Glycoprotein IIb/IIIa receptor antagonists: clinical pharmacology in cardiovascular diseases of aging.

The aging process is accompanied by a series of anatomical and physiological cardiovascular changes, including a generalised loss of vascular compliance, neuroendocrine alterations and endothelial dysfunction. Superimposed on this, there is an age-related increase in common cardiovascular disorders, such that the majority of deaths and much disability in older populations are caused by coronary artery disease. Most acute vascular events are mediated by thrombosis in which the formation of platelet aggregates forms an integral part. Research over recent years has led to the characterisation of the platelet glycoprotein (GP) IIb/IIIa receptor as the ultimate mechanism by which activated platelets cross-link by binding fibrinogen and other ligands. This knowledge has resulted in novel pharmacological strategies targeting this receptor which have proven to be potent inhibitors of thrombosis. The prototype drug, abciximab, is a chimeric monoclonal antibody directed against GP IIb/IIIa. Synthesis of new drugs has followed, based on the identification of the molecular sequences to which GP IIb/IIIa is attracted. This includes the emergence of oral agents which can be used for long term therapy. Clinical trials with these agents in the setting of percutaneous coronary interventions and unstable ischaemic syndromes have demonstrated a beneficial effect on thrombosis-related end-points. Trials of GP IIb/IIIa antagonists for direct percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction have also shown benefit, while their use in combination with fibrinolytic drugs is currently being evaluated. Other potential indications including neurovascular disease and primary haematological disorders are also being explored.