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Nitrate tolerance — a therapeutic dilemma
International Elsevier
Journal of Cardiology,
207
21 (1988) 207-210
IJC 00750
Editorial
Nitrate tolerance - a therapeutic dilemma Norman Sharpe Department
of Medicrne,
Universrty of Auckland
(Received
Key words: Nitroglycerin;
School of Medicine, Auckland.
6 April 1988; accepted
New Zealand
26 April 1988)
Drug tolerance
It has become evident in recent years that prolonged or frequent administration of nitrates intravenously [l], orally [2] or transdermally [3,4], can result in tolerance and in attenuation of their haemodynamic and antianginal effects. The clinical importance of such tolerance is the subject of continuing debate, particularly in relation to optimal usage of the long-acting nitrates and transdermal systems for delivery of nitroglycerin. Clinicians are faced with a therapeutic dilemma when considering the results of clinical studies which appear conflicting and also when interpreting current information for prescription, which generally recommends continuous system application. It is necessary to emphasise the limitations of many of the clinical studies that have been performed in this area. Generally, the anti-angina1 effects of nitrates have been studied in relatively small heterogeneous groups of patients with severe coronary arterial disease receiving varied concomitant medications. The relevance of such group data for individual therapy may be questioned. Individual responsiveness to nitrates varies greatly and yet dose titration has often not been carried out. Nitroglycerin has dose-dependent effects on the venous and arterial beds. Maximal venodilatation occurs at relatively low doses and may be less rapidly attenuated than arterial dilatation. Just as nitrate responsiveness varies, there is likewise probably variation in individual susceptibility to tolerance. Patient assessment has generally been based on exercise testing. There may, however, be dissociation between symptoms and exercise evaluation. Certainly one larger study has demonstrated reduction in the frequency of angina with continuous nitrate treatment in patients who showed attenuation of the effect of treatment as judged by exercise testing [5]. A true perspective on silent ischaemia is gradually emerging and may have considerable therapeutic implications.
Correspondence to: Dr. N. Sharpe. Auckland. New Zealand.
0167-5273/88/$03.50
Dept.
of Medicine.
0 1988 Elsevier Science Publishers
University
of Auckland
B.V. (Biomedical
Division)
School
of Medicine,
208
It is also relevant to consider the mode of action of nitrates and their possible mechanisms of tolerance. Relaxation of vascular smooth muscle in response to nitroglycerin is mediated primarily through direct activation of guanylate cyclase and production of cyclic guanosine monophosphate [6] and indirectly through release of prostaglandin 12 from vascular endothelium [7]. Binding of nitroglycerin to smooth muscle receptors appears dependent on the availability of tissue sulfhydryl groups. Continuous administration of nitrates. therefore, may produce tolerance through sulfhydryl depletion and receptor alteration [8]. Thus, theoretically, nitrate tolerance might be averted by increased dosage to overcome receptor refractoriness, exogenous sulfhydryl repletion or introduction of a nitrate-free interval to allow restoration of receptor status. These theoretical possibilities have been incorporated into clinical strategies in attempts to avoid tolerance with long-term nitrate therapy. Regular high dosage of nitrates is probably unlikely to be a successful means of countering tolerance and, in fact, may only determine the more rapid development of more complete tolerance which will require a longer nitrate-free interval for reversal. It does appear, however, that tolerance with long-term treatment can be overcome through the use of sublingual nitroglycerin [9], suggesting that the introduction of a sudden high peak of plasma nitroglycerin may overcome transiently the refractory status of the receptors. Sulfhydryl repletion does appear an effective option. Infusion of the sulfhydryl donor N-acetylcysteine in patients undergoing diagnostic cardiac catheterization has been shown to potentiate the lowering effect of intravenous nitroglycerin on blood pressure and pulmonary wedge pressure [lo]. Furthermore. the attenuation of the coronary vasodilator effect of nitroglycerin with prolonged intravenous infusion can be reversed by administration of N-acetylcysteine [ll]. Similarly, oral N-acetylcysteine appears to reverse the tolerance known to occur with continuous infusion of intravenous nitroglycerin in patients with congestive heart failure [l]. This approach to sulfhydryl repletion, however, appears practical only for short-term treatment. There is an experimental basis, nonetheless, for the use of the sulfhydryl containing angiotensin-converting enzyme inhibitor, captopril. in combination with nitrates to prevent tolerance with long-term use [12]. Provision of a nitrate-free interval with oral or transdermal nitroglycerin does allow maintenance of haemodynamic and antianginal effects [13-151, and this approach appears most practical for long-term treatment. Thus, oral isosorbide dinitrate should not be given more frequently than three times daily while transderma1 nitroglycerin should be used with an overnight patch-free interval of approximately 8 hours. The obvious concern with such intermittent treatment is that ischaemia, silent or otherwise, may be exacerbated during the nitrate-free interval. While there is no firm evidence from published studies that this is so, such a consideration strengthens the rationale for combination treatment with other agents to cover the nitrate-free interval. While continuous application of transdermal nitroglycerin may still be appropriate in some patients in whom it is possible to judge that responsiveness is maintained long term, it is important (as with any form of continuous nitrate treatment) to be aware of the possibility of tolerance. At present, there remains a disparity between the approach of many clinicians
209
and the prescribing recommendations from the pharmaceutical companies concerned. Clinicians are commonly employing intermittent nitrate therapy with a nitrate-free interval whereas most prescribing information for the transdermal systems at present does not advise this. This difference is clearly attributable to the different approach that clinicians have to individual patients compared with the attitude of companies. The latter, whilst perhaps accepting the clinical reality of tolerance, maintain concern about the safety of intermittent treatment as a general recommendation. This concern must be weighed against the desirability of continuing to recommend continuous application of transdermal systems which, for many patients, and perhaps the majority, is no better than placebo. The prevailing uncertainty is a reflection of the many variables involved and the relative crudity of our methods of assessment. It emphasises the need for further careful clinical research in this area. Ongoing clinical studies will, no doubt, provide useful information which will be helpful in improving treatment of individual patients. Precise characterisation of responsiveness and susceptibility of patients to tolerance is the ideal which would allow regimens to be optimised. This ideal will not be easily achieved. The results of studies with transdermal nitroglycerin in higher dosage, and also with shorter nitrate free intervals, are awaited with interest. Similarly, Holter monitoring studies of silent ischaemia should more clearly define the need for combination treatment in different patient groups. As in other areas of therapeutics, significant improvements in management should result from a more careful individualised approach with existing treatment. Nitrates have long been a mainstay in the treatment of angina and if used appropriately, should remain so in the future.
References 1 Packer M, Lee WH, Kessler PD, Gottleib SS, Medina N. Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med 1987;317:799-804. 2 Thadani U, Fung HL, Darke AC, Parker JO. Oral isosorbide dinitrate in angina patients: comparison of duration of action and dose response relation during acute and sustained therapy. Am J Cardiol 1982;49:411-419. 3 Parker JO, Fung HL. Transdermal nitroglycerin in angina pectotis. Am J Cardiol 1984;54:471-476. 4 Reichek N, Priest CJ, Zimrin D, Chandler T, St John Sutton M. Antianginal effects of nitroglycerin patches. Am J Cardiol 1984;54:1-7. 5 Muiesan G. Agabiti-Rosei E, Muiesan L, et al. A multicenter trial of transdermal nitroglycerin in exercise-induced angina: individual antianginal response after repeated administration. Am Heart J 1986;112:233-238. 6 Axelsson KL, Andersson RG. Tolerance towards nitroglycerin induced in viva is correlated to a reduced cGMP response and an alteration in cGMP turnover. Eur J Pharmacol 1983:88:71-79. 7 Trimarco B, Cuoculo A, Van Dome D, et al. Late phase of nitroglycerin-induced coronary vasodilatation blunted by inhibition of prostaglandin synthesis. Circulation 1985;71:840-848. 8 Ignarro LJ, Lippton H, Edward JC, et al. Mechanism of vascular smooth muscle relaxation by organic nitrates. nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981;218:739-749. 9 Dalal JJ, Yao L, Parker JO. Nitrate tolerance: influence of isosorbide din&rate on the hemodynamic and antianginal effects of nitroglycerin. J Am Co11 Cardiol 1985;2:115-120. 10 Horowitz JD. Antman EM, Lore11 BH, Barry WH, Smith TW. Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine. Circulation 1983;68:1247-1253.
210 11 May DC, Popma JJ. Black WH, et al. In viva induction and reversal of nitroglycerin tolerance in human coronary arteries. N Engl J Med 1987;317:805-809. 12 Van Gilst WH, De Graeff PA, Scholtens E, De Langen CDJ, Wesseling H. Potentiation of isosorbide dinitrate-induced coronary dilatation by captopril. J Cardiovasc Pharmacol 1987:9:254-255. 13 Parker JO, Farrell B. Lahey KA. Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N Engl J Med 1987;316:1440-1444. 14 Sharpe N, Coxon R, Webster M, Luke R. Hemodynamic effects of intermittent transdermal nitroglycerin in chronic congestive heart failure. Am J Cardiol 1987:59:895-899. 15 Luke R, Sharpe N, Coxon R. Transdermal nitroglycerin in angina pectoris: efficacy of intermittent application. J Am Co11 Cardiol 1987;10:642-646.
Journal of Cardiology,
207
21 (1988) 207-210
IJC 00750
Editorial
Nitrate tolerance - a therapeutic dilemma Norman Sharpe Department
of Medicrne,
Universrty of Auckland
(Received
Key words: Nitroglycerin;
School of Medicine, Auckland.
6 April 1988; accepted
New Zealand
26 April 1988)
Drug tolerance
It has become evident in recent years that prolonged or frequent administration of nitrates intravenously [l], orally [2] or transdermally [3,4], can result in tolerance and in attenuation of their haemodynamic and antianginal effects. The clinical importance of such tolerance is the subject of continuing debate, particularly in relation to optimal usage of the long-acting nitrates and transdermal systems for delivery of nitroglycerin. Clinicians are faced with a therapeutic dilemma when considering the results of clinical studies which appear conflicting and also when interpreting current information for prescription, which generally recommends continuous system application. It is necessary to emphasise the limitations of many of the clinical studies that have been performed in this area. Generally, the anti-angina1 effects of nitrates have been studied in relatively small heterogeneous groups of patients with severe coronary arterial disease receiving varied concomitant medications. The relevance of such group data for individual therapy may be questioned. Individual responsiveness to nitrates varies greatly and yet dose titration has often not been carried out. Nitroglycerin has dose-dependent effects on the venous and arterial beds. Maximal venodilatation occurs at relatively low doses and may be less rapidly attenuated than arterial dilatation. Just as nitrate responsiveness varies, there is likewise probably variation in individual susceptibility to tolerance. Patient assessment has generally been based on exercise testing. There may, however, be dissociation between symptoms and exercise evaluation. Certainly one larger study has demonstrated reduction in the frequency of angina with continuous nitrate treatment in patients who showed attenuation of the effect of treatment as judged by exercise testing [5]. A true perspective on silent ischaemia is gradually emerging and may have considerable therapeutic implications.
Correspondence to: Dr. N. Sharpe. Auckland. New Zealand.
0167-5273/88/$03.50
Dept.
of Medicine.
0 1988 Elsevier Science Publishers
University
of Auckland
B.V. (Biomedical
Division)
School
of Medicine,
208
It is also relevant to consider the mode of action of nitrates and their possible mechanisms of tolerance. Relaxation of vascular smooth muscle in response to nitroglycerin is mediated primarily through direct activation of guanylate cyclase and production of cyclic guanosine monophosphate [6] and indirectly through release of prostaglandin 12 from vascular endothelium [7]. Binding of nitroglycerin to smooth muscle receptors appears dependent on the availability of tissue sulfhydryl groups. Continuous administration of nitrates. therefore, may produce tolerance through sulfhydryl depletion and receptor alteration [8]. Thus, theoretically, nitrate tolerance might be averted by increased dosage to overcome receptor refractoriness, exogenous sulfhydryl repletion or introduction of a nitrate-free interval to allow restoration of receptor status. These theoretical possibilities have been incorporated into clinical strategies in attempts to avoid tolerance with long-term nitrate therapy. Regular high dosage of nitrates is probably unlikely to be a successful means of countering tolerance and, in fact, may only determine the more rapid development of more complete tolerance which will require a longer nitrate-free interval for reversal. It does appear, however, that tolerance with long-term treatment can be overcome through the use of sublingual nitroglycerin [9], suggesting that the introduction of a sudden high peak of plasma nitroglycerin may overcome transiently the refractory status of the receptors. Sulfhydryl repletion does appear an effective option. Infusion of the sulfhydryl donor N-acetylcysteine in patients undergoing diagnostic cardiac catheterization has been shown to potentiate the lowering effect of intravenous nitroglycerin on blood pressure and pulmonary wedge pressure [lo]. Furthermore. the attenuation of the coronary vasodilator effect of nitroglycerin with prolonged intravenous infusion can be reversed by administration of N-acetylcysteine [ll]. Similarly, oral N-acetylcysteine appears to reverse the tolerance known to occur with continuous infusion of intravenous nitroglycerin in patients with congestive heart failure [l]. This approach to sulfhydryl repletion, however, appears practical only for short-term treatment. There is an experimental basis, nonetheless, for the use of the sulfhydryl containing angiotensin-converting enzyme inhibitor, captopril. in combination with nitrates to prevent tolerance with long-term use [12]. Provision of a nitrate-free interval with oral or transdermal nitroglycerin does allow maintenance of haemodynamic and antianginal effects [13-151, and this approach appears most practical for long-term treatment. Thus, oral isosorbide dinitrate should not be given more frequently than three times daily while transderma1 nitroglycerin should be used with an overnight patch-free interval of approximately 8 hours. The obvious concern with such intermittent treatment is that ischaemia, silent or otherwise, may be exacerbated during the nitrate-free interval. While there is no firm evidence from published studies that this is so, such a consideration strengthens the rationale for combination treatment with other agents to cover the nitrate-free interval. While continuous application of transdermal nitroglycerin may still be appropriate in some patients in whom it is possible to judge that responsiveness is maintained long term, it is important (as with any form of continuous nitrate treatment) to be aware of the possibility of tolerance. At present, there remains a disparity between the approach of many clinicians
209
and the prescribing recommendations from the pharmaceutical companies concerned. Clinicians are commonly employing intermittent nitrate therapy with a nitrate-free interval whereas most prescribing information for the transdermal systems at present does not advise this. This difference is clearly attributable to the different approach that clinicians have to individual patients compared with the attitude of companies. The latter, whilst perhaps accepting the clinical reality of tolerance, maintain concern about the safety of intermittent treatment as a general recommendation. This concern must be weighed against the desirability of continuing to recommend continuous application of transdermal systems which, for many patients, and perhaps the majority, is no better than placebo. The prevailing uncertainty is a reflection of the many variables involved and the relative crudity of our methods of assessment. It emphasises the need for further careful clinical research in this area. Ongoing clinical studies will, no doubt, provide useful information which will be helpful in improving treatment of individual patients. Precise characterisation of responsiveness and susceptibility of patients to tolerance is the ideal which would allow regimens to be optimised. This ideal will not be easily achieved. The results of studies with transdermal nitroglycerin in higher dosage, and also with shorter nitrate free intervals, are awaited with interest. Similarly, Holter monitoring studies of silent ischaemia should more clearly define the need for combination treatment in different patient groups. As in other areas of therapeutics, significant improvements in management should result from a more careful individualised approach with existing treatment. Nitrates have long been a mainstay in the treatment of angina and if used appropriately, should remain so in the future.
References 1 Packer M, Lee WH, Kessler PD, Gottleib SS, Medina N. Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med 1987;317:799-804. 2 Thadani U, Fung HL, Darke AC, Parker JO. Oral isosorbide dinitrate in angina patients: comparison of duration of action and dose response relation during acute and sustained therapy. Am J Cardiol 1982;49:411-419. 3 Parker JO, Fung HL. Transdermal nitroglycerin in angina pectotis. Am J Cardiol 1984;54:471-476. 4 Reichek N, Priest CJ, Zimrin D, Chandler T, St John Sutton M. Antianginal effects of nitroglycerin patches. Am J Cardiol 1984;54:1-7. 5 Muiesan G. Agabiti-Rosei E, Muiesan L, et al. A multicenter trial of transdermal nitroglycerin in exercise-induced angina: individual antianginal response after repeated administration. Am Heart J 1986;112:233-238. 6 Axelsson KL, Andersson RG. Tolerance towards nitroglycerin induced in viva is correlated to a reduced cGMP response and an alteration in cGMP turnover. Eur J Pharmacol 1983:88:71-79. 7 Trimarco B, Cuoculo A, Van Dome D, et al. Late phase of nitroglycerin-induced coronary vasodilatation blunted by inhibition of prostaglandin synthesis. Circulation 1985;71:840-848. 8 Ignarro LJ, Lippton H, Edward JC, et al. Mechanism of vascular smooth muscle relaxation by organic nitrates. nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981;218:739-749. 9 Dalal JJ, Yao L, Parker JO. Nitrate tolerance: influence of isosorbide din&rate on the hemodynamic and antianginal effects of nitroglycerin. J Am Co11 Cardiol 1985;2:115-120. 10 Horowitz JD. Antman EM, Lore11 BH, Barry WH, Smith TW. Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine. Circulation 1983;68:1247-1253.
210 11 May DC, Popma JJ. Black WH, et al. In viva induction and reversal of nitroglycerin tolerance in human coronary arteries. N Engl J Med 1987;317:805-809. 12 Van Gilst WH, De Graeff PA, Scholtens E, De Langen CDJ, Wesseling H. Potentiation of isosorbide dinitrate-induced coronary dilatation by captopril. J Cardiovasc Pharmacol 1987:9:254-255. 13 Parker JO, Farrell B. Lahey KA. Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N Engl J Med 1987;316:1440-1444. 14 Sharpe N, Coxon R, Webster M, Luke R. Hemodynamic effects of intermittent transdermal nitroglycerin in chronic congestive heart failure. Am J Cardiol 1987:59:895-899. 15 Luke R, Sharpe N, Coxon R. Transdermal nitroglycerin in angina pectoris: efficacy of intermittent application. J Am Co11 Cardiol 1987;10:642-646.