An Overview of the Direct Thrombin Inhibitor Argatroban

Abstract

Argatroban is a small molecule direct thrombin inhibitor. The main attributes of this synthetic drug are its rapid onset of anti-thrombin action, rapid reversibility of its anticoagulant effect, potent inhibition of clot-bound thrombin, absence of antibody formation and no need for initial dosage adjustment in patients with renal impairment. It is eliminated by hepatic metabolism. These properties make argatroban a predictable anticoagulant with intravenous use in a routine clinical setting. Argatroban is approved in the US and Canada for both prophylaxis and treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT); and it is approved in Japan and Korea for treatment of various thrombotic disorders. Argatroban has been shown in limited trials to provide reliable anticoagulation during percutaneous coronary interventions on HIT and non-HIT patients. Preliminary reports document the feasibility of using argatroban for anticoagulation during peripheral vascular interventions, hemodialysis and as adjunct to thrombolysis for treatment of myocardial infarction. Current recommendations for argatroban monitoring are to use the activated partial thromboplastin time for low doses and the activated clotting time for high doses. The ease of monitoring argatroban, its ‘turn-on/turn-off’ characteristic and its consistent safety profile provide the rationale to continue studies of argatroban as an anticoagulant in clinical settings.

Direct thrombin inhibitors – a survey of recent developments

“…Argatroban 10 is a rather selective reversible inhibitor (K i = 38 nM for human thrombin) with only minor inhibitory activity against other serine proteases such as trypsin, factor Xa and kallikrein [93]. Compared to the hirudins, argatroban 10 is advantageous since it does not induce antibodies [94] and is capable of neutralizing clot-bound thrombin [95]. It has a short duration of action (t 1/2 : 40 min).…”

Looking at the proteases from a simple perspective

“…Argatroban is a synthetic heterocyclic peptide that binds with moderate high affinity to a site near of the thrombin catalytic site (Gurm and Bhatt, 2005). Due to its small size, argatroban does not face steric hindrance and thus neutralize clot-bound thrombin (Berry et al, 1994;Walenga, 2002). Differently, melagatran is a potent, rapidly binding, competitive and reversible direct inhibitor of soluble and clot-bound thrombin.…”

Direkte Thrombinhemmung

“…Eine Zulassung in Deutschland für die Behandlung von Patienten mit HIT wird für 2005 erwartet. Argatroban hat eine Plasmaeiweißbindung von etwa 54% und eine HWZ von 39-51 min [2]. Die Elimination ist unabhängig von Nierenfunktion, Alter und Geschlecht.…”

“…Die Elimination ist unabhängig von Nierenfunktion, Alter und Geschlecht. Der Abbau von Argatroban erfolgt durch eine Metabolisierung in der Leber; daher wurde bei Patienten mit eingeschränkter Leberfunktion eine etwa vierfache Verlängerung der Eliminationshalbwertszeit beob achtet [2].…”