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The long-term efficacy of once-daily atenolol cardioselective beta-blockade therapy for chronic stable angina pectoris was studied in nine coronary disease patients. After a placebo-controlled single-blind dose-ranging trial with 2-week drug periods of 25, 50, 100, and 200 mg, they continued on 100 or 200 mg daily for 1 year. Treadmill exercise test (ET) were performed at times at peak and trough serum atenolol concentrations and 24-hour ECG ambulatory recordings were obtained after placebo, after 2 weeks of 100 and 200 mg atenolol, and after 2 weeks of 100 and 200 mg atenolol, and after 3, 6, 9, and 12 months of 100 or 200 mg atenolol. During early and chronic atenolol therapy, angina frequency and nitroglycerin consumption were decreased (p less than 0.01 to less than 0.001). Twenty-four hour ECG and ET showed sustained heart rate suppression. Exercise duration until angina onset was prolonged during all periods of atenolol administration. Maximal improvement in exercise tolerance and angina relief was not reached until 3 months of atenolol therapy despite stable serum drug concentrations. During the 14 months fatigue occurred in three patients which was dose-limiting in only one. Thus atenolol 100 or 200 mg given once daily, proved well-tolerated and potent anti-ischemic myocardial actions which were effectively maintained during chronic therapy of angina pectoris.

Many investigators have studied the potential interactions between calcium-channel antagonists and digoxin. Digoxin is usually well absorbed, and its excretion is dependent on renal mechanisms, primarily glomerular filtration. Several studies have reported a decrease in digoxin clearance and an increase of approximately 50% in digoxin levels when verapamil was added to digoxin therapy. Because renal digoxin clearance was decreased but no concomitant change in creatinine clearance was shown, the presumed major mechanism for decreased renal digoxin clearance is an alteration in renal tubular secretion of digoxin. Although an early report described a digoxin-nifedipine interaction, several subsequent studies have shown no significant changes in digoxin kinetics during nifedipine administration. Four studies found no significant decrease in creatinine clearance of digoxin during nifedipine administration. Thus significant changes in glomerular filtration are unlikely. Physiologic endpoints were measured by 2 groups describing a digoxin-nifedipine interaction and, although there was an increase in serum digoxin concentration, no changes were found in electrophysiologic,correlates. Thus, if a digoxin-nifedipine interaction does exist, steady-state digoxin levels might increase from 24 to 45 % when nifedipine therapy is added. Studies to date have involved small numbers of subjects with and without cardiac disease and have used different study protocols. Nonetheless, little evidence exists for any clinically significant increase in physiologic effects and no adverse effects have been found in patients receiving combined nifedipine and digoxin.

SUMMARY The safety, efficacy, and pharmacologic effect of combined verapamil and digoxin were studied in 10 patients with chronic atrial fibrillation. Heart rate recordings, treadmill exercise tests, physical examinations and serum digoxin concentrations during chronic digoxin therapy were compared with those after the acute administration of verapamil and 1, 2, 4, 6 and 10 weeks after the addition of oral verapamil to digoxin therapy. After both i.v. and chronic oral verapamil administration, resting and exercise heart rates were significantly lower. Increasing serum concentrations of verapamil correlated with increasing suppression of heart rate at rest and during exercise. The mean resting heart rate by 24-hour ambulatory ECG decreased from 87 ± 9 beats/min to 72 6 beats/min. The mean treadmill exercise heart rate decreased more markedly, from a mean of 151 26 beats/min to 106 ± 22 beats/min (both p < 0.001). During chronic therapy, heart rate reductions were seen 1 week after the addition of verapamil and were maintained without change for the duration of the trial. Blood pressures at rest and during exercise were unchanged. Cardiomegaly was present on the entry chest x-ray in six patients; after verapamil, heart size decreased in three and was unchanged in one; two patients had transient congestive heart failure that responded to diuretics. Serum digoxin levels increased from a mean of 1.6 ± 0.4 ng/ml to 2.7 + 0.9 ng/ml (p < 0.001) during verapamil. The increase was observed in hine of 10 patients but was not related to clinical signs of digitalis excess and no episodes of asystole were seen on the serial 24-hour ECGs. Chronic oral administration of verapamil, 320 mg/ day, resulted ih mean verapamil concentrations of 130–280 ng/ml (mean interdose concentration 140 ± 41 ng/ml) with great intersubject and intrasubject variability. We conclude that verapamil is effective in further suppressing the ventricular response rate in atrial fibrillation when given in combination with digitalis and can serve as an adjunct to digitalis therapy in the chronic management of patients with atrial fibrillation.

Drug interactions with digoxin are being increasingly recognized. Some calcium antagonists have been shown to alter digoxin kinetics and changes in digoxin dosage have been recommended. To determine whether nifedipine affects serum digoxin concentrations in patients during combined drug administration, serum digoxin concentrations were determined before and during concomitant drug administration in 14 cardiac patients. The mean (+/- SD) digoxin concentration was 0.92 +/- 0.5 ng/ml before and 0.96 +/- 0.5 ng/ml after 4 days of nifedipine therapy in eight inpatients. For the group of 14 patients, the mean level was 0.78 +/- 0.4 ng/ml before nifedipine and 0.8 +/- 0.4 ng/ml after 1 week of combined drug administration, and 0.84 +/- 0.5 ng/ml after 2 weeks of combined drug administration. These data suggest that nifedipine does not significantly alter serum digoxin concentrations in cardiac patients receiving combined digoxin and nifedipine in the clinical setting.

To study the effect of cardiac glycosides on platelet function, we obtained serial blood samples from 18 normal male volunteers before and 3, 5, and 7 weeks after beginning digoxin therapy (0.375 mg daily). The combined effect of digoxin and nifedipine (mean dose, 57 mg/day) was assessed during the 5th week. Spontaneous platelet aggregation and platelet response to adenosine diphosphate (ADP) were measured in whole blood by electronic particle sizing. Digoxin (mean serum concentration, 0.9 ng/ml) caused significant reduction in total volume and mean size of platelet aggregates formed in response to ADP. However, with addition of nifedipine, the volume and mean size of aggregates returned to baseline measurements. In vitro administration of digoxin to whole blood failed to inhibit ADP-induced platelet aggregation. The volume of spontaneously induced aggregates decreased with digoxin; however, the decrease was not statistically significant. These data indicate that digoxin given in vivo for several weeks inhibits platelet response to ADP; this effect is reversed by the addition of nifedipine.

The effect of cimetidine or ranitidine administration on responses to single and multiple doses of nifedipine were studied in 11 subjects who received cimetidine (300 mg q.i.d.) and 12 who received ranitidine (150 mg b.i.d.) in combination with nifedipine. After single doses of nifedipine, cimetidine decreased apparent oral clearance (dose/AUC) from 66 ± 32 L/hr to 33 ± 14 L/hr (p < 0.01); elimination half-life increased from 4.0 ± 2.2 to 4.9 ± 2.9 hours (p < 0.07). Increases in heart rate were greater (26 ± 13 vs 13 ± 11 beats/min standing; 19 ± 11 vs 9 ± 9 beats/min supine) and lasted longer than after nifedipine alone. Hypotensive effects were similar (10 ± 7 mm Hg decrease vs 9 ± 9 mm Hg). During nifedipine multiple-dose administration, cimetidine decreased the apparent oral clearance from 76 ± 39 to 43 ± 20 L/hr (p < 0.01). Blood pressure responses were not altered by cimetidine but heart rate increased more (18 ± 9 vs 9 ± 9 beats/min supine; 18 ± 13 vs 13 ± 14 beats/min standing). Ranitidine coadministration did not alter nifedipine elimination or dynamic responses. During administration of nifedipine alone, the ratio of oral clearances (multiple to single doses) was 1.1 ± 0.5. Thus (1) cimetidine but not ranitidine alters responses to nifedipine and (2) nifedipine kinetics do not differ between single- vs multiple-dose conditions. Clinical Pharmacology and Therapeutics (1988) 43, 673–680; doi:10.1038/clpt.1988.94

We studied verapamil pharmacodynamics and disposition in seven young, ten elderly, and seven very elderly hypertensive males. Maximal decrease in mean (+/- SD) blood pressure tended to be greater in the elderly (-13.5 +/- 5.9 mm Hg) and the very elderly patients (-15.9 +/- 9.6 mm Hg) compared with that in young patients (-7.3 +/- 4.2 mm Hg). Disparate effects on heart rate responses were noted with reflex tachycardia in young patients compared with decreases in heart rate among the elderly and very elderly. Sensitivity to verapamil-induced prolongation in electrocardiographic P-R interval was less in the very elderly, and maximal prolongation in P-R interval induced by verapamil was less in the elderly and very elderly. Verapamil disposition was also age related. Total verapamil clearance was decreased in elderly (10.5 +/- 3.5 mL/min X kg; p less than 0.05) and very elderly (8.0 +/- 4.1 mL/min X kg; p less than 0.01) when compared with that in young patients (15.5 +/- 4.5 mL/min X kg). Elimination half-life was prolonged in the elderly (7.4 +/- 3.3 h; p less than 0.01) and very elderly (8.0 +/- 1.2 h; p less than 0.01) compared with that in young patients (3.8 +/- 1.1 h). Our data indicate age- and hypertension-related physiologic changes result in predictable pharmacokinetic changes. However, the complex alterations in verapamil pharmacodynamic responses indicate an interaction between direct drug effects and age- and disease-related changes in hemodynamic and autonomic nervous system function.