- Email: [email protected]
Nitrates and angina pectoris
Nitrates and Angina Pectoris John 0. Parker,
the mechanisms of action of the organk nkrates, nltrate tolerance, and the effects ofnttrates in patients with stable angina pectods. The nltrates are prodrugs that enter the vascular smooth muscle, where they are denibated to form the active agent nitrk oxkk (NO). NO activates guanyiate cydase, whkh results in cyclk guano&w mowphosphate (cGMP) productionandvasodllatknasaresuRofreuptakeof caklum by the sarwplasmk retkulum. NO is eMothelium-derivedrelaxingfactor -to (EDRF),whkh inducesvasodilath~, inhibtts platelet -Ion, reduces endothelium adhesion, and has antkoagulant andflbrlnolytk effects. Thus, the nitrates may be more than vasodilators and, in addition to redudng lschemia, may affect theprocessofatS.‘Chevasculareffects of nltrates are attenuated during sustained therapy. AMough the basis for the phenomenon of nitrate tolerance is not completely understood, sulfhydryl depktkm as well as neurohormonal acthMkn and hweased plasma volume may be involved. The admlnlstration of N-acetyL cystehe, anptktensin-converting enzyme (ACE) InhMCors, br diuretks do not consistently prevent nttrate Wetance. At present, intenntttent nttrate therapy is the only way to avold nttrate tolerance. l’he intermlttent adminlstratlon of nitrates, however, cannot provide continuous therapeutk benefMs, and thus monotberapy with nitrates is not suitablefor many patientswith stable anghw pectoris. (Am J Cardiol1993;72:3CHC) lllkrevlewdbusses
From the Kingston General Hospital, Kingston, Ontario, Canada. Address for reprints: John 0. Parker, MD, Cardiovascular Laboratory, Kidd 3, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7.
MD
illiam Murrell, in an article published in Lancet in 1879, was aware of the similarity between the effects of nitroglycerin and those of amyl nitrite when he employed a 1% nitroglycerin solution for the relief of acute episodes of angina pect0ris.l This was the first documentation of the usefulness of nitroglycerin in angina pectoris. After > 100 years, our knowledge of the mechanisms of action of organic nitrates has increased substantially but remains incomplete. It is recognized that organic nitrates enter vascular smooth muscle, where they are denitrated to form the active agent nitric oxide (NO). NO activates guanylate cyclase to produce cyclic guanosine monophosphate (cGMP), which leads to vasodilation via reuptake of calcium by the sarcoplasmic reticulum. The effects of NO are identical to those of endothelium-derived relaxing factor (EDRF), which is synthesized by normal endothelial cells. EDRF is important in the maintenance of normal vascular tone. In addition, it inhibits platelet aggregation, reduces endothelial adhesion, modifies macrophage adhesion, has anticoagulant and fibrinolytic effects, and reduces growth factors. If NO shares the effects of EDRF, the nitrates may be very important drugs, perhaps not only in treating myocardial ischemia, but also in preventing or modifying atherosclerosis.
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NITRATE TOLERANCE Nitrate tolerance has been observed for many years, but only during the past decade has it been recognized as an important clinical problem. Animal studies have demonstrated that increasing doses of nitrates resulted in attenuated hemodynamic effects. Furthermore, munitions workers commonly developed intense headaches on initial exposure to nitrates in the manufacturing process, but these usually stopped after short periods in the work environment. However, the headaches often reoccurred on Monday after a weekend away from the job. Thus, nitrate tolerance develops rapidly and also clears very quickly. These properties of nitrates have been exploited in the management of patients with coronary artery disease.2-7 A SYMPOSIUM: MANAGING MYOCARDIAL ISCHEMIA
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From clinical studies dating back to the 19th century, when nitrates were used as antihypertensive agents, it was recognized that increasing doses had to be administered to induce effects previously obtained with a lower dose. Hemodynamic studies in humans also showed that the rapid development of tolerance and cross-tolerance existed among the various organic nitrates. A subject of controversy in the 1970s and early 1980~,~~~ it is now known that tolerance develops with all nitrates when they are given in an attempt to provide continued effects for 24 hours each day.‘@‘” The basis of nitrate tolerance is still not completely understood, but various mechanisms have been suggested to explain this phenomenon. These mechanisms are discussed below. Sulfhydryl group depletion: Sulfhydryl groups are required for the denitration of the organic nitrate to form NO. Sulfhydryl group depletion may occur with continued nitrate exposure, and this may be a factor in the development of nitrate tolerance.10J1J6Studies have shown that the administration of N-acetylcysteine (NAC) will reverse nitrate tolerance in humans.10911 Other studies have reported continued tolerance when NAC was given during therapy with isosorbide dinitrate.17 In heart failure, continuous nitroglycerin infusion resulted in a return of left ventricular filling pressures toward the preinfusion levels; the subsequent oral administration of NAC during continued nitroglycerin infusion resulted in a moderate reduction of ventricular filling pressures, indicating a partial reversal of tolerance.‘O Our studies showed that the administration of isosorbide dinitrate four times daily produced tolerance, as assessed by treadmill walking time.17 When NAC was administered, no improvement in exercise time was seen, indicating that NAC had no effect on tolerance to isosorbide dinitrate. It is not clear whether these conflicting results reflect a difference between nitroglycerin and isosorbide dinitrate. Neurohormonal activation: The role of neurohormonal activation in tolerance also has been studied.ls It was hypothesized that continuous nitroglycerin therapy would lead to the release of vasoactive hormones that might be associated with the retention of salt and water. To test this theory, normal subjects were hospitalized in a metabolic ward for 1 week. A steady-state condition was obtained with a fixed caloric and sodium intake; 24-hour urine samples were collected throughout the hospital stay, and body weight and hematocrit were measured twice daily. Nitroglycerin patch @
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application started on the 5th hospital day and was continued for 3 days. In 10 subjects nitroglycerin patches (1.2 mg/hour) were applied for 24 hours (continuous nitroglycerin group), and in 10 subjects nitroglycerin patches were applied at 8 A.M. and removed at 8 P.M. (intermittent nitroglycerin group). Neurohormonal evaluation was performed on days 4 through 7. Tolerance was assessed by monitoring standing systolic blood pressure and heart rate during therapy. In the continuous nitroglycerin group, a hypotensive effect was seen on the initial treatment day, but tolerance was observed by the second day. In contrast, in the intermittent nitroglycerin group a decrease in blood pressure occurred during the first day, and a similar decrease in blood pressure occurred each day after the application of the nitroglycerin patches. Thus, no tolerance was observed when the patch was removed for 12 hours. Plasma norepinephrine levels became elevated in the continuous nitroglycerin group. Interestingly, in the intermittent nitroglycerin group norepinephrine levels rose each day following patch application and then fell to baseline levels by the following morning. Thus, intermittent activation of catecholamines was seen. Similarly, a modest increase was observed in plasma renin activity during the first 2 days of continuous patch application. In the intermittent nitroglycerin group, the plasma renin level was normal each morning and rose during the period of patch application, indicating activation of the renin-angiotensin system. Urinary sodium excretion decreased dramatically in the continuous nitroglycerin group but not in the intermittent nitroglycerin group. The continuous nitroglycerin group gained 1 kg over a 4% hour period; in contrast, the intermittent group had no significant weight gain. The increase in weight and the retention of sodium in the continuous nitroglycerin group were associated with a decrease of hematocrit of approximately 5 units, whereas only small changes in these values occurred in the intermittent nitroglycerin group. Thus, continuous transdermal nitroglycerin ther‘apy at the dosage used (1.2 mg/hour) led to the release of vasoactive hormones, to salt and water retention, and presumably to an increase in plasma volume. These changes could readily modify the effect or nitrate-induced vasodilation. The role of activation of the renin-angiotensin system in nitrate tolerance has been studied. Katz and coworkers have documented that the administration of angiotensin-converting enzyme (ACE) inhibitors prevents tolerance to continuous trans-
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dermal nitroglycerin application, as assessed by treadmill walking time was seen, but thereafter no changes in forearm vascular volume.19 We con- effect was observed. In contrast, when patients ducted a study to evaluate the effect of benazapril, were treated with buccal nitroglycerin (3 mg 3 an ACE inhibitor without sulfhydryl groups, on times daily), with removal each night to allow a nitrate tolerance.20 After 1 week of benazapril nitrate-free interval, no difference in exercise tolerance was observed between the 1st and the 14th administration, tolerance developed during nitroglycerin patch therapy just as rapidly as during day. This finding was consistent with the absence of benazapril placebo administration. tolerance during intermittent nitrate therapy. Plasma volume expansion: Our initial studies In the Nitroglycerin Co-operative Study,i5 conwith the continuous administration of transdermal tinuous patch application resulted in increased nitroglycerin (1.2 mg/hour) suggested that the exercise tolerance 4 hours after the patch applicadecrease in hematocrit was secondary to renal tion (0.6 mg/hour) on the first day, but by 24 hours sodium and water retention, with a resultant in- complete tolerance to the patch was seen. Even crease in plasma volume.18 Later studies with with high doses of continuous patch applications, smaller doses of transdermal nitroglycerin (0.6 no differences were noted among the placebo mg/hour) documented that sodium retention was group and any of the active treatment groups at transient and that no weight gain occurred.20 De- either 4 or 24 hours after patch application. Thus, spite this, a decrease in hematocrit was observed. complete tolerance to this regimen was observed in In patients with heart failure, Dupuis and cowork- the majority of patients. ers21documented a similar decrease in hematocrit An intermittent patch study by DeMots and and an increase in plasma volume as tolerance Glasser,’ in which the patch was on for 12 hours developed during intravenous nitroglycerin admin- and off for 12 hours, demonstrated an improveistration, without a change in sodium balance or ment in exercise performance at 4,8, and 12 hours body weight. These observations suggest that de- on days 1,15, and 29. Some drawbacks to intermitspite the development of tolerance, as assessedby tent nitrate therapy exist, however. First, the therathe usual hemodynamic parameters, the nitrates peutic effects cannot be maintained throughout all continue to exert vascular effects. Thus, the de- 24 hours of a day. Second, there has been a crease in hematocrit may be secondary to contin- question of rebound, which may or may not be ued postcapillary venous effects that alter fluid related to neurohormonal activation. Rebound exchange between the intra- and extravascular may be explained by a dissociation between the spaces by altering Starling forces (cf. Starling’s law rate of nitrate washout and the reversal of counterof the heart). regulatory mechanisms. Parker and coworkers22 studied the effect of Thus, patients who were receiving active nitrate diuretic therapy on the responses to transdermal therapy in the study by DeMots and Glasser’ had nitroglycerin (0.6 mg/hour) in normal subjects. an increase in rest angina during the patch-off During placebo therapy, tolerance developed within period. Furthermore, in the morning when patients 24 hours of continuous nitroglycerin patch applica- were off their patch, whether they were receiving tion. When subjects were pretreated for 1 week active nitrate therapy or placebo for a period of 12 with hydrochlorothiazide (50 mg/day), tolerance hours, the morning exercise test (the zero-hour also developed within 24 hours of the initiation of test) increased in all groups, but increased more in continuous transdermal nitroglycerin patches. This the placebo group than in the active treatment does not rule out a role for plasma volume expangroup. This result suggests that rebound prevented sion as a factor in nitrate tolerance, since a reducthe nitrate group from doing as well as the placebo tion of plasma volume may not persist during group early in the morning. In another study of continued diuretic administration in patients withpatients with unstable angina during intermittent out major hemodynamic abnormalities. therapy, an increase in the number of episodes of rest angina was observed.23 Thus, these 2 reports suggest that there may be a downside to intermitINTERMIITENT NlTRATE ADMINISTRATION In a group of patients treated with isosorbide tent patch therapy in terms of rebound. We recently completed a multicenter trial in dinitrate (30 mg 4 times daily), treadmill walking (5, 10, or 20 mg) time to the development of moderate angina was which isosorbide-5mononitrate increased throughout a 5-hour observation period or placebo was given to 214 patients at 8 A.M. and on the first treatment day.’ The same dosage of at 3 P.M.24 The frequency of angina was recorded drug was given for 2 weeks; a l-hour increase in during the 3-week study period. In the higher dose A SYMPOSIUM:
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groups, a decrease was observed in the overall number of episodes of angina. More importantly, from midnight to 8 A.M. no augmentation of angina was observed in the nitrate treatment group compared with the placebo group. Thus, in this large study of patients with stable angina there was no evidence of rebound, as assessed by the diary recording of episodes of angina. CONCLUSION
nism for tolerance development, vasodilation and mitochondrial and enzyme reactions. In: Needleman P, ed. Organic Nitrates: Handbook of Expetimental Pharmacology.New York Springer-Verlag, 197597-114. 17. Parker JO, Farrell B, Lahey K, Rose BF. Nitrate tolerance: the lack of effect of N-acetykysteine. Cirrulation 1987;76:572-576. l8. Parker JD, Farrell B, Fenton T, Cohanim M, Parker JO. Counterregulatory responsesto continuous and intermittent therapy with nitroglycerin. CiJcldalian1991$42336x345. l.9. Katz RJ, Levy WS, Buff L WassermanAG. Prevention of nitrate tolerance with angiotensin-convertingenzyme inhibitors. Circulation 1991;83:12711277. 20. Parker JD, Parker JO. Effect of therapy with an angiotensinconverting enzyme inhibitor on hemodynamic and counter-regulatory responsesduring mntinuous therapy with nitroglycerin. JAm Co11CamYol (in press). 2l. Dupuis J, Lalonde G, Lemieux R, Rouleau JL. Tolerance to intravenous nitroglycerin in patients with congestiveheart failure: role of increasedintravascular volume, neurohormonaJactivation and lack of prevention with N-acetylqs teine. JAm Coil Cardio11990,16:923-931. 22. Parker JD, Farrell B, Fenton T, Parker JO. Effects of diuretic therapy on the development of tolerance during continuous therapy with nitroglycerin. J Am Coil Cardi 1~2th616-622. 29. Ferratini M, Piielli S, Merlini P, Siia T, PoUaviniG. Intermittent trqtsdermat nitroglycerin monotherapy in stable exercise-inducedangina: a mmparison with a continuous schedule.Ew Heat? J 1989;10:99~1002. 24. Parker JO, SchneeweissA, Weiss M, Wagle S. Eccentric dosing with isosorbide-5-mononitratein angina pectoris. (Abstr.) Ctirr 1992$6(suppl I):&714.
Organic nitrates are denitrated to form the active agent NO, which has effects that are identical to those of EDRF. EDRF, in addition to causing vasodilation, has antiplatelet and antithrombolytic effects that may slow the process of atherosclerosis. The administration of nitrates to patients with chronic stable angina increases exercise tolerance and decreases the incidence of angina attacks. Tolerance to nitrates constitutes a major problem in clinical practice. Intermittent therapy is currently the only practical way to avoid DISCUSSIDN nitrate tolerance. Dr. Alfred F. Parlsi (PmvWnce, Rhode Island): Dr. Parker, how long does the nitrate-free interval have to last to prevent tolerance? It would REFERENCES seem that 12 hours is a long time. I Murrell W. Use of nitrite of amyl in anginapectoris.Lancer 1879;i:ml. 2. Parker 0, Van Koughnett KA, Farrell B. Comparison of buccal nitroglycDr. Parker: With oral isosorbide dinitrate, when erin and oral isosorbidedmitrate for nitrate tolerance in stable angina pectoris. the last tablet was given with the evening meal, Am J Cardid 1985;56:7%-728. 2. Silber S, Vogler AC, Krause KH, Vogel M, Thiesen K. Induction and tolerance was prevented or modified. This would circumvention of nitrate tolerance applyins different dosage intervals. Am J have left nitrate in the system for another 4-5 Med 1987$33:860-870. hours, so the interval would have been between 11 4. Cowan JC, Bourke JP, Reid DS, Julian DG. Prevention of tolerance to nitroglycerin patchesby oven&t removal.Am J Caniiol1987;60:271-275. P.M. and 8 or 9 A.M. Therefore, we are talking about 15.Luke R, Sharpe N, Coxon R. Transdetmal nitroglycerin in angina pectorisz 9-10 hours during which the plasma levels would efficacy of intermittent application.JAm Coil Canihl1987;10:642-646. be low. With reference to the patch, a lO-12-hour 8. Parker JO, Farrell B, Lahey KA, Moe G. Effects of intervals between doses on the developmentof tolerance to isosorbidedinitrate. N Engl JMed 1987;316: off interval seemsto be adequate to prevent toler1440-1444. ance. 7. DeMots H, Glasser SP. Intermittent transdermal nitroglycerin therapy in the treatment of chronic stable angina.JAm CoU Cam?01 1989;13:786-788. 8. Danahy DT, Aronow W. Hemodynamicsand anti-anginal effects of highdose oral isosorbidediitrate after chronic use. Cirrularion 1977,563205-212. 9. Lee G, Mason DT, DeMaria A Effects of long-term oral admiistration of isowrbide dmitrate on the anti-angina1response to nitrogylcetim absenceof cross-tolerance and se&tolerance shown by exercise testing. Am J Cardiol 1978;41:82-87. 10. Packer M, Lee WH, Kessler PD, Gottheb SS, Medma N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Erg1 J Med 1987;317:7~04. U May DC, PopmaJJ, Black WH, Schafer S, Lee HR, Levine BD, Hiiis LD. In viva induction and reversal of nitroglycerin tolerance in human coronary arteries. N Engl J Med 1987;317:805-809. il. Tbadani U, Fung H-f., Darke AC, Parker JO. Oral isosorbide din&rate in angina pectoriszcomparison of duration of action and dose-responserelation during acute and sustainedtherapy.Am J Car&’ 1982;49:411-419. 13. Dalal JJ, Parker JO. Nitrate cross-tolerance:Effect of sublingualisosorbide dinitrate and nitroglycerin during sustained nitrate therapy. Am J Cam301 1984;54:28&288. l4. Parker JO. Nitrate therapy in stable anginapectoris.N EnglJMed 1987;316: 1635-1642. l5. Steering Committee, Transdermal Nitroglycerin Cooperative Study. Acute and chronic antianginal efficacy of continuous twenty-four hour application of transdermalnitroglycerin.Am J Cam?011991;68:1263-1273. l6. Needleman P, JohnsonEM. The pharmacologicaland biochemical interaction of organic nitrates with sulfbydtylszpossible correlations wim the mecha6c
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Dr. Michael
D. Klein (Boston,
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setts): From your own experience with this large multicenter study, is there much interpatient variability in the number of hours for the development of tolerance? Dr. Parker: It is difficult to know; clearly, every patient does not become tolerant. We have patients who show effectiveness despite continued patch therapy. The interpatient variability in the duration of the period of low nitrate exposure necessaryto prevent the development of tolerance has not been carefully studied. Tolerance begins to develop within minutes of introducing the drug into the system. We are just beginning to get information about whether the second tablet is as effective as the first one, and probably it is not! A study done recently in Israel evaluated the effect of oral isosorbide dinitrate during therapy 3 times daily.’ The second tablet was found to produce
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much less improvement than the first tablet. When the third dose was given in the evening, it had an effect for just 1 hour. This was, however, a very unusual study, with a small number of patients who were able to exercise every hour for a 16-hour period. Dr. EMott M. Antman (Boston, Massachusetts): Dr. Parker, is there any evidence to suggest that tolerance is seen with continuous intravenous nitroglycerin in patients with unstable angina? I am struck by the clinical observation that patients in the coronary care unit who have their nitroglycerin tapered because we think they are controlled quite often have an episode of breakthrough angina, which makes us restart the nitroglycerin or increase the dose. Dr. Parker: That is a common problem, but it may be part of the variability of unstable angina. The other question that comes up is why, after 6 days of nitrate therapy when hemodynamic tolerance is well established, does one still have evidence of hemodilution? There must still be vascular effects. Exercise testing tells us about tolerance, but there must still be something going on at the vascular level. Perhaps a minor nitrate effect on coronary vessels may be adequate to prevent ischemia. What about the effects on platelets? Platelet effects may persist after the development of nitrate tolerance. We talked about fibrinolytic activity of nitrates that may lead to the production of tissue plasminogen activator locally. So there are many factors that may provide potential explanations for that finding, even though we know that these patients are tolerant, as assessedby hemodynamic parameters. Dr. Richard Gorlin (New York, New York): Dr. Parker, are there differential effects that we need to look at with respect to time of dose and the vascular effect? The differences among veins, small arteries, and large arteries may explain some of these differences that are seen. Dr. Parker: I think there may be differences in the rate of development and extent of tolerance in the venous and arterial circulation. The effect of nitrates on small vessels may be different from that on large vessels. Dr. Jay Cohn knows a lot about the nitrate effects on blood vessels. Would you like to comment on that, Dr. Cohn? Dr. Jay N. Cohn (Mhmeapoiis, Mhmesota): It is the usual problem of the various sites of action of nitrates, all the way from dilation of the arteriole, to increased compliance of the larger arteries, to venous smooth muscle, to a myocyte growthinhibiting effect. I do not think that we fully
understand the relative influence of tolerance on these various sites of action. Most of the tolerance data have been concerned with hemodynamic tolerance, which mainly involves either arteriolar or perhaps venous effects, and not at some of the other sites of action that may be important. Obviously, the effect in angina is largely at the level of the conductance coronary arteries and at the site of stenosis, especially in unstable angina. We have very little data on what happens to coronary arteries when they are exposed to the repeated or prolonged administration of nitrates. Some studies are looking at angiographic coronary artery caliber, but I do not think these studies have been definitive enough to tell us that the coronary artery ceases to dilate in response to the drug. From our data, I believe very strongly that nitrate tolerance is not an all-or-nothing phenomenon in heart failure and that nitrates maintain efficacy. Dr. Nevllle Btttar (Mad&m, Wisconsin): I would like to return to the clinical use of these agents. Should we really be satisfied with intermittent therapy? Is it really safe to use nitrates as monotherapy in a patient with coronary artery disease? Dr. Parker: I think it depends on the clinical setting. If I have a patient who has angina predictably during the day while engaged in activities, has angina occasionally with emotional stress, does not have nocturnal angina, and has good exercise tolerance, I think it is quite appropriate to treat that patient during the active part of the day and to accept the fact that you are not providing a nitrate effect for several hours. If, however, a patient has unpredictable angina with episodes at night and has low exercise tolerance, and the patient may have significant “silent” ischemia, then perhaps monotherapy would be inappropriate. That patient should probably be given another agent, perhaps a l3 blocker, with possibly the addition of nitrates, if necessary, during the day. Dr. John D. Rutherford (Boston, Massachusetts): I have a practical question regarding patients with chronic stable angina who are receiving long-acting nitrates. I have tried to change the dosing schedule in our hospital to achieve a lohour nitrate-free interval. I would give a dose in the morning, a dose around noon, and the last dose at 4 P.M. How would you advise us to handle this situation from the point of view of writing orders and achieving what we want to achieve by delivering the drug to the patients? Dr. Parker: Clearly, the nurses are resistant, and the house staff are surreptitiously trying to get A SYMPOSIUM: MANAGING MYOCARDIAL ISCHEMIA
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around it. In fact, when we started doing this, the house staff, often not recognizing the problem of cross-tolerance, would give the oral nitrate three times a day and then give patients a patch at night. It is basically a problem of education. In most of the letters that I send out to referring physicians, I include a paragraph that indicates why I have changed the patient’s dosing, and it has gradually worked. Dr. John D. Parker (Toronto, Canada): I would like to make a comment regarding some of the issues raised by Dr. Cohn and others. I think we need a new nomenclature for the problem of nitrate tolerance becauseit is clear that, in obstructive coronary artery disease and stable angina, nitrates lose their effect with continuous dosing. However, in that setting, sublingual nitroglycerin exerts its usual beneficial effects. Thus, if you look at it from that perspective, those patients are clearly not tolerant. It really depends on the endpoint that you are using. Although treadmill walking time to angina represents a means to define a dose-response relation, it appears that often there is a shift in that relation. It is a very confusing issue of exogenous sulfhydryl donation. We have begun to recognize the distinction between the exaggeration of nitrate effects and the prevention of tolerance. In my opinion, the whole matter represents merely a shift in the doseresponse relation. In one case, you have not had the dose before, and in another case you have. Several investigators have suggestedimproving our nomenclature in this field. Dr. Thomas W. Smith (Boston, Massachu-
function would show very different responses. In our laboratory, for example, when we infuse nitrates into patients with heart failure, they show no sympathoexcitatory response, as reflected by direct intraneural recordings, and they do not demonstrate an increase in plasma norepinephrine levels. Yet, their clinical responses are very similar to those found in subjects with normal cardiac function. Therefore, I think that the role of neurohormonal mechanisms in the development of tolerance is an interesting concept, but I wonder how important it is, particularly in view of the fact that tolerance occurs in patients in whom the mechanisms that regulate the neurohormonal excitatory state do not work. Dr. Parker: You are quite right that there are differences between patients with normal and abnormal left ventricular function. I would suggest, however, that the majority of patients with angina probably would respond much like normal subjects in terms of the neurohormonal response, since they do not have heart failure and have relatively normal left ventricular function. Dr. Cohn: In regard to the nomenclature, the one issue that we have not clearly dealt with is whether there is a difference between nitrate tolerance and rebound. This is a very serious issue because rebound occurs when nitrates are withdrawn. This rebound probably reflects activation of some vasoactivesystem.I think that such a system, incidentally, is at the level of the vascular smooth muscle and not at the neurohormonal level. Is that really what we are seeing with tolerance, or are tolerance and rebound two independent processes? Dr. Smith: I would surmise that it is at least in part a dose-response shift. Dr. Cohn: I think that rebound is more than a dose-response shift. I believe that rebound is created by some other system that has been activated during nitrate therapy.
setts): In the nitrate literature, it is typically very difficult to know whether there has been a change in efficacy or just a shift in the dose-response curve. The latter is easily dealt with, whereas the former obviously is not. Dr. Marc D. l’hames (Cleveland, Ohlo): I think it is important to recognize, Dr. Parker, that the study you described of the neurohormonal response to nitrate administration was done in normal subjects with normal cardiac function. It is REFERENCE L Bassan MM. The daylong pattern of the antianginal effect of long-term almost certain that patients with congestive heart three times daily administered isosorbide din&rate. JAm CoU Car&Z 1990,16: failure and moderate left ventricular systolic dys- 936-940.
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the mechanisms of action of the organk nkrates, nltrate tolerance, and the effects ofnttrates in patients with stable angina pectods. The nltrates are prodrugs that enter the vascular smooth muscle, where they are denibated to form the active agent nitrk oxkk (NO). NO activates guanyiate cydase, whkh results in cyclk guano&w mowphosphate (cGMP) productionandvasodllatknasaresuRofreuptakeof caklum by the sarwplasmk retkulum. NO is eMothelium-derivedrelaxingfactor -to (EDRF),whkh inducesvasodilath~, inhibtts platelet -Ion, reduces endothelium adhesion, and has antkoagulant andflbrlnolytk effects. Thus, the nitrates may be more than vasodilators and, in addition to redudng lschemia, may affect theprocessofatS.‘Chevasculareffects of nltrates are attenuated during sustained therapy. AMough the basis for the phenomenon of nitrate tolerance is not completely understood, sulfhydryl depktkm as well as neurohormonal acthMkn and hweased plasma volume may be involved. The admlnlstration of N-acetyL cystehe, anptktensin-converting enzyme (ACE) InhMCors, br diuretks do not consistently prevent nttrate Wetance. At present, intenntttent nttrate therapy is the only way to avold nttrate tolerance. l’he intermlttent adminlstratlon of nitrates, however, cannot provide continuous therapeutk benefMs, and thus monotberapy with nitrates is not suitablefor many patientswith stable anghw pectoris. (Am J Cardiol1993;72:3CHC) lllkrevlewdbusses
From the Kingston General Hospital, Kingston, Ontario, Canada. Address for reprints: John 0. Parker, MD, Cardiovascular Laboratory, Kidd 3, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7.
MD
illiam Murrell, in an article published in Lancet in 1879, was aware of the similarity between the effects of nitroglycerin and those of amyl nitrite when he employed a 1% nitroglycerin solution for the relief of acute episodes of angina pect0ris.l This was the first documentation of the usefulness of nitroglycerin in angina pectoris. After > 100 years, our knowledge of the mechanisms of action of organic nitrates has increased substantially but remains incomplete. It is recognized that organic nitrates enter vascular smooth muscle, where they are denitrated to form the active agent nitric oxide (NO). NO activates guanylate cyclase to produce cyclic guanosine monophosphate (cGMP), which leads to vasodilation via reuptake of calcium by the sarcoplasmic reticulum. The effects of NO are identical to those of endothelium-derived relaxing factor (EDRF), which is synthesized by normal endothelial cells. EDRF is important in the maintenance of normal vascular tone. In addition, it inhibits platelet aggregation, reduces endothelial adhesion, modifies macrophage adhesion, has anticoagulant and fibrinolytic effects, and reduces growth factors. If NO shares the effects of EDRF, the nitrates may be very important drugs, perhaps not only in treating myocardial ischemia, but also in preventing or modifying atherosclerosis.
W
NITRATE TOLERANCE Nitrate tolerance has been observed for many years, but only during the past decade has it been recognized as an important clinical problem. Animal studies have demonstrated that increasing doses of nitrates resulted in attenuated hemodynamic effects. Furthermore, munitions workers commonly developed intense headaches on initial exposure to nitrates in the manufacturing process, but these usually stopped after short periods in the work environment. However, the headaches often reoccurred on Monday after a weekend away from the job. Thus, nitrate tolerance develops rapidly and also clears very quickly. These properties of nitrates have been exploited in the management of patients with coronary artery disease.2-7 A SYMPOSIUM: MANAGING MYOCARDIAL ISCHEMIA
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From clinical studies dating back to the 19th century, when nitrates were used as antihypertensive agents, it was recognized that increasing doses had to be administered to induce effects previously obtained with a lower dose. Hemodynamic studies in humans also showed that the rapid development of tolerance and cross-tolerance existed among the various organic nitrates. A subject of controversy in the 1970s and early 1980~,~~~ it is now known that tolerance develops with all nitrates when they are given in an attempt to provide continued effects for 24 hours each day.‘@‘” The basis of nitrate tolerance is still not completely understood, but various mechanisms have been suggested to explain this phenomenon. These mechanisms are discussed below. Sulfhydryl group depletion: Sulfhydryl groups are required for the denitration of the organic nitrate to form NO. Sulfhydryl group depletion may occur with continued nitrate exposure, and this may be a factor in the development of nitrate tolerance.10J1J6Studies have shown that the administration of N-acetylcysteine (NAC) will reverse nitrate tolerance in humans.10911 Other studies have reported continued tolerance when NAC was given during therapy with isosorbide dinitrate.17 In heart failure, continuous nitroglycerin infusion resulted in a return of left ventricular filling pressures toward the preinfusion levels; the subsequent oral administration of NAC during continued nitroglycerin infusion resulted in a moderate reduction of ventricular filling pressures, indicating a partial reversal of tolerance.‘O Our studies showed that the administration of isosorbide dinitrate four times daily produced tolerance, as assessed by treadmill walking time.17 When NAC was administered, no improvement in exercise time was seen, indicating that NAC had no effect on tolerance to isosorbide dinitrate. It is not clear whether these conflicting results reflect a difference between nitroglycerin and isosorbide dinitrate. Neurohormonal activation: The role of neurohormonal activation in tolerance also has been studied.ls It was hypothesized that continuous nitroglycerin therapy would lead to the release of vasoactive hormones that might be associated with the retention of salt and water. To test this theory, normal subjects were hospitalized in a metabolic ward for 1 week. A steady-state condition was obtained with a fixed caloric and sodium intake; 24-hour urine samples were collected throughout the hospital stay, and body weight and hematocrit were measured twice daily. Nitroglycerin patch @
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application started on the 5th hospital day and was continued for 3 days. In 10 subjects nitroglycerin patches (1.2 mg/hour) were applied for 24 hours (continuous nitroglycerin group), and in 10 subjects nitroglycerin patches were applied at 8 A.M. and removed at 8 P.M. (intermittent nitroglycerin group). Neurohormonal evaluation was performed on days 4 through 7. Tolerance was assessed by monitoring standing systolic blood pressure and heart rate during therapy. In the continuous nitroglycerin group, a hypotensive effect was seen on the initial treatment day, but tolerance was observed by the second day. In contrast, in the intermittent nitroglycerin group a decrease in blood pressure occurred during the first day, and a similar decrease in blood pressure occurred each day after the application of the nitroglycerin patches. Thus, no tolerance was observed when the patch was removed for 12 hours. Plasma norepinephrine levels became elevated in the continuous nitroglycerin group. Interestingly, in the intermittent nitroglycerin group norepinephrine levels rose each day following patch application and then fell to baseline levels by the following morning. Thus, intermittent activation of catecholamines was seen. Similarly, a modest increase was observed in plasma renin activity during the first 2 days of continuous patch application. In the intermittent nitroglycerin group, the plasma renin level was normal each morning and rose during the period of patch application, indicating activation of the renin-angiotensin system. Urinary sodium excretion decreased dramatically in the continuous nitroglycerin group but not in the intermittent nitroglycerin group. The continuous nitroglycerin group gained 1 kg over a 4% hour period; in contrast, the intermittent group had no significant weight gain. The increase in weight and the retention of sodium in the continuous nitroglycerin group were associated with a decrease of hematocrit of approximately 5 units, whereas only small changes in these values occurred in the intermittent nitroglycerin group. Thus, continuous transdermal nitroglycerin ther‘apy at the dosage used (1.2 mg/hour) led to the release of vasoactive hormones, to salt and water retention, and presumably to an increase in plasma volume. These changes could readily modify the effect or nitrate-induced vasodilation. The role of activation of the renin-angiotensin system in nitrate tolerance has been studied. Katz and coworkers have documented that the administration of angiotensin-converting enzyme (ACE) inhibitors prevents tolerance to continuous trans-
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dermal nitroglycerin application, as assessed by treadmill walking time was seen, but thereafter no changes in forearm vascular volume.19 We con- effect was observed. In contrast, when patients ducted a study to evaluate the effect of benazapril, were treated with buccal nitroglycerin (3 mg 3 an ACE inhibitor without sulfhydryl groups, on times daily), with removal each night to allow a nitrate tolerance.20 After 1 week of benazapril nitrate-free interval, no difference in exercise tolerance was observed between the 1st and the 14th administration, tolerance developed during nitroglycerin patch therapy just as rapidly as during day. This finding was consistent with the absence of benazapril placebo administration. tolerance during intermittent nitrate therapy. Plasma volume expansion: Our initial studies In the Nitroglycerin Co-operative Study,i5 conwith the continuous administration of transdermal tinuous patch application resulted in increased nitroglycerin (1.2 mg/hour) suggested that the exercise tolerance 4 hours after the patch applicadecrease in hematocrit was secondary to renal tion (0.6 mg/hour) on the first day, but by 24 hours sodium and water retention, with a resultant in- complete tolerance to the patch was seen. Even crease in plasma volume.18 Later studies with with high doses of continuous patch applications, smaller doses of transdermal nitroglycerin (0.6 no differences were noted among the placebo mg/hour) documented that sodium retention was group and any of the active treatment groups at transient and that no weight gain occurred.20 De- either 4 or 24 hours after patch application. Thus, spite this, a decrease in hematocrit was observed. complete tolerance to this regimen was observed in In patients with heart failure, Dupuis and cowork- the majority of patients. ers21documented a similar decrease in hematocrit An intermittent patch study by DeMots and and an increase in plasma volume as tolerance Glasser,’ in which the patch was on for 12 hours developed during intravenous nitroglycerin admin- and off for 12 hours, demonstrated an improveistration, without a change in sodium balance or ment in exercise performance at 4,8, and 12 hours body weight. These observations suggest that de- on days 1,15, and 29. Some drawbacks to intermitspite the development of tolerance, as assessedby tent nitrate therapy exist, however. First, the therathe usual hemodynamic parameters, the nitrates peutic effects cannot be maintained throughout all continue to exert vascular effects. Thus, the de- 24 hours of a day. Second, there has been a crease in hematocrit may be secondary to contin- question of rebound, which may or may not be ued postcapillary venous effects that alter fluid related to neurohormonal activation. Rebound exchange between the intra- and extravascular may be explained by a dissociation between the spaces by altering Starling forces (cf. Starling’s law rate of nitrate washout and the reversal of counterof the heart). regulatory mechanisms. Parker and coworkers22 studied the effect of Thus, patients who were receiving active nitrate diuretic therapy on the responses to transdermal therapy in the study by DeMots and Glasser’ had nitroglycerin (0.6 mg/hour) in normal subjects. an increase in rest angina during the patch-off During placebo therapy, tolerance developed within period. Furthermore, in the morning when patients 24 hours of continuous nitroglycerin patch applica- were off their patch, whether they were receiving tion. When subjects were pretreated for 1 week active nitrate therapy or placebo for a period of 12 with hydrochlorothiazide (50 mg/day), tolerance hours, the morning exercise test (the zero-hour also developed within 24 hours of the initiation of test) increased in all groups, but increased more in continuous transdermal nitroglycerin patches. This the placebo group than in the active treatment does not rule out a role for plasma volume expangroup. This result suggests that rebound prevented sion as a factor in nitrate tolerance, since a reducthe nitrate group from doing as well as the placebo tion of plasma volume may not persist during group early in the morning. In another study of continued diuretic administration in patients withpatients with unstable angina during intermittent out major hemodynamic abnormalities. therapy, an increase in the number of episodes of rest angina was observed.23 Thus, these 2 reports suggest that there may be a downside to intermitINTERMIITENT NlTRATE ADMINISTRATION In a group of patients treated with isosorbide tent patch therapy in terms of rebound. We recently completed a multicenter trial in dinitrate (30 mg 4 times daily), treadmill walking (5, 10, or 20 mg) time to the development of moderate angina was which isosorbide-5mononitrate increased throughout a 5-hour observation period or placebo was given to 214 patients at 8 A.M. and on the first treatment day.’ The same dosage of at 3 P.M.24 The frequency of angina was recorded drug was given for 2 weeks; a l-hour increase in during the 3-week study period. In the higher dose A SYMPOSIUM:
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groups, a decrease was observed in the overall number of episodes of angina. More importantly, from midnight to 8 A.M. no augmentation of angina was observed in the nitrate treatment group compared with the placebo group. Thus, in this large study of patients with stable angina there was no evidence of rebound, as assessed by the diary recording of episodes of angina. CONCLUSION
nism for tolerance development, vasodilation and mitochondrial and enzyme reactions. In: Needleman P, ed. Organic Nitrates: Handbook of Expetimental Pharmacology.New York Springer-Verlag, 197597-114. 17. Parker JO, Farrell B, Lahey K, Rose BF. Nitrate tolerance: the lack of effect of N-acetykysteine. Cirrulation 1987;76:572-576. l8. Parker JD, Farrell B, Fenton T, Cohanim M, Parker JO. Counterregulatory responsesto continuous and intermittent therapy with nitroglycerin. CiJcldalian1991$42336x345. l.9. Katz RJ, Levy WS, Buff L WassermanAG. Prevention of nitrate tolerance with angiotensin-convertingenzyme inhibitors. Circulation 1991;83:12711277. 20. Parker JD, Parker JO. Effect of therapy with an angiotensinconverting enzyme inhibitor on hemodynamic and counter-regulatory responsesduring mntinuous therapy with nitroglycerin. JAm Co11CamYol (in press). 2l. Dupuis J, Lalonde G, Lemieux R, Rouleau JL. Tolerance to intravenous nitroglycerin in patients with congestiveheart failure: role of increasedintravascular volume, neurohormonaJactivation and lack of prevention with N-acetylqs teine. JAm Coil Cardio11990,16:923-931. 22. Parker JD, Farrell B, Fenton T, Parker JO. Effects of diuretic therapy on the development of tolerance during continuous therapy with nitroglycerin. J Am Coil Cardi 1~2th616-622. 29. Ferratini M, Piielli S, Merlini P, Siia T, PoUaviniG. Intermittent trqtsdermat nitroglycerin monotherapy in stable exercise-inducedangina: a mmparison with a continuous schedule.Ew Heat? J 1989;10:99~1002. 24. Parker JO, SchneeweissA, Weiss M, Wagle S. Eccentric dosing with isosorbide-5-mononitratein angina pectoris. (Abstr.) Ctirr 1992$6(suppl I):&714.
Organic nitrates are denitrated to form the active agent NO, which has effects that are identical to those of EDRF. EDRF, in addition to causing vasodilation, has antiplatelet and antithrombolytic effects that may slow the process of atherosclerosis. The administration of nitrates to patients with chronic stable angina increases exercise tolerance and decreases the incidence of angina attacks. Tolerance to nitrates constitutes a major problem in clinical practice. Intermittent therapy is currently the only practical way to avoid DISCUSSIDN nitrate tolerance. Dr. Alfred F. Parlsi (PmvWnce, Rhode Island): Dr. Parker, how long does the nitrate-free interval have to last to prevent tolerance? It would REFERENCES seem that 12 hours is a long time. I Murrell W. Use of nitrite of amyl in anginapectoris.Lancer 1879;i:ml. 2. Parker 0, Van Koughnett KA, Farrell B. Comparison of buccal nitroglycDr. Parker: With oral isosorbide dinitrate, when erin and oral isosorbidedmitrate for nitrate tolerance in stable angina pectoris. the last tablet was given with the evening meal, Am J Cardid 1985;56:7%-728. 2. Silber S, Vogler AC, Krause KH, Vogel M, Thiesen K. Induction and tolerance was prevented or modified. This would circumvention of nitrate tolerance applyins different dosage intervals. Am J have left nitrate in the system for another 4-5 Med 1987$33:860-870. hours, so the interval would have been between 11 4. Cowan JC, Bourke JP, Reid DS, Julian DG. Prevention of tolerance to nitroglycerin patchesby oven&t removal.Am J Caniiol1987;60:271-275. P.M. and 8 or 9 A.M. Therefore, we are talking about 15.Luke R, Sharpe N, Coxon R. Transdetmal nitroglycerin in angina pectorisz 9-10 hours during which the plasma levels would efficacy of intermittent application.JAm Coil Canihl1987;10:642-646. be low. With reference to the patch, a lO-12-hour 8. Parker JO, Farrell B, Lahey KA, Moe G. Effects of intervals between doses on the developmentof tolerance to isosorbidedinitrate. N Engl JMed 1987;316: off interval seemsto be adequate to prevent toler1440-1444. ance. 7. DeMots H, Glasser SP. Intermittent transdermal nitroglycerin therapy in the treatment of chronic stable angina.JAm CoU Cam?01 1989;13:786-788. 8. Danahy DT, Aronow W. Hemodynamicsand anti-anginal effects of highdose oral isosorbidediitrate after chronic use. Cirrularion 1977,563205-212. 9. Lee G, Mason DT, DeMaria A Effects of long-term oral admiistration of isowrbide dmitrate on the anti-angina1response to nitrogylcetim absenceof cross-tolerance and se&tolerance shown by exercise testing. Am J Cardiol 1978;41:82-87. 10. Packer M, Lee WH, Kessler PD, Gottheb SS, Medma N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Erg1 J Med 1987;317:7~04. U May DC, PopmaJJ, Black WH, Schafer S, Lee HR, Levine BD, Hiiis LD. In viva induction and reversal of nitroglycerin tolerance in human coronary arteries. N Engl J Med 1987;317:805-809. il. Tbadani U, Fung H-f., Darke AC, Parker JO. Oral isosorbide din&rate in angina pectoriszcomparison of duration of action and dose-responserelation during acute and sustainedtherapy.Am J Car&’ 1982;49:411-419. 13. Dalal JJ, Parker JO. Nitrate cross-tolerance:Effect of sublingualisosorbide dinitrate and nitroglycerin during sustained nitrate therapy. Am J Cam301 1984;54:28&288. l4. Parker JO. Nitrate therapy in stable anginapectoris.N EnglJMed 1987;316: 1635-1642. l5. Steering Committee, Transdermal Nitroglycerin Cooperative Study. Acute and chronic antianginal efficacy of continuous twenty-four hour application of transdermalnitroglycerin.Am J Cam?011991;68:1263-1273. l6. Needleman P, JohnsonEM. The pharmacologicaland biochemical interaction of organic nitrates with sulfbydtylszpossible correlations wim the mecha6c
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Dr. Michael
D. Klein (Boston,
Massachu-
setts): From your own experience with this large multicenter study, is there much interpatient variability in the number of hours for the development of tolerance? Dr. Parker: It is difficult to know; clearly, every patient does not become tolerant. We have patients who show effectiveness despite continued patch therapy. The interpatient variability in the duration of the period of low nitrate exposure necessaryto prevent the development of tolerance has not been carefully studied. Tolerance begins to develop within minutes of introducing the drug into the system. We are just beginning to get information about whether the second tablet is as effective as the first one, and probably it is not! A study done recently in Israel evaluated the effect of oral isosorbide dinitrate during therapy 3 times daily.’ The second tablet was found to produce
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much less improvement than the first tablet. When the third dose was given in the evening, it had an effect for just 1 hour. This was, however, a very unusual study, with a small number of patients who were able to exercise every hour for a 16-hour period. Dr. EMott M. Antman (Boston, Massachusetts): Dr. Parker, is there any evidence to suggest that tolerance is seen with continuous intravenous nitroglycerin in patients with unstable angina? I am struck by the clinical observation that patients in the coronary care unit who have their nitroglycerin tapered because we think they are controlled quite often have an episode of breakthrough angina, which makes us restart the nitroglycerin or increase the dose. Dr. Parker: That is a common problem, but it may be part of the variability of unstable angina. The other question that comes up is why, after 6 days of nitrate therapy when hemodynamic tolerance is well established, does one still have evidence of hemodilution? There must still be vascular effects. Exercise testing tells us about tolerance, but there must still be something going on at the vascular level. Perhaps a minor nitrate effect on coronary vessels may be adequate to prevent ischemia. What about the effects on platelets? Platelet effects may persist after the development of nitrate tolerance. We talked about fibrinolytic activity of nitrates that may lead to the production of tissue plasminogen activator locally. So there are many factors that may provide potential explanations for that finding, even though we know that these patients are tolerant, as assessedby hemodynamic parameters. Dr. Richard Gorlin (New York, New York): Dr. Parker, are there differential effects that we need to look at with respect to time of dose and the vascular effect? The differences among veins, small arteries, and large arteries may explain some of these differences that are seen. Dr. Parker: I think there may be differences in the rate of development and extent of tolerance in the venous and arterial circulation. The effect of nitrates on small vessels may be different from that on large vessels. Dr. Jay Cohn knows a lot about the nitrate effects on blood vessels. Would you like to comment on that, Dr. Cohn? Dr. Jay N. Cohn (Mhmeapoiis, Mhmesota): It is the usual problem of the various sites of action of nitrates, all the way from dilation of the arteriole, to increased compliance of the larger arteries, to venous smooth muscle, to a myocyte growthinhibiting effect. I do not think that we fully
understand the relative influence of tolerance on these various sites of action. Most of the tolerance data have been concerned with hemodynamic tolerance, which mainly involves either arteriolar or perhaps venous effects, and not at some of the other sites of action that may be important. Obviously, the effect in angina is largely at the level of the conductance coronary arteries and at the site of stenosis, especially in unstable angina. We have very little data on what happens to coronary arteries when they are exposed to the repeated or prolonged administration of nitrates. Some studies are looking at angiographic coronary artery caliber, but I do not think these studies have been definitive enough to tell us that the coronary artery ceases to dilate in response to the drug. From our data, I believe very strongly that nitrate tolerance is not an all-or-nothing phenomenon in heart failure and that nitrates maintain efficacy. Dr. Nevllle Btttar (Mad&m, Wisconsin): I would like to return to the clinical use of these agents. Should we really be satisfied with intermittent therapy? Is it really safe to use nitrates as monotherapy in a patient with coronary artery disease? Dr. Parker: I think it depends on the clinical setting. If I have a patient who has angina predictably during the day while engaged in activities, has angina occasionally with emotional stress, does not have nocturnal angina, and has good exercise tolerance, I think it is quite appropriate to treat that patient during the active part of the day and to accept the fact that you are not providing a nitrate effect for several hours. If, however, a patient has unpredictable angina with episodes at night and has low exercise tolerance, and the patient may have significant “silent” ischemia, then perhaps monotherapy would be inappropriate. That patient should probably be given another agent, perhaps a l3 blocker, with possibly the addition of nitrates, if necessary, during the day. Dr. John D. Rutherford (Boston, Massachusetts): I have a practical question regarding patients with chronic stable angina who are receiving long-acting nitrates. I have tried to change the dosing schedule in our hospital to achieve a lohour nitrate-free interval. I would give a dose in the morning, a dose around noon, and the last dose at 4 P.M. How would you advise us to handle this situation from the point of view of writing orders and achieving what we want to achieve by delivering the drug to the patients? Dr. Parker: Clearly, the nurses are resistant, and the house staff are surreptitiously trying to get A SYMPOSIUM: MANAGING MYOCARDIAL ISCHEMIA
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around it. In fact, when we started doing this, the house staff, often not recognizing the problem of cross-tolerance, would give the oral nitrate three times a day and then give patients a patch at night. It is basically a problem of education. In most of the letters that I send out to referring physicians, I include a paragraph that indicates why I have changed the patient’s dosing, and it has gradually worked. Dr. John D. Parker (Toronto, Canada): I would like to make a comment regarding some of the issues raised by Dr. Cohn and others. I think we need a new nomenclature for the problem of nitrate tolerance becauseit is clear that, in obstructive coronary artery disease and stable angina, nitrates lose their effect with continuous dosing. However, in that setting, sublingual nitroglycerin exerts its usual beneficial effects. Thus, if you look at it from that perspective, those patients are clearly not tolerant. It really depends on the endpoint that you are using. Although treadmill walking time to angina represents a means to define a dose-response relation, it appears that often there is a shift in that relation. It is a very confusing issue of exogenous sulfhydryl donation. We have begun to recognize the distinction between the exaggeration of nitrate effects and the prevention of tolerance. In my opinion, the whole matter represents merely a shift in the doseresponse relation. In one case, you have not had the dose before, and in another case you have. Several investigators have suggestedimproving our nomenclature in this field. Dr. Thomas W. Smith (Boston, Massachu-
function would show very different responses. In our laboratory, for example, when we infuse nitrates into patients with heart failure, they show no sympathoexcitatory response, as reflected by direct intraneural recordings, and they do not demonstrate an increase in plasma norepinephrine levels. Yet, their clinical responses are very similar to those found in subjects with normal cardiac function. Therefore, I think that the role of neurohormonal mechanisms in the development of tolerance is an interesting concept, but I wonder how important it is, particularly in view of the fact that tolerance occurs in patients in whom the mechanisms that regulate the neurohormonal excitatory state do not work. Dr. Parker: You are quite right that there are differences between patients with normal and abnormal left ventricular function. I would suggest, however, that the majority of patients with angina probably would respond much like normal subjects in terms of the neurohormonal response, since they do not have heart failure and have relatively normal left ventricular function. Dr. Cohn: In regard to the nomenclature, the one issue that we have not clearly dealt with is whether there is a difference between nitrate tolerance and rebound. This is a very serious issue because rebound occurs when nitrates are withdrawn. This rebound probably reflects activation of some vasoactivesystem.I think that such a system, incidentally, is at the level of the vascular smooth muscle and not at the neurohormonal level. Is that really what we are seeing with tolerance, or are tolerance and rebound two independent processes? Dr. Smith: I would surmise that it is at least in part a dose-response shift. Dr. Cohn: I think that rebound is more than a dose-response shift. I believe that rebound is created by some other system that has been activated during nitrate therapy.
setts): In the nitrate literature, it is typically very difficult to know whether there has been a change in efficacy or just a shift in the dose-response curve. The latter is easily dealt with, whereas the former obviously is not. Dr. Marc D. l’hames (Cleveland, Ohlo): I think it is important to recognize, Dr. Parker, that the study you described of the neurohormonal response to nitrate administration was done in normal subjects with normal cardiac function. It is REFERENCE L Bassan MM. The daylong pattern of the antianginal effect of long-term almost certain that patients with congestive heart three times daily administered isosorbide din&rate. JAm CoU Car&Z 1990,16: failure and moderate left ventricular systolic dys- 936-940.
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