Br. J. clin. Pharmac. (1992), 34, 96-101
Avoiding nitrate tolerance J. CAMPBELL COWAN Department of Cardiology, The General Infirmary at Leeds, Leeds LS1 3EX
A few years ago, one could have been forgiven for believing that our knowledge and understanding of nitrates had reached its zenith. Following a century of clinical use, many physicians perceived nitrates as oldfashioned therapy, superseded by newer anti-anginal agents. In the last few years, however, there has been a revival of interest in nitrates. The demonstration that organic nitrates share the same mechanism of action as the body's endogenous vasodilator, EDRF (endothelium-derived relaxing factor) (Ignarro, 1989) (Figure 1), has led this renaissance. We have a growing appreciation that nitrates may have a special role in angina patients, as an EDRF substitute. EDRF production is reduced in diseased coronary segments (Luscher, 1989; Vanhoutte & Shimokawa, 1989), and exogenous nitrates may substitute for this deficiency. There is even evidence of increased sensitivity to exogenous nitrates (Rafflenbeul et al., 1989), suggesting that the vasodilator action of nitrates may be specifically targeted where it is most needed. This specific role as a physiological substitute has led to renewed interest in both the mechanisms of action and therapeutic applications of nitrates. Despite this renewed interest in an old drug, a longstanding problem still remains, the problem of tolerance. Our knowledge of nitrate tolerance is almost as old as the therapeutic use of nitrates, dating back to experience in the munitions industry in the early 1900s (Stewart, 1905). Yet it is only in the last decade that the extent of the problem in the therapeutic use of the drugs has become fully appreciated (Abrams, 1989; Cowan, 1986; Parker, 1987). Carefully controlled clinical trials have demonstrated beyond doubt that the magnitude and duration of antianginal benefits of nitrate therapy are reduced during chronic, continuous administration (Rudolph et al., 1983; Silber et al., 1983; Thadani et al., 1982). We now appreciate that extent of tolerance is related to constancy of plasma nitrate concentrations. When patients receive a nitrate regimen which results in continuous elevation of nitrate concentrations, a high degree of tolerance results. Conversely, numerous studies have shown that tolerance may be minimised by intermittent dosage regimens providing a nitrate-free or nitrate-low period each day (Cowan et al., 1987; Parker et al., 1985, 1987a; Silber et al., 1987).
Limited sulphydryl availability within smooth muscle cells was suggested some twenty years ago as a possible mechanism of tolerance (Needleman & Johnson, 1973). The actions of nitrates within smooth muscle are mediated by the release of cyclic guanosine monophosphate (cGMP) (Figure 1). cGMP is formed when guanylate cyclase is stimulated by nitric oxide. Nitric oxide is released from organic nitrates through a number of enzymatic steps, a process of 'biotransformation'. One or more sulphydryl groups are necessary for this biotransformation to occur. There has been clearcut evidence in vitro that loss of nitrate efficacy due to tolerance can be reversed by administration of sulphydryl-yielding compounds (Needleman et al., 1973). These experiments have led to a number of studies which have assessed whether the sulphydryl donor, N-acetylcysteine, can reverse nitrate tolerance in vivo. Evidence from these clinical investigations is conflicting. On the one hand, large doses of N-acetylcysteine have been shown to restore the efficacy of intravenous nitrates in lowering pulmonary artery pressure (Packer et al., 1986). On the other hand, N-acetylcysteine failed to prevent tolerance to the antianginal actions of oral nitrates (Parker et al., 1987b). Moreover the effects of N-acetylcysteine, when present, may be non-specific and independent of tolerance, arising from an extracellular interaction with glyeryl trinitrate (GTN) (Munzel et al., 1987; Fung et al., 1988). The reasons for this and other conflicting evidence is unclear. One possible explanation relates to differing
Vascular lumen
Endothelial cells Smooth muscle cells
Organic nitrate
EDRF (NO) R SH R 55 NO rganic 4cA nitrate // IG~~~~~Fu-anylate GTP
cls
/
cGMP
Figure 1 Relationship between EDRF and the organic nitrates. Endothelium-derived relaxing factor (EDRF) is either nitric oxide (NO) or a nitroso compound which spontaneously releases nitric oxide. Nitric oxide stimulates guanylate cyclase resulting in the formation of cyclic guanosine monophosphate (cGMP), which causes relaxation. The organic nitrates utilize the same pathway, but must first undergo 'biotransformation' to yield nitric oxide (NO). The biotransformation process is dependent on the presence of intracellular sulphydryl groups-limited sulphydryl availability is one potential mechanism of tolerance.
Mechanism of tolerance The mechanism of tolerance remains uncertain. Theories to explain tolerance fall into two broad categories, those based on a loss of effect of the drug in the smooth muscle end organ and those based on neurohumoral reflex adaptation.
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Avoiding nitrate tolerance Sublingual GTN
ad libitum
~~~~~~i-
6----wb ---------------
Buccal GTN
-- -- -- ---- -
Three
_times daily Three
ISDN
times daily
Assymetrical
ISMN
twice doily
S.R. ISMN
daily
GTN patch
1rrnight
06.00 24.00 18.00 Time (h) Figure 2 Nitrate dosage regimens to avoid tolerance. Schematic representation of dosage regimens for some
06.00
12.00
commonly used nitrate preparations which have been shown to minimize the development of tolerance.
actions of N-acetylcysteine in different vascular beds. The evidence that sulphydryl donors can reverse tolerance is stronger in the venous circulation than in the arterial (Cowan & Zaman, 1992). However, even when reversal of tolerance has been demonstrated, it is not clear whether this represents a genuine reversal or merely an apparent reversal due to potentiation of nitrate action by the sulphydryl donor. In general, therefore, there is little support clinically for the sulphydryl hypothesis. In the last few years much attention has been centred on the possible contribution of neurohumoral adaptation to the development of tolerance. It is clear, for example, that administration of nitrates leads to a rise in renin concentrations (Dupuis et al., 1990). This has led to the suggestion that angiotensin converting enzyme inhibition might prevent tolerance. Unfortunately, evidence is once again conflicting. Katz and coworkers (1991) found that captopril or enalapril could prevent the loss of venodilator response to sublingual GTN, which occurred after 72 h of administration of a GTN patch. However, other authors have failed to substantiate reversal of nitrate tolerance with ACE inhibitors (Dakak et al., 1990). The role of the reninangiotensin system in tolerance therefore remains uncertain. A further possible mechanism of tolerance has recently been suggested. Nitrates have been shown to cause a rapid increase in plasma volume (Dupuis et al., 1990; Lis et al., 1984). This occurs within hours of commencing therapy and can simply be demonstrated as a fall in haematocrit. The mechanism of the effect remains uncertain, but it seems probable that it is due to a redistribution of fluid between the extracellular and
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intravascular compartments. This arises due to venodilation in the capillary bed, which causes a resetting of the Starling equilibrium and a net movement of fluid from the extracellular to intravascular compartments. The resultant change in blood volume may contribute to the development of tolerance. Some years ago, the significance of blood volume changes for angina threshold was demonstrated. Reduction in blood volume by as little as 276 ml has been shown to increase pacing threshold to angina (Parker et al., 1970). It is therefore to be anticipated that an increase in blood volume might conversely reduce angina threshold. Intermittent therapy has been found to prevent the fall in haematocrit which occurs with continuous therapy, suggesting that this may indeed be an important mechanism in the development of tolerance (Parker et al., 1990). These findings suggest the attractive hypothesis that preventing the increase in blood volume might be a simple way of preventing nitrate tolerance. There is some limited evidence that this may indeed be the case. A recent preliminary communication showed that the coadministration of a diuretic was able to prevent the tolerance occurring with four times daily isosorbide dinitrate therapy (Sussex et al., 1990). Although this hypothesis is attractive, confirmation of a role for diuretics awaits further investigation. As yet the exciting revelations concerning EDRF and its relation to exogenous nitrates have done little to advance our understanding of tolerance. However, there are some interesting recent developments in relation to EDRF which may alter this. It has been demonstrated in rabbit hearts that inhibition of EDRF synthesis with N-monomethyl-L-arginine (L-NMMA) potentiates the vasodilator response to GTN (Smith et al., 1991). The mechanisms of this effect are as yet unclear but the implication is that reduced EDRF synthesis potentiates the response to exogenous nitrates. It is unclear whether the converse is also the case, namely that exogenous nitrate administration might reduce sensitivity to EDRF. If this were the case, this would represent another potential explanation both for the development of tolerance and indeed for the occurrence of rebound on cessation of nitrate exposure. In conclusion, the mechanism of tolerance remains uncertain. It seems increasingly probable that there is no single mechanism, but rather a number of diverse mechanisms. The relative contribution of these various mechanisms may differ in different vascular beds. For example, neurohumoral adaptation may play a dominant role in arterial tolerance, whereas cellular adaptation may be of greater significance in relation to venous tolerance. There is already some limited evidence to favour this suggestion (Stewart et al., 1986). While this hypothesis is almost certainly too simple, it does provide a framework for further investigation. It is as yet unclear whether the mechanism of tolerance in the coronary arterial bed corresponds with the rest of the arterial vasculature or with the venous system. If the mechanism of tolerance does differ in different vascular beds, this would go some way to explaining differences between patients in susceptibility to tolerance. In some patients, venodilation might represent the predominant mechanism of nitrate action, in others direct coronary vasodilation. The extent and mechan-
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J. Campbell Cowan
isms of tolerance may differ in the two groups, with the implication that approaches to prevention of tolerance might also differ.
of some value, benefits are substantially less than during intermittent therapy. Numerous studies, totalling over 500 randomised patients, have demonstrated the benefits of intermittent patch therapy over con-
The role of intermittent therapy
tinuous (Cowan et al., 1987; De Milliano et al., 1989; DeMots & Glasser, 1989; Fox et al., 1991; Luke et al., 1987; Scardi et al., 1991; Schaer et al., 1988). For this reason, where possible, intermittent therapy is prefer-
It is possible that further advances in our understanding of the mechanism of tolerance may lead to specific means of prevention. For the present, however, the only practical means of preventing tolerance is to use intermittent regimens. The role of intermittent therapy is now well established. For any nitrate preparation, it is possible to select a regimen which will minimise or prevent the development of tolerance (Figure 2). Regimens which have been shown to adequately prevent tolerance include three times daily buccal GTN (Parker et al., 1985), three times daily isosorbide dinitrate (last dose at 18.00 h) (Parker et al., 1987a), twice daily isosorbide mononitrate (second dose at 14.00 h) (unpublished results), intermittent patch therapy with the patch removed overnight (Cowan et al., 1987; Luke et al., 1987; Schaer et al., 1988), and finally once daily slow release isosorbide mononitrate (Wisenberg et al., 1989). All these regimens are successful in minimising the problem of tolerance. Choice of a particular agent is therefore determined by patient preference and physician familiarity. Cost should also be a consideration. The value of intermittent therapy is most clearly illustrated with reference to the GTN patch. Despite or perhaps because of its recent introduction, this preparation has been more intensively studied than other nitrate preparations. The continuous use of GTN patches provides an excellent model for studying tolerance, reflecting the efficiency of this preparation in providing constant nitrate levels. There is general agreement that patches do confer antianginal benefit acutely on first application. However, there has been considerable debate as to whether these benefits are maintained during chronic continuous therapy. Some studies have found evidence of continuing benefit (Cerri et al., 1984; Rezakovic & Stalec, 1988), while others have shown benefits to be abolished (Crean et al., 1984; Parker & Fung, 1984; Transdermal Nitroglycerin Cooperative Study, 1991). The 'truth' almost certainly lies between these two extremes. A substantial degree of tolerance does occur, but tolerance is not complete. It seems probable that a relatively small benefit does persist during continuous therapy. This is most clearly illustrated by a recent investigation (Scardi et al., 1991) which compared intermittent therapy, continuous therapy and placebo in a Latin square crossover design. Continuous therapy did confer significant benefit, but this was approximately half that of intermittent therapy. However, this small benefit is difficult to detect because of the inherent variability of angina studies and, consequently, some studies are able to detect benefit whereas others are not. The fact that benefits may be partially maintained during continuous nitrate therapy should not be taken as an argument in favour of using continuous regimens in some patients. Although continuous therapy may be
able to continuous. Generalising from the patch to other nitrate preparations, continuous nitrate therapy causes a substantial, but not complete, loss of efficacy, whereas with intermittent therapy benefits are maintained. The question arises whether all patients are equally susceptible to tolerance. Invasive monitoring studies during infusions of intravenous nitrates have shown that this is not the case (Elkayam et al., 1987). Some individuals are more susceptible than others. However, any attempt to differentiate susceptible from nonsusceptible individuals on clinical grounds is unlikely to succeed. The inherent variability of exercise testing would make an exercise laboratory based approach meaningless. For this reason it is best to assume that all individuals are potentially susceptible to tolerance and to select intermittent nitrate regimens wherever possible.
Intermittent therapy-potential disadvantages It is important to consider whether intermittent therapy carries a price. Is there a possibility that overnight nitrate withdrawal might lead to an exacerbation of anginal symptoms and to rebound angina? It was established many years ago, in the munitions industry, that rebound can occur following sudden cessation of nitrate exposure, with serious adverse consequences including myocardial infarction and death (Lange et al., 1972; Morton, 1977). It is therefore of particular importance to consider whether rebound might similarly occur with intermittent nitrate regimens. The preparation which has been most closely scrutinised in this regard is once again the GTN patch. There is evidence that rebound angina may indeed occur in a small proportion of patients, following patch removal. De Mots & Glasser (1989) found evidence of rebound angina in 9 of 138 patients during intermittent patch therapy. More worryingly, Ferratini et al. (1989) found a high incidence of anginal symptoms following patch removal, in comparison with continuous patch therapy. Six of 10 patients had anginal symptoms at this time. However, many other studies have failed to show any evidence whatsoever for rebound (Cowan et al., 1987; Fox et al., 1991; Luke et al., 1987; Scardi et al., 1991; Schaer et al., 1988). The best currently available estimate for the incidence of rebound with intermittent patch therapy, based on the published data in randomised studies totalling over 500 patients, suggests that rebound angina may occur in 2-4% of patients. Reassuringly, there is no evidence for any exacerbation of silent ischaemia during overnight patch withdrawal (Fox et al., 1991). In conclusion rebound almost certainly does occur during intermittent patch therapy, but only in a small
Avoiding nitrate tolerance minority of patients. Nonetheless, that rebound should occur at all is a cause for concern. For this reason, it is advisable, where possible, to prescribe concomitant antianginal medication to accompany intermittent nitrate therapy. ,-adrenoceptor blockers are of particular value in this regard, as they have been shown to be protective against early morning angina (Mulcahy et al., 1988). The addition of a ,3-adrenoceptor blocker is not a major inconvenience. Nitrates and ,-adrenoceptor blockers are known to have synergistic benefits (Bassan & Weiler-Ravell, 1983; Russek, 1968). Their combined use, in any case, reflects routine clinical practice. It remains uncertain whether the rapidity of decline of nitrate levels following nitrate withdrawal may be a determinant of rebound. As discussed above, much of the current evidence for rebound relates to intermittent patch therapy. It is possible that rebound may be due to the rapid fall in nitrate levels which occurs on patch removal. However, it is fair to say that the patch has been more extensively investigated than other nitrate preparations. As rebound is rare, it may have been overlooked with other intermittent nitrate preparations and regimens. If other preparations were as extensively studied as the patch, it is possible that occasional cases of rebound would similarly become apparent. Just as the mechanism of tolerance is uncertain, the mechanism of rebound is also unclear. The two are likely to be related. It is easy to understand how such a relation might arise in the neurohumoral adaptation theory of tolerance. The neurohumoral mechanisms which cause tolerance could, on nitrate withdrawal, act unopposed to cause rebound. Alternatively rebound could be related to exogenous nitrates suppressing responsiveness to EDRF. On removal of the exogenous nitrate, reduced responsiveness to endogenous EDRF might result in an increased susceptibility to vasospasm. In either case, the factors underlying tolerance and rebound would be closely linked, that is rebound would represent the obverse of tolerance. The best way of preventing rebound would, therefore, be to prevent tolerance arising in the first place. Despite these slight concerns over the occasional occurrence of rebound, the safety of intermittent regimens is well established. Intermittent therapy is the treatment of choice in patients with stable angina. This conclusion should, however, not be extrapolated to patients with unstable angina or frequent nocturnal symptoms. Such patients have been excluded from the studies of intermittent therapy which have been conducted hitherto. The risk of rebound may be greater in these groups and intermittent therapy should only be used with caution. Caution is also necessary in patients with recent myocardial infarction. Currently, there is a particular interest in the use of nitrates in this patient group to prevent infarct expansion (Jugdutt & Warnica, 1988). The safety of intermittent therapy in the early post-infarction period will require further evaluation. There is one final issue in relation to intermittent nitrate therapy which is as yet unexplained. For years doctors have reassured their patients that nitrate headaches will resolve within a few days of commencing therapy, a beneficial manifestation of tolerance. One might expect, therefore, that intermittent nitrate
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regimens designed to prevent tolerance would result in the persistence of nitrate headaches. Fortunately, this does not appear to be the case. While there is some limited anecdotal evidence of headaches being more troublesome during intermittent therapy, the available clinical trials have failed to substantiate exacerbation of headache. Why this should be the case remains unclear. A possible explanation lies in the suggestion that the mechanism of tolerance may differ in different vascular beds. Thus, headaches may be related to the arterial effects of nitrates, while the therapeutic antianginal benefits may be related mainly to venous effects. There is some evidence that intermittent therapy does not prevent tolerance in the arterial bed, in contrast to preventing tolerance to the therapeutic benefits of nitrates (Cowan et al., 1987). Other indications
Nitrates are unique amongst cardiovascular drugs in their range of applicability throughout the spectrum of cardiovascular disease. They are of value in stable angina, unstable angina, acute myocardial infarction and heart failure. Is tolerance equally implicated in the use of nitrates in all syndromes of ischaemic heart disease? The answer to this question is unclear. It is certainly possible that the heterogeneity of sites of action when used for differing clinical indications might result in differing degrees of tolerance in different syndromes. Most information relates to chronic stable angina. However, we also know that tolerance arises in the management of patients with heart failure (Elkayam et al., 1987; Parker et al., 1987). As a general rule it seems advisable to adopt intermittent regimens, whatever the indication for treatment. The one possible exception to this rule is in the management of unstable angina. Intravenous nitrate infusions are frequently used in patients with unstable angina, for ease of titration against symptoms. In such patients, interruption of an infusion may lead to a return of anginal symptoms. It can also be argued that, if interrupted therapy is tolerated, then the patient does not require the constancy of nitrate levels provided by intravenous administration, and that an intermittent oral regimen will suffice. Intermittent infusions are therefore best avoided. However, it is important to appreciate that even with an infusion duration as short as 24 h, a substantial degree of tolerance may occur (Elkayam et al., 1987). This tolerance can generally be temporarily overcome by increasing the infusion rate. If symptoms continue unstable after 1 to 2 days, then alternative forms of management should be considered. As discussed above, caution is also necessary in the use of intermittent regimens in the early post-infarction
period. Remaining questions
Many issues remain unresolved. Foremost amongst these is the mechanism or mechanisms of tolerance. Future emphasis will address the heterogeneity of
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tolerance. Is there a heterogeneity of mechanism in different vascular beds? Does the predominant site of nitrate action differ in different patients? Does this, in combination with heterogeneity of mechanism, explain heterogeneity in the extent of tolerance between patients? Does this heterogeneity have implications for tolerance prevention and are there alternative means of prevention to intermittent therapy?
These issues exemplify some of the remaining problems. Nitrate research has received a new lease of life, both from the EDRF discoveries and from advances in the understanding and prevention of tolerance. Important questions have emerged and, despite their longevity, nitrates remain interesting and exciting drugs.
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Avoiding nitrate tolerance Armstrong, P. W. (1970). The influence of changes in blood volume on angina pectoris. A study of the effect of phlebotomy. Circulation, 41, 593-604. Parker, J. O., Farrell, B., Lahey, K. A. & Moe, G. (1987a). Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. New Engl. J. Med., 316, 1440-1444. Parker, J. O., Farrell, B., Lahey, K. A. & Rose, B. F. (1987b). Nitrate tolerance: the lack of effect of N-acetylcysteine. Circulation, 76, 572-576. Parker, J. 0. & Fung, H. L. (1984). Transdermal nitroglycerin in angina pectoris. Am. J. Cardiol., 54, 471-476. Parker, J. O., VanKoughnett, K. A. & Farrell, B. (1985). Comparison of buccal nitroglycerin and oral isosorbide dinitrate for nitrate tolerance in stable angina pectoris. Am. J. Cardiol., 56, 724-728. Raffenbeul, W., Bassenge, E. & Lichtlen, P. (1989). Competition between endothelium-dependent and nitroglycerininduced coronary vasodilation. Z. Kardiol., 78 (Suppl. 2), 45-47. Rezakovic, E. D. & Stalec, J. (1988). Acute and chronic efficacy of 10 mg nitroglycerin patch in stable angina pectoris. Am. J. Cardiol., 61, 52E-58E. Rudolph, W., Blasini, R., Reiniger, G. & Brugmann, U. (1983). Tolerance development during isosorbide dinitrate treatment: Can it be circumvented? Z. Kardiol., 72 (suppl. 3), 195-198. Russek, H. I. (1968). Propranolol and isosorbide dinitrate synergism in angina pectoris. Am. J. Cardiol., 21, 44-54. Scardi, S., Camerini, F., Pandullo, C., Pollavini, G. & the Collaborative Nitro Group (1991). Efficacy of continuous and intermittent transdermal treatment with nitroglycerin in effort angina pectoris: a multicentre study. Int. J. Cardiol., 32, 241-248. Schaer, D. H., Buff, L. A. & Katz, R. J. (1988). Sustained antianginal efficacy of transdermal nitroglycerin patches using an overnight 10-hour nitrate-free interval. Am. J. Cardiol., 61, 46-50. Silber, S., Krause, K. H., Garner, C., Theisen, K. & Jahrmarker, H. (1983). Anti-ischemic effects of an 80 mg tablet of isosorbide dinitrate in sustained release form before and
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after 2 weeks treatment with 80 mg once daily or twice daily. Z. Kardiol., 72 (suppl. 3), 211-217. Silber, A., Vogler, A., Krause, K-H., Vogel, M. & Theisen, K. (1987). Induction and circumvention of nitrate tolerance applying different dosage intervals. Am. J. Med., 83, 860-870. Smith, R. E. A., Palmer, R. M. J., Bucknall, C. A. & Moncada, S. (1991). The coronary vasodilator response to glyceryl trinitrate is potentiated by the inhibition of endogenous nitric oxide synthesis. Eur. Heart J., 12, 346 (abstract). Stewart, D. D. (1905). Tolerance to nitroglycerin. J. Am. Med. Ass., 44, 1678-1679. Stewart, D. J., Elsner, D., Sommer, O., Holtz, J. & Bassenge, E. (1986). Altered spectrum of nitroglycerin action in long-term treatment: nitroglycerin-specific venous tolerance with maintenance of arterial vasodepressor potency. Circulation, 74, 573-582. Sussex, B. A., Campbell, N. R. C. & Raju, M. K. (1990). Nitrate tolerance is modified by diuretic treatment. Abstract. Circulation, 82, Suppl III: 200. Thadani, U., Fung, H-L., Darke, A. C. & Parker, J. 0. (1982). Oral isosorbide dinitrate in angina pectoris: comparison of duration of action and dose-response relation during acute and sustained therapy. Am. J. Cardiol., 49, 411-419. Transdermal Nitroglycerin Cooperative Study (1991). Acute and chronic antianginal efficacy of continuous twentyfour-hour application of transdermal nitroglycerin. Am. J. Cardiol., 68, 1263-1273. Vanhoutte, P. M. & Shimokawa, H. (1989). Endotheliumderived relaxing factor and coronary vasospasm. Circulation, 80, 1-9. Wisenberg, G., Roks, C., Nichol, P. & Goddard, M. D. (1989). Sustained effect of and lack of development of tolerance to controlled-release isosorbide-5-mononitrate in chronic stable angina pectoris. Am. J. Cardiol., 64, 569-576.
(Received 21 October 1991, accepted 17 February 1992)
Avoiding nitrate tolerance J. CAMPBELL COWAN Department of Cardiology, The General Infirmary at Leeds, Leeds LS1 3EX
A few years ago, one could have been forgiven for believing that our knowledge and understanding of nitrates had reached its zenith. Following a century of clinical use, many physicians perceived nitrates as oldfashioned therapy, superseded by newer anti-anginal agents. In the last few years, however, there has been a revival of interest in nitrates. The demonstration that organic nitrates share the same mechanism of action as the body's endogenous vasodilator, EDRF (endothelium-derived relaxing factor) (Ignarro, 1989) (Figure 1), has led this renaissance. We have a growing appreciation that nitrates may have a special role in angina patients, as an EDRF substitute. EDRF production is reduced in diseased coronary segments (Luscher, 1989; Vanhoutte & Shimokawa, 1989), and exogenous nitrates may substitute for this deficiency. There is even evidence of increased sensitivity to exogenous nitrates (Rafflenbeul et al., 1989), suggesting that the vasodilator action of nitrates may be specifically targeted where it is most needed. This specific role as a physiological substitute has led to renewed interest in both the mechanisms of action and therapeutic applications of nitrates. Despite this renewed interest in an old drug, a longstanding problem still remains, the problem of tolerance. Our knowledge of nitrate tolerance is almost as old as the therapeutic use of nitrates, dating back to experience in the munitions industry in the early 1900s (Stewart, 1905). Yet it is only in the last decade that the extent of the problem in the therapeutic use of the drugs has become fully appreciated (Abrams, 1989; Cowan, 1986; Parker, 1987). Carefully controlled clinical trials have demonstrated beyond doubt that the magnitude and duration of antianginal benefits of nitrate therapy are reduced during chronic, continuous administration (Rudolph et al., 1983; Silber et al., 1983; Thadani et al., 1982). We now appreciate that extent of tolerance is related to constancy of plasma nitrate concentrations. When patients receive a nitrate regimen which results in continuous elevation of nitrate concentrations, a high degree of tolerance results. Conversely, numerous studies have shown that tolerance may be minimised by intermittent dosage regimens providing a nitrate-free or nitrate-low period each day (Cowan et al., 1987; Parker et al., 1985, 1987a; Silber et al., 1987).
Limited sulphydryl availability within smooth muscle cells was suggested some twenty years ago as a possible mechanism of tolerance (Needleman & Johnson, 1973). The actions of nitrates within smooth muscle are mediated by the release of cyclic guanosine monophosphate (cGMP) (Figure 1). cGMP is formed when guanylate cyclase is stimulated by nitric oxide. Nitric oxide is released from organic nitrates through a number of enzymatic steps, a process of 'biotransformation'. One or more sulphydryl groups are necessary for this biotransformation to occur. There has been clearcut evidence in vitro that loss of nitrate efficacy due to tolerance can be reversed by administration of sulphydryl-yielding compounds (Needleman et al., 1973). These experiments have led to a number of studies which have assessed whether the sulphydryl donor, N-acetylcysteine, can reverse nitrate tolerance in vivo. Evidence from these clinical investigations is conflicting. On the one hand, large doses of N-acetylcysteine have been shown to restore the efficacy of intravenous nitrates in lowering pulmonary artery pressure (Packer et al., 1986). On the other hand, N-acetylcysteine failed to prevent tolerance to the antianginal actions of oral nitrates (Parker et al., 1987b). Moreover the effects of N-acetylcysteine, when present, may be non-specific and independent of tolerance, arising from an extracellular interaction with glyeryl trinitrate (GTN) (Munzel et al., 1987; Fung et al., 1988). The reasons for this and other conflicting evidence is unclear. One possible explanation relates to differing
Vascular lumen
Endothelial cells Smooth muscle cells
Organic nitrate
EDRF (NO) R SH R 55 NO rganic 4cA nitrate // IG~~~~~Fu-anylate GTP
cls
/
cGMP
Figure 1 Relationship between EDRF and the organic nitrates. Endothelium-derived relaxing factor (EDRF) is either nitric oxide (NO) or a nitroso compound which spontaneously releases nitric oxide. Nitric oxide stimulates guanylate cyclase resulting in the formation of cyclic guanosine monophosphate (cGMP), which causes relaxation. The organic nitrates utilize the same pathway, but must first undergo 'biotransformation' to yield nitric oxide (NO). The biotransformation process is dependent on the presence of intracellular sulphydryl groups-limited sulphydryl availability is one potential mechanism of tolerance.
Mechanism of tolerance The mechanism of tolerance remains uncertain. Theories to explain tolerance fall into two broad categories, those based on a loss of effect of the drug in the smooth muscle end organ and those based on neurohumoral reflex adaptation.
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Avoiding nitrate tolerance Sublingual GTN
ad libitum
~~~~~~i-
6----wb ---------------
Buccal GTN
-- -- -- ---- -
Three
_times daily Three
ISDN
times daily
Assymetrical
ISMN
twice doily
S.R. ISMN
daily
GTN patch
1rrnight
06.00 24.00 18.00 Time (h) Figure 2 Nitrate dosage regimens to avoid tolerance. Schematic representation of dosage regimens for some
06.00
12.00
commonly used nitrate preparations which have been shown to minimize the development of tolerance.
actions of N-acetylcysteine in different vascular beds. The evidence that sulphydryl donors can reverse tolerance is stronger in the venous circulation than in the arterial (Cowan & Zaman, 1992). However, even when reversal of tolerance has been demonstrated, it is not clear whether this represents a genuine reversal or merely an apparent reversal due to potentiation of nitrate action by the sulphydryl donor. In general, therefore, there is little support clinically for the sulphydryl hypothesis. In the last few years much attention has been centred on the possible contribution of neurohumoral adaptation to the development of tolerance. It is clear, for example, that administration of nitrates leads to a rise in renin concentrations (Dupuis et al., 1990). This has led to the suggestion that angiotensin converting enzyme inhibition might prevent tolerance. Unfortunately, evidence is once again conflicting. Katz and coworkers (1991) found that captopril or enalapril could prevent the loss of venodilator response to sublingual GTN, which occurred after 72 h of administration of a GTN patch. However, other authors have failed to substantiate reversal of nitrate tolerance with ACE inhibitors (Dakak et al., 1990). The role of the reninangiotensin system in tolerance therefore remains uncertain. A further possible mechanism of tolerance has recently been suggested. Nitrates have been shown to cause a rapid increase in plasma volume (Dupuis et al., 1990; Lis et al., 1984). This occurs within hours of commencing therapy and can simply be demonstrated as a fall in haematocrit. The mechanism of the effect remains uncertain, but it seems probable that it is due to a redistribution of fluid between the extracellular and
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intravascular compartments. This arises due to venodilation in the capillary bed, which causes a resetting of the Starling equilibrium and a net movement of fluid from the extracellular to intravascular compartments. The resultant change in blood volume may contribute to the development of tolerance. Some years ago, the significance of blood volume changes for angina threshold was demonstrated. Reduction in blood volume by as little as 276 ml has been shown to increase pacing threshold to angina (Parker et al., 1970). It is therefore to be anticipated that an increase in blood volume might conversely reduce angina threshold. Intermittent therapy has been found to prevent the fall in haematocrit which occurs with continuous therapy, suggesting that this may indeed be an important mechanism in the development of tolerance (Parker et al., 1990). These findings suggest the attractive hypothesis that preventing the increase in blood volume might be a simple way of preventing nitrate tolerance. There is some limited evidence that this may indeed be the case. A recent preliminary communication showed that the coadministration of a diuretic was able to prevent the tolerance occurring with four times daily isosorbide dinitrate therapy (Sussex et al., 1990). Although this hypothesis is attractive, confirmation of a role for diuretics awaits further investigation. As yet the exciting revelations concerning EDRF and its relation to exogenous nitrates have done little to advance our understanding of tolerance. However, there are some interesting recent developments in relation to EDRF which may alter this. It has been demonstrated in rabbit hearts that inhibition of EDRF synthesis with N-monomethyl-L-arginine (L-NMMA) potentiates the vasodilator response to GTN (Smith et al., 1991). The mechanisms of this effect are as yet unclear but the implication is that reduced EDRF synthesis potentiates the response to exogenous nitrates. It is unclear whether the converse is also the case, namely that exogenous nitrate administration might reduce sensitivity to EDRF. If this were the case, this would represent another potential explanation both for the development of tolerance and indeed for the occurrence of rebound on cessation of nitrate exposure. In conclusion, the mechanism of tolerance remains uncertain. It seems increasingly probable that there is no single mechanism, but rather a number of diverse mechanisms. The relative contribution of these various mechanisms may differ in different vascular beds. For example, neurohumoral adaptation may play a dominant role in arterial tolerance, whereas cellular adaptation may be of greater significance in relation to venous tolerance. There is already some limited evidence to favour this suggestion (Stewart et al., 1986). While this hypothesis is almost certainly too simple, it does provide a framework for further investigation. It is as yet unclear whether the mechanism of tolerance in the coronary arterial bed corresponds with the rest of the arterial vasculature or with the venous system. If the mechanism of tolerance does differ in different vascular beds, this would go some way to explaining differences between patients in susceptibility to tolerance. In some patients, venodilation might represent the predominant mechanism of nitrate action, in others direct coronary vasodilation. The extent and mechan-
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J. Campbell Cowan
isms of tolerance may differ in the two groups, with the implication that approaches to prevention of tolerance might also differ.
of some value, benefits are substantially less than during intermittent therapy. Numerous studies, totalling over 500 randomised patients, have demonstrated the benefits of intermittent patch therapy over con-
The role of intermittent therapy
tinuous (Cowan et al., 1987; De Milliano et al., 1989; DeMots & Glasser, 1989; Fox et al., 1991; Luke et al., 1987; Scardi et al., 1991; Schaer et al., 1988). For this reason, where possible, intermittent therapy is prefer-
It is possible that further advances in our understanding of the mechanism of tolerance may lead to specific means of prevention. For the present, however, the only practical means of preventing tolerance is to use intermittent regimens. The role of intermittent therapy is now well established. For any nitrate preparation, it is possible to select a regimen which will minimise or prevent the development of tolerance (Figure 2). Regimens which have been shown to adequately prevent tolerance include three times daily buccal GTN (Parker et al., 1985), three times daily isosorbide dinitrate (last dose at 18.00 h) (Parker et al., 1987a), twice daily isosorbide mononitrate (second dose at 14.00 h) (unpublished results), intermittent patch therapy with the patch removed overnight (Cowan et al., 1987; Luke et al., 1987; Schaer et al., 1988), and finally once daily slow release isosorbide mononitrate (Wisenberg et al., 1989). All these regimens are successful in minimising the problem of tolerance. Choice of a particular agent is therefore determined by patient preference and physician familiarity. Cost should also be a consideration. The value of intermittent therapy is most clearly illustrated with reference to the GTN patch. Despite or perhaps because of its recent introduction, this preparation has been more intensively studied than other nitrate preparations. The continuous use of GTN patches provides an excellent model for studying tolerance, reflecting the efficiency of this preparation in providing constant nitrate levels. There is general agreement that patches do confer antianginal benefit acutely on first application. However, there has been considerable debate as to whether these benefits are maintained during chronic continuous therapy. Some studies have found evidence of continuing benefit (Cerri et al., 1984; Rezakovic & Stalec, 1988), while others have shown benefits to be abolished (Crean et al., 1984; Parker & Fung, 1984; Transdermal Nitroglycerin Cooperative Study, 1991). The 'truth' almost certainly lies between these two extremes. A substantial degree of tolerance does occur, but tolerance is not complete. It seems probable that a relatively small benefit does persist during continuous therapy. This is most clearly illustrated by a recent investigation (Scardi et al., 1991) which compared intermittent therapy, continuous therapy and placebo in a Latin square crossover design. Continuous therapy did confer significant benefit, but this was approximately half that of intermittent therapy. However, this small benefit is difficult to detect because of the inherent variability of angina studies and, consequently, some studies are able to detect benefit whereas others are not. The fact that benefits may be partially maintained during continuous nitrate therapy should not be taken as an argument in favour of using continuous regimens in some patients. Although continuous therapy may be
able to continuous. Generalising from the patch to other nitrate preparations, continuous nitrate therapy causes a substantial, but not complete, loss of efficacy, whereas with intermittent therapy benefits are maintained. The question arises whether all patients are equally susceptible to tolerance. Invasive monitoring studies during infusions of intravenous nitrates have shown that this is not the case (Elkayam et al., 1987). Some individuals are more susceptible than others. However, any attempt to differentiate susceptible from nonsusceptible individuals on clinical grounds is unlikely to succeed. The inherent variability of exercise testing would make an exercise laboratory based approach meaningless. For this reason it is best to assume that all individuals are potentially susceptible to tolerance and to select intermittent nitrate regimens wherever possible.
Intermittent therapy-potential disadvantages It is important to consider whether intermittent therapy carries a price. Is there a possibility that overnight nitrate withdrawal might lead to an exacerbation of anginal symptoms and to rebound angina? It was established many years ago, in the munitions industry, that rebound can occur following sudden cessation of nitrate exposure, with serious adverse consequences including myocardial infarction and death (Lange et al., 1972; Morton, 1977). It is therefore of particular importance to consider whether rebound might similarly occur with intermittent nitrate regimens. The preparation which has been most closely scrutinised in this regard is once again the GTN patch. There is evidence that rebound angina may indeed occur in a small proportion of patients, following patch removal. De Mots & Glasser (1989) found evidence of rebound angina in 9 of 138 patients during intermittent patch therapy. More worryingly, Ferratini et al. (1989) found a high incidence of anginal symptoms following patch removal, in comparison with continuous patch therapy. Six of 10 patients had anginal symptoms at this time. However, many other studies have failed to show any evidence whatsoever for rebound (Cowan et al., 1987; Fox et al., 1991; Luke et al., 1987; Scardi et al., 1991; Schaer et al., 1988). The best currently available estimate for the incidence of rebound with intermittent patch therapy, based on the published data in randomised studies totalling over 500 patients, suggests that rebound angina may occur in 2-4% of patients. Reassuringly, there is no evidence for any exacerbation of silent ischaemia during overnight patch withdrawal (Fox et al., 1991). In conclusion rebound almost certainly does occur during intermittent patch therapy, but only in a small
Avoiding nitrate tolerance minority of patients. Nonetheless, that rebound should occur at all is a cause for concern. For this reason, it is advisable, where possible, to prescribe concomitant antianginal medication to accompany intermittent nitrate therapy. ,-adrenoceptor blockers are of particular value in this regard, as they have been shown to be protective against early morning angina (Mulcahy et al., 1988). The addition of a ,3-adrenoceptor blocker is not a major inconvenience. Nitrates and ,-adrenoceptor blockers are known to have synergistic benefits (Bassan & Weiler-Ravell, 1983; Russek, 1968). Their combined use, in any case, reflects routine clinical practice. It remains uncertain whether the rapidity of decline of nitrate levels following nitrate withdrawal may be a determinant of rebound. As discussed above, much of the current evidence for rebound relates to intermittent patch therapy. It is possible that rebound may be due to the rapid fall in nitrate levels which occurs on patch removal. However, it is fair to say that the patch has been more extensively investigated than other nitrate preparations. As rebound is rare, it may have been overlooked with other intermittent nitrate preparations and regimens. If other preparations were as extensively studied as the patch, it is possible that occasional cases of rebound would similarly become apparent. Just as the mechanism of tolerance is uncertain, the mechanism of rebound is also unclear. The two are likely to be related. It is easy to understand how such a relation might arise in the neurohumoral adaptation theory of tolerance. The neurohumoral mechanisms which cause tolerance could, on nitrate withdrawal, act unopposed to cause rebound. Alternatively rebound could be related to exogenous nitrates suppressing responsiveness to EDRF. On removal of the exogenous nitrate, reduced responsiveness to endogenous EDRF might result in an increased susceptibility to vasospasm. In either case, the factors underlying tolerance and rebound would be closely linked, that is rebound would represent the obverse of tolerance. The best way of preventing rebound would, therefore, be to prevent tolerance arising in the first place. Despite these slight concerns over the occasional occurrence of rebound, the safety of intermittent regimens is well established. Intermittent therapy is the treatment of choice in patients with stable angina. This conclusion should, however, not be extrapolated to patients with unstable angina or frequent nocturnal symptoms. Such patients have been excluded from the studies of intermittent therapy which have been conducted hitherto. The risk of rebound may be greater in these groups and intermittent therapy should only be used with caution. Caution is also necessary in patients with recent myocardial infarction. Currently, there is a particular interest in the use of nitrates in this patient group to prevent infarct expansion (Jugdutt & Warnica, 1988). The safety of intermittent therapy in the early post-infarction period will require further evaluation. There is one final issue in relation to intermittent nitrate therapy which is as yet unexplained. For years doctors have reassured their patients that nitrate headaches will resolve within a few days of commencing therapy, a beneficial manifestation of tolerance. One might expect, therefore, that intermittent nitrate
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regimens designed to prevent tolerance would result in the persistence of nitrate headaches. Fortunately, this does not appear to be the case. While there is some limited anecdotal evidence of headaches being more troublesome during intermittent therapy, the available clinical trials have failed to substantiate exacerbation of headache. Why this should be the case remains unclear. A possible explanation lies in the suggestion that the mechanism of tolerance may differ in different vascular beds. Thus, headaches may be related to the arterial effects of nitrates, while the therapeutic antianginal benefits may be related mainly to venous effects. There is some evidence that intermittent therapy does not prevent tolerance in the arterial bed, in contrast to preventing tolerance to the therapeutic benefits of nitrates (Cowan et al., 1987). Other indications
Nitrates are unique amongst cardiovascular drugs in their range of applicability throughout the spectrum of cardiovascular disease. They are of value in stable angina, unstable angina, acute myocardial infarction and heart failure. Is tolerance equally implicated in the use of nitrates in all syndromes of ischaemic heart disease? The answer to this question is unclear. It is certainly possible that the heterogeneity of sites of action when used for differing clinical indications might result in differing degrees of tolerance in different syndromes. Most information relates to chronic stable angina. However, we also know that tolerance arises in the management of patients with heart failure (Elkayam et al., 1987; Parker et al., 1987). As a general rule it seems advisable to adopt intermittent regimens, whatever the indication for treatment. The one possible exception to this rule is in the management of unstable angina. Intravenous nitrate infusions are frequently used in patients with unstable angina, for ease of titration against symptoms. In such patients, interruption of an infusion may lead to a return of anginal symptoms. It can also be argued that, if interrupted therapy is tolerated, then the patient does not require the constancy of nitrate levels provided by intravenous administration, and that an intermittent oral regimen will suffice. Intermittent infusions are therefore best avoided. However, it is important to appreciate that even with an infusion duration as short as 24 h, a substantial degree of tolerance may occur (Elkayam et al., 1987). This tolerance can generally be temporarily overcome by increasing the infusion rate. If symptoms continue unstable after 1 to 2 days, then alternative forms of management should be considered. As discussed above, caution is also necessary in the use of intermittent regimens in the early post-infarction
period. Remaining questions
Many issues remain unresolved. Foremost amongst these is the mechanism or mechanisms of tolerance. Future emphasis will address the heterogeneity of
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tolerance. Is there a heterogeneity of mechanism in different vascular beds? Does the predominant site of nitrate action differ in different patients? Does this, in combination with heterogeneity of mechanism, explain heterogeneity in the extent of tolerance between patients? Does this heterogeneity have implications for tolerance prevention and are there alternative means of prevention to intermittent therapy?
These issues exemplify some of the remaining problems. Nitrate research has received a new lease of life, both from the EDRF discoveries and from advances in the understanding and prevention of tolerance. Important questions have emerged and, despite their longevity, nitrates remain interesting and exciting drugs.
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(Received 21 October 1991, accepted 17 February 1992)
