Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states

Abstract

Ticlopidine is an inhibitor of platelet action that has been used in the treatment of a variety of disease states in which platelets play a prominent role. Studies in animals and man have demonstrated that ticlopidine is a potent inhibitor of platelet aggregation induced by adenosine diphosphate (ADP), and variably inhibits aggregation due to collagen, adrenaline (epinephrine), arachidonic acid, thrombin, and platelet activating factor. Inhibition of platelet aggregation is both dose- and time-related, with its onset of activity being 24 to 48 hours, its maximal activity occurring after 3 to 5 days, and its activity still being present 72 hours after a final dose. Ticlopidine also inhibits the release reaction of platelets, prolongs bleeding time, reduces plasma levels of platelet factor 4 and beta-thromboglobulin in patients in whom these proteins are elevated, and may also inhibit platelet adhesion, increase red cell filtrability and decrease whole blood viscosity. In a large number of animal models, ticlopidine markedly inhibits thrombus formation or graft occlusion. Ticlopidine is well absorbed after oral administration. It is extensively metabolised and at least one of its metabolites is pharmacologically active. Therapeutic trials in patients with chronic arterial occlusion due to thrombangitis obliterans or arteriosclerosis obliterans, post-myocardial infarction, cerebrovascular thromboembolic disease, subarachnoid haemorrhage, vascular shunts or fistulas for haemodialysis, and sickle cell disease have shown promise for the use of ticlopidine. However, trials of patients with intermittent claudication, angina pectoris, diabetes mellitus with microvascular disease, aortocoronary bypass grafts, and vascular prostheses have had conflicting results or have shown an unfavourable side effect profile. Further studies are clearly required to establish the role of ticlopidine in many of these areas, some of which are already in progress. Overall, side effects occur in 10 to 15% of patients receiving ticlopidine. The most common side effects are gastrointestinal disturbances and skin rashes. Neither of these necessarily require discontinuation of therapy in most patients. Agranulocytosis, thrombocytopenia, and cholestatic jaundice have also been reported. Bleeding is infrequent except possibly in patients receiving ticlopidine prior to some surgical procedures.