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Antianginal drugs. Part II. Human pharmacology of nitroglycerin
Appraisal therapy
Antianginal Part
and reappraisalofcardiac Edited
by Arthur
C. DeGraff
and
Alan
F. Lyon
drugs.
II. Human
pharmacology
of nitroglycerin
Solomon Fisch, M.D.* Bronx, N. Y.
N
itroglycerin is the antianginal drug that is most widelv used and most generally accepted as clinically effective. It is the prototype of a class of inorganic nitrite and organic nitrate congeners. Sodium nitrite, amyl nitrite, ethyl nitrite, erythritol tetranitrate, pentaerythritol nitrate, isosorbide dinitrate, and other organic nitrates share many important pharmacologic properties of nitroglycerin. Nitroglycerin (glyceryl trinitrate) is a smooth-muscle relaxant with predominant direct cellular action. It causes relaxation of most smooth muscles of the body, including bronchial, biliary, ureteral, uterine, and gastrointestinal. The possible exception is that of the small intestine. The most important pharmacologic effects are seen on the vascular musculature. Vascular e#ects. The drug dilates all large arteries, such as the temporal, radial, and coronary arteries, as well as arterioles, capillaries, and venules. The most marked effect is seen in the postarteriolar bed, as has been confirmed in the skin, retinal, meningeal, and splanchnic circulations. Nitroglycerin is thus a universal vasodilator. As a vasodilator it causes a drop in blood pressure, more prominently systolic than diastolic, and results in a diminution of the pulse pressure. In the hypertensive Received *Director, Bronx,
417
for publication Nov. 18, 1965. Cardiac Therapy Research Unit. N. Y., 10468.
Bronx
individual there is a greater absolute drop in blood pressure than in the normotensive individual; this effect is also longer in duration. As a result of vasodilatation, venous return may diminish, resulting in diminution of cardiac output and stroke volume, and a secondary increase in heart rate. The drop in systolic pressure and stroke volume temporarily reduces the work of the heart. This has been the basis for the presumed usefulness of this agent in the treatment of the paroxysmal dyspnea of acute left ventricular failure. In the hypersensitive subject, or in one to whom an excessive dose is administered, the decrease in venous return may lead to marked hypotension, which, in turn, can cause syncope. The latter subsides when the subject assumesthe horizontal position and increases venous return. Efect on the coronary circulation and on cardiac dynamics. In the normal subject or in subjects with mild cardiac disease who are devoid of coronary artery disease, nitroglycerin produces an increase in coronary blood flow which, on the average, amounts to 50 per cent of the resting value, and an increase in myocardial oxygen consumption; the A-V oxygen difference remains unchanged. The coronary diastolic vascular resistance drops, as does the aortic Veterans
Administration
Hospital,
130
West
Kingsbridge
Road,
blood pressure; Ihc heart r-ale inc-rwses, tho pulinonar\capillary and right atrial pressures drop, indicating dinlinution of tilling of both sides of the heart, left ventrirular work decreases, and an increase ill the expenditure of myocardial energ!’ for the generation of pressure occurs. By contrast, in the patient with signifirant coronary atherosclerosis, nitroglycerin usually produces a drop in coronary blood flea-. Either a modest increase or a decrease, or no change, can occur, depending on the individual patient. Furthermore, no change in coronary vascular resistance is noted, the myocardial oxygen consumption is louvered, the blood pressure decreases more than in the normal control group, and the heart rate shon-s no significant change. The cardiac filling pressures and work decline as in the normal individual. The ratio of pressure generated to oxygen cost is basically unchanged. These findings contradict those of coronary cineangiography which seem to demonstrate that nitroglycerin induces vasodilation of sclerosed coronaries. The hemodynamic findings described above which resulted from coronar!’ sinus catheterization studies must be considered to be more valid since cineangiography does noi measure blood doby; it only demonstrates changes in the caliber of a vessel. On the basis of radioisotopic precordial measurements, it is stated that nitroglycerin improves coronary blood flow. The method is so gross that the validity of these observaLions must be questioned. Furthermore, it does not differentiate which coronar) branches, whether healthy or diseased, are responding to the drug. In view of the responsiveness of a normal coronary artery to nitroglycerin, and the apparent absence of response in the atherosclerotic artery,, one may properly ask whether diversion of blood flop- to the less diseased coronaq arterial bed, where it is least needed, ma>not be fostered bv the administration of this drug. It remajns to be explained \vh\: in diseased coronary arteries, which remain unresponsive to nitroglycerin, the arterial flow can be increased by effort. EYectrocardiogram. The electrocardiogram is unchanged by nitroglycerin. In the hypertensive subject \vho demonstrates a left ventricular strain pattern, the drug
prod~ice 111ini11w1 ch,ingc5 t0\\m-d 1101’~ nialit).. III the tlnusll~~l I~;\tit*rll \\ ith thcb so-c-nlled reproducibly \Iastcr’s two-srri~ test, nitrogl!cwiil adlllirlistcwd proph\,lactically c211 ciiniinish or prevent the ap pcarance of thcb S-T scgnient depressions seen after exercise. 111 thr usual patient \vith coronar\’ atherosclrrosis \~ho on exercise manifests il positive t\\.o-step electrocardiographic Lest, this effect cannot tw demonstrated on a statistiwlly significant basis. 1 t is difficult to assign pharlnacologic significance to these observations. Thus, although all these data art’ inwnclusivr Lo variable interpretation, it 2111 d subject seems to be likeI\, that whatever beneficial effect iiiLrogl!,ce;in exerts on angina pet.-. toris is due Lo a reduction in the work of the heart rather than to an increase in its blood SupplJ.. Absorpfio72 and nzetnbolism. Nitroglycerin is more effective]! absorbed sublingually than or&.. \Vhen given sublingually, the drug appears in the blood in about 2. minutes, its level in the blood reaches a plateau in 1 nlinutes, begins to disappear by the tenth minute, and is virtually dissipated by t-he fifteenth tninute. (iauged by vasodepression, the vasodilating effect does not c-orrelate perfect]). with levels of the drug in thr- blood. Thus, the drug induces an onset of fall in blood pressure in 1 to 5 minutes, 11 ~naxiinuni fall in 5 to 10 nlinutes, and a return to the initial blood pressure \vithin 1.5 Lo 40 mirlutes. The fate of the drug iu the hod>, is unkno\yn ; approximateI>. 60 to 70 per cent of it disappears from the body and cannot be tracbed. ‘There is nluch evidence to support the contention that the pharmacologic effect of nitroglycerin is clue lo the organic nitrate per se rather than to its conversion to a nitrite. I,iLtle is knonn of the basic metabolic effects of nitroglycerin. It has been stated that oxidative phosphorylation is inhibited b!- the nitrates. This may account for the apparent nastirig of oxygen found in coronary sinus catheterization studies. Side effects mm’ toxicity. Nitroglycerin is unusually safe when used in reconmended doses, but should be used \\ith c.aution in patients \\,ith incipient glaucoma, because of the possibilit\of producing ;I (wi
Antionginal
rise in intraocular pressure. Headache, by far the most common complaint, is transient with nitroglycerin but can be protracted and severe with the longer-acting nitrates; it appears to be related to dosage. Methemoglobinemia is not a clinical problem with this drug. Tolerance. It appears to be well established that, with the continuous administration of nitroglycerin, the pharmacodynamic effects diminish to the point at which the patient can accept progressively larger dosesof the nitrate without evincing any side effects. This also holds for other nitrates and nitrites. The mechanism of the development of tolerance is unknown. However, cross-tolerance between drugs
drugs.
Part
II
419
of this group is known to develop. Discontinuance of the drug restores the originaI sensitivity of the individual. This tolerance is often disregarded in clinical use of short-acting and long-acting nitrates. REFERENCES Gorlin, R., Brachfeld, N., MacLeod, C., and Bopp, P.: Effect of nitroglycerin on the coronary circulation in patients with coronary artery disease or increased left ventricular work, Circulation 19:705, 1959. Gorlin, R.: Drugs and angina pectoris, Am. J. Cardiol. 9:419, 1962. Wagman, R. J., Levine, H. J., Wesser, J. V., Neill, W. A., Kransow, N., and Gorlin, R.: Coronary insufficiency in man. Physiologic and electrocardiographic correlation, Am. J. Cardiol. 9:439, 1962.
Antianginal Part
and reappraisalofcardiac Edited
by Arthur
C. DeGraff
and
Alan
F. Lyon
drugs.
II. Human
pharmacology
of nitroglycerin
Solomon Fisch, M.D.* Bronx, N. Y.
N
itroglycerin is the antianginal drug that is most widelv used and most generally accepted as clinically effective. It is the prototype of a class of inorganic nitrite and organic nitrate congeners. Sodium nitrite, amyl nitrite, ethyl nitrite, erythritol tetranitrate, pentaerythritol nitrate, isosorbide dinitrate, and other organic nitrates share many important pharmacologic properties of nitroglycerin. Nitroglycerin (glyceryl trinitrate) is a smooth-muscle relaxant with predominant direct cellular action. It causes relaxation of most smooth muscles of the body, including bronchial, biliary, ureteral, uterine, and gastrointestinal. The possible exception is that of the small intestine. The most important pharmacologic effects are seen on the vascular musculature. Vascular e#ects. The drug dilates all large arteries, such as the temporal, radial, and coronary arteries, as well as arterioles, capillaries, and venules. The most marked effect is seen in the postarteriolar bed, as has been confirmed in the skin, retinal, meningeal, and splanchnic circulations. Nitroglycerin is thus a universal vasodilator. As a vasodilator it causes a drop in blood pressure, more prominently systolic than diastolic, and results in a diminution of the pulse pressure. In the hypertensive Received *Director, Bronx,
417
for publication Nov. 18, 1965. Cardiac Therapy Research Unit. N. Y., 10468.
Bronx
individual there is a greater absolute drop in blood pressure than in the normotensive individual; this effect is also longer in duration. As a result of vasodilatation, venous return may diminish, resulting in diminution of cardiac output and stroke volume, and a secondary increase in heart rate. The drop in systolic pressure and stroke volume temporarily reduces the work of the heart. This has been the basis for the presumed usefulness of this agent in the treatment of the paroxysmal dyspnea of acute left ventricular failure. In the hypersensitive subject, or in one to whom an excessive dose is administered, the decrease in venous return may lead to marked hypotension, which, in turn, can cause syncope. The latter subsides when the subject assumesthe horizontal position and increases venous return. Efect on the coronary circulation and on cardiac dynamics. In the normal subject or in subjects with mild cardiac disease who are devoid of coronary artery disease, nitroglycerin produces an increase in coronary blood flow which, on the average, amounts to 50 per cent of the resting value, and an increase in myocardial oxygen consumption; the A-V oxygen difference remains unchanged. The coronary diastolic vascular resistance drops, as does the aortic Veterans
Administration
Hospital,
130
West
Kingsbridge
Road,
blood pressure; Ihc heart r-ale inc-rwses, tho pulinonar\capillary and right atrial pressures drop, indicating dinlinution of tilling of both sides of the heart, left ventrirular work decreases, and an increase ill the expenditure of myocardial energ!’ for the generation of pressure occurs. By contrast, in the patient with signifirant coronary atherosclerosis, nitroglycerin usually produces a drop in coronary blood flea-. Either a modest increase or a decrease, or no change, can occur, depending on the individual patient. Furthermore, no change in coronary vascular resistance is noted, the myocardial oxygen consumption is louvered, the blood pressure decreases more than in the normal control group, and the heart rate shon-s no significant change. The cardiac filling pressures and work decline as in the normal individual. The ratio of pressure generated to oxygen cost is basically unchanged. These findings contradict those of coronary cineangiography which seem to demonstrate that nitroglycerin induces vasodilation of sclerosed coronaries. The hemodynamic findings described above which resulted from coronar!’ sinus catheterization studies must be considered to be more valid since cineangiography does noi measure blood doby; it only demonstrates changes in the caliber of a vessel. On the basis of radioisotopic precordial measurements, it is stated that nitroglycerin improves coronary blood flow. The method is so gross that the validity of these observaLions must be questioned. Furthermore, it does not differentiate which coronar) branches, whether healthy or diseased, are responding to the drug. In view of the responsiveness of a normal coronary artery to nitroglycerin, and the apparent absence of response in the atherosclerotic artery,, one may properly ask whether diversion of blood flop- to the less diseased coronaq arterial bed, where it is least needed, ma>not be fostered bv the administration of this drug. It remajns to be explained \vh\: in diseased coronary arteries, which remain unresponsive to nitroglycerin, the arterial flow can be increased by effort. EYectrocardiogram. The electrocardiogram is unchanged by nitroglycerin. In the hypertensive subject \vho demonstrates a left ventricular strain pattern, the drug
prod~ice 111ini11w1 ch,ingc5 t0\\m-d 1101’~ nialit).. III the tlnusll~~l I~;\tit*rll \\ ith thcb so-c-nlled reproducibly \Iastcr’s two-srri~ test, nitrogl!cwiil adlllirlistcwd proph\,lactically c211 ciiniinish or prevent the ap pcarance of thcb S-T scgnient depressions seen after exercise. 111 thr usual patient \vith coronar\’ atherosclrrosis \~ho on exercise manifests il positive t\\.o-step electrocardiographic Lest, this effect cannot tw demonstrated on a statistiwlly significant basis. 1 t is difficult to assign pharlnacologic significance to these observations. Thus, although all these data art’ inwnclusivr Lo variable interpretation, it 2111 d subject seems to be likeI\, that whatever beneficial effect iiiLrogl!,ce;in exerts on angina pet.-. toris is due Lo a reduction in the work of the heart rather than to an increase in its blood SupplJ.. Absorpfio72 and nzetnbolism. Nitroglycerin is more effective]! absorbed sublingually than or&.. \Vhen given sublingually, the drug appears in the blood in about 2. minutes, its level in the blood reaches a plateau in 1 nlinutes, begins to disappear by the tenth minute, and is virtually dissipated by t-he fifteenth tninute. (iauged by vasodepression, the vasodilating effect does not c-orrelate perfect]). with levels of the drug in thr- blood. Thus, the drug induces an onset of fall in blood pressure in 1 to 5 minutes, 11 ~naxiinuni fall in 5 to 10 nlinutes, and a return to the initial blood pressure \vithin 1.5 Lo 40 mirlutes. The fate of the drug iu the hod>, is unkno\yn ; approximateI>. 60 to 70 per cent of it disappears from the body and cannot be tracbed. ‘There is nluch evidence to support the contention that the pharmacologic effect of nitroglycerin is clue lo the organic nitrate per se rather than to its conversion to a nitrite. I,iLtle is knonn of the basic metabolic effects of nitroglycerin. It has been stated that oxidative phosphorylation is inhibited b!- the nitrates. This may account for the apparent nastirig of oxygen found in coronary sinus catheterization studies. Side effects mm’ toxicity. Nitroglycerin is unusually safe when used in reconmended doses, but should be used \\ith c.aution in patients \\,ith incipient glaucoma, because of the possibilit\of producing ;I (wi
Antionginal
rise in intraocular pressure. Headache, by far the most common complaint, is transient with nitroglycerin but can be protracted and severe with the longer-acting nitrates; it appears to be related to dosage. Methemoglobinemia is not a clinical problem with this drug. Tolerance. It appears to be well established that, with the continuous administration of nitroglycerin, the pharmacodynamic effects diminish to the point at which the patient can accept progressively larger dosesof the nitrate without evincing any side effects. This also holds for other nitrates and nitrites. The mechanism of the development of tolerance is unknown. However, cross-tolerance between drugs
drugs.
Part
II
419
of this group is known to develop. Discontinuance of the drug restores the originaI sensitivity of the individual. This tolerance is often disregarded in clinical use of short-acting and long-acting nitrates. REFERENCES Gorlin, R., Brachfeld, N., MacLeod, C., and Bopp, P.: Effect of nitroglycerin on the coronary circulation in patients with coronary artery disease or increased left ventricular work, Circulation 19:705, 1959. Gorlin, R.: Drugs and angina pectoris, Am. J. Cardiol. 9:419, 1962. Wagman, R. J., Levine, H. J., Wesser, J. V., Neill, W. A., Kransow, N., and Gorlin, R.: Coronary insufficiency in man. Physiologic and electrocardiographic correlation, Am. J. Cardiol. 9:439, 1962.