Summary
We have studied the effects of intravenous nicorandil, a mixed arterial and venous vasodilator, in 48 healthy volunteers. Nicorandil (20, 28, 39, 54, 74, 103, 144, or 200 μg·kg−1) or placebo were given over 5 min to subjects supine (16 subjects, 2 doses) or sitting (32 subjects, 1 dose) in a single-blind crossover design. Electro-cardiographic intervals, blood pressure, and heart rate were measured before and for 8 h after dosing. Blood and urine safety laboratory studies were also performed before and after dosing.
All intravenous infusions of nicorandil and placebo were well tolerated and there were no clinically important safety concerns. The most frequent adverse event after nicorandil was headache (24 events by 19 subjects), although its occurrence was not strictly dose related. One subject experienced transient symptomatic hypotension (144 μg·kg−1).
Mean plasma nicorandil concentrations were dose-related and fell with a half-life of 0.7 to 1.2 h. Systemic clearance and volume of distribution tended to decrease as dose increased. Sitting subjects showed marginally lower (<20%) systemic clearances and larger values of Cmax and AUC.
Nicorandil produced dose-related reductions in blood pressure, with consistent statistically significant differences from placebo after the 144 and 200 μg·kg−1 doses. The falls in blood pressure were greater for diastolic pressure and in this supine position. At 200 μg·kg−1, the mean falls in systolic/diastolic pressures (mm Hg) during the first hour were 10.9/14.7 supine and 6.1/9.1 sitting; systolic pressure returned to baseline after 8 h and diastolic pressure after 4 h. Heart rate increased transiently (mean peak increase of 17–24 bpm at the end of the 144 and 200 μg·kg−1 infusions). Blood pressure and heart rate changes over time were statistically significantly correlated with plasma nicorandil concentrations. Individual areas under the blood pressure and heart rate change curves likewise correlated with plasma concentration curve areas.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Sakai K, Nakano H, Nagano H, Uchida Y (1983) Nicorandil. In: Scriabine A (ed) New drugs annual: cardiovascular drugs. Raven Press, New York, pp 227–239
Kinoshita M, Sakai K (1990) Pharmacology and therapeutic effects of nicorandil. Cardiovasc Drugs Ther 4: 1075–1088
Belz GG, Matthews JH, Beck A, Wagner G, Schneider B (1985) Hemodynamic effects of nicorandil, isosorbide dinitrate, and dihydralazine in healthy volunteers. J Cardiovasc Pharmacol 7: 1107–1112
Coltart DJ, Signy M (1989) Acute hemodynamic effects of single-dose nicorandil in coronary artery disease. Am J Cardiol 63: 34J-39J
Thormann J, Schlepper M, Kramer W, Gottwik M, Kindler M (1983) Effectiveness of nicorandil (SG-75), a new long-acting drug with nitroglycerin effects, in patients with coronary artery disease: improved left ventricular function and regional wall motion and abolition of pacing-induced angina. J Cardiovasc Pharmacol 5: 371–377
Solal AC, Jaeger P, Bouthier J, Juliar J-M, Dahan M, Gourgon R (1989) Hemodynamic action of nicorandil in chronic congestive heart failure. Am J Cardiol 63: 44J-48J
Tice FD, Binkley PF, Cody RJ, Moeschberger ML, Mohrland JS, Wolf DL, Leier CV (1990) Hemodynamic effects of oral nicorandil in congestive heart failure. Am J Cardiol 65: 1361–1367
Frydman AM, Chapelle P, Diekmann H, Bruno R, Thebault JJ, Bouthier J, Caplain H, Ungethuem W, Gaillard C, Le Liboux A, Renard A, Gaillot J (1989) Pharmacokinetics of nicorandil. Am J Cardiol 63: 25J-33J
Searle SR (1987) Linear models for unbalanced data. Wiley, New York, pp 340–359
Snedecor GW, Cochran WG (1980) Statistical methods, 7th edn. The Iowa State University Press, Ames. pp 89–95, pp 175–178
Middlemiss RR (1946) Differential and integral calculus. McGraw-Hill, New York, pp 340–359
Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn. Dekker, New York, pp 409–417
Belz GG, Matthews J, Heinrich J, Wagner G (1984) Controlled comparison of the pharmacodynamic effects of nicorandil (SG-75) and isosorbide dinitrate in man. Eur J Clin Pharmacol 26: 681–685
Flaherty JT (1982) Intravenous nitroglycerin. Johns Hopkins Med J 151: 36–40
Wilkinson GR (1975) Pharmacokinetics of drug disposition: hemodynamic considerations. Ann Rev Pharmacol 15: 11–27
Modi MW, Hassett JM, Lalka D (1988) Influence of posture on hepatic perfusion and the presystemic biotransformation of propranolol: simulation of the food effect. Clin Pharmacol Ther 44: 268–274
Van Harten J, Van Brummelen P, Doms P, Danhoff M, Blauw G-J, Breimer DD (1989) Variability in the pharmacokinetics of nisoldipine as caused by differences in liver blood flow response. J Clin Pharmacol 29: 714–721
Imhof PR, Sieber A, Hodler J, Muller P, Ott B, Frankhauser P, Chu L-C, Gerardin A (1982) Plasma concentrations and haemodynamic effects of nitroglycerin during and after intravenous infusion in healthy volunteers. Eur J Clin Pharmacol 23: 99–106
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wolf, D.L., Ferry, J.J., Hearron, A.E. et al. The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers. Eur J Clin Pharmacol 44, 27–33 (1993). https://doi.org/10.1007/BF00315276
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00315276