective cloth covering. The ampule can be crushed with the fingers, resulting in rapid release of inhalable vapors through the cloth covering. The inhalation route provides very rapid absorption and, like the sublingual route, avoids the hepatic first-pass effect. Because of its unpleasant odor and short duration of action, amyl nitrite is now obsolete for angina. Once absorbed, the unchanged nitrate compounds have half-lives of only 2-8 minutes. The partially denitrated metabolites have much longer half-lives (up to 3 hours). Of the nitroglycerin metabolites (two dinitroglycerins and two mononitro forms), the dinitro derivatives have significant vasodilator efficacy; they probably provide most of the therapeutic effect of orally administered nitroglycerin. The 5-mononitrate metabolite of isosorbide dinitrate is an active metabolite of the latter drug and is available for clinical use as isosorbide mononitrate. It has a bioavailability of 100%. Excretion, primarily in the form of glucuronide derivatives of the denitrated metabolites, is largely by way of the kidney. Pharmacodynamics A. MECHANISM OF ACTION IN SMOOTH MUSCLE Nitroglycerin is denitrated by glutathione S-transferase. Free nitrite ion is released, which is then converted to nitric oxide. A different unknown enzymatic reaction releases nitric oxide directly from the parent drug molecule. As shown in Figure 2, nitric oxide (or an S-nitrosothiol derivative) causes activation of guanylyl cyclase and an increase in cGMP, which are the first steps toward smooth muscle relaxation. The production of prostaglandin E or prostacyclin (PGI2) and membrane hyperpolarization may also be involved. There is no evidence that autonomic receptors are involved in the primary nitrate response (although autonomic reflex responses are evoked when hypotensive doses are given). As described below, tolerance is an important consideration in the use of nitrates. While tolerance may be caused in part by a decrease in tissue sulfhydryl groups, it can
be only partially prevented or reversed with a sulfhydryl-regenerating agent. Increased generation of oxygen free radicals during nitrate therapy may be another important mechanism of tolerance. Nicorandil and several other investigational antianginal agents appear to combine the activity of nitric oxide release with potassium channel-opening action,thus providing an additional mechanism for causing vasodilation. B.ORGAN SYSTEM EFFECTS Nitroglycerin relaxes all types of smooth muscle irrespective of the cause of the preexisting muscle tone (Figure 3).It has practically no direct effect on cardiac or skeletal muscle. 1.Vascular smooth muscle All segments of the vascular system from large arteries through large veins relax in response to nitroglycerin.Veins respond at the lowest concentrations,arteries at slightly higher ones.Arterioles and precapillary sphincters are dilated less than the large arteries and the veins,partly because of reflex responses and partly because different vessels vary in their ability to release nitric oxide.The primary direct result of an effective dose of nitroglycerin is marked relaxation of veins with increased venous capacitance and decreased ventricular preload.Pulmonary vascular pressures and heart size are significantly reduced.In the absence of heart failure,cardiac output is reduced.Because venous capacitance is increased,orthostatic hypotension may be marked and syncope can result.Dilation of some large arteries (including the aorta)may be significant because of their large increase in compliance.Temporal artery pulsations and a throbbing headache associated with meningeal artery pulsations are frequent effects of nitroglycerin and amyl nitrite.In heart failure,preload is often abnormally high;the nitrates and other vasodilators,by reducing preload,may have a beneficial effect on cardiac output in this condition. The indirect effects of nitroglycerin consist of those compensatory responses evoked by baroreceptors and hormonal mechanisms responding to decreased arterial pressure; this consistently results in tachycardia and increased cardiac contractility.Retention of salt and water may also be significant,especially with intermediate-and long-acting nitrates.These compensatory responses contribute to the development of tolerance. In normal subjects without coronary disease,nitroglycerin can induce a significant,if transient,increase in total coronary blood flow.In contrast,there is no evidence that total coronary flow is increased in patients with angina due to atherosclerotic obstructive coronary artery disease.However,some studies suggest that redistribution of coronary flow from normal to ischemic regions may play a role in nitroglycerin's therapeutic effect.Nitroglycerin also exerts a weak negative inotropic effect via nitric oxide. 7
7 be only partially prevented or reversed with a sulfhydryl-regenerating agent. Increased generation of oxygen free radicals during nitrate therapy may be another important mechanism of tolerance. Nicorandil and several other investigational antianginal agents appear to combine the activity of nitric oxide release with potassium channel-opening action, thus providing an additional mechanism for causing vasodilation. B. ORGAN SYSTEM EFFECTS Nitroglycerin relaxes all types of smooth muscle irrespective of the cause of the preexisting muscle tone (Figure 3). It has practically no direct effect on cardiac or skeletal muscle. 1. Vascular smooth muscle All segments of the vascular system from large arteries through large veins relax in response to nitroglycerin. Veins respond at the lowest concentrations, arteries at slightly higher ones. Arterioles and precapillary sphincters are dilated less than the large arteries and the veins, partly because of reflex responses and partly because different vessels vary in their ability to release nitric oxide. The primary direct result of an effective dose of nitroglycerin is marked relaxation of veins with increased venous capacitance and decreased ventricular preload. Pulmonary vascular pressures and heart size are significantly reduced. In the absence of heart failure, cardiac output is reduced. Because venous capacitance is increased, orthostatic hypotension may be marked and syncope can result. Dilation of some large arteries (including the aorta) may be significant because of their large increase in compliance. Temporal artery pulsations and a throbbing headache associated with meningeal artery pulsations are frequent effects of nitroglycerin and amyl nitrite. In heart failure, preload is often abnormally high; the nitrates and other vasodilators, by reducing preload, may have a beneficial effect on cardiac output in this condition. The indirect effects of nitroglycerin consist of those compensatory responses evoked by baroreceptors and hormonal mechanisms responding to decreased arterial pressure; this consistently results in tachycardia and increased cardiac contractility. Retention of salt and water may also be significant, especially with intermediate- and long-acting nitrates. These compensatory responses contribute to the development of tolerance. In normal subjects without coronary disease, nitroglycerin can induce a significant, if transient, increase in total coronary blood flow. In contrast, there is no evidence that total coronary flow is increased in patients with angina due to atherosclerotic obstructive coronary artery disease. However, some studies suggest that redistribution of coronary flow from normal to ischemic regions may play a role in nitroglycerin's therapeutic effect. Nitroglycerin also exerts a weak negative inotropic effect via nitric oxide
2.Other smooth muscle organs Relaxation of smooth muscle of the bronchi, gastrointestinal tract (including biliary system),and genitourinary tract has been demonstrated experimentally.Because of their brief duration,these actions of the nitrates are rarely of any clinical value.During recent years,the use of amyl nitrite and isobutyl nitrite by inhalation as purported recreational(sex-enhancing)drugs has become popular with some segments of the population.Nitrites release nitric oxide in erectile tissue as well as vascular smooth muscle and activate guanylyl cyclase.The resulting increase in cGMP causes dephosphorylation of myosin light chains and relaxation(Figure 2),which enhances erection. 3.Action on platelets Nitric oxide released from nitroglycerin stimulates guanylyl cyclase in platelets as in smooth muscle.The increase in cGMP that results is responsible for a decrease in platelet aggregation.Unfortunately,recent prospective trials have established no survival benefit when nitroglycerin is used in acute myocardial infarction. 4.Other effects Nitrite ion reacts with hemoglobin(which contains ferrous iron)to produce methemoglobin (which contains ferric iron).Because methemoglobin has a very low affinity for oxygen,large doses of nitrites can result in pseudocyanosis, tissue hypoxia,and death.Fortunately,the plasma level of nitrite resulting from even large doses of organic and inorganic nitrates is too low to cause significant methemoglobinemia in adults.However,sodium nitrite is used as a curing agent for meats.In nursing infants,the intestinal flora is capable of converting significant amounts of inorganic nitrate,eg,from well water,to nitrite ion.Thus,inadvertent exposure to large amounts of nitrite ion can occur and may produce serious toxicity. One therapeutic application of this otherwise toxic effect of nitrite has been discovered.Cyanide poisoning results from complexing of cytochrome iron by the CN ion.Methemoglobin iron has a very high affinity for CN;thus,administration of sodium nitrite (NaNO2)soon after cyanide exposure will regenerate active cytochrome.The cyanmethemoglobin produced can be further detoxified by the intravenous administration of sodium thiosulfate (Na2S2O3);this results in formation of thiocyanate ion (SCN),a less toxic ion that is readily excreted. Methemoglobinemia,if excessive,can be treated by giving methylene blue intravenously. DRUGS USED IN THE TREATMENT OF ERECTILE DYSFUNCTION Erectile dysfunction in men has long been the subject of research(by both amateur and professional scientists).Among the substances used in the past and generally discredited are "Spanish Fly"(a bladder and urethral irritant),yohimbine,nutmeg,and 8
8 2. Other smooth muscle organs Relaxation of smooth muscle of the bronchi, gastrointestinal tract (including biliary system), and genitourinary tract has been demonstrated experimentally. Because of their brief duration, these actions of the nitrates are rarely of any clinical value. During recent years, the use of amyl nitrite and isobutyl nitrite by inhalation as purported recreational (sex-enhancing) drugs has become popular with some segments of the population. Nitrites release nitric oxide in erectile tissue as well as vascular smooth muscle and activate guanylyl cyclase. The resulting increase in cGMP causes dephosphorylation of myosin light chains and relaxation (Figure 2), which enhances erection. 3. Action on platelets Nitric oxide released from nitroglycerin stimulates guanylyl cyclase in platelets as in smooth muscle. The increase in cGMP that results is responsible for a decrease in platelet aggregation. Unfortunately, recent prospective trials have established no survival benefit when nitroglycerin is used in acute myocardial infarction. 4. Other effects Nitrite ion reacts with hemoglobin (which contains ferrous iron) to produce methemoglobin (which contains ferric iron). Because methemoglobin has a very low affinity for oxygen, large doses of nitrites can result in pseudocyanosis, tissue hypoxia, and death. Fortunately, the plasma level of nitrite resulting from even large doses of organic and inorganic nitrates is too low to cause significant methemoglobinemia in adults. However, sodium nitrite is used as a curing agent for meats. In nursing infants, the intestinal flora is capable of converting significant amounts of inorganic nitrate, eg, from well water, to nitrite ion. Thus, inadvertent exposure to large amounts of nitrite ion can occur and may produce serious toxicity. One therapeutic application of this otherwise toxic effect of nitrite has been discovered. Cyanide poisoning results from complexing of cytochrome iron by the CN- ion. Methemoglobin iron has a very high affinity for CN- ; thus, administration of sodium nitrite (NaNO2) soon after cyanide exposure will regenerate active cytochrome. The cyanmethemoglobin produced can be further detoxified by the intravenous administration of sodium thiosulfate (Na2S2O3); this results in formation of thiocyanate ion (SCN- ), a less toxic ion that is readily excreted. Methemoglobinemia, if excessive, can be treated by giving methylene blue intravenously. DRUGS USED IN THE TREATMENT OF ERECTILE DYSFUNCTION Erectile dysfunction in men has long been the subject of research (by both amateur and professional scientists). Among the substances used in the past and generally discredited are "Spanish Fly" (a bladder and urethral irritant), yohimbine, nutmeg, and
mixtures containing lead,arsenic,or strychnine.Substances currently favored by practitioners of herbal medicine include ginseng and kava. Scientific studies of the process have shown that erection requires relaxation of the nonvascular smooth muscle of the corpora cavernosa.This relaxation permits inflow of blood at nearly arterial pressure into the sinuses of the cavernosa,and it is the pressure of the blood that causes erection.Physiologic erection occurs in response to the release of nitric oxide from nonadrenergic-noncholinergic nerves associated with parasympathetic discharge.Thus,parasympathetic innervation must be intact and nitric oxide synthesis must be active.(It appears that a similar process occurs in female erectile tissues.)Certain other smooth muscle relaxants eg,PGE analogs or antagonists if present in high enough concentration,can independently cause sufficient cavernosal relaxation to result in erection.As noted in the text,nitric oxide activates guanylyl cyclase,which increases the concentration of cGMP,and the latter messenger stimulates the dephosphorylation of myosin light chains(see Figure 2)and relaxation of the smooth muscle.Thus,any drug that increases cGMP might be of value in erectile dysfunction if normal innervation is present.Sildenafil(Viagra)acts to increase cGMP by inhibiting its breakdown by phosphodiesterase isoform 5.The drug has been very successful in the marketplace because it can be taken orally. However,sildenafil is of little or no value in men with loss of potency due to cord injury or other damage to innervation and in men lacking libido.Furthermore, sildenafil potentiates the action of nitrates used for angina,and severe hypotension and a few myocardial infarctions have been reported in men taking both drugs.It is recommended that at least 6 hours pass between use of a nitrate and the ingestion of sildenafil.Sildenafil also has effects on color vision,causing difficulty in blue-green discrimination.Two similar PDE-5 inhibitors,tadalafil and vardenafil,are available. The drug most commonly used in patients who do not respond to sildenafil is alprostadil,a PGE analog that can be injected directly into the cavernosa or placed in the urethra as a minisuppository,from which it diffuses into the cavernosal tissue. Phentolamine can be used by injection into the cavernosa.These drugs will cause erection in most men who do not respond to sildenafil. 9
9 mixtures containing lead, arsenic, or strychnine. Substances currently favored by practitioners of herbal medicine include ginseng and kava. Scientific studies of the process have shown that erection requires relaxation of the nonvascular smooth muscle of the corpora cavernosa. This relaxation permits inflow of blood at nearly arterial pressure into the sinuses of the cavernosa, and it is the pressure of the blood that causes erection. Physiologic erection occurs in response to the release of nitric oxide from nonadrenergic-noncholinergic nerves associated with parasympathetic discharge. Thus, parasympathetic innervation must be intact and nitric oxide synthesis must be active. (It appears that a similar process occurs in female erectile tissues.) Certain other smooth muscle relaxants eg, PGE1 analogs or antagonists if present in high enough concentration, can independently cause sufficient cavernosal relaxation to result in erection. As noted in the text, nitric oxide activates guanylyl cyclase, which increases the concentration of cGMP, and the latter messenger stimulates the dephosphorylation of myosin light chains (see Figure 2) and relaxation of the smooth muscle. Thus, any drug that increases cGMP might be of value in erectile dysfunction if normal innervation is present. Sildenafil (Viagra) acts to increase cGMP by inhibiting its breakdown by phosphodiesterase isoform 5. The drug has been very successful in the marketplace because it can be taken orally. However, sildenafil is of little or no value in men with loss of potency due to cord injury or other damage to innervation and in men lacking libido. Furthermore, sildenafil potentiates the action of nitrates used for angina, and severe hypotension and a few myocardial infarctions have been reported in men taking both drugs. It is recommended that at least 6 hours pass between use of a nitrate and the ingestion of sildenafil. Sildenafil also has effects on color vision, causing difficulty in blue-green discrimination. Two similar PDE-5 inhibitors, tadalafil and vardenafil, are available. The drug most commonly used in patients who do not respond to sildenafil is alprostadil, a PGE1 analog that can be injected directly into the cavernosa or placed in the urethra as a minisuppository, from which it diffuses into the cavernosal tissue. Phentolamine can be used by injection into the cavernosa. These drugs will cause erection in most men who do not respond to sildenafil
10 mN 10 mN K NTG NE NE K 10 min 10mN T NE NTG 10 min 10 mN K+Verapamil Figure 3.Effects of vasodilators on contractions of human vein segments studied in vitro.Panel A shows contractions induced by two vasoconstrictor agents, norepinephrine (NE)and potassium(K).Panel B shows the relaxation induced by nitroglycerin (NTG),4 umol/L.The relaxation is prompt.Panel C shows the relaxation induced by verapamil,2.2 umol/L.The relaxation is slower but more sustained.(Modified and reproduced,with permission,from Mikkelsen E,Andersson KE,Bengtsson B:Effects of verapamil and nitroglycerin on contractile responses to potassium and noradrenaline in isolated human peripheral veins.Acta Pharmacol Toxicol1978,42:14.) Toxicity.Tolerance A.ACUTE ADVERSE EFFECTS The major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation:orthostatic hypotension,tachycardia,and throbbing headache.Glaucoma, once thought to be a contraindication,does not worsen,and nitrates can be used safely in the presence of increased intraocular pressure.Nitrates are contraindicated, however,if intracranial pressure is elevated. B.TOLERANCE With continuous exposure to nitrates,isolated smooth muscle may develop complete tolerance (tachyphylaxis),and the intact human becomes progressively more tolerant when long-acting preparations(oral,transdermal)or continuous intravenous infusions are used for more than a few hours without interruption. Continuous exposure to high levels of nitrates can occur in the chemical industry, especially where explosives are manufactured.When contamination of the workplace with volatile organic nitrate compounds is severe,workers find that upon starting their work week(Monday),they suffer headache and transient dizziness.After a day or so, o
10 Figure 3. Effects of vasodilators on contractions of human vein segments studied in vitro. Panel A shows contractions induced by two vasoconstrictor agents, norepinephrine (NE) and potassium (K+ ). Panel B shows the relaxation induced by nitroglycerin (NTG), 4 umol/L. The relaxation is prompt. Panel C shows the relaxation induced by verapamil, 2.2 umol/L. The relaxation is slower but more sustained. (Modified and reproduced, with permission, from Mikkelsen E, Andersson KE, Bengtsson B: Effects of verapamil and nitroglycerin on contractile responses to potassium and noradrenaline in isolated human peripheral veins. Acta Pharmacol Toxicol 1978;42:14.) Toxicity Tolerance A. ACUTE ADVERSE EFFECTS The major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation: orthostatic hypotension, tachycardia, and throbbing headache. Glaucoma, once thought to be a contraindication, does not worsen, and nitrates can be used safely in the presence of increased intraocular pressure. Nitrates are contraindicated, however, if intracranial pressure is elevated. B. TOLERANCE With continuous exposure to nitrates, isolated smooth muscle may develop complete tolerance (tachyphylaxis), and the intact human becomes progressively more tolerant when long-acting preparations (oral, transdermal) or continuous intravenous infusions are used for more than a few hours without interruption. Continuous exposure to high levels of nitrates can occur in the chemical industry, especially where explosives are manufactured. When contamination of the workplace with volatile organic nitrate compounds is severe, workers find that upon starting their work week (Monday), they suffer headache and transient dizziness. After a day or so
