Two more Pharmacological Interactions involving Glyceryl Trinitrate Aspirin suppresses its vasodilatory effects . ..

Seven healthy adult volunteers were recently recruited into a study designed to determine if any pharmacological interaction occurs between glyceryl trinitrate [nitroglycerin] and aspirin . On 3 separate occasions , each subject received: glyceryl trinitrate O.Bmg as a sublingual spray (treatment 1); glyceryl trinitrate O.8mg, with aspirin 0.5g administered every 48 hours for 8 days beforehand, the final dose being given 30 hours before the nitrate (treatment 2); and glyceryl trinitrate 0.8mg, with aspirin 1 g given 2 hours prior to the nitrate (treatment 3). Seated heart rate, diastolic arterial pressure, end diastolic diameter and end systolic diameter were recorded 30 min after administration of glyceryl trinitate; plasma levels were monitored, 2,4, 6, 10, 15, 20 and 30 min after glyceryl trinitrate administration .

The mean peak glyceryl trinitrate level was higher after treatment 3 (0.62 ng/ml) than after Treatment 1 (0.37 ng/ml) or treatment 2 (0.39 ng/ml); and the time of the peak occurred earlier in treatment 1 (0.13 hours) than in treatment 2 (0.24 hours) or treatment 3 (0.26 hours), The mean AUC rose from 0.0991 ng/ml· hours after treatment 1 to 0.138 ng/ml • hours and 0.172 ng/ml • hours after treatments 2 and 3, respectively.

Treatment 1 was associated with an increase in heart rate , a reduction in diastolic arterial pressure, end diastolic diameter and end systolic diameter; treatment 3 significantly enhanced all of these parameters. The findings of this investigation suggest a complex pharmacodynamic and pharmacokinetic interaction between glyceryl trinitrate and aspirin, which may be attributable to the inhibitory action of aspirin on the synthesis of prostaglandins, thought to account for glyceryl trinitrate's vasodilatory effect, Rey. E. el al. . European Journal of Clinical Pharmacology 25: 779 (No 6, 1983)

... whereas acetylcysteine potentiates them In vitro research has indicated that glyceryl trinitrate exerts its vasodilatory effect by activating guanylate

cyclase, through a sequence of enzymatic reactions that are modulated by the availability of sulphydryl moieties. Cysteine seems to be effective in enhanging guanylate cyclase activation by glyceryl trinitrate, A study, involving 15 patients undergoing diagnostic cardiac catheterisation and coronary arteriography for assessment of chest pain, has been undertaken to determine whether this is the case in man. After a baseline evaluation , each patient received a glyceryl trinitrate infusion (started at a rate of 1 ~g/min, then increased at 5 min intervals to 50 ~g/min over 30 min). After a further 5 min, 10 patients received an infusion of acetylcysteine 100 mg/kg, over 15 min. After a further 10 min, glyceryl trinitrate infusion was repeated.

Although the acetylcysteine infusion had no significant haemodynamic effect, it was associated with a significant decrease both in the glyceryl trinitrate infusion rate (from 25.8 to 9.3 Jlg/min) needed to produce a 10"10 reduction in mean arterial pressure and in the infusion rate (13.6 to 4.2 Jlg/min) causing a 30"10 decrease in pulmonary capillary wedge pressure, In the 5 patients who did not receive acetylcysteine infusion, no significant alteration in response to glyceryl trinitrate was noted between infusions These results indicate that sulphydryl availability and redox state could determine the human response to glyceryl trinitrate, Horowitz. JD. el al.. Clfculalion 68 1247 (Dec 1983)

14 INPHARMA O) 14 Apr 1984 0156-2703/ 84/ 0414-0014/ 0$01.00/ 0 @ ADIS Press