DRUG METABOLISM REVIEWS, 4(1), 135-138 (1975)
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CURRENT TOPICS IN DRUG METABOLISM AND PHARMACOLOGY
Organic Nitrates in Perspective JEAN C. PARKER and IVAN W. F. DAVIDSON Department of Physiology Section on Pharmacology Bowman Gray School of Medicine Winston-Salem, North Carolina 271 03
In the long clinical and investigational history of nitroglycerin (NG) and other organic nitrates, the pharmacology and clinical value of these drugs has never been of greater interest. After a century of use, NG retains its unique place in the therapeutic armamentarium of the physician for the relief of acute angina pectoris. Currently in question i s the clinical value of the “long-acting” organic nitrates which for the past two decades have been in use for prophylactic therapy. The rationale for their use exists in their chemical similarity to NG and their vasodilator activity. The literature is r e dundant with clinical studies demonstrating effectiveness of these drugs; thus they a r e widely prescribed with the objective of decreasing the frequency and severity of anginal attacks and decreasing the need to use NG. Nevertheless, many other studies report little o r no clinical benefit. The differing clinical experience with these drugs appears to be the result of two major factors: 1) the difficulties of objective assessment of the clinical effectiveness of compounds when given to prevent episodes of angina pectoris, and 2) the presumption of equality of effectiveness of the members of this group, associated with a lack of the basic information on pharmacokinetics and biotransformation that is necessary for their effective use. Accumulated studies in the past few years provide a firmer pharmacological basis for evaluating these compounds for therapeutic use, However, for only a pair of these drugs (the pentaerythritol nitrates, PETN and PE trinitrate) have the pharmacokinetics and metabolism 135 Copyright 0 1 9 7 5 by Marcel Dekker. Inc All Rights K e ~ r v e d . Neither this work nor any part may be reproduced o r transmitted in any form or by any means. electronic or nirchanical. including photocopying, microfilming, and recording, or hy any inforniation storage and retrieval system. without permission i n writing from the puhlisher.
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136
PARKER AND DAVIDSON
been studied in detail in man [l-31. The clinical effectiveness of many of the others may obviously be precluded when this information becomes available. The current controversy over the clinical value of the “longacting” nitrates was sparked by a recent study (1972) of Needleman and his associates [4] which received considerable notoriety in the medical and lay literature. In effect these investigators claimed that a single passage through the liver of rats completely degrades all organic nitrate esters. Since most “long-acting” organic nitrates, including some NG preparations, are administered per 06, then ips0 facto these nitrates must be therapeutically ineffective. In addition to the fact that these experiments are open to serious criticism on the basis of methodology, they a r e also in direct conflict with many studies of other investigators. Experiments in animals and man show that a t least two clinically used “long-acting’’ organic nitrates appear as the intact drug in the systemic blood after passage through the liver, and produce vasodilator and vasodepressor effects after oral o r portal vein administration [5-91. Both in vivo and vitro studies show that the rate of liver denitration of the nitrates is a function of the rate of absorption, the total dose, and, more importantly, the substrate specificity of the nitrate ester compounds for the denitrating enzyme system of the liver [2, 6, 10-151. The “long-acting” organic nitrates are degraded by this system (organic nitrate reductase) at a far slower rate than NG. But there are also large differences in the susceptibility of the “long-acting’’ nitrates themselves to denitration [ll-151. In addition, some of the drugs a r e converted to glucuronides which are more resistant to denitration during passage through the liver (e.g., pentaerythritol trinitrate) [7, 13, 16, 171. These glucuronides can represent a plasma depot, since they can be released to free drug by deconjugation enzymes in the liver and possibly also at peripheral cardiovascular sites of action [8, 131. It is now clear from the recent studies (1975) of Parker, Di Carlo, and Davidson [18]that there is a wide range of vasodilator activity for clinically used nitrate drugs at vascular sites of action. No obvious structure-activity relationship is apparent, although a common mechanism of action is evident. Vasodilator activity does not correlate with the number of nitrate ester moieties. Also, the lesser nitrated biometabolites of several of the drugs, although retaining various numbers of nitrate esters, a r e virtually inactive. The surprising conclusion is that vasodilator activity is dependent on the entire drug molecule. Thus clinical effectiveness of this group of drugs relates not only to practical considerations of rates of absorption, liver degradation, and distribution, but also to the nature of the
Drug Metabolism Reviews Downloaded from informahealthcare.com by University of North Carolina on 11/14/14 For personal use only.
ORGANIC NITRATES
137
drug molecule itself and its interaction a t cardiovascular sites of action. The commonly held notion that one organic nitrate is as good as another has been demonstrated to be untrue. Thus some organic nitrate drugs may possess far greater clinical effectiveness than others. In view of their clinical importance and long history of study, the lack of knowledge of the biochemical mechanisms of relaxation of vascular smooth muscle cells by NG and other organic nitrates is surprising. Clearly, the vasodilator actions of these drugs are specific effects and indicate a specific mechanism of action on vascular smooth muscle. They can act as physiological antagonists to norepinephrine, acetylcholine, histamine, and many other agents. Two general hypotheses are current: 1) the nitrates act on specific receptors on the membranes of smooth muscle, and 2) the nitrates enter smooth muscle cells and are denitrated to release nitrite ions which are capable of inducing relaxation. There is no preponderance of evidence at present for either mode of action. A definitive answer to this single question could greatly facilitate future studies on the precise mechanism of smooth muscle relaxation by the nitrates. The explanation of both the clinical effectiveness as vasodilators as well as the extended duration of action of the “long-acting’’ nitrate esters now appears to reside in the mode of action of these compounds a t the cellular level. Studies at the cellular level might also be expected to shed more light on the nature of the development of tolerance to nitrates. The phenomenon of organic nitrate tolerance and cross-tolerance probably has less clinical significance than the emphasis it has received. There is no universality of opinion that the effect of NG is attenuated in the patient chronically taking “long-acting” nitrates. If the novel concept proposed by Parker e t al. [18]is correct, namely that plasma accumulation of metabolites with longer half-lives than the parent drug is responsible for tolerance, then the rational therapeutic approach to tolerance development is periodic interruption of daily administration of drug for a few days to allow levels of metabolites to fall. However, further studies of the phenomena of tolerance and cross-tolerance could be fruitful. They may contribute to a n understanding of structure-activity relationships, including determination of which of the many nitrate drugs o r metabolites has the least influence on tolerance development. In summary, to the often asked question, “Is there such a thing as a ‘long-acting’ organic nitrate?”, the present evidence supports an affirmative answer. Recent advances have provided a pharmacological basis for their therapeutic use. But it is also probable that not all the currently used nitrates are equally effective clinically.
PARKER AND DAVIDSON
Drug Metabolism Reviews Downloaded from informahealthcare.com by University of North Carolina on 11/14/14 For personal use only.
138
However, the requisite knowledge is now a t hand to enable a systematic selection of nitrate ester structures resistant to metabolic degradation and capable of maximum sustained activity a t vascular sites of action. Future studies may be expected eventually to provide an understanding of the biochemical mechanism of their vasodilator activity
.
REFERENCES
I. W. F. Davidson, H. S. Miller, Jr., and F. J. Di Carlo, J. Pharmacol. Exp. Ther., 175,42(1970). I. W.F. Davidson, H. S.Miller, Jr., and F. J. Di Carlo, J. Pharrn. Sci., 60,274 (1971). I. W. F. Davidson, F. 0. Rollins, F. J. Di Carlo, and H. S. Miller, Jr., Clin. Pharmacol. Ther., 12,972(1971). P. Needleman, J. Phormacol. Exp. Ther., 181,489(1972). H. S. Miller, Jr. and I. W. F. Davidson, Ann. Meeting Program,Amer. SOC.Clin. Pharmacol. Ther., 40 (abstr.) (1970). M. A. Comrnarato, M. M. Winbury and H. R. Kaplan, J. Phormacol. Exp. Ther.. 187,300(1973). S. F. S i n w i n e , and H. W. Ruelius, Ibid., 176,296 (1971). M. C. Crew, M. D. Melgar and F. J. Di Carlo, Ibid., 192,218 (1975). M. -T. Rosseel, and M. G. Bogaert, J. Pharm. Sci., 62,754(1973). R. L.Wendt,J. Pharmacol. Exp. Ther., 180,732(1972). P. Needleman, and F. E. Hunter, Jr., Mol. Pharmacol., 1, 77 (1965). P. Needleman, D. J. Blehm, and K. S. Rotskoff,J. Pharmacol. Exp. Ther., 165, 286 (1969). M. D. Melgar, F. J. Leinweber, M. C. Crew, and F. J. Di Carlo, Drug Metob. Dispos., 2,46 (1974). E. M. Johnson, Jr., A. B. Harkey, D. J. Blehm, and P. Needleman, J. Phormacol. Exp. Ther., 182,56(1972). P. Needleman, and A. B. Harkey,Biochem. Pharmacol., 20,1867(1971). D. E. Reed, J. F. May, L. G. Hart, and D. H. McCurdy, Arch. I n t . Pharmacodyn. Ther., 191,318(1971). M. C. Crew, R. L. Gala, L. J. Haynes and F. J. Di Carlo, Biochem. Pharmacol., 20,3077(1971). J. C. Parker, F. J. Di Carlo and I. W. F. Davidson, Eur. J. Pharmacol., 31, 29 (1975).
Drug Metabolism Reviews Downloaded from informahealthcare.com by University of North Carolina on 11/14/14 For personal use only.
CURRENT TOPICS IN DRUG METABOLISM AND PHARMACOLOGY
Organic Nitrates in Perspective JEAN C. PARKER and IVAN W. F. DAVIDSON Department of Physiology Section on Pharmacology Bowman Gray School of Medicine Winston-Salem, North Carolina 271 03
In the long clinical and investigational history of nitroglycerin (NG) and other organic nitrates, the pharmacology and clinical value of these drugs has never been of greater interest. After a century of use, NG retains its unique place in the therapeutic armamentarium of the physician for the relief of acute angina pectoris. Currently in question i s the clinical value of the “long-acting” organic nitrates which for the past two decades have been in use for prophylactic therapy. The rationale for their use exists in their chemical similarity to NG and their vasodilator activity. The literature is r e dundant with clinical studies demonstrating effectiveness of these drugs; thus they a r e widely prescribed with the objective of decreasing the frequency and severity of anginal attacks and decreasing the need to use NG. Nevertheless, many other studies report little o r no clinical benefit. The differing clinical experience with these drugs appears to be the result of two major factors: 1) the difficulties of objective assessment of the clinical effectiveness of compounds when given to prevent episodes of angina pectoris, and 2) the presumption of equality of effectiveness of the members of this group, associated with a lack of the basic information on pharmacokinetics and biotransformation that is necessary for their effective use. Accumulated studies in the past few years provide a firmer pharmacological basis for evaluating these compounds for therapeutic use, However, for only a pair of these drugs (the pentaerythritol nitrates, PETN and PE trinitrate) have the pharmacokinetics and metabolism 135 Copyright 0 1 9 7 5 by Marcel Dekker. Inc All Rights K e ~ r v e d . Neither this work nor any part may be reproduced o r transmitted in any form or by any means. electronic or nirchanical. including photocopying, microfilming, and recording, or hy any inforniation storage and retrieval system. without permission i n writing from the puhlisher.
Drug Metabolism Reviews Downloaded from informahealthcare.com by University of North Carolina on 11/14/14 For personal use only.
136
PARKER AND DAVIDSON
been studied in detail in man [l-31. The clinical effectiveness of many of the others may obviously be precluded when this information becomes available. The current controversy over the clinical value of the “longacting” nitrates was sparked by a recent study (1972) of Needleman and his associates [4] which received considerable notoriety in the medical and lay literature. In effect these investigators claimed that a single passage through the liver of rats completely degrades all organic nitrate esters. Since most “long-acting” organic nitrates, including some NG preparations, are administered per 06, then ips0 facto these nitrates must be therapeutically ineffective. In addition to the fact that these experiments are open to serious criticism on the basis of methodology, they a r e also in direct conflict with many studies of other investigators. Experiments in animals and man show that a t least two clinically used “long-acting’’ organic nitrates appear as the intact drug in the systemic blood after passage through the liver, and produce vasodilator and vasodepressor effects after oral o r portal vein administration [5-91. Both in vivo and vitro studies show that the rate of liver denitration of the nitrates is a function of the rate of absorption, the total dose, and, more importantly, the substrate specificity of the nitrate ester compounds for the denitrating enzyme system of the liver [2, 6, 10-151. The “long-acting” organic nitrates are degraded by this system (organic nitrate reductase) at a far slower rate than NG. But there are also large differences in the susceptibility of the “long-acting’’ nitrates themselves to denitration [ll-151. In addition, some of the drugs a r e converted to glucuronides which are more resistant to denitration during passage through the liver (e.g., pentaerythritol trinitrate) [7, 13, 16, 171. These glucuronides can represent a plasma depot, since they can be released to free drug by deconjugation enzymes in the liver and possibly also at peripheral cardiovascular sites of action [8, 131. It is now clear from the recent studies (1975) of Parker, Di Carlo, and Davidson [18]that there is a wide range of vasodilator activity for clinically used nitrate drugs at vascular sites of action. No obvious structure-activity relationship is apparent, although a common mechanism of action is evident. Vasodilator activity does not correlate with the number of nitrate ester moieties. Also, the lesser nitrated biometabolites of several of the drugs, although retaining various numbers of nitrate esters, a r e virtually inactive. The surprising conclusion is that vasodilator activity is dependent on the entire drug molecule. Thus clinical effectiveness of this group of drugs relates not only to practical considerations of rates of absorption, liver degradation, and distribution, but also to the nature of the
Drug Metabolism Reviews Downloaded from informahealthcare.com by University of North Carolina on 11/14/14 For personal use only.
ORGANIC NITRATES
137
drug molecule itself and its interaction a t cardiovascular sites of action. The commonly held notion that one organic nitrate is as good as another has been demonstrated to be untrue. Thus some organic nitrate drugs may possess far greater clinical effectiveness than others. In view of their clinical importance and long history of study, the lack of knowledge of the biochemical mechanisms of relaxation of vascular smooth muscle cells by NG and other organic nitrates is surprising. Clearly, the vasodilator actions of these drugs are specific effects and indicate a specific mechanism of action on vascular smooth muscle. They can act as physiological antagonists to norepinephrine, acetylcholine, histamine, and many other agents. Two general hypotheses are current: 1) the nitrates act on specific receptors on the membranes of smooth muscle, and 2) the nitrates enter smooth muscle cells and are denitrated to release nitrite ions which are capable of inducing relaxation. There is no preponderance of evidence at present for either mode of action. A definitive answer to this single question could greatly facilitate future studies on the precise mechanism of smooth muscle relaxation by the nitrates. The explanation of both the clinical effectiveness as vasodilators as well as the extended duration of action of the “long-acting’’ nitrate esters now appears to reside in the mode of action of these compounds a t the cellular level. Studies at the cellular level might also be expected to shed more light on the nature of the development of tolerance to nitrates. The phenomenon of organic nitrate tolerance and cross-tolerance probably has less clinical significance than the emphasis it has received. There is no universality of opinion that the effect of NG is attenuated in the patient chronically taking “long-acting” nitrates. If the novel concept proposed by Parker e t al. [18]is correct, namely that plasma accumulation of metabolites with longer half-lives than the parent drug is responsible for tolerance, then the rational therapeutic approach to tolerance development is periodic interruption of daily administration of drug for a few days to allow levels of metabolites to fall. However, further studies of the phenomena of tolerance and cross-tolerance could be fruitful. They may contribute to a n understanding of structure-activity relationships, including determination of which of the many nitrate drugs o r metabolites has the least influence on tolerance development. In summary, to the often asked question, “Is there such a thing as a ‘long-acting’ organic nitrate?”, the present evidence supports an affirmative answer. Recent advances have provided a pharmacological basis for their therapeutic use. But it is also probable that not all the currently used nitrates are equally effective clinically.
PARKER AND DAVIDSON
Drug Metabolism Reviews Downloaded from informahealthcare.com by University of North Carolina on 11/14/14 For personal use only.
138
However, the requisite knowledge is now a t hand to enable a systematic selection of nitrate ester structures resistant to metabolic degradation and capable of maximum sustained activity a t vascular sites of action. Future studies may be expected eventually to provide an understanding of the biochemical mechanism of their vasodilator activity
.
REFERENCES
I. W. F. Davidson, H. S. Miller, Jr., and F. J. Di Carlo, J. Pharmacol. Exp. Ther., 175,42(1970). I. W.F. Davidson, H. S.Miller, Jr., and F. J. Di Carlo, J. Pharrn. Sci., 60,274 (1971). I. W. F. Davidson, F. 0. Rollins, F. J. Di Carlo, and H. S. Miller, Jr., Clin. Pharmacol. Ther., 12,972(1971). P. Needleman, J. Phormacol. Exp. Ther., 181,489(1972). H. S. Miller, Jr. and I. W. F. Davidson, Ann. Meeting Program,Amer. SOC.Clin. Pharmacol. Ther., 40 (abstr.) (1970). M. A. Comrnarato, M. M. Winbury and H. R. Kaplan, J. Phormacol. Exp. Ther.. 187,300(1973). S. F. S i n w i n e , and H. W. Ruelius, Ibid., 176,296 (1971). M. C. Crew, M. D. Melgar and F. J. Di Carlo, Ibid., 192,218 (1975). M. -T. Rosseel, and M. G. Bogaert, J. Pharm. Sci., 62,754(1973). R. L.Wendt,J. Pharmacol. Exp. Ther., 180,732(1972). P. Needleman, and F. E. Hunter, Jr., Mol. Pharmacol., 1, 77 (1965). P. Needleman, D. J. Blehm, and K. S. Rotskoff,J. Pharmacol. Exp. Ther., 165, 286 (1969). M. D. Melgar, F. J. Leinweber, M. C. Crew, and F. J. Di Carlo, Drug Metob. Dispos., 2,46 (1974). E. M. Johnson, Jr., A. B. Harkey, D. J. Blehm, and P. Needleman, J. Phormacol. Exp. Ther., 182,56(1972). P. Needleman, and A. B. Harkey,Biochem. Pharmacol., 20,1867(1971). D. E. Reed, J. F. May, L. G. Hart, and D. H. McCurdy, Arch. I n t . Pharmacodyn. Ther., 191,318(1971). M. C. Crew, R. L. Gala, L. J. Haynes and F. J. Di Carlo, Biochem. Pharmacol., 20,3077(1971). J. C. Parker, F. J. Di Carlo and I. W. F. Davidson, Eur. J. Pharmacol., 31, 29 (1975).
