Relationship between plasma diltiazem and cardiovascular responses in conscious dogs

Conscious dogs were given diltiazem hydrochloride (DTZ) orally for 5 successive days at doses of 1, 3, and 10 mg/kg/day. During the 5th day, cardiovascular responses were monitored at various timed intervals after dosing. Arterial blood was sampled concomitantly for drug analysis. DTZ produced a dose-related decrease in blood pressure. The maximum reduction amounted to -30/-33 mm Hg in systolic/diastolic pressure, which occurred 90-150 min after the dose of 10 mg/kg. Heart rate and respiration were not significantly changed. There were dose-related alterations in the electrocardiogram tracing components, ranging from PR interval prolongation to junctional rhythms and ectopic beats. No overt physical responses were apparent. The mean DTZ peak plasma levels were approximately 708 ng/ml after 10 mg/kg, 224 ng/ml after 3 mg/kg, and 98 ng/ml after 1 mg/kg. The estimated t1/2 values for the 3- and 10-mg/kg/day dosings were 142 and 150 min, respectively. Correlations between the DTZ plasma level and the magnitude of the cardiovascular responses were highly significant in terms of blood pressure and PR interval changes. Low levels of DTZ were found 23 h after dosing. These levels were not associated with any meaningful cardiovascular activity.