Glyceryl Trinitrate (Nitroglycerin) Ointment and Isosorbide …elkayam/articles/44.pdf · isosorbide dinitrate) resulted in a significant increase in exercise time which lasted for

.", :.. Drugs 23: 165-194 (1982) 0012-6667/82/0003-0165/$07.50/0 iC ADIS Press Australasia Pty Ltd. All rights reserved.

Glyceryl Trinitrate (Nitroglycerin) Ointment and Isosorbide Dinitrate: A Review of their Pharmacological Properties and Therapeutic Use

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Uri E/kayam and Wi/bertS.Aronow Division of Cardiology, Department of Medicine, University of California Irvine Medical Center, Orange, California, and Division of Cardiology, Department of Medicine, Veterans Administration .Medical Center, Long Beach, California

Various sections of the manuscript reviewed by: RN. Brogden, Australasian Drug Information Services. Auckland, New Zealand; JA. Franciosa, Cardiology Section, Veterans Administration Hospital, Philadelphia, Pennsylvania, USA; RM. 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 Melboume Hospital, Melbourne, Australia.

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Contents

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Summary...........................................................................................................................................166I. Pharmacodynamic Studies ............................................................................................................168 1.1 Effect on the Peripheral Circulation.....................................................................................168 1.2 Effect on Systemic Blood Pressure ......................................................................................169 1.3 Effect on Cardiac Output......................................................................................................169 1.4 Effect on Heart Rate .............................................................................................................169 1.5 Effect on Coronary Circulation ............................................................................................169 1.6 Effect on Pulmonary Circulation .........................................................................................170 I. 7 Effect on Electrical Stability and the Conduction System ..................................................170 1.8 Effects on Left Ventricular Function ...................................................................................170 1.9 Antianginal Action of Nitrates - Mechanism......................................................................1712. Pharmacokinetic Studies ..............................................................................................................172 2.1 Glyceryl Trinitrati: ...............................................................................................................172 2.1.1 Absorption ...................................................................................................................172 2.1.2 Distribution and Elimination.......................................................................................172 2.2 lsosorbide Dinitrate ..................... : .......................................................................................172 2.2.1 Absorption ...................................................................................................................172 2.2.2 Elimination ..................................................................................................................1743. Therapeutic Trials.........................................................................................................................174 3.1 Angina Pectoris ....................................................................................................................174 3.1.1 Glyceryl Trinitrate Ointment in the Treatment of Angina Pectoris............................174 3.1.2 Orallsosorbide Dinitrate in the Treatment of Angina Pectoris ...................................175 3.1.3 Nitrates plus ~-Blocking Agents in the Treatment of Angina Pectoris ......................176 3.2 Variant Angina Pectoris .......................................................................................................177 3.3 Congestive Heart Failure......................................................................................................177 3.3.1 Glyceryl Trinitrate Ointment in the Treatment of Congestive Heart Failure .............177 3.3.2 Oral Nitrates in the Treatment of Congestive Heart Failure.......................................180

3.3.3 Long Acting Nitrates plus Hydralazine in the Treatment of Congestive Heart Failure181

Glyceryl Trinitrate Ointment and Isosorbide Dinitrate: A Review

3.4 Acute Myocardial Infarction.................................................................. , ................................................ 183

3.4.1 Theoretical Considerations of Nitrate Therapy in Acute Myocardial Infarction ......................... 183

3.4.2 Glyceryl Trinitrate Ointment in Acute Myocardial Infarction ..................................................... 184

3.4.3 Oral Nitrates in Acute Myocardial Infarction............................................................................... 184

3.5 Glyceryl Trinitrate Ointment in the Treatment of Peripheral Vascular Diseases.................................... 184

4. Nitrate Tolerance ..................................................................................................................... :. 186 5. Nitrate Dependence......................................................................................................... ... ........ 188 6. Side Effects ................................................................................................................................. 188' 6.1 Headache ............................................................................................................................. 188 6.2 Postural Hypotension .~.........................................................................................188 6.3 Methaemoglobinaemia........................................................................................................ 188 6.4 Other Adverse Effects ......................................................................................................... 189 7. Drug Interactions ...................................., ..........................................: .......................189 8. Dosage and Administration ........................................................................................................ 189 8.1 lsosorbide Dinitrate ............................................................................................................. 189 8.2 Glyceryl Trinitrate Ointment .............................................................................189 'c.

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Summary

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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 investi gations have shown that some longer acting nitrates administered ora/~v or topically have a

long acting antianginahlfect. The mechanism of the antianginal effect 'of nitrates is multi factorial. Nitrates increase oxygen supply to the myocardium by causing redistribuTion of cor onary 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 Qf 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 litft ventricular jllling pressure. The effect oJ nitrates on the arteriolar circulation is small, and there is usually little or no change In cardiac oU/put. Some reduction in systemic blood pressure can be seen, while there is usually no change in heart rate. In a small number o.fpatients with myocardial infarction complicated by congestive heart failure, the use of long acting nitrates has resulted in haemodynamic and sympto matic 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, in cluding headache, postural hypotension, and methaemoglobinaemia.

Pharmacodynamic Studies: The predominant circulatory effect of nitrates is direct relaxa tion of the smooth muscle in the systemic venous bed, resulting in pooling of blood in the dil ated 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 posi tion. 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 tachY cardiac response usually seen with a significant reduction in blood pressure is very often at tenuated in patients with chronic congestive heart failure. The effect of nitrates on the coron ary 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 in crease 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 airl10w obstruction. In addition, nitrat~ (~ have been de1I10nstrated to enhance ventricular electrical stability after myocardial ischaemia and also to improve conduction through the A-V node.

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Glyceryl Trinitrate 'Ointment and Isosorbide Dinitrate: A Review

Thus, the mechanisms of the antianginal effect of nitrates are multifactorial. These drugs increase myocardial oxygen supply by causing a redistribution of coronary 110w and augmentation of blood 110w to the ischaemic zones. At the same time, nitrates decrease myocardial oxygen demand by reducing ventricular volume, intramyocardial tension and left ventricular afterload.

Pharmacokinelic 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 achi~vement 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 de nitration 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 x 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 fining 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 discontinua

tion 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

167 -,.., ."

of the dose, changing the route of administration, and analgesics can decrease the severity"of headaches. Postural hypotension occurs in some patients and ~n be manifested by dizziness weakness and even syncope. This may be aggravated by consumption of alcohol. Ingestion ofnitrates by infants can result in methaemoglobinaemia and severe poisonirig. Ingested nitrates havealmost no toxicity in older children and adults. Drug rash can occasionally be productd by allorganic nitrates. Hypoxaemia due to pulmonary ventilation perfusion mismatch bas been alsoreported following treatment with a nitrate.

Drug lnteractiOlis: Phenobarbitone (phenobarbital) may enhance nitrate metabolism, while ethanol inhibits it. Nitrates Can potentiate the antihypertensive effect of tricyclic antidepres_ santsand slow the catabolic process of narcotic drugs. Indomethacin may inhibit the Vasodilatory effect of nitrates.

Dosage and Administration: The usual dosage for oral isos9rbide 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 individuallytailored based on clinical responses.

Glyceryl Trinitrate Ointment and lsosorbide Dinitrate: A Review

Since the introduction of glyceryl trinitrate (nitroglycerin) as an antianginal agent a century ago, it has become the most widely used drug in the treatment of angina pectoris (Aronow, 1972, I 979a). Recent extensive evaluation of the haemodynamic etTects of this drug resulted in its wide application in the treatment of acute and chronic congestive heart failure (Aronow, I 979b). In addition, glyceryl trinitrate has been suggested by some investigators to be beneficial iri the treatment of acute myocardial infarction (A wan, 1976; ChiarielIo et al., 1976; Delgado et al., 1975). Glyceryl trinitrate has been used in the control of blood pressure during coronary artery bypass graft surgery and has been found to enhance ventricular electrical stability during myocardial ischaemia (Kent et aI., 1974; Mihalick, 1974). Furthermore, in patients with resting segmental wall motion abnormalities due to previous myocardial in-farction, glyceryl trinitrate improves performance of dysynergic areas, decreases the size of the heart, and increases shortening and velocity of contraction in ad-jacent normal segments (Henning et aI., 1976).

Despite these areas of potential usefulness, the clinical use of glyceryl trinitrate has been significantly limited dueto its short acting etTect. Several oral and sublingual long acting nitrates have therefore been developed and investigated. Additionally, the cutaneous application of glyceryl trinitrate, which had been forgotten for many years, has been regaining popularity, and its effect has come under intensive in

vestigation. The purpose of this article is to review the current knowledge of the usefulness and limitati~ns of long acting nitrates, using isosorbide dinitrate as ~ 'prototype' for discussion of oralIy administered long acting nitrates, and with a special emphasis o~ glyceryl trinitrate ointment.

J. Pharmacodynamic Studies

1.1 EtTect on the Peripheral Circulation

A direct relaxation of the smooth muscle in the systemic venous bed is' the predominant circulatory etTect of nitrates (Mason and Braunwald, I 965i. Mason et aI., 1971; Williams, 1977). The resultan!. decrease in peripheral venous tone is followed b~i pooling of blood in the dilated venous capacitance cir;: culation, and in a decrease of blood returned to the' heart. The etTect of nitrates on the systemic arteriolar, circulation is less prominent, but can be manifested, regionally by a fall in forearm vascular resistance and' an increase in blood flow (Mason and Braunwai~.. 1965), and systemically by a decrease in peripher.aI~ resistance (Flaherty et aI., 1979). This is usually acoi~ companied by a modest decrease in systemic bloOd pressure (Bernstein et aI., 1966; Gorlin et al., 195?;: Gray et aI., 1975). The etTect of nitrates on the arteriolar circulation seems to be dose-dependent, in~ {, creasing with high doses (Packer et aI., 1979).

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Glyceryl Trinitrate Ointment and Isosorbide Dinitrate: A Review '0 ,I

1.2 Effect on Systemic Blood Pressure

Systemic blood pressure is a function of systemic . vascular resistance and cardiac output. A fall in cardiac output without a compensatory increase in resistance results in a decrease in blood pressure. The direct venodilatory effect of nitrates, with consequent pooling of blood volume in the capacitance system and decreased venous return to the heart, can lead to a fall in left ventricular filling or preload and therefore in cardiac output. This phenomenon plus the mild arteriolar dilatory effect' of these drugs can result in a fall in systemic blood pressure, especially in the upright position (Awan et aI., 1978; Williams et aI., 1975).

In patients with congestive heart failure, when the left ventricular function curve is depressed and the ventricular preload is elevated (Ross et aI., 1966), the administration of nitrates is' usually associated with a less significant change in blood pressure (Franciosa et aI., 1977; Gold et aI., 1972; Taylor et aI., 1976).

1.3 Effect on Cardiac Output

The effect of nitrates on cardiac output depends on multiple factors (Franciosa et aI., 1978). The status of left ventricular function before administration of the drug, and the magnitude of the effect of glyceryl tri-nitrate on the venous and arteriolar circulation, play an important role in determining the cardiac output changes foIl owing therapy. A significant reduction in left ventricular preload, the predominant effect of the drug, is associated with decreased cardiac output in most. of the patients with normal left ventricular function (A wan et aI., 1978; Bussmann et aI., 1977). On the other hand, venodilatation and reduction of left ventricular filling pressure in patients with an elevated left ventricular preload due to congestive heart failure isusually foIlowed by no change or, in some patients, even by an increase in cardiac output

. (Bussmann et aI., 1977). This augmentation of cardiac output is mostly associated. with arteriolar dilatation and decreased peripheral resistance (Taylor

169

et aI., 1976). The effect of glyceryItrinitrate on the ar-teriolar circulation, and therefore on systemic vascular resistance and cardiac output, seems to be dose-de-pendent (Packeret aI., 1979).

1.4 Effect on Heart Rate

In patients with elevated left ventricular end-diastolic pressure, therapy with glyceryl trinitrate seldom causes an appreciable increase in heart rate, despite a mild decline in systemic blood pressure (Franciosa et aI., 1977; Meister et aI., 1976; Taylor,1976). The attenuation or absence of the baroreceptor response may reflect a defect in the autonomic control of heart rate in patients with heart failure which apparently involves the sympathetic and parasympathetic systems (Goldstein et aI., 1975). However, in patients with normal left ventricular end-diastolic pressure, a decrease in blood pressure foIlowing glyceryl trinitrate may result in reflex tachycardia (A wan et aI., 1978).

1.5 EffeCt on Coronary Circulation

Little is known about the effect of long acting nitrates on the coronary circulation through direct investigation with these agents, although this subject has been extensively investigated using short acting glyceryl trinitrate. As both short and long acting nitrates have been shown to have similar antianginal and haemodynamic effects, it would be reasonable to assume these drugs also have a similar effect on the coronary circulation.

Although sublingual glyceryl trinitrate and other short acting sublingual nitrates relax vascular smooth muscle and dilate the coronary arteries in normal subjects, these drugs do not increase coronary blood flow in patients with coronary artery disease at rest or while doing exercise (Aronow, 1972). This is not surprising as it is difficult to conceive of a drug producing vasodilatation in diseased sclerotic vessels. Horwitz et aI. (1971), however, showed that glyceryl trinitrate can cause redistribution of coronary blood flow so that the greater proportion of the coronary

'j Glyceryl Trinitrate Ointment and lsosorbide Dinitrate: A Review

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blood flow is delivered to ischaemic regions. Becker et al. (1971) also demonstrated that in the canine ischaemic heart, glyceryl trinitrate preferentially increased blood flow to the subendocardium. In addition, numerous experiments have shown that glyceryl trinitrate can increase collateral blood flow during acute myocardial ischaemia (Capurro et al., 1977; Chiariello et aI., 1976; Leighninger et al., 1959; Mathes and Rival, 1971 ; Weisse et al., 1972)."

1.6 Effect on Pulmonary Circulation

Glyceryl tri~itrate may have a direct vasodilatory effect on the mammalian pulmonary circulation (Ferrer et al., 1966). Lappe et al. (1977) showed a reduction in pulmonary vascular resistance as well as air flow obstruction following glyceryl trinitrate administration in patients with acute respiratory failure and pulmonary hypertension.

1.7 Effect on Electrical Stability and the Conduction System

Glyceryl trinitrate has been found to decrease the frequency of spontaneous ventricular fibrillation. and to enhance ventricular electrical stability after ischaemic injury in both experimental animals and in man (Borer et al., 1974; Mihalick et al., 1974). In ad. dition, it has been shown to raise the ventricular fibrillation threshold in non-ischaemic canine myocardium (Dashkoff et al., 1976). Gould et al. (I 976) showed that glyceryl trinitrate improved conduction through the A-V node in patients with organic heart disease.

i.8 Effects on Left Ventricular Function

Hardarson et al. (I 977) have assessed the effect of orally and topically administered nitrates on left ventricular function in II patients with previous myocardial infarction. Oral isosorbide dinitrate 20mg, 12.5 to 40mg glyceryl trinitrate ointment, and a placebo ointment were compared in a double-blind 'study. The effect on left ventricular dimension was

evaluated by echocardiography, while regionall~ti: ventricular function was studied by wall motian'

video tracking (Kazamias et al." 1971). The appliCil; .~

tion of glyceryl trinitrate ointment resulted in an l~ ................................................................................................................................ ~ crease in the number of normal segments from 38.(0" 53 % at I hour of therapy and to 55 % at 3 hourS. A, total of 9 segments showed qualitative improvement: after I hour and 12 segments showed improvem~f after 3 hours. The effect of glyceryl trinitrate oirif,i ment on regional wall motion was comparable to the, effect of oral isosorbide dinitrate. There were ni> qualitative changes in segmental wall motion after ~~. plication of the placebo ointment. Quantitative analysis showed a significant increase in the magnitude and velocity of systolic inward motion after therapy with glyceryl trinitrate ointment in the nor~ mal and dyskinetic segments. The echocardiograplij~) left ventricular end-diastolic and end-systolic dim~;o sions decreased significantly after botlf'glyceryl tri;: nitrate ointment and oral isosorbide dinitrate. "v.

In another double-blind study, Abrams and. Kochukosky (1976) evaluated the effect of 2 %', glyceryl trinitrate ointment on left ventricular volume utilising serial echocardiography. Glyceryl trinitrate ointment resulted in a significant sustained decrease

in left ventricular end-diastolic volume and end~ ,. systolic volume lasting for 15 to 180 minutes. Max;; imal reduction in mean end-diastolic volume occurred at 60 minutes (range 30 to 180 minutes). The effect ~f, glyceryl trinitrate ointment was comparable with an~ even greater than the effect of usual doses oJ. sublingual glyceryl trinitrate.

The effect of glyceryl trinitrate administered. sublingually and topically on left ventricular functio~ was studied in a double-blind fashion by W ayn~ (I 977), using apex cardiography and systolic tim:e intervals. Left ventricular function was improved ii!., 8 of 10 patients studied after both sublingual glycerY.t trinitrate and 2 % glyceryl trinitrate ointment (3 inches), and was unchanged after the application'of a placebo ointment. The apex cardiogr ~

show~ reduction of the amplitude and duratio of the N wave, indicating an improvement in left entricular. compliance and therefore an improvement in diastolic

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Glyceryl Trinitrate Ointment and Isosorbide Dinitrate: A Review 171

(1971) suggested that glyceryl trinitrate is an effective antianginal agent partially because it causes redistribution of coronary blood flow so that the greater proportion of the flow is delivered to ischaemic regions. Becker et at. (J 971 ) also demonstrated that in the ischaemic heart, glyceryl trinitrate preferentially increased blood flow to the subendocardium. However, Ganz and Marcus (1972) observed that intracoronary injection of glyceryl trinitrate in 25 patients increased coronary sinus blood flow in 14 cases, but did not relieve pacing-induced anginal pain or reduce its intensity. Whether the glyceryl trinitrate was injected into the right or left coronary artery, into the obstructed coronary artery, or into the artery supplying collaterals to the obstructed coronary artery did not seem to influence these findings. These obser- .

vations suggested that the increase in coronary blood flow did not occur in ischaemic areas, but rather in the non-ischaemic areas, where the arterioles were not maximally dilated. Intravenous administration of glyceryl trinitrate to 6 of the 25 patients relieved anginal pain in each of these cases. This effect was associated with a reduction in arterial pressure and coronary sinus blood flow, suggesting that a reduction in myocardial demand was the mechanism of relieving ischaemia.

An important factor in the antianginal effect of nitrates is related to their ability to reduce myocardial oxygen demand. Nitrates cause pooling of blood in the peripheral veins (Mason and Braunwald, 1965), decreasing venous return to the heart, and thereby reducing ventricular volume (Williams et al., 1965). This reduction in ventricular volume, according to Laplace's law, decreases intramyocardial tension and reduces myocardial oxygen demand. Nitrate therapy can also lower the arterial pressure by causing ar. teriolar dilatation with Ii reduction in systemic vas" cular resistance (Mason and Braunwald, 1965). By reducing systolic intraventricular pressure and resistance to ventricular ejection, myocardial oxygen de. mand is further decreased. A reduction in the arterial pressure, cardiac output and stroke volume causes a decrease in left ventricular external work, leading to a reduction in myocardial oxygen consumption.

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filling (Voigt and Friesinger, 1970). A significant increase in the isovolumic relaxation time indicated reduction in left atrial pressure. Simultaneous improvement in the slope of the systolic wave suggested improvement of wall motion (Lane et al., 1968). Both sublingual and topical glyceryl trinitrate therapy resulted in significant shortening of the left ventricular ejection time, suggesting a decrease in stroke volume (Braunwald et al., 1958), most probablY due to a decrease in left ventriculal: preload. None of the parameters changed significantly during the control period or after application of the placebo ointment. The time to onset' of the effect after sublingual ad-ministration of glyceryl trinitrate was 3 to 5 minutes, with a duration of 15 to 30 minutes. Glyceryl trio nitrate ointment had its onset of action at 20 to 30 minutes, peak effect at 90 minutes, and a significant effect was still seen at 3 hours.

1.9 Antianginal Action of Nitrates - Mechanism

The mechanism of action of nitrates in the relief of angina pectoris is probably multifactorial. The con-tribution of the coronary vasodilator effect of nitrate to the antianginal action is not clearly established. It is also not entirely clear whether the change in coronary blood flow following administration of glyceryl trinitrate is a result of a direct action on coronary ar. teriolar resistance (Becker, 1976; Cohen et al., 1973), or due to the indirect increase in the transmyocardial pressure. gradient caused by the decrease in left ventricular end-diastolic pressure (Parker et al., 1970, which is also accompanied by diminished extrinsic compression of small vessels (Figueras and Forrester, 1978). Although glyceryl trinitrate relaxes vascular Smooth muscle and dilates coronary arteries in normal subjects, the drug does not increase coronary

. blood flow in patients with coronary artery disease either at rest or during exercise (Aronow, 1 972). In fact, glyceryl trinitrate has a greater vasodilator ac-tion on large coronary arteries than on small ones. The coronary vasodilator action of nitrates is important in relieving angina pectoris at rest or after exercise due to coronary artery spasm. Horwitz et al.

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,titi~ in rat urine after 24 hours. Analysis of: pooled urine from rats treated with glyceryl trini ~ at timed

intervals showed excretion of glyceryl

2.2 Isosorbide Dinitrate

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nitrate have shown that the parent molecule is d~n)

ated rapidly and does not appear in significant Q

ia

I., 1971). /n ~ivo metabolic studies of glyceryl:

II II

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., 1. >,

2. Pharmacokinetic Studies

2. t Glyceryl Trinitrate

2././ Absorption Glyceryl trinitrate is readily absorbed from the

sublingual mucosa. The gastrointestinal tract and the skin are also useful routes of absorption. While sublingual administration of glyceryl trifiltrate results in very rapid absorption and almost instantaneous achievement of high serum drug levels (bolus effect), there is a much slower increase in blood levels when the drug is given orally or topically. Blumenthal et aI. (1977), who used a gas chromatographic assay allowing Quantitation of gl~ceryl trinitrate in human plasma to levels as low as O.tng/ml, found t .Ong/ml of glyceryl trinitrate 3 minutes after the sublingual administration of a 0.3mg tablet. Levels of about 0.1 ngl ml of the drug could not be detected until 20 minutes after application of I inch glyceryl trinitrate ointment 2 % (corresponding to 16mg of glyceryl tri nitrate) and until 20 minutes after administration of one 6.5mg sustained release oral capsule.

Sublingual absorption of glyceryl trinitrate depends on salivary secretion. In some cardiac patients who are treated with atropine for disturbances in their conduction system, salivary secretion is markedly diminished, the mouth becomes dry, and the rate of glyceryl trinitrate absorption is significantly decreased. Oral absorption can be decreased in patients with functional or gastrointestinal hypermotility or malabsorption syndrome. Qinical studies have suggested that the rate of glyceryl trinitrate sic in absorption will be affected by the area of application, cutaneous blood flow at the site of administration, the rate of evaporation, and the dose (Armstrong et aI., 1976; Davis and Weisel, 1955).

2./.2 Distribution and Elimination 60 % of glyceryl trinitrate was found by Dicarlo and Megler (] 969) to be protein-bound in rat plasma.

Glyceryl trinitrate is degraded primarily in the liver bya partial denitration process mediated by glutathione

organic nitrate reductase (Needleman et

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nitrate with a larger amount of 1,2 and 1,3 glyce' initrates and a trace of glycerol mononitrate. Moho; and dinitrates which are almost completely in

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circulate in the blood for many hours (Goodman '

Gilman, I 975). Stauch. et aI. (1975) have challeng this and found marked haemodynamic respo~ after intravenous administration of 2-isosorbi<i mononitrate and 5-isosorbide mononitrate. After 21 hours, glyceryl trinitrate is almost absent and dinm; ates are the major excreted metabolites. After, ~O

hours, excretion appears to be essentially compl~ I 'on (Needleman and Krantz, 1965). ,,;~

Part of glyceryl trinitrate metabolism may take place in the blood, since incubation with rat seruID Ie resulted in dinitration of 76% of the drug withill}l. hour (Dicarlo and Megler, 1970). . >' "

Denitration of glyceryl trinitrate may be IimiJfil by the availability of-endogenous hepatic glutathi0I!f Circulation of a large amount of organic nitraIC

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through the liver can result in glutathione depleti~~

and therefore can greatly slow inactivation (Goodm~ and Gilman, 1975). The clinical importance of tJU:

consideration is not entirely clear, but it may explaijl GI some differences in clinical findings with 'small' and 1£ 'large' doses (see section 3.1.2). ,~

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2.2./ Absorption Following sublingual administration isosorbi~1,

dinitrate is rapidly absorbed, peak serum concen~: tions of parent drug occurring within about ,10 minutes in healthy subjects (SpOrl-Radun et aI~, 1980). Oral administration also results in rapid achievement of peak plasma concentrations of parerit drug (10 and 20 minutes after administration in) healthy subjects), but the systemic availability of

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Glyceryl Trinitrate Ointment and Isosorbide Dinitrate: A Review 173

Table I. Clinical trials of the anti-anginal effect of long term therapy with glyceryl trinitrate (nitroglycerin) ointment or oral isosorbide dinitrate

Reference

No. of pts.

Study Dosage design'

End-point criteria

srudies using glyceryl rrinirrate ointment (usually specified as 2%) Awan et al. 9 Open 30mg Exercise duration. 11978) ST-segment depression.

Exercise-induced angina

Davidov and Mroczek ( 1976)

12 2 inchesDb,co

Karsch et al. (1978) 10 Db, r, co 2-3 inches

Parker et al. (1976)

Open 12 15mg

Reichek et al. (1974)

14 Open 1.5-19mg

Studies using orally administered isosdrbide dinitrateDanahy et a!. 21 Db;r. co 20-5Omg (1977) (mean dose Danahy and 29mg) Aronow (1977)

Exercise duration. ST -seg,ment changes. Exercise-induced angina

Exercise duration. ST -segment depression. Exercise-induced angina

Exercise-induced angina. ST -segment depression

Exercise capacity. ST -segment depression

Exercise duration. ST -segment depression. Exercise-induced angina

Glancy et al. 10 Db,r 7.5-2Omg Exercise duration (1977)

lee et al. 28 Db,r 40mg Exercise duration. (1978) ST-segment depression

Markis et al. (1978)

10 Db,r 20mg Duration of exercise. Exercise-induced angina. ST -segment depression

Results of therapy'

Increase in duration of exercise from 6.04 to 7.33 min. Improvement of ST -depression from 1.76 to 0.77mm. Decrease in angina in 6/6 patients 49 % increase in exercise duration 3h post-NTGO. No change with placebo. Decreased ST -segment depression and angina on NTGO Increase in exercise duration from 13.7 to 16.8 minutes. Improvement of exercise-induced ST -segment depression from 2.2 to 1.8mm No chest pain in 10 of 12 patients. Decrease in pain in 2 patients. Improvement of ST-depression in 6/6 patients Greater exercise capacity (from 5 to 8 minI. Less ST -depression in 4/4 '

patients

Significant increase of exercise duration for 5h post-admin istration. Improvement of ST -depression in 6/21 patients. No chest pain in 7/21 patients

Increase in exercise capacity in 9/10 patients (mean values of 7.57 versus 10.11 minI

Increase in exercise duration from 310.8 to 386.5 sec at 2h and from 301.8 to 372.3 sec at 6h after administration of drug. No change in ST -depression at peak exercise but less ST -depression at interval identical to duration of control exercise

Significant increase in duration of exercise for 4h. Significantly less depression durin'g exercise. Only 4/9 patients stopped exercise because of angina

Abbreviations: Db = double-bfind; r = randomised; co = crossover; NTGO = glyceryl trinitrate (nitroglycerin) ointment;

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Glyceryl Trinitrate Ointment and Isosorbide Oinitrate: A Review 175

Davidov and Mroczek. (\ 97McOnoucted a double- by electrocardiographic evidence of previous myo

blind, crossover study comparing the effects of cardial infarction. All patients had a history of angina glyceryl trinitrate ointment 296 and placebo on exer- pectoris and ischaemic electrocardiographic

responses cise tolerance in 12 patients with angina pectoris. The to treadmill stress testing. Application of 1.5

inches glyceryl trinitrate ointment significantly increased the of glyceryl trinitrate ointment to the anterior

chest duration of exercise both at 1- and 3-hour evalua- wall resulted in a significant increase in exercise

dura tions. These results were statistically significant from tion (p < 0.05) and improvement of SoT

segment the baseline values' and were significantly different depression (p < 0.05). This was associated with a from the placebo treatment periods. An analysis of marked increase in the total body oxygen consumpthe quantified workload revealed a 91 96 increase tion:' after I hour and a 9496 increase after 3 hours in the Reichek et al. (1974) demonstrated that 2 % glyceryl trinitrate ointment treatment group, whereas glyceryl trinitrate ointment (1.5 to 19m9) caused an after placebo administration the respective increases increase in exercise capacity (p < 0.00 I) and a reducwere 41 and 12 %. Statistical analysis revealed sig- tion in exercise-induced ST -segment depression nificant differences following glyceryl trinitrate oint- (p < 0.05) which persisted for at least 3 hours in 14 ment treatment at both the 1- and 3-hour intervals. patients with angina pectoris. Karsh et al. (\ 978) ob Analysis of the exercise termination variables (S-T served in a randomised, double-blind study that 2 % segment depression and/ or anginal pain) revealed glyceryl trinitrate ointment (dose of 2 to 3 inches) that there was significantly less SoT segment depres- caused an increase in exercise capacity(p < 0.005) and sion and a decreased incidence of angina noted during a reduction in exercise-induced ST -segment depres: . glyceryl trinitrate therapy. Pharmacological activity sion (p < 0.05) which persisted for at least3 hours in was also evidenced by an increase in heart rate found 10 patients with angina pectoris.

at the 1- and 3-hour intervals in the group treated .

with glyceryl trinitrate. 3.J .2 Oral Jsosorbide Dinitrate in the Improvement in exercise performance following Treatment of Angina Pectoris

therapy with glyceryl trinitrate ointment was also Needleman et al. (1972) have demonstrated thatdemonstrated by Parker et al. (\ 976) in 12 patients orally administered organic nitrates are directly withangina pectoris and significant coronary artery transported to the liver via the portal vein, and are disease documented by coronary cineangiography. In rapidly and completely degraded in the liver in ratsaddition to the improvement in exercise capacity, total before reaching the systemic circulation. Their experiprevention of chest pain was achieved in 10 of the 12 mental findings have been thought to providean expatients, while the other 2 patients had delayed and planation for the results of numerous double-blind less severe symptoms. Of 6 patients who had SoT seg- studies which have shown the ineffectiveness of small ment depression of 2mm or more during initial exer- doses of oral nitrates as antianginal agents (Aronow cise, only I had such depression during the second and Kaplan, 1969;Goldbarg et aI., 1969; Stipe and exercise period performed 60 minutes after the ap-~k, 1973). In contrast, the haemodynamic and antiplication of glyceryl trinitrate ointment. The anginal effects of large doses oforal nitrates in beneficial clinical and electrocardiographic effects of patients with angina pectoris have been well therapy in these patients were accompanied by signifi- established, the larger doses presumably overcoming

cant haemodynamic improvement (fig. I). to some extent the loss of the systemically availableAwan et aI. (I978) studied the cardiocirculatory drug due to 'first-pass' metabolism. Danahy et al. and

antianginal action of glyceryl trinitrate ointment (I 977) demonstrated in a double-blind, randomised, in 9 patients with coronary artery disease docu- crossover study that the acute administration of 20 to tnented either by selective coronary angiography or 50mg of oral isosorbide dinitrate (mean dose 29mg)

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Glyceryl Trinitrate Ointment and Isosorbide Dinitrate: A Review In a double-blind study, Williams et al. (1977) ad-

ministered 20mg of oral isosorbide dinitrate or placebo to 25 patients with congestive heart failure; 15 patients received oral isosorbide dinitrate and 10 received a placebo. Left ventricular filling pressure was reduced 5 minutes after oral isosorbide dinitrate, was maximally decreased from 23 to 14mm Hg I hour after drug administration and was reduced for 4 hours, but was not significantly different after placebo. No significant change in heart rate occurred after oral isosorbide dinitrate or placebo. Mean blood pressure was reduced 15 minutes after oral isosorbide dinitrate, was' maximally decreased from 97 to 81 mm Hg I hour after drug 'administration and was reduced for 5 hours, but was not significantly different after placebo. Systemic vascular resistance was reduced 30 minutes after oral isosorbide dinitrate, was maximally reduced from 2129 to 1808 dyne . see . em -, I hour after isosorbide dinitrate, but was not significantly different after placebo. At the time of maximal reduction of left ventricular filling pressure after oral isosorbide dinitrate, the cardiac index increased in 9 patients, decreased in 5, and was unchanged in I. In 13 of 15 patients (87 %), the change in cardiac index was less than 20 %. No significant change in mean cardiac index occurred after oral isosorbide dinitrate or placebo. However, of 7 patients in whom the left ventricular filling pressure after oral isosorbide dinitrate was above 12mm Hg, 6 (86 %) had an increase in cardiac index, with a significant improvement from 1.8 to 1.96L/min/m2. No significant change in stroke index or stroke work index occurred after oral isosorbide dinitrate or placebo. However, a slight but significant increase in stroke index and in stroke work index occurred after oral isosorbide dinitrate in patients with a left ventricular filling pressure greater than 12mm Hg.

3.3.3 Long Acting Nitrates plus Hydralazine in the Treatment of Congestive Heart Failure (table IV) As noted above (section 3.3.2), the administration

of nitrates to patients with congestive heart failure causes a significant reduction in pulmonary and

181

systemic venous pressures with little or no increase in cardiac output. On the other hand, hydralazine therapy in patients with heart failure increases cardiac output significantly without much effect on the venous circulation and, therefore, on left ventricular filling pressure (Chatterjee et a!., 1976). Most patients with chronic congestive heart failure have low cardiac output as well as elevated pulmonary capillary wedge pressure. Massie et al. (J 977) and Pierpont et al. (1978) demonstrated that combined therapy with hydralazine and nitrates provided an additive beneficial effect in patients with congestive heart failure and resulted in a concomitant reduction of left ventricular filling pressure and elevation of cardiac output (fig. 5). Recent studies have shown that this therapeutic combination is also effective haemodynamically during exercise (Franciosa and Cohn, 1979).

Massie et al. (J 980) have recently shown that the haemodynamic effect of the combined therapy. (oral nitrates plus hydralazine) during exercise was associated with an increase in maximal oxygen consumption, a' finding which was not seen with hydralazine or nitrates alone. A recent report has shown postural hypotension and tachycardia occur during continuous hydralazine-isosorbide dinitrate therapy in patients with chronic heart failure. Although the postural changes appeared to lessen with time, the need for particular caution in patients with ischaemic heart disease has been discussed (Massie et al., 198 O. The optimal dose of both nitrates and hydralazine should be titrated individually. The commencing dose of hydralazine should be small, for instance 12.5mg 2 or 3 times daily, and then gradually increased as needed. Up to 100mg of hydralazine 3 times a day should be adequate to cause sustained arteriolar dilation in most patients with congestive heart failure, but higher doses are needed in some cases. Doses of 40mg oral isosorbide dinitrate or I to 2 inches of glyceryl trinitrate ointment every 4 hours in combination with oral hydralazine produce haemodynamic changes which should be. beneficial in treating most patients with congestive heart failure refractory to digitalis and diuretic therapy.

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Glyceryl Trinitrate Ointment and Isosorbide Dinitrate: A Review 6.4 Other Adverse Effects q," '"

Drug rash occasionally can be produced by all organic nitrates. Hypoxaemia following glyceryl tri-nitrate administration has been reported and can be caused by increased pulmonary ventilation perfusion mismatch (Weygandt et a!., 1979).

7. Drug Interactions

Concomitant phenobarbitone (phenobarbital) ad.ministration may enhance glyceryl trinitrate metabolism and result i~ lower peak glyceryl trinitrate levels(DiCarlo, 1975), but probably has no effect on thehaemodynamic response (Dauwe et al., 1979). Ethanolcauses inhibition of glyceryl trinitrate metabolism and may enhance its activity (DiCarlo, 1975). Glyceryl trinitrate can potentiate the hypotensive effect oftricyclic antidepressant drugs (DiCarlo, 1975; Elkayamet a!., 1979) and may slow the catabolic process ofnarcotic drugs (Hill et al., 1981). Preliminary data haverecently suggested that indo~ethacin can inhibit theperipheral vasodilatory ef. feet of nitrates, presumably by the suppression ofprostaglandin E synthesis (VanDusen and Fischl, 1981),

8. Dosage and Administration

8.1 Isosorbide Dinitrate

Although numerous long acting nitrates are com-mercially available, oral isosorbide dinitrate has been the one most commonly evaluated and clinically used. The onset of action usually occurs within 15 to 30 minutes after administration of the drug, and the duration of effect usually lasts from 3 to 4 or 5 hours. 20 to 60mg every 4 to 6 hours may be needed for the treatment of angina pectoris and congestive heart failure. Doses as high as 100mg every 3 to 4 hours have been used safely in patients with severe conges

, live heart failure (Packer et al., 1979). '

8.2 Glyceryl Trinitrate Ointment The onset of effect is within 30 to 60 minutes after

administration of the drug. The duration of effect is 4 to 6 hours in most cases. 0.5 to 2 inches of the ointment is therefore recommended every 4 to 6 hours. However, considerable interindividual variation in dose responsiveness occurs, and individual tailoring of the frequency of administration may be required based on clinical responses. The starting dose is '~suallY one-half inch and can be increased gradually if indicated, until the desired effect is reached or side effects prevent any further dose increase, up to a maximum of 4 to 5 inches. The ointment should be spread in a thin, uni(orm layer on the skin. For 'psychological reasons, the ointment is usually applied to the chest wall in patients with angina Pectoris or chronic congestive heart failure, but the same effect can be achieved when the drug is applied to any other part of the skin.

Acknowledgements

We are indebted to Linda Shaw and Cynthia McDaniel for expert assistance in typing the manuscript.

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Glyceryl Trinitrate Ointment and Isosorbide Dinitrate: A Review ",":J '"

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193

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, , ~~ Author's address: Dr Uri Elkayam, Division of Cardiology, University

of California, Irvine Medical Center, 101 City Drive South, Orange, CA 92668 (USA). 'J';'

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Glyceryl Trinitrate (Nitroglycerin) Ointment and Isosorbide …elkayam/articles/44.pdf · isosorbide dinitrate) resulted in a significant increase in exercise time which lasted for