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Chapter: Modern Medical Toxicology: Cardiovascular Poisons: Anticoagulants and Related Drugs

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Antiplatelet Drugs - Antifibrinolytic Cardiovascular Poison

Common examples include aspirin, dipyridamole, and ticlopi-dine. While the former two have been discussed in detail else-where (refer Index), ticlopidine will be discussed here.

Antiplatelet Drugs

Common examples include aspirin, dipyridamole, and ticlopi-dine. While the former two have been discussed in detail else-where , ticlopidine will be discussed here.

Ticlopidine is a thienopyridine which inhibits plateletfunction by inducing a thrombasthenia-like state. It is used for prevention of thrombosis in cerebral vascular and coronary artery disease that can lead to myocardial infarction, peripheral arterial disease, and stroke. It is also used to prevent thrombo-embolic occlusion of newly implanted coronary stents.

The oral bioavailability of ticlopidine is 80 to 90 per cent, with peak concentrations occurring at approximately 2 hours. It is reported to reversibly (98%) bind to plasma proteins, mainly to serum albumin and lipoproteins, and is extensively metabo-lised by the liver. Approximately 60 per cent of a radiolabeled dose is recoverable in the urine, mainly as metabolites; about 23 per cent is excreted in the faeces. The elimination half-life of ticlopidine ranges from 24 to 33 hours.

Adverse effects include bleeding, nausea, vomiting, abdominal pain, diarrhoea, cholestatic jaundice, elevated liver enzyme levels, agranulocytosis, anaemia, and throm-bocytopenia. Neutropenia has also been reported. Aplastic anaemia has occurred. Skin rashes are a common side effect with this agent. They are usually either urticarial or macu-lopapular.

Cases of fatal thrombotic thrombocytopenia purpura (TTP) have occurred following ticlopidine therapy. Chronic diarrhoea resulting in weight loss has been reported in patients taking ticlopidine therapeutically. Reversible cholestatic jaundice (occurring at a reported incidence of 1%) may also occur with therapeutic use of this drug. Elevated hepatic serum enzymes can occur following therapeutic doses, usually noted between 10 days and 12 weeks after starting therapy. These patients develop jaundice, generally without fever, with laboratory tests revealing elevation of transaminase concentrations and/ or cholestasis.

Agranulocytosis may occur alone, or with thrombo-cytopenia and/or anaemia. Thrombotic thrombocytopenic purpura (TTP), a potentially life-threatening condition, has been reported as an adverse event in approximately one case per 2000 to 4000 patients exposed. Clinical symptoms include changes in mental status, mild renal dysfunction, and fever. Laboratory findings include severe thrombocytopenia and microangiopathic haemolytic anaemia. Thrombotic Thrombocytopenic Purpura-Haemolytic Uraemic Syndrome (TTP-HUS) has uncommonly been associated with therapeutic use of ticlopidine. It is suggested that this is an immune-mediated reaction. High mortality and morbidity is associated with this condition. Plasma exchange therapy appears to be beneficial.

Ticlopidine has been rarely implicated in overdoses. Agitation, tachycardia, hypotension, hypoxia, metabolic acidosis, and bleeding have been reported. Treatment is symp-tomatic and supportive. Granulocyte colony-stimulating factor (G-CSF) has been used to treat severe neutropenia/leukopenia associated with ticlopidine therapy. The mortality from ticlo-pidine induced thrombotic thrombocytopenic purpura may be reduced by plasma exchange or plasmapheresis.


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