Hemodynamic and pharmacokinetic aspects of the interactions between verapamil and pindolol

Combined administration of verapamil, a phenylalkylamine calcium-entry antagonist, with a pure beta-adrenoceptor blocker, propranolol, produces profound cardiovascular depression associated with decreased hepatic clearance of both drugs. We have therefore studied the combination of verapamil and pindolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity (ISA), to evaluate whether or not the property of ISA will confer protection from the usual toxic effects observed with verapamil and a beta-adrenoceptor blocking agent. In an anesthetized dog model, dosing regimens which produced stable plasma concentrations of either verapamil and/or pindolol resulted in drug effects which were closely related to the plasma levels of the individual agents. When pindolol was combined with verapamil, profound depression of cardiac pump function occurred, similar to that previously found with propranolol. Further, plasma concentrations of verapamil promptly increased into a toxic range during combined administration with pindolol. In summary, since the cardiovascular depression resulting from verapamil and pindolol in combination is similar to that which occurs with verapamil and propranolol, ISA does not appear to obviate the toxic effects of verapamil and a beta-adrenoceptor agent in combination.