DRUG-INTERACTIONS WITH THROMBOLYTIC AGENTS - CURRENT PERSPECTIVES

Thrombolytic agents are widely used for the treatment of acute thrombo embolic diseases, especially acute myocardial infarction (AMI). These compounds include streptokinase, anistreplase, alteplase, urokinase an d, although not commercially available yet, saruplase (prourokinase). The therapeutic window of these compounds is relatively small and subt herapeutic or toxic plasma concentrations may have serious clinical im plications (insufficient thrombolysis, reocclusion and bleeding). Amon g the factors that affect the pharmacokinetics and pharmacodynamics of thrombolytic agents, comedication is especially relevant since these drug interactions are partly predictable and sometimes preventable. Ba sed on knowledge of the pharmacology of thrombolytic agents and genera l mechanisms by which pharmacokinetic drug interactions occur, interac tions with alteplase and saruplase are expected. The clearance of alte plase is dependent on hepatic blood flow (HBF), and scientific evidenc e is emerging that saruplase is also a high-clearance compound. Each p harmacological agent that alters HBF and is given concurrently with on e of these agents can change the plasma concentrations of those thromb olytics. Although there are no published data confirming drug-induced changes in the metabolism of alteplase or saruplase by this mechanism in humans, indirect supportive evidence (clinical observations and ani mal experiments) is available. An overview is presented of the anticip ated effects of compounds that are frequently coadministered with thro mbolytic agents on the pharmacokinetics of the thrombolytics with high -clearance properties. Since the clearance of these thrombolytics may be strongly affected by hypoperfusion of the liver as a result of card iogenic haemodynamic failure, the role of circulatory changes in poten tial drug-drug interactions is also discussed. Pharmacodynamic drug in teractions are highly relevant in the treatment of acute thrombotic le sions and are still being evaluated to further optimise treatment stra tegies. As most of these treatments exist as combinations of thromboly tic, antithrombin and antiplatelet compounds, beneficial effects are p artly offset by bleeding complications. Changes in the pharmacokinetic s and/or pharmacodynamics of thrombolytic agents may have serious cons equences. It becomes imperative for the practising physician to be awa re of benefits and risks of interactions with thrombolytic agents and especially of the fact that the principal way by which the pharmacokin etics of alteplase and, presumably, saruplase can be affected is by dr ug- and/or haemodynamic failure-induced changes of HBF.