THERAPY AND PREVENTION ANGINA Antianginal effects of intravenous nitroglycerin over 24 hours

To determine the constancy of hemodynamic and antianginal effects of the constant infusion of intravenous nitroglycerin (NTG) and their relationship to infusion rate and plasma NTG concentration, we administered maximal tolerated doses of intravenous NTG (range 10 to 120 ,g/min, mean = 52 + 33 ,ug/min) and placebo to 10 patients with chronic stable angina for 25 hr each in a randomized, double-blind fashion. Sublingual NTG (0.4 mg) was given at 24.5 hr of infusion as a positive control. Bicycle exercise time (NIH protocol), blood pressure, heart rate, exercise ST response, and venous plasma NTG were determined before and at 1, 4, 8, 24, and 24.5 hr. Plasma NTG was linearly related to infusion rate, reached a steady state within 15 min and was unchanged over 24 hr (mean = 5.5 1.2 ng/ml). Mean plasma NTG clearance was 9.3 liters/min. However, during dose titration, patients demonstrated different relationships between plasma NTG and hemodynamic effects, with widely varying slopes and intercepts. Intravenous NTG produced a sustained reduction in blood pressure and a rise in heart rate at rest, and a reduction in blood pressure during submaximal exercise at as late as 24 hr, associated with reduced submaximal ST segment abnormality. In contrast, exercise tolerance to onset of angina showed a marked initial increase on intravenous NTG but fell progressively and did not differ from that with placebo at 24 hr. Increased exercise tolerance was associated with an increase in maximal heart rate and double product (heart rate X blood pressure), suggesting that direct coronary vasodilation and/or reduced left ventricular volume were the principal determinants of increased exercise tolerance. The rates of fall in exercise tolerance over time varied widely among patients. Sublingual NTG produced a marked increase in exercise tolerance after a 24.5 hr placebo infusion, but not after intravenous NTG, despite similar exercise tolerance on intravenous NTG and placebo at 24 hr. The plasma NTG concentrations achieved with intravenous NTG were at least twice those reported for the peak sublingual NTG effect and up to 50 times those reported for 5 mg/24 hr release NTG patches. Thus, constant NTG infusion can result in constant high plasma NTG, but the initial marked increase in exercise tolerance diminishes progressively over 24 hr, as previously observed with NTG patches, consistent with development of tolerance. After prolonged high plasma NTG concentrations, the effect of sublingual NTG on exercise tolerance can be abolished. We conclude that rapid attenuation of antianginal effects during exercise is an inherent result of the continuous administration ofNTG. It remains uncertain whether similar tolerance limits the efficacy of intravenous NTG in patients with cardiac ischemia at rest. Circulation 77, No. 6, 1376-1384, 1988. TRANSDERMAL nitroglycerin patches can provide constant nitroglycerin (NTG) release over 24 hr.'-' Early studies reported sustained antianginal activity of NTG patches.6 However, a number of recent studies From the Noninvasive Laboratory, Cardiovascular Section, Department of Medicine, Hospital of the University of Pennsylvania School of Medicine and the Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo. Supported in part by Public Health Services Research grant RROO040 from the Division of Research Resources, NIH, a Commonwealth of Pennsylvania Health Services Contract, and by grants from Ciba-Geigy, Key Pharmaceuticals, and Searle. Address for correspondence: Nathaniel Reichek, M.D., Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104. Received July 14, 1987; revision accepted March 10, 1988. have shown marked attenuation of NTG patch effect over 24 hr, and little or no effect during long-term administration.7"10 It has been suggested that this attenuation is due to nitrate tolerance.8 1 However, it is also possible that conventional NTG patch doses provide inadequate NTG delivery since reported plasma concentrations of NTG are quite low, averaging 0.1 to 0.15 ng/ml for a device that releases 5 mg NTG over 24 hr. 1-5 In contrast, peak plasma concentrations after sublingual NTG can exceed 3 ng/ml. 12 Thus, it remains uncertain whether assured, constant, high-dose NTG can provide continuous 24 hr benefit in patients with exertional angina due to coronary disease. Given the limitations of transdermal, oral, and sublingual NTG CIRCULATION 1376 by gest on A ril 7, 2017 http://ciajournals.org/ D ow nladed from THERAPY AND PREVENTION-ANGINA delivery, this question might be best answered by intravenous NTG. Furthermore, intravenous NTG itself is an important therapeutic agent, but data with respect to the relationship of infusion rate, plasma concentration, circulatory response, and antianginal effects are limited. Therefore, we performed a double-blind placebo-controlled crossover study of the effects of 24 hr of high-dose intravenous NTG in patients with chronic stable exertional angina. Effects on exercise tolerance were correlated with NTG plasma levels along with resting, submaximal, and maximal hemodynamic effects and ST segment responses to exercise. In addition, responses to sublingual NTG before and after a 24 hr infusion of intravenous NTG and placebo were evaluated.