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Nitrate tolerance
Nitrate Tolerance JOHN 0. PARKER, MD
Nitrate tolerance may be defined as that condition in which increasing nitrate doses are required to induce a given hemodynamic or antianginal effect. Tolerance may be due to changes in pharmacokinetics or to alterations in the property of target tissues, making them less sensitive to the nitrate effect. The question of nitrate tolerance has been addressed using 4times-a-day therapy with oral isosorbide dinitrate, daily therapy with long-acting isosorbide dinitrate ointment and once-a-day therapy with nitroglycerin patches. Each of these treatment modalities is associated with initial beneficial effects, but during sustained therapy, there is marked attenuation of the effect both in magnitude and duration. Thus the concept that stable nitroglycerin blood levels over 24 hours are desirable appears to be incorrect. Preliminary hemodynamic studies suggest that short periods of nitrate withdrawal restore the hemodynamic effect of the nitrates, and it is postulated that intermittent nitrate therapy may be desirable in the management of angi-
na. Transmucosal nitroglycerin administration for a 15hour period with a O-hour washout period was recently undertaken. The results demonstrated that this method of nitrate administration is not associated with development of tolerance to its antianginal effects. Large doses of transdermal nitroglycerin, varying from 45 to 100 mg during short-term studies, have been shown to result in only minimal increases in exercise tolerance at 24 hours. These findings, plus evidence that with smaller doses tolerance occurs after only 1 week of once-a-day therapy,. challenge the concept that larger nitroglycerin dosages, administered once a day by transdermal patches, could be effective throughout a 24hour period in patients with angina pectoris. The current information suggests that it would be necessary to apply larger doses, but to remove them after a period of 12 to 14 hours and allow a washout period to prevent tolerance. (Am J Cardiol 1985;58:281-3 1I)
Nitrate tolerance may be defined as that condition in which increasing nitrate doses are required to induce a given hemodynamic or antianginal effect. Tolerance may be due to changes in pharmacokinetics or to alterations in the property of target tissues, making them less sensitive to the nitrate effects. There is substantial evidence of the development of tolerance to the organic nitrates. This has been demonstrated in munitions workers,l patients with angina pectoris2T3and patients with left ventricular dysfunction.4 The fall in systolic blood pressure after the administration of nitrates has been shown to be markedly attenuated during sustained therapy in animals,5 patients with angina3 and patients with heart failure.4 The effect of these agents on left ventricular filling pressures in cardiac
failure persists during sustained therapy, but the magnitude of response is diminished.4l6 There has been substantial controversy as to the relevance of hemodynamic tolerance to the antianginal effects of the organic nitrates. Clinical studies have reported prolongation of exercise times for periods of several hours after oral isosorbide dinitrate (ISDN) during sustained therapy.7v8 Our studies have repeatedly shown that during 4-times-a-day oral therapy with ISDN, the antianginal effects persist for only 1 to 2 hours, rather than the 8 hours seen during acute dosing.273rg The basis for these conflicting observations is not clear but may be related to study design. Tolerance to lsosorbide Dinitrate Twelve male patients with chronic stable angina entered a placebo-controlled, double-blind study in which the hemodynamic and antianginal effects of ISDN were studied during short- and long-term therap~.~ During the short-term phase, each patient’was
From the Division of Cardiology, Department of Medicine, Queen’s University, Kingston, Qntario, Canada. Address for reprints: John 0. Parker, MD, Division of Cardiology, Departbent of Medicine, Queen’s University, Kingston, Ontario, Canada K7L 3N6.
281
studied twice a week with at least 2 days separating study days. Following preliminary treadmill exercise testing, patients were given identical-appearing tablets that contained either placebo or ISDN in doses of l&30,60 or 120 mg. Each patient received placebo on 2 occasions. Investigations were carried out in the morning; patients were in the fasting state and heart rate and blood pressure were recorded in the supine and standing positions. Patients then performed treadmill testing, and the times to the onset of angina and development of moderate angina were recorded. Immediately after this control test, the scheduled medication was administered, and resting hemodynamic indexes were measured and’treadmill exercise was performed after 1, 2, 4, 6 and 8 hours. All 12 patients received 15,30 and 60 mg of ISDN, but only 7 received the 120-mg dose in this short-term phase, as headache or hypotension developed with 60 mg in 5 patients, ‘After completion of the short-term phase, patients were placed on placebo tablets 4 times a day for 2 weeks. At the end of this period, hemodynamic and treadmill exercise testing were carried out before and 8 hours after the final morning dose of placebo. In consecutive weeks, patients received l&30,60 and 120 mg of active ISDN 4 times a day (at 8 AM and 12,4 and 8 PM). At the end of each of these treatment periods, the patients came to the laboratory without taking the morning medications. Treadmill exercise testing was performed, the scheduled dose of ISDN administered and then hemodynamic and treadmill exercise testing performed over an &hour period. During short-term therapy with each dose of ISDN, systolic blood pressure dropped at 1 hour and remained below placebo values for the 8-hour observation period. There was an apparent dose-response relation with greater decreases in systolic blood pressure with the higher doses. This hypotension was accompanied by reflex increases in heart rate. During longterm therapy, each dose of ISDN produced a reduction in systolic blood pressure at 1,2 and 4 hours, but not at 6 or 8 hours. There was no apparent dose-response relation. During the short-term study, significant prolongation of treadmill exercise time to the onset of angina and development of moderate angina was seen with each dose of ISDN. This effect, which was greater with the larger doses, was apparent over the entire 8-hour observation period. During long-term, C-times-a-day therapy, exercise times to the onset of angina and development of moderate angina were prolonged for only 2 hours after each dose, and thereafter, there was no difference compared with placebo. The magnitude of the improvement seen at 2 hours was less pronounced than that seen during short-term therapy. The attenuated hypotensive and antianginal effects occurred despite the presence of significantly higher plasma ISDN concentrations during the long-term compared with the short-term study. Since this initial observation, we have completed further studies that have confirmed the development
of tolerance: treadmill exercise time is prolonged for 2 hours after a given dose, but no effect is seen thereafter.39g Tolerance to Transdermal lsosorbide Dinitrate In a recent study, we documented the development of tolerance to other modes of ISDN administration.10 Twelve patients were studied after the single application of 100 mg of ISDN ointment spread over a 200 cm2 area. This preparation was formulated to provide an effect over a 24-hour period. This investigation showed that treadmill walking time was prolonged for 8 hours after a single application, but there was no effect at 24 hours. When similar doses were applied once a day for a period of 7 to 10 days, treadmill walking time over the El-hour period was identical to that seen with placebo ointment. This was further confirmation of the rapid development of tolerance during long-term therapy. When sublingual nitroglycerin (NTG) was administered, a normal hypotensive response was seen and there was a marked improvement in treadmill walking time. Tolerance to Transdermal Nitroglycerin NTG ointment has been used for several years for the management of patients with anginall and congestive heart failure.12 Studies have shown prolongation of treadmill walking time for periods of 3 to 7 hour&i3 with this product, but little information is available regarding long-term therapy. Reichek et alli studied a small subgroup of patients after several months of 3times-a-day therapy with NTG ointment and found no attenuation of the antianginal effects. There are, however, no well-controlled studies that have assessed the antianginal effect of NTG ointment during longterm therapy. NTG patches have been available for approximately 3 years in the United States and they have received widespread clinical acceptance. The patches are designed to provide a steady infusion of NTG and to lead to stable plasma concentrations over the 24-hour dosing interval. The early studies claimed that patches delivering 5 mg over 24 hours induced plasma NTG concentrations of approximately 1 ng/ml.14 Subsequent investigations have not confirmed this; generally, the patches produce much lower plasma 1evels.i” Clinical studies have shown that during short-term therapy with NTG patches, exercise tolerance is prolonged for periods ranging from 4 to 8 hours, but with the usual doses used, there have been no reports of prolongation for longer periods throughout the 24 hours.i5J6 In a group of 6 patients who received 45-mg patches, we did show a 24-hour effect during shortterm therapy (Fig. l), but no data are available regarding long-term therapy. l5 In an uncontrolled study, we observed 4 patients before and after applications of 50- to lOO-mg NTG patches and found effects at 12 and 24 hours in 3 patients. We have demonstrated that during long-term therapy there is attenuation of the antianginal effects with
301
A SYMPOSIUM:
TRANSDERMAL
NiTROGLYCERIN-MAXIMIZING
THERAPEUTIC
the currently available doses of transdermal NTG. Thus, after 7 to 10 days of once-a-day therapy with NTG patches that deliver 15 mg/day, treadmill walking time throughout the testing period was similar to that seen with placebo.15 It would appear from the data from oral ISDN, transdermal ISDN and transdermal NTG studies that long-term therapy with each of these nitrate preparations is associated with .diminution of the hemodynamic and antianginal effects. The complete lack of efficacy of transdermal ISDN and transdermal NTG during long-term therapy suggests that the concept of providing steady-state plasma levels for continuous antianginal protection is incorrect, Rate of Tolerance Development The studies just outlined have demonstrated that tolerance to the antianginal effects of the nitrates occurs within 7 to 10 days of sustained therapy. There is little information regarding the minimal period of time required for such tolerance to develop in man.i7 We used a challenge with 5 mg of sublmgual ISDN to assess nitrate responsiveness (Fig. 2). On day 1, the effect of sublingual ISDN (5 mg) on heart rate and systolic blood pressure was assessedover a 3-hour period. Patients then received 15 mg of ISDN every 6 hours for 48 hours. On day 2, after only 3 tablets of ISDN, the hypotensive effect of sublingual ISDN was attenuated. The reduction in systolic blood pressure was approximately 50% of that present during the control study day. A similar pattern was seen on the third day, 48 hours after the institution of oral ISDN therapy. Patients were then placed on oral ISDN placebo, and on day 4, when they had received only 3 placebo tablets, the blood pressure response to sublingual ISDN was similar to the control values. The response persisted on day 5. This study demonstrated that within less than 24 hours there was 0 30 cm*
EFhCACY
evidence of hemodynamic tolerance, and that within less than 24 hours of withdrawal of oral ISDN the hemodynamic response to the ISDN challenge was normal. Is Intermittent Nitrate Therapy Less Likely to Be Assoiziated with Nitiate Tolerance? As demonstrated, the delivery systems designed to produce steady-state nitrate levels are associated with complete loss of antianginal efficacy in a short period of time. When oral medications are given 4 times a day, the antianginal effect is diminished but is still evident. It has been suggested that a period of drug washout might prevent the development of tolerance. We assessedthis by comparing the antianginal effects of oral ISDN administered 4 times a day with transmucosal NTG administered 3 times a day, which provided a 9hour washout period overnight9 This study confirmed the development of toierance during sustained, 4times-a-day therapy with ISDN. This study showed that treadmill walking time was prolonged 1 hour after a given oral ISDN dose, but no subsequent effect was seen, On the other hand, when buccal NTG was given 3 times a day with a g-hour washout period, treadmill exercise time was prolonged for a period of 5 hours after a single dose. The response during therapy with transmucosal NTG was similar during the short- and long-term phases of this study. Recent studies from Germany suggest that single daily doses of sustainedrelease oral ISDN are not associated with tolerance, whereas more frequent dosing is associated with marked diminution of the antianginal effects.18 At the present time, it appears desirable to prescribe oral nitrates on a 3-times-a-day basis, with no medication after the supper dose. With transdermal preparations, one could postulate that it would be best to remove the patches after 12 to 16 hours of application to allow overnight washout.
140-
A6Ocm*
x 90 cm* 0 Placebo T SEM
120 -
A0A 100 --:
A *
%
Yl
80 -
0
2
4
-,
24
TIME (hours) FIGURE 1. Exercise tolerance with transdermal nitroglycerin (acute). Reproduced with permission from Am J CardioLi5
therapy
m W A -A -5
0
60
120
DAY 1 DAY 3 DAY 5 180
TIME (min) FIGURE 2. Hemodynamic response to sublingual isosorbide dinitrate challenge. Reproduced with permission from Circulation.17
3ecember
In summary, studies have clearly documented the organic nitrates to be potent vasodilators and to induce major hemodynamic and antianginal effects. During sustained therapy with oral ISDN, transderma1 ISDN and transdermal NTG, the hemodynamic and antianginal effects are attenuated. Nitrate tolerance has been shown to develop promptly but can be reversed during short periods of nitrate withdrawal. Intermittent low-dose nitrate therapy is suggested to produce prolonged clinical effects without development of clinically relevant tolerance to the hemodynamic and antianginal effects. References 1. Elbright GE. The effects of nitroglycerin on those engaged in its manufacture. JAMA 1914;62:201-202. 2. Thadani U, Fung H-L, Darke AC, Parker JO. Oral isosorbide dinitrate in angina pectoris. Comparison of duration of action and dose response F;;!ion during acute and sustained therapy. Am J Cardiol 1982;49:41 l3. Dalal JJ, Yao L, Parker JO. Nitrate tolerance: influence of isosorbide dinitrate on the hemodynamic and antianginal effects of nitroglycerin. JACC 1983;2:115-120. 4. Leier CV, Huss P, Magorlin RD, Unverferth DV. Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure. Circulation 1983; 67~817-822. 5. Bogaerf MG, Deschaepdryer AF. Tolerance towards glyceryl trinitrate (Trinitrin) in dogs. Arch Int Pharmacodyn Ther 1968;171:221-224.
27, 1985
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 56
311
6. Franciosa JA, Cohn JN. Sustained hemodynamic effects without toierante during long term isosorbide dinitrate treatment of chronic left ventricular failure. Am J Cardiol 1980;45:648-654. 7. Danahy DT, Burwel DT, Aronow WS, Prakash Ft. Sustained hemodynamic and antianainal effects of hiqh oral dose isosorbide dinitrate. Circulation 1977;55:38f-387. 8. Lee G, Mason DT, Amsterdam EA, Miller RR, Demaria AM. Antianginal efficacv of oral theraov with isosorbide dinitrate caosules: orolonaed benefit-shown by exe&e testinq in oatients with ische’mic heat? disease. Chest 1978;73:827-332. - ’ 9. Parker JO, VanKoughnett KA, Farrell B. Nitrate tolerance: comparison of buccal nitroglycerin and oral isosorbide dinitrate. Am J Cardiol, in press. 10. Parker JO, VanKoughnett KA, Fung H-L. Transdermal isosorbide dinitrate in angina pectoris: effect of acute and sustained therapy. Am J Cardiol 1984;54:8-13. 11. Reichek N, Goldstein RE, Redwood OR, Epstein SE. Sustained effects of nitroglycerin ointment in patients with angina pectoris. Circulation 1974:50:348-352. 12. Armstrong PW, Armstrong JA, Marks GS. Pharmacokinetic hemodynamic studies-of nitroglyceriri ointment in congestive cardiac failure. Am J Cardiol 1980:46:670-676, 13. Kala R, H&men P, Gordin A, Sundberg S, Auvinen J, Halonen PI. Nitroglycerin ointment effective for seven hours in severe angina pectoris. Acta Med Stand 1983:213:165-170. 14. Golfer H, Stetson P, Lucchesi BR, Wagner J, Pitt 8. The nitroglycerin polymer gel matrix system: a new method for administering nitroglycerin evaluated with plasma nitroglycerin levels. J Cardiovasc Pharmacol 1982;4521-525. 15. Parker JO, Fung H-L. Transdermal nitroglycerin in angina pectoris. Am J Cardiol 1984;54:471-476. 16. Reichek N. Priest C. Zimrin 0. Chandler T. Sutton MSJ. Antianainal effects of &roglycerih patches. ‘Am J Cardiol’1984;54:1-7. 17. Parker JO, Fung H-L, Ruggirello D, Stone JA. Tolerance to isosorbide dinitrate. Rate of develooment and reversal. Circulation 1983:68:1074, 1080. 16. Silber S, Krause K, Theisen K. Nitrate tolerance: dependence on dosage intervals (abstr). Circulation 1984;7O:suppl 1:189.
Nitrate tolerance may be defined as that condition in which increasing nitrate doses are required to induce a given hemodynamic or antianginal effect. Tolerance may be due to changes in pharmacokinetics or to alterations in the property of target tissues, making them less sensitive to the nitrate effect. The question of nitrate tolerance has been addressed using 4times-a-day therapy with oral isosorbide dinitrate, daily therapy with long-acting isosorbide dinitrate ointment and once-a-day therapy with nitroglycerin patches. Each of these treatment modalities is associated with initial beneficial effects, but during sustained therapy, there is marked attenuation of the effect both in magnitude and duration. Thus the concept that stable nitroglycerin blood levels over 24 hours are desirable appears to be incorrect. Preliminary hemodynamic studies suggest that short periods of nitrate withdrawal restore the hemodynamic effect of the nitrates, and it is postulated that intermittent nitrate therapy may be desirable in the management of angi-
na. Transmucosal nitroglycerin administration for a 15hour period with a O-hour washout period was recently undertaken. The results demonstrated that this method of nitrate administration is not associated with development of tolerance to its antianginal effects. Large doses of transdermal nitroglycerin, varying from 45 to 100 mg during short-term studies, have been shown to result in only minimal increases in exercise tolerance at 24 hours. These findings, plus evidence that with smaller doses tolerance occurs after only 1 week of once-a-day therapy,. challenge the concept that larger nitroglycerin dosages, administered once a day by transdermal patches, could be effective throughout a 24hour period in patients with angina pectoris. The current information suggests that it would be necessary to apply larger doses, but to remove them after a period of 12 to 14 hours and allow a washout period to prevent tolerance. (Am J Cardiol 1985;58:281-3 1I)
Nitrate tolerance may be defined as that condition in which increasing nitrate doses are required to induce a given hemodynamic or antianginal effect. Tolerance may be due to changes in pharmacokinetics or to alterations in the property of target tissues, making them less sensitive to the nitrate effects. There is substantial evidence of the development of tolerance to the organic nitrates. This has been demonstrated in munitions workers,l patients with angina pectoris2T3and patients with left ventricular dysfunction.4 The fall in systolic blood pressure after the administration of nitrates has been shown to be markedly attenuated during sustained therapy in animals,5 patients with angina3 and patients with heart failure.4 The effect of these agents on left ventricular filling pressures in cardiac
failure persists during sustained therapy, but the magnitude of response is diminished.4l6 There has been substantial controversy as to the relevance of hemodynamic tolerance to the antianginal effects of the organic nitrates. Clinical studies have reported prolongation of exercise times for periods of several hours after oral isosorbide dinitrate (ISDN) during sustained therapy.7v8 Our studies have repeatedly shown that during 4-times-a-day oral therapy with ISDN, the antianginal effects persist for only 1 to 2 hours, rather than the 8 hours seen during acute dosing.273rg The basis for these conflicting observations is not clear but may be related to study design. Tolerance to lsosorbide Dinitrate Twelve male patients with chronic stable angina entered a placebo-controlled, double-blind study in which the hemodynamic and antianginal effects of ISDN were studied during short- and long-term therap~.~ During the short-term phase, each patient’was
From the Division of Cardiology, Department of Medicine, Queen’s University, Kingston, Qntario, Canada. Address for reprints: John 0. Parker, MD, Division of Cardiology, Departbent of Medicine, Queen’s University, Kingston, Ontario, Canada K7L 3N6.
281
studied twice a week with at least 2 days separating study days. Following preliminary treadmill exercise testing, patients were given identical-appearing tablets that contained either placebo or ISDN in doses of l&30,60 or 120 mg. Each patient received placebo on 2 occasions. Investigations were carried out in the morning; patients were in the fasting state and heart rate and blood pressure were recorded in the supine and standing positions. Patients then performed treadmill testing, and the times to the onset of angina and development of moderate angina were recorded. Immediately after this control test, the scheduled medication was administered, and resting hemodynamic indexes were measured and’treadmill exercise was performed after 1, 2, 4, 6 and 8 hours. All 12 patients received 15,30 and 60 mg of ISDN, but only 7 received the 120-mg dose in this short-term phase, as headache or hypotension developed with 60 mg in 5 patients, ‘After completion of the short-term phase, patients were placed on placebo tablets 4 times a day for 2 weeks. At the end of this period, hemodynamic and treadmill exercise testing were carried out before and 8 hours after the final morning dose of placebo. In consecutive weeks, patients received l&30,60 and 120 mg of active ISDN 4 times a day (at 8 AM and 12,4 and 8 PM). At the end of each of these treatment periods, the patients came to the laboratory without taking the morning medications. Treadmill exercise testing was performed, the scheduled dose of ISDN administered and then hemodynamic and treadmill exercise testing performed over an &hour period. During short-term therapy with each dose of ISDN, systolic blood pressure dropped at 1 hour and remained below placebo values for the 8-hour observation period. There was an apparent dose-response relation with greater decreases in systolic blood pressure with the higher doses. This hypotension was accompanied by reflex increases in heart rate. During longterm therapy, each dose of ISDN produced a reduction in systolic blood pressure at 1,2 and 4 hours, but not at 6 or 8 hours. There was no apparent dose-response relation. During the short-term study, significant prolongation of treadmill exercise time to the onset of angina and development of moderate angina was seen with each dose of ISDN. This effect, which was greater with the larger doses, was apparent over the entire 8-hour observation period. During long-term, C-times-a-day therapy, exercise times to the onset of angina and development of moderate angina were prolonged for only 2 hours after each dose, and thereafter, there was no difference compared with placebo. The magnitude of the improvement seen at 2 hours was less pronounced than that seen during short-term therapy. The attenuated hypotensive and antianginal effects occurred despite the presence of significantly higher plasma ISDN concentrations during the long-term compared with the short-term study. Since this initial observation, we have completed further studies that have confirmed the development
of tolerance: treadmill exercise time is prolonged for 2 hours after a given dose, but no effect is seen thereafter.39g Tolerance to Transdermal lsosorbide Dinitrate In a recent study, we documented the development of tolerance to other modes of ISDN administration.10 Twelve patients were studied after the single application of 100 mg of ISDN ointment spread over a 200 cm2 area. This preparation was formulated to provide an effect over a 24-hour period. This investigation showed that treadmill walking time was prolonged for 8 hours after a single application, but there was no effect at 24 hours. When similar doses were applied once a day for a period of 7 to 10 days, treadmill walking time over the El-hour period was identical to that seen with placebo ointment. This was further confirmation of the rapid development of tolerance during long-term therapy. When sublingual nitroglycerin (NTG) was administered, a normal hypotensive response was seen and there was a marked improvement in treadmill walking time. Tolerance to Transdermal Nitroglycerin NTG ointment has been used for several years for the management of patients with anginall and congestive heart failure.12 Studies have shown prolongation of treadmill walking time for periods of 3 to 7 hour&i3 with this product, but little information is available regarding long-term therapy. Reichek et alli studied a small subgroup of patients after several months of 3times-a-day therapy with NTG ointment and found no attenuation of the antianginal effects. There are, however, no well-controlled studies that have assessed the antianginal effect of NTG ointment during longterm therapy. NTG patches have been available for approximately 3 years in the United States and they have received widespread clinical acceptance. The patches are designed to provide a steady infusion of NTG and to lead to stable plasma concentrations over the 24-hour dosing interval. The early studies claimed that patches delivering 5 mg over 24 hours induced plasma NTG concentrations of approximately 1 ng/ml.14 Subsequent investigations have not confirmed this; generally, the patches produce much lower plasma 1evels.i” Clinical studies have shown that during short-term therapy with NTG patches, exercise tolerance is prolonged for periods ranging from 4 to 8 hours, but with the usual doses used, there have been no reports of prolongation for longer periods throughout the 24 hours.i5J6 In a group of 6 patients who received 45-mg patches, we did show a 24-hour effect during shortterm therapy (Fig. l), but no data are available regarding long-term therapy. l5 In an uncontrolled study, we observed 4 patients before and after applications of 50- to lOO-mg NTG patches and found effects at 12 and 24 hours in 3 patients. We have demonstrated that during long-term therapy there is attenuation of the antianginal effects with
301
A SYMPOSIUM:
TRANSDERMAL
NiTROGLYCERIN-MAXIMIZING
THERAPEUTIC
the currently available doses of transdermal NTG. Thus, after 7 to 10 days of once-a-day therapy with NTG patches that deliver 15 mg/day, treadmill walking time throughout the testing period was similar to that seen with placebo.15 It would appear from the data from oral ISDN, transdermal ISDN and transdermal NTG studies that long-term therapy with each of these nitrate preparations is associated with .diminution of the hemodynamic and antianginal effects. The complete lack of efficacy of transdermal ISDN and transdermal NTG during long-term therapy suggests that the concept of providing steady-state plasma levels for continuous antianginal protection is incorrect, Rate of Tolerance Development The studies just outlined have demonstrated that tolerance to the antianginal effects of the nitrates occurs within 7 to 10 days of sustained therapy. There is little information regarding the minimal period of time required for such tolerance to develop in man.i7 We used a challenge with 5 mg of sublmgual ISDN to assess nitrate responsiveness (Fig. 2). On day 1, the effect of sublingual ISDN (5 mg) on heart rate and systolic blood pressure was assessedover a 3-hour period. Patients then received 15 mg of ISDN every 6 hours for 48 hours. On day 2, after only 3 tablets of ISDN, the hypotensive effect of sublingual ISDN was attenuated. The reduction in systolic blood pressure was approximately 50% of that present during the control study day. A similar pattern was seen on the third day, 48 hours after the institution of oral ISDN therapy. Patients were then placed on oral ISDN placebo, and on day 4, when they had received only 3 placebo tablets, the blood pressure response to sublingual ISDN was similar to the control values. The response persisted on day 5. This study demonstrated that within less than 24 hours there was 0 30 cm*
EFhCACY
evidence of hemodynamic tolerance, and that within less than 24 hours of withdrawal of oral ISDN the hemodynamic response to the ISDN challenge was normal. Is Intermittent Nitrate Therapy Less Likely to Be Assoiziated with Nitiate Tolerance? As demonstrated, the delivery systems designed to produce steady-state nitrate levels are associated with complete loss of antianginal efficacy in a short period of time. When oral medications are given 4 times a day, the antianginal effect is diminished but is still evident. It has been suggested that a period of drug washout might prevent the development of tolerance. We assessedthis by comparing the antianginal effects of oral ISDN administered 4 times a day with transmucosal NTG administered 3 times a day, which provided a 9hour washout period overnight9 This study confirmed the development of toierance during sustained, 4times-a-day therapy with ISDN. This study showed that treadmill walking time was prolonged 1 hour after a given oral ISDN dose, but no subsequent effect was seen, On the other hand, when buccal NTG was given 3 times a day with a g-hour washout period, treadmill exercise time was prolonged for a period of 5 hours after a single dose. The response during therapy with transmucosal NTG was similar during the short- and long-term phases of this study. Recent studies from Germany suggest that single daily doses of sustainedrelease oral ISDN are not associated with tolerance, whereas more frequent dosing is associated with marked diminution of the antianginal effects.18 At the present time, it appears desirable to prescribe oral nitrates on a 3-times-a-day basis, with no medication after the supper dose. With transdermal preparations, one could postulate that it would be best to remove the patches after 12 to 16 hours of application to allow overnight washout.
140-
A6Ocm*
x 90 cm* 0 Placebo T SEM
120 -
A0A 100 --:
A *
%
Yl
80 -
0
2
4
-,
24
TIME (hours) FIGURE 1. Exercise tolerance with transdermal nitroglycerin (acute). Reproduced with permission from Am J CardioLi5
therapy
m W A -A -5
0
60
120
DAY 1 DAY 3 DAY 5 180
TIME (min) FIGURE 2. Hemodynamic response to sublingual isosorbide dinitrate challenge. Reproduced with permission from Circulation.17
3ecember
In summary, studies have clearly documented the organic nitrates to be potent vasodilators and to induce major hemodynamic and antianginal effects. During sustained therapy with oral ISDN, transderma1 ISDN and transdermal NTG, the hemodynamic and antianginal effects are attenuated. Nitrate tolerance has been shown to develop promptly but can be reversed during short periods of nitrate withdrawal. Intermittent low-dose nitrate therapy is suggested to produce prolonged clinical effects without development of clinically relevant tolerance to the hemodynamic and antianginal effects. References 1. Elbright GE. The effects of nitroglycerin on those engaged in its manufacture. JAMA 1914;62:201-202. 2. Thadani U, Fung H-L, Darke AC, Parker JO. Oral isosorbide dinitrate in angina pectoris. Comparison of duration of action and dose response F;;!ion during acute and sustained therapy. Am J Cardiol 1982;49:41 l3. Dalal JJ, Yao L, Parker JO. Nitrate tolerance: influence of isosorbide dinitrate on the hemodynamic and antianginal effects of nitroglycerin. JACC 1983;2:115-120. 4. Leier CV, Huss P, Magorlin RD, Unverferth DV. Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure. Circulation 1983; 67~817-822. 5. Bogaerf MG, Deschaepdryer AF. Tolerance towards glyceryl trinitrate (Trinitrin) in dogs. Arch Int Pharmacodyn Ther 1968;171:221-224.
27, 1985
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 56
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6. Franciosa JA, Cohn JN. Sustained hemodynamic effects without toierante during long term isosorbide dinitrate treatment of chronic left ventricular failure. Am J Cardiol 1980;45:648-654. 7. Danahy DT, Burwel DT, Aronow WS, Prakash Ft. Sustained hemodynamic and antianainal effects of hiqh oral dose isosorbide dinitrate. Circulation 1977;55:38f-387. 8. Lee G, Mason DT, Amsterdam EA, Miller RR, Demaria AM. Antianginal efficacv of oral theraov with isosorbide dinitrate caosules: orolonaed benefit-shown by exe&e testinq in oatients with ische’mic heat? disease. Chest 1978;73:827-332. - ’ 9. Parker JO, VanKoughnett KA, Farrell B. Nitrate tolerance: comparison of buccal nitroglycerin and oral isosorbide dinitrate. Am J Cardiol, in press. 10. Parker JO, VanKoughnett KA, Fung H-L. Transdermal isosorbide dinitrate in angina pectoris: effect of acute and sustained therapy. Am J Cardiol 1984;54:8-13. 11. Reichek N, Goldstein RE, Redwood OR, Epstein SE. Sustained effects of nitroglycerin ointment in patients with angina pectoris. Circulation 1974:50:348-352. 12. Armstrong PW, Armstrong JA, Marks GS. Pharmacokinetic hemodynamic studies-of nitroglyceriri ointment in congestive cardiac failure. Am J Cardiol 1980:46:670-676, 13. Kala R, H&men P, Gordin A, Sundberg S, Auvinen J, Halonen PI. Nitroglycerin ointment effective for seven hours in severe angina pectoris. Acta Med Stand 1983:213:165-170. 14. Golfer H, Stetson P, Lucchesi BR, Wagner J, Pitt 8. The nitroglycerin polymer gel matrix system: a new method for administering nitroglycerin evaluated with plasma nitroglycerin levels. J Cardiovasc Pharmacol 1982;4521-525. 15. Parker JO, Fung H-L. Transdermal nitroglycerin in angina pectoris. Am J Cardiol 1984;54:471-476. 16. Reichek N. Priest C. Zimrin 0. Chandler T. Sutton MSJ. Antianainal effects of &roglycerih patches. ‘Am J Cardiol’1984;54:1-7. 17. Parker JO, Fung H-L, Ruggirello D, Stone JA. Tolerance to isosorbide dinitrate. Rate of develooment and reversal. Circulation 1983:68:1074, 1080. 16. Silber S, Krause K, Theisen K. Nitrate tolerance: dependence on dosage intervals (abstr). Circulation 1984;7O:suppl 1:189.