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Ticlopidine

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in Platelet-Dependent Disease States

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Summary

Synopsis

Ticlopidine1 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 β-throm-boglobulin in patients in whom these proteins are elevated, and may also inhibit platelet adhesion, increase red cell ftltrability 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 micro-vascular 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.

Pharmacodynamic Properties

In vitro, ticlopidine is a weak inhibitor of platelet aggregation, however it does inhibit Properties endothelial cell growth. After in vivo administration, ex vivo studies show that ticlopidine is a potent inhibitor of platelet aggregation induced by ADP, however, its ability to inhibit aggregation due to thrombin, collagen, arachidonic acid, adrenaline and platelet activating factor is very variable. Unlike other antiplatelet agents, ticlopidine inhibits both the first and second phases of platelet aggregation, and its effects are both dose- and time-related. The onset of its effects is 24 to 48 hours, with maximal antiaggregating effect measurable after 3 to 5 days of dosing, and its effects are still present up to 72 hours after a final dose. Ticlopidine also prolongs the bleeding time by 2- to 5-fold in a dose-and time-related fashion and inhibits the platelet release reaction. Ticlopidine’s effects on prostaglandins are complex and not fully understood; malondialdehyde synthesis in response to collagen, thrombin, or adrenaline is partially inhibited (as with aspirin), serum thromboxane concentrations are reduced, and the effects of prostacyclin enhanced. Ticlopidine may act by modifying platelet membrane affinity for fibrinogen and/or ADP. Its effects on platelet adhesion are again variable. In patients with elevated β-thromboglobulin and platelet factor 4 ticlopidine therapy reduces the levels of these proteins. Ticlopidine generally prolongs platelet survival in patients with disease states in which it is reduced, especially in patients shortly after an acute myocardial infarction. Ticlopidine binds to red cell membrane in vitro and reduces the tendency to haemolyse in hypotonic solution. In high concentrations, it delays sickling of red cells of patients with sickle cell disease. Red cell deformability and filtrability may also be increased by ticlopidine. Whole blood, but not plasma, viscosity may also be decreased; thus, rheological activity may contribute to ticlopidine’s overall effects. In a large number of coagulation-dependent animal models, thrombosis induced by chemical, mechanical or electrical methods, or by implantation of artificial surfaces was almost invariably markedly inhibited. In addition, in models of coagulation where platelets play little or no role, ticlopidine consistently prevented pathological changes.

Pharmacokinetics

Approximately 80 to 90% of an oral dose of ticlopidine is absorbed, with peak plasma concentrations occurring after 1 to 3 hours. Peak concentrations after a single 500mg dose are approximately 0.6 to 0.8 mg/L, whereas a single 1000mg dose has produced peaks of about 2.1 mg/L. Peak ticlopidine concentrations after 250mg doses were given twice daily for 21 days were about 0.9 mg/L. Ticlopidine is rapidly and extensively metabolised. Overall recovery of a radiolabelled dose is about 85%, with unchanged ticlopidine representing only about 2%. At least one metabolite is active.

Elimination half-lives of 24 to 33 hours have been reported, but single- and multiple-dose studies have demonstrated a rapid 4-fold reduction in plasma concentrations over 4 to 12 hours. Thus, the true half-life of ticlopidine is not known. No studies on the pharmacokinetics of ticlopidine have been performed in patients with decreased renal or hepatic function.

Therapeutic Trials

Ticlopidine has been studied in patients with various disease states in which platelets play a major role. In patients with atherosclerotic disease and intermittent claudication, conflicting results have been obtained, with some studies demonstrating an improvement in maximum walking distance and pain-free distance, and others demonstrating no benefit. Five large multicentre trials are under way to help define a role for ticlopidine in this disease. In patients with chronic arterial occlusion due to thrombangitis obliterans or arteriosclerosis obliterans, ticlopidine therapy has been associated with a clear improvement in lower extremity ulcer healing rate and vascular improvements.

In patients with angina pectoris, ticlopidine has produced mixed results although the weight of evidence would suggest little, if any, role for ticlopidine in these patients. However, in patients started on ticlopidine within 12 hours of an acute myocardial infarction, platelet survival was improved and cardiac enzyme concentrations were reduced compared to placebo. A role for ticlopidine in the post-infarction period is promising, although large controlled studies are needed.

In a large multicentre study, patients with a recent transient ischaemic attack were treated with ticlopidine, with the result of fewer cerebrovascular or cardiovascular ‘events’ than observed with aspirin therapy. Similarly, patients with cerebral infarction treated with ticlopidine suffered fewer relapses than those receiving dipyridamole. In patients with subarachnoid haemorrhages, treated surgically within 3 days of the haemorrhage, ticlopidine reduced the incidence of neurological deficit plus mortality at the time of discharge. Those with angiographically documented vasospasm were especially benefited by ticlopidine, despite a lack of effect of the drug on vasospasm per se. Further large studies are in progress to compare ticlopidine and aspirin.

In studies examining the effects of ticlopidine in patients with diabetes mellitus, there has been no evidence of reduced progression of retinopathy, nephropathy, neuropathy, or cardiovascular illness.

In uraemic patients in whom AV shunts or fistulas were inserted for vascular access, presurgical initiation of ticlopidine has reduced the incidence of vascular occlusion, and thus the need for clot removal or reconstruction of the vascular device. Additionally, ticlopidine may reduce the degree of leucocyte count drop during dialysis, improve dialyser function, and reduce the dose of heparin needed to prevent clotting during dialysis.

In patients undergoing open heart surgery, preoperative initiation of ticlopidine reduces the degree of platelet count drop during extracorporeal circulation. However, the effect of the drug on peri- and postoperative bleeding has been varied, with some studies demonstrating an increase in the degree of bleeding and a requirement for reoperation. Very variable results have been achieved in the use of ticlopidine to prevent occlusion of coronary bypass grafts. Several trials have reported no clinical benefit, whereas the largest study showed significant decreases in graft occlusion compared with placebo. In any event, the initiation of ticlopidine before these operations should be approached with great caution. Patients with ‘Dacron’ prosthetic vascular grafts have undergone clinical trials with ticlopidine, but the drug has not demonstrated efficacy in reducing the degree of platelet adhesion to the graft membrane.

In patients with primary glomerulonephritis ticlopidine reduced the degree of proteinuria as well as dipyridamole, but has a greater potential to reduce the degree of haematuria, and a greater effect on improving creatinine clearance.

In two studies in patients with sickle cell disease, ticlopidine reduced the incidence, duration, and severity of infarctive crises, and reduced the degree of pulmonary arteriovenous shunting.

Side Effects

Approximately 10 to 15% of patients receiving ticlopidine have experienced side effects, the most common of which have been gastrointestinal complaints and skin rash. Approximately 10% experience gastrointestinal discomfort, nausea, or diarrhoea, occasionally requiring discontinuation of therapy. Administration of the drug with food may reduce the problem. Bleeding during ticlopidine therapy is an unusual side effect, but is dangerous in patients who must undergo surgery or another invasive procedure. In patients undergoing AV access insertion, there has been no increase in bleeding, but in patients undergoing open heart surgery, the risk of bleeding may be increased with ticlopidine.

Agranulocytosis, neutropenia, thrombocytopenia, and erythroleukaemia have been reported during therapy with ticlopidine. Elevation of liver function tests are unusual with ticlopidine therapy, but occasionally cholestatic jaundice or hepatitis have been reported. Ticlopidine may increase total serum cholesterol, as well as LDL- and VLDL-cholesterol and other lipoproteins, without affecting HDL-cholesterol.

Drug Interactions

In three separate trials, the combination of aspirin and ticlopidine seemed to display additive to synergistic activity as platelet inhibitors. Corticosteroids, given orally or as a single intravenous injection, can reduce the prolonged bleeding time caused by ticlopidine, without altering its inhibition of platelet aggregation.

Dosage and Administration

In the majority of clinical trials, the dose of ticlopidine has been 500 mg/day, given as 2 equally divided doses per day, generally with meals. In some studies, 750 mg/day has been given, and this higher dose may be more efficacious in some settings. Dosing of ticlopidine prior to surgery may possibly increase the risk of operative bleeding.

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    Emmanuel Saltiel & Alan Ward

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    Emmanuel Saltiel & Alan Ward

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Various sections of the manuscript reviewed by: U. Berglund, Department of Internal Medicine, University Hospital, Linköping, Sweden; J.L. David, Unité Thrombose-Hémostase, Université de Liege, Liege, Belgium; H.J. Day, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; J.L. Gordon, Vascular Biology Section, Clinical Research Centre, Harrow, England; J.E. Goyan, School of Pharmacy, University of California, San Francisco, California, USA; T. Katsumura, Division of Thoracic and Cardiovascular Surgery, Kawasaki Medical School, Okayama, Japan; M. Rothlin, HerzZentrum, Zürich, Switzerland; J.J. Thebault, Institute de Recherches et d’études Biomedicales Hôpital Cognacq-Jay, Paris, France; H. Tohgi, Department of Neurology, Iwate Medical University, Iwate, Japan; R. Verhaege, Universitair Zienhuis, Leuren, Belgium.

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Saltiel, E., Ward, A. Ticlopidine. Drugs 34, 222–262 (1987). https://doi.org/10.2165/00003495-198734020-00003

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