Neuroleptic drugs attenuate calcium influx and tension development in rabbit thoracic aorta: effects of pimozide, penfluridol, chlorpromazine, and haloperidol.

This study was designed to determine whether neuroleptic drugs have calcium channel blocking activity in isolated rings of rabbit thoracic aorta. The results confirm previous findings that pimozide and penfluridol are calcium channel blockers. However, the data do not support the conclusion that these agents are selective for the voltage-sensitive calcium channel. The results also show that both haloperidol and chlorpromazine (which represent different classes of neuroleptic drugs) are also calcium channel blockers in vascular smooth muscle.

Effects of zomepirac on hemostasis in healthy adults and on platelet function in vitro.

Zomepirac, a new nonnarcotic analgesic, was studied in 25 healthy adults for possible effects on hemostasis. Given in a single 200-mg dose or for 15 days at 300 mg/day, zomepirac prolonged template bleeding time and caused transient decreases in platelet adhesiveness, in stimulated platelet aggregation, and in the release of platelet serotonin. The short duration of these effects contrasts with the known week-long duration of the effects of aspirin. Data from in vitro platelet function studies, correlated with plasma level determinations, indicate that these effects on platelet function in man are probably dependent only on the presence of intact zomepirac and not on any metabolites. The qualitative effects of zomepirac on platelets are assumed to be the consequence of reversible inhibition of prostaglandin synthetase in these cells. Platelet concentration and the humoral clotting mechanism were not affected by zomepirac. Although no unusual bleeding has been noted in patients given zomepirc postoperatively, it should be used with the same caution as aspirin in patients with known defects in platelet function or coagulation.

Review of the pharmacokinetics and metabolism of zomepirac in man and animals.

Zomepirac has been shown to be rapidly and completely absorbed after oral administration to man. Urinary excretion is the principal route for removal of zomepirac and its metabolites in man and in animals. Zomepirac is highly bound to plasma protein. The pharmacokinetics of zomepirac after single and multiple doses in man can be adequately described by a two-compartment oral absorption model. There is a linear relationship between dose and peak plasma concentration, AUC, and urinary excretion of zomepirac. The bioavailability of zomepirac was unaffected by single or repeated doses of antacid. The rhesus monkey has been shown to be a good predictive animal model for zomepirac's metabolism and pharmacokinetics in man, with glucuronidation found to be the principal route of metabolism in both species.

Evaluation of the analgesic properties of zomepirac.

Zomepirac, an inhibitor of prostaglandin biosynthesis, was evaluated for analgesic activity in a number of pharmacological screens. In the acetylcholine writhing test, zomepirac was found to be more potent than codeine, pentazocine, aspirin, and acetaminophen and equivalent in potency to morphine. Zomepirac was inactive in a number of tests that detect narcotic agents, suggesting that the drug will not induce physical dependence. The possibility of a central nonnarcotic as well as a peripheral analgesic mechanism merits consideration.