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