Pharmacokinetic and pharmacodynamic interactions between diltiazem and quinidine.

OBJECTIVES: To examine the pharmacokinetic and pharmacodynamic interactions between quinidine and diltiazem because both drugs can inhibit drug metabolism. METHODS: Twelve fasting, healthy male volunteers (age, 24 +/- 5 years; weight, 75 +/- 10 kg) received a single oral dose of diltiazem (60 mg) or quinidine (200 mg), alone and on a background of the other drug, in a crossover study. Background treatment consisted of 100 mg quinidine twice a day or 90 mg sustained-release diltiazem twice a day for 2 day before the study day. RESULTS: Pretreatment with diltiazem significantly (p < 0.05) increased the area under the curve of quinidine from 7414 +/- 1965 to 11,213 +/- 2610 ng.hr/ml and increased its terminal elimination half-life (t1/2) from 6.8 +/- 1.1 to 9.3 +/- 1.5 hours. Its oral clearance was decreased from 0.39 +/- 0.1 to 0.25 +/- 0.1 L/hr/kg, whereas the maximal concentration was not significantly affected. Diltiazem disposition was not significantly affected by pretreatment with quinidine. Diltiazem pretreatment increased QTc and PR intervals and decreased heart rate and diastolic blood pressure. No significant pharmacodynamic differences were shown for diltiazem alone versus quinidine pretreatment. CONCLUSION: Diltiazem significantly decreased the clearance and increased the t1/2 of quinidine, but quinidine did not alter the kinetics of diltiazem with the dose used. No significant pharmacodynamic interaction was shown for the combination that would not be predicted from individual drug administration.

Effect of amlodipine, atenolol and their combination on myocardial ischemia during treadmill exercise and ambulatory monitoring. Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS) Investigators.

OBJECTIVES: This study compared the effects of amlodipine, atenolol and their combination on ischemia during treadmill testing and 48-h ambulatory monitoring. BACKGROUND: It is not known whether anti-ischemic drugs exert similar effects on ischemia during ambulatory monitoring and exercise treadmill testing. METHODS: Patients with stable coronary artery disease and ischemia during treadmill testing and ambulatory monitoring were randomized to receive amlodipine (n = 51) or atenolol (n = 49). Each group underwent a counterbalanced, crossover evaluation of single drug and placebo, followed by evaluation of the combination. RESULTS: Amlodipine and the combination prolonged exercise time to 0.1-mV ST segment depression by 29% and 34%, respectively (p < 0.001) versus 3% for atenolol (p = NS). During ambulatory monitoring, the frequency of ischemic episodes decreased by 28% with amlodipine (p = 0.083 [NS]), by 57% with atenolol (p < 0.001) and by 72% with the combination (p < 0.05 vs. both single drugs; p < 0.001 vs. placebo). Suppression of ischemia during exercise testing and ambulatory monitoring was similar in patients with and without exercise-induced angina. Exercise time to angina improved by 29% with amlodipine (p < 0.01), by 16% with atenolol (p < 0.05) and by 39% with the combination (p < 0.005 vs. placebo, atenolol and amlodipine). In patients with angina, total exercise time improved by 16% with amlodipine (p < 0.001), by 4% with atenolol (p = NS) and by 19% with the combination (p < 0.05 vs. placebo and either single drug). In those patients without angina, no therapy significantly improved total exercise time. CONCLUSIONS: Ischemia during treadmill testing was more effectively suppressed by amlodipine, whereas ischemia during ambulatory monitoring was more effectively suppressed by atenolol. The combination was more effective than either single drug in both settings.