An investigation into the comparative effects of two histamine H2-receptor antagonists, cimetidine and raniditine, on the pharmacokinetics and pharmacodynamics of propranolol
1. The pithed rat has been used to simultaneously investigate the effects of two histamine H2-receptor antagonists, cimetidine and ranitidine, on the pharmacokinetics and pharmacodynamics of propranolol. Propranolol was administered either via the jugular vein or, alternatively, to simulate oral administration, via a cannulated side branch of the hepatic portal vein. 2. Cimetidine, in the form of a continuous intravenous infusion (5 mg.kg -1h-1 or in a single infusion by the simulated oral route (5 mg.kg-1), produced a significant increase in the area under the blood concentration-time curve of jugular venous administered propranolol (0.2 mg.kg-1). As a result, the pharmacological effect of propranolol, in terms of an inhibition of an electrically induced tachycardia, was also enhanced. No difference was detected in the kinetics or dynamics of propranolol given by the simulated oral route. These observations implied an effect of cimetidine on liver blood flow rather than on protein binding or metabolism. 3. Cimetidine, in the form of a single hepatic portal venous infusion, at a higher dose (50 mg.kg-1 ), produced an increase in area under the blood concentration-time curve of propranolol given by the simulated oral route, although this failed to reach statistical significance. The degree of beta-adrenoceptor blockade caused by propranolol was, however, statistically enhanced. This indicated an effect of cimetidine towards an inhibition of the metabolism of propranolol, but protein binding is unlikely to be affected. 4. Ranitidine, in the form of a single hepatic portal venous infusion (2.5 mg.kg-1), had no significant effect on the pharmacokinetics or pharmacodynamics of jugular venous or hepatic portal venous administered propranolol. This implied that the cimetidine- induced reduction in liver blood flow could not be explained entirely by an antagonism of histamine H2-receptors in the vasculature. 5. The effects of cimetidine and ranitidine on liver blood flow Were independently assessed using the more direct method of radiolabelled microspheres. Ciraietidine (5 mg.kg-1., hpv) significantly reduced both hepatic portal venous and hepatic arterial flow. Ranitidine (2.5 mg.kg-1., hpv) also reduced flow in both vessels but the difference was not statistically significant. 6. The magnitude of the cimetidine-induced reduction in liver. Blood flow correlated closely with that of the increase in area under the blood concentration-time curve of jugular venous administered propranolol. This supported the original interpretation of the kinetic data in terms of liver blood flow. 7. The observable differences between cimetidine and ranitidine render the mechanism by which cimetidine may be acting open to question. It is likely that histaminergic receptors are involved in the regulation of liver blood flow. However, differences in pharmacological effect between drugs of the same general group may necessitate clarification of the entire classification of histamine antagonists.