Summary
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.
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Various sections of the manuscript reviewed by: R.N. Brogden, Australasian Drug Information Services, Auckland, New Zealand; J.A. Franciosa, Cardiology Section, Veterans Administration Hospital, Philadelphia, Pennsylvania, USA; R.M. Norris, Coronary Care Unit, Green Lane Hospital, Auckland, New Zealand; L.H. Opie, Department of Medicine, University of Cape Town Medical School, Cape Town, South Africa; G. Sloman, Department of Cardiology, Royal Melbourne Hospital, Melbourne, Australia.
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Elkayam, U., Aronow, W.S. Glyceryl Trinitrate (Nitroglycerin) Ointment and Isosorbide Dinitrate: A Review of their Pharmacological Properties and Therapeutic Use. Drugs 23, 165–194 (1982). https://doi.org/10.2165/00003495-198223030-00001
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DOI: https://doi.org/10.2165/00003495-198223030-00001