Mechanism of Action

Argatroban is a potent, selective inhibitor of thrombin (Okamoto and Hijikata, 1981; Kikumoto et al., 1984). Argatroban was developed using rational drug design through the mimicry of thrombin substrates. It displays an inhibitory constant (Ki) of 0.04 pmol/L for thrombin and has little or no effect on related serine proteases (Ki values of 5 mmol/L for trypsin, 210 mmol/L for factor Xa, and 800 mmol/L for plasmin) (Kikumoto et al., 1984). Argatroban exerts its anticoagulant effects without need of any cofactor by inhibiting thrombin-catalyzed or induced reactions, such as fibrin formation, activation of factors V, VIII, and XIII, and platelet aggregation (Okamoto and Hijikata-Okunomiya, 1993).

Argatroban effectively inhibits free and clot-bound thrombin (Berry et al., 1994; Hantgan et al., 1998) and is over 500-fold more potent than r-hirudin in its relative ability to inhibit clot-bound versus free thrombin (Berry et al., 1994). Argatroban binds tightly to thrombin (Fig. 2) by inserting the dual hydrophobic moieties on its arginine backbone into deep clefts near the thrombin active site (Banner and Hadvary, 1991). Thus, physiological substrates of thrombin are sterically hindered from access to the catalytic pocket of thrombin. This interaction is reversible, unlike the irreversible interaction between r-hirudin and thrombin (see Chapter 14). The combination of effective inhibition of clot-bound thrombin, reversible binding, and a short elimination half-life (see next subsection) may be particularly beneficial in treating hypercoagulable states, reducing the extension of existing thrombosis, and controlling anticoagulation in the intensive care setting.

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