Glyceryl Trinitrate (Nitroglycerin) Ointment and Isosorbide Dinitrate: A Review of their Pharmacological Properties and Therapeutic Use
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Synopsis: Sublingual glyceryl trinitrate (nitroglycerin) is the most widely used drug in the treatment of angina pectoris, but its use is limited due to its short acting effect. Recent investigations have shown that some longer acting nitrates administered orally or topically have a long acting antianginal effect. The mechanism of the antianginal effect of nitrates is multi-factorial. Nitrates increase oxygen supply to the myocardium by causing redistribution of coronary blood flow. In addition, nitrates decrease myocardial oxygen demand by reducing left ventricular volume, intramyocardial tension, and left ventricular afterload. The use of nitrates for the treatment of congestive heart failure has also been established in recent years. Nitrates have a predominant venodilatory effect resulting in peripheral blood pooling and decreased venous return to the heart, thereby decreasing left ventricular filling pressure. The effect of nitrates on the arteriolar circulation is small, and there is usually little or no change in cardiac output. Some reduction in systemic blood pressure can be seen, while there is usually no change in heart rate. In a small number of patients with myocardial infarction complicated by congestive heart failure, the use of long acting nitrates has resulted in haemodynamic and symptomatic improvement. Nitrates have also been shown to improve variant angina. Nitrates are usually well tolerated in most patients. However, some troublesome side effects can occur, including headache, postural hypotension, and methaemoglobinaemia.
Pharmacodynamic Studies: The predominant circulatory effect of nitrates is direct relaxation of the smooth muscle in the systemic venous bed, resulting in pooling of blood in the dilated venous capacitant circulation and decreased blood return to the heart. Nitrates can also exert a mild dilatory effect on the arteriolar circulation with a small decrease in peripheral vascular resistance. The vasodilatory response to nitrates can lead to a fall in systemic blood pressure, especially in patients with normal left ventricular pressure and in the upright position. In patients with elevated left ventricular filling pressure, the effect on systemic blood pressure is small. The change in cardiac output after nitrates depends on pretreatment left ventricular function and pressures. A significant reduction in cardiac output can be seen in patients with normal left ventricular pressures, whereas no change or a mild increase in cardiac output is usually seen in patients with depressed left ventricular function. The tachycardiac response usually seen with a significant reduction in blood pressure is very often attenuated in patients with chronic congestive heart failure. The effect of nitrates on the coronary circulation is still not entirely clear. Although the drugs dilate normal coronary arteries, they do not increase total coronary blood flow in patients with coronary artery disease. On the other hand, nitrates have been shown to cause redistribution of coronary flow and to increase collateral circulation, and thus to augment blood flow to ischaemic regions. In patients with pulmonary hypertension due to acute respiratory failure, nitrate administration resulted in a reduction of pulmonary arterial resistance and airflow obstruction. In addition, nitrates have been demonstrated to enhance ventricular electrical stability after myocardial ischaemia and also to improve conduction through the A-V node.
Thus, the mechanisms of the antianginal effect of nitrates are multifactorial. These drugs increase myocardial oxygen supply by causing a redistribution of coronary flow and augmentation of blood flow to the ischaemic zones. At the same time, nitrates decrease myocardial oxygen demand by reducing ventricular volume, intramyocardial tension and left ventricular afterload.
Pharmacokinetic Studies: Nitrates are absorbed from the sublingual mucosa, the gastrointestinal tract and the skin. While sublingual absorption is very rapid and results in almost instantaneous achievement of high serum drug concentrations, there is much slower absorption when the drug is administered orally or topically. Metabolic degradation of nitrates occurs primarily in the liver by a partial denitration process mediated by a glutathione organic nitrate reductase. In vivo metabolic studies have shown that the parent nitrate molecule is denitrated rapidly, and its metabolites circulate in the blood for many hours. Although early studies demonstrated the lack of pharmacological activity of nitrate metabolites, recent studies reported marked haemodynamic responses after adequate intravenous doses of mononitrates, the main nitrate metabolites.
Therapeutic Trials: Numerous studies have demonstrated the long acting antianginal effect of glyceryl trinitrate ointment. In most of the patients studied, the application of the drug resulted in a significant improvement in exercise capacity, partial or total prevention of chest pain, a marked decrease in the magnitude of S-T segment depression during exercise, and a significant increase in total body oxygen consumption.
Results of many studies have shown the ineffectiveness of small doses of oral nitrates in the treatment of angina pectoris. In contrast, the administration of larger doses (20 to 50mg of oral isosorbide dinitrate) resulted in a significant increase in exercise time which lasted for as long as 5 hours in some of the patients.
The effects of long acting nitrates in acute myocardial infarction were studied in a small group of patients. Treatment resulted in a significant fall in left ventricular filling pressure and in the product of heart rate × systolic blood pressure. The cardiac output response to nitrates was related to the initial level of the left ventricular filling pressure and to the degree of its reduction. In spite of a significant decrease in systemic blood pressure, there was no change in transmyocardial pressure gradient. Although the available data suggest that nitrates can reduce the determinant of myocardial oxygen consumption in patients with myocardial infarction while maintaining coronary perfusion pressure, further studies are needed to establish more clearly the effectiveness of this therapy. Long acting nitrates also have been shown to improve abnormally contracting myocardial segments in patients with previous myocardial infarction, and to successfully treat variant angina.
The effect of long acting nitrates in patients with congestive heart failure is characterised by a significant decrease in left ventricular filling pressure. There is usually no change or a mild increase in cardiac output. Both systemic vascular resistance and systemic blood pressure may decrease, while the heart rate usually remains unchanged. The combined use of long acting nitrates with hydralazine has been shown to produce a fall in left ventricular filling pressure and a concomitant increase in cardiac output. Long term studies have demonstrated persistence of haemodynamic and symptomatic effects of nitrates, alone or in combination with hydralazine, in the treatment of chronic congestive heart failure.
Nitrate Tolerance and Dependence: The development of tolerance to nitrates has been documented in animals and humans. Recent studies, however, showed that long term therapy with long acting nitrates, even in large doses, is not associated with clinically important tolerance to these drugs or cross-tolerance to sublingual glyceryl trinitrate in patients treated for angina pectoris or congestive heart failure. An abrupt withdrawal of nitrates has resulted in the development of non-atherosclerotic ischaemic heart symptoms in munitions workers and worsening of ischaemic disease in congestive heart failure patients, consistent with nitrate dependence. Gradual reduction of long term nitrate therapy rather than abrupt discontinuation is therefore recommended.
Side Effects: The most frequent side effect of nitrate therapy is headache. Continuation of treatment is usually associated with the development of tolerance to this side effect. Reduction of the dose, changing the route of administration, and analgesics can decrease the severity of headaches. Postural hypotension occurs in some patients and can be manifested by dizziness, weakness and even syncope. This may be aggravated by consumption of alcohol. Ingestion of nitrates by infants can result in methaemoglobinaemia and severe poisoning. Ingested nitrates have almost no toxicity in older children and adults. Drug rash can occasionally be produced by all organic nitrates. Hypoxaemia due to pulmonary ventilation perfusion mismatch has been also reported following treatment with a nitrate.
Drug Interactions: Phenobarbitone (phenobarbital) may enhance nitrate metabolism, while ethanol inhibits it. Nitrates can potentiate the antihypertensive effect of tricyclic antidepressants and slow the catabolic process of narcotic drugs. Indomethacin may inhibit the vasodilatory effect of nitrates.
Dosage and Administration: The usual dosage for oral isosorbide dinitrate is 20 to 60mg every 4 to 6 hours. For glyceryl trinitrate ointment, 0.5 to 2 inches are applied every 4 to 6 hours in most patients, although the frequency of administration may need to be individually tailored based on clinical responses.
KeywordsAcute Myocardial Infarction Angina Pectoris Glyceryl Trinitrate Pulmonary Capillary Wedge Pressure Hydralazine
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- Abrams, J. and Kochukosky, R.: Hemodynamic effects of nitroglycerin ointment and sublingual nitroglycerin: Reduction in left ventricular volume. Chest 70: 418 (1976).Google Scholar
- Aronow, W.S. and Chesluk, H.M.: Sublingual isosorbide dinitrate versus sublingual placebo in angina pectoris. Circulation 42: 869–874 (1970a).Google Scholar
- Bogaert, G.: Tolerance towards glyceryl trinitrates (trinitrin) in rabbits. Archives of Internal Pharmacology 172: 228–230 (1968).Google Scholar
- Borer, J.S.; Redwood, D.R.; Levitt, B.; Cagin, N.; Bianchi, C.; Vallin, H. and Epstein, S.F.: Reduction in myocardial ischemia with nitroglycerin ischemic injury during acute myocardial infarction. Circulation 54: 766–773 (1976).Google Scholar
- Braunwald, E.; Sarnoff, S.J. and Stainshy, W.N.: Determinants of duration and mean rate of ventricular ejection. Circulation Research 6: 318–325 (1958).Google Scholar
- Buck, J.D.; Gross, G.J.; Warltier, D.C.; Jolly, S.R. and Hardman, H.F.: Comparative effects of cardioselective versus non-cardioselective beta blockade on subendocardial blood flow and contractile function in ischemic myocardium. American Journal of Cardiology 44: 657–663 (1979).PubMedGoogle Scholar
- Bussman, W.D.; Lohner, J. and Kaltenbach, M.: Orally administered isosorbide dinitrate in patients with and without left ventricular failure due to acute myocardial infarction. American Journal of Cardiology 39: 91–96 (1977).Google Scholar
- Buttler, A.; Ross, J., Jr; Slutsky, R.; Pfisterer, M.; Ashburn, W. and Froelicher, V.: Improvement of exercise induced left ventricular dysfunction with oral propranolol in patients with coronary heart disease. American Journal of Cardiology 44: 318–324(1979).Google Scholar
- Cohn, P.F. and Braunwald, E.: Chronic coronary artery disease; in Braunwald (Ed.) Heart Disease, p. 1414 (W.B. Saunders, Philadelphia 1980).Google Scholar
- Come, P.C.; Flaherty, J.T.; Baird, M.S.; Rouleau, J.R.; Weisfeldt, M.L.; Greene, L; Becker, L. and Pitt, B.: Reversal by phenylephrine of the beneficial effects of intravenous nitroglycerin in patients with acute myocardial infarction. New England Journal of Medicine 293: 1003–1007 (1975).PubMedGoogle Scholar
- Crandall, LA.; Leake, CD.; Loevenhart, A.S. and Muehlberger, C.W.: Acquired tolerance to and cross tolerance between the nitrous and nitric acid esters and sodium nitrate in man. Journal of Pharmacology and Experimental Therapeutics 41: 103–119 (1931).Google Scholar
- Dauwe, F.; Attaki, G.; Waters, D.D.; Theroux, P. and Mizgala, H.F.: Intravenous nitroglycerin in refractory unstable angina. American Journal of Cardiology 43: 416 (1979).Google Scholar
- Davis, J.A. and Weisel, B.H.: The treatment of angina pectoris with a nitroglycerin ointment. American Journal of Medical Science 230: 259–263 (1955).Google Scholar
- Dicarlo, F.J.; Vian, J.P. and Melgar, M.D.: Incorporation of radioactivity from 14C nitroglycerin into rat liver glycogen, lipid, protein ribonucleic acid and deoxyribonucleic acid. Biochemical Pharmacology 18: 965–970 (1969).Google Scholar
- Dollery, C.T.: Pharmacodynamics of beta adrenergic blockade. Primary Cardiology, Supplement 1: 8–14 (1980).Google Scholar
- Elkayam, U.; Weinberg, D. and Frishman, W.: Cardiovascular complications of desipramine hydrochloride overdosage. Cardiovascular Medicine 4: 77–79 (1979).Google Scholar
- Ferrer, M.I.; Bradley, S.E. and Wheeler, H.O.: Some effects of nitroglycerin upon the splanchnic, pulmonary and systemic circulation. Circulation 833: 357–373 (1966).Google Scholar
- Flaherty, J.T.; Come, P.C.; Baird, M.G.; Rouleau, J.; Taylor, D.R.; Weisfelt, M.L; Greene, L.; Becker, L.C. and Pitt, B.: Effects of intravenous nitroglycerin on left ventricular function and ST segment changes in acute myocardial infarction. British Heart Journal 38: 612–621 (1976).PubMedGoogle Scholar
- Flaherty, J.T.; MacAllister, N.; Magee, P. and Gardner, T.: Usefulness of intravenous nitroglycerin as an arterial vasodilator in patients developing hypertension following coronary bypass surgery. Circulation 60(II): 84 (1979).Google Scholar
- Franciosa, J.A. and Conn, J.N.: Immediate effects of hydralazine-isosorbide dinitrate combination on exercise capacity and exercise hemodynamics in patients with left ventricular failure. Circulation 49: 1085–1091 (1979).Google Scholar
- Franciosa, J.A.; Blank, R.C.; Cohn, J.N. and Mikulic, E.: Hemodynamic effects of topical, oral and sublingual nitroglycerin in left ventricular failure. Current Therapeutic Research 22: 231–245 (1977).Google Scholar
- Friedberg, C.R.: Acute coronary occlusion and myocardial infarction; in Friedberg (Ed.) Diseases of the Heart, 3rd ed.; p.913 (W.B. Saunders, Philadelphia 1973).Google Scholar
- Fung, H.-L.; McNiff, E.; Ruggirello, D.; Darke, A.; Parker, J.O. and Thadani, U.: Pharmacokinetics and pharmacologic effects after single and chronic doses of isosorbide dinitrate. American Journal of Cardiology 45: 438 (1980).Google Scholar
- Goldbarg, A.N.; Moran, J.F.; Butterfield, T.K.; Nemickas, R. and Bermudez, G.A.: Therapy of angina pectoris with propranolol and long acting nitrates. Circulation 40: 847–853 (1969).Google Scholar
- Goodman, L.S. and Gilman, A.: Vasodilator Drugs. The Pharmacological Basis of Therapeutics, 5th ed.; pp. 727–735 (Mac-Millan, New York 1975).Google Scholar
- Gorlin, R.: Beta blocker therapy of cardiac abnormalities: Summary. Primary Cardiology, Supplement 1: 118–119 (1980).Google Scholar
- Groves, B.M.: Variant angina: An electrocardiographic and arteriographic spectrum produced by coronary artery spasm. Current Problems in Cardiology 2: 62–63 (1977).Google Scholar
- Hirshfield, J.W.; Borer, J.S.; Goldstein, R.E.; Barrett, M.J. and Epstein, S.E.: Reduction in severity and extent of myocardial infarction when nitroglycerin and methoxamine are administered during coronary occlusion. Circulation 49: 291–297 (1974).Google Scholar
- Klausner, S.; Chatterjee, K. and Parmley, W.W.: Therapy of chronic heart failure with nitroglycerin ointment: The necessity for measuring hemodynamics to determine nonresponders. Circulation 53 & 54: 11–66 (1976).Google Scholar
- Kleckner, M.S., Jr; Allen, E.V. and Wakim, K.G.: The use of glyceryl trinitrate (nitroglycerin) ointment in the treatment of Raynaud’s disease and Raynaud’s phenomenon. Proceedings of Staff Meeting, Mayo Clinic 25: 657–659 (1950).Google Scholar
- Lappe, D.; Summer, W.; Terry, P. and Pitt, B.: Reduction of pulmonary vascular resistance and airflow obstruction with intravenous nitroglycerin in acute respiratory failure. Circulation 56: 138 (1977).Google Scholar
- Litchfield, M.H.: Aspect of nitrate ester. Metabolism 60: 1599–1607 (1971).Google Scholar
- Lund, F.: Percutaneous nitroglycerin treatment in cases of peripheral circulatory disorders, especially Raynaud’s disease. Acta Medica Scandinavica 206: 196–206 (1948).Google Scholar
- Massie, B.; Chatterjee, K.; Werner, J.; Greenberg, B.; Hart, R. and Parmley, W.W.: Hemodynamic advantage of combined administration of hydralazine orally and nitrates nonparenterally in the vasodilator therapy of chronic heart failure. American Journal of Cardiology 40: 794–801 (1977).PubMedGoogle Scholar
- Massie, B.; Kramer, B.; Shen, E. and Haughorn, F.: Exercise hemodynamic effects of hydralazine and nitrates: Contrast with response at rest. Circulation 62: 111–262 (1980).Google Scholar
- Mihalick, M.J.; Rasmusson, S. and Knoebel, S.B.: The effect of nitroglycerin on premature ventricular complexes in acute myocardial infarction. American Journal of Cardiology 33: 157 (1974).Google Scholar
- Needleman, P. and Krantz, J.C., Jr: The biotransformation of nitroglycerin. Biochemical Pharmacology 4: 1225–1230 (1965).Google Scholar
- Needleman, P.; Lang, S. and Johnson, E.M.: Organic nitrates: Relationship between biotransformation and rational angina pectoris therapy. Journal of Pharmacology and Experimental Therapeutics 18: 489–497 (1972).Google Scholar
- O’Rourke, R.A. and Crawford, M.H.: Medical treatment of angina pectoris. Cardiovascular Medicine 3: 839–848 (1977).Google Scholar
- Packer, M.; Meller, J.; Medina, N.; Gorlin, R. and Herman, M.: Equivalent hemodynamic effects of intravenous nitroprusside and high doses of oral isosorbide dinitrate in severe heart failure. Circulation 60: 11–182 (1979).Google Scholar
- Reid, P.; Flaherty, J. and Taylor, D.: Effect of nitroglycerin on ST segments in acute myocardial infarction. Circulation 48: IV–207 (1973).Google Scholar
- Salerno, J.A.; Previtali, M.; Medici, A.; Chimienti, M.; Bramucci, E.; Lepore, R.; Specchia, G. and Bobba, P.: Treatment of vasospastic angina pectoris at rest with nitroglycerin ointment: A short term controlled study in the coronary care unit. American Journal of Cardiology 47: 1128–1133 (1981).PubMedGoogle Scholar
- Shappel, S.D. and Orr, W.C.: Variant angina and sleep: A case report with therapeutic considerations. Diseases of the Nervous System 36: 295–298 (1975).Google Scholar
- Smith, E.R.; Redwood, D.R.; McCarron, W.E. and Epstein, S.E.: Coronary occlusion in the conscious dog. Effects of alterations in arterial pressure produced by nitroglycerin, hemorrhage, and alpha-adrenergic agonists on the degree of myocardial ischemia. Circulation 47: 51–57 (1973).PubMedGoogle Scholar
- Sostman, H.D. and Langon, R.A.: Contemporary medical management of stable angina pectoris. American Heart Journal 95: 755–788 (1978).Google Scholar
- Taylor, T.; Chasseaud, L.F.; Doyle, E.; Darragh, A.; O’Kelly, D.A. and Fitzgerald, D.: Pharmacokinetics of isosorbide dinitrate after intravenous infusion in human subjects. Biopharmaceutics and Drug Disposition 1: 149–156 (1980).Google Scholar
- Van Dusen, J. and Fischl, J.: Inhibition of nitroglycerin effect in humans by suppression of prostaglandin. American Journal of Cardiology 47: 390 (1981).Google Scholar
- Weygandt, G.R.; Kopman, E.A.; Bauer, S. and Landbrook, P.A.: The cause of hypoxemia induced by nitroglycerin. American Journal of Cardiology 43: 427 (1979).Google Scholar