Antithrombin III Antithrombin III Independent Independent

AnticoagulantsAnticoagulants

Benedict R. Lucchesi, M.D., Ph.D.Department of Pharmacology

University of Michigan Medical School

Antithrombin III Independent Anticoagulants• Hirudin

– From the medicinal leech

– Synthesized by recombinant DNA techniques

– Direct inhibitor of thrombin

• Lepirudin (Refludin™) – desulfohirudin - a recombinant hirudin* derived from yeast cells.

• Hirugen (bivalirudin, Angiomax™)– Synthetic dodecapeptide derived from hirudin.

• Argatroban– Arginine based compound

– Weak competitive inhibitor of thrombin.

• These compounds are used in those patients who have developed thrombocytopenia during treatment with heparin.

Lepirudin Lepirudin (Refludin™)(Refludin™)

Lepirudin [rDNA] (Refludan™)

• highly specific direct inhibitor of thrombin - [Leu1-Thr2]-63-desulfohirudin - a recombinant hirudin* derived from yeast cells.

• polypeptide - 65 amino acids MW=6979.5

• identical to natural hirudin except for the substitution of leucine for isoleucine at the N-terminal end of the molecule and the absence of a sulfate group on tyrosine 63.

• action independent of ATIII and not inhibited by platelet factor 4

• one molecule of lepirudin binds one molecule of thrombin - all thrombin-dependent coagulation pathways are affected

• approved for clinical use in the treatment of heparin-induced thrombocytopenia type II.

* Hirudin derived from the leech Hirudo medicinalis

Bivalirudin Bivalirudin (Hirulog, (Hirulog,

AngiomaxAngiomax™™))

Bivalirudin (Hirulog, Angiomax™)Bivalirudin (Hirulog, Angiomax™)

• Synthetic 20-amino acid peptide analog of naturally occurring hirudin

• Bivalirudin is a specific and reversible direct thrombin inhibitor that binds to the catalytic site and the anion-binding exosite of circulating and clot-bound thrombin.

• Inhibition of thrombin prevents activation of factors V, VIII, and XIII; conversion of fibrinogen to fibrin; platelet activation and aggregation).

Bivalirudin (Hirulog, Angiomax™)Bivalirudin (Hirulog, Angiomax™)

• The effects of bivalirudin are reversed as thrombin slowly cleaves the bilvalirudin-Arg3-Pro4 bond, resulting in recovery of thrombin active site function.

• The onset of anticoagulant effect is immediate after direct IV injection of bivalirudin.

• Bivalirudin therapy prolongs several coagulation assays:–activated clotting time (ACT),–activated partial thromboplastin time (aPTT), – thrombin time (TT), –prothrombin time (PT)–Coagulation times return to the normal range approximately 1—2

hours after discontinuance of the drug.

• (A) Structure of bivalirudin and (B) bivalirudin / hirudin complexes

• Bivalirudin consists of an active site-directed moiety linked by a poly-glycine spacer to a dodeca-peptide analogue of the carboxy terminal of hirudin.

• Once bivalirudin complexes thrombin, it is converted from a noncompetitive inhibitor that interacts with both the active site and exosite 1 on thrombin to a competitive inhibitor that only binds to exosite 1.

• Potential for enhanced protein C activation by bivalirudin. Fluid-phase thrombin is complexed and inhibited by bivalirudin.

• Upon arrival to the microcirculation where thrombomodulin is concen-trated, the amino-terminal domain of bivalirudin is released, leaving only the carboxy-terminal domain bound to exosite 1 on thrombin.

• The affinity of thrombomodulin for thrombin is higher than that of the carboxy-terminal dodecapeptide of bivalirudin, thus thrombin binds to thrombomodulin, where it activates protein C.

ArgatrobanArgatroban

ArgatrobanArgatroban

• Argatroban, a synthetic piperidine carboxylic acid derivative of l-arginine, is an anticoagulant.

• Commercially available argatroban is a racemic mixture of the R- and S-diastereoisomers in a ratio of approximately 65 to 35, with the S-isomer having about twice the thrombin-inhibitory potency of the R-isomer.

• Argatroban, a highly selective, reversible, small-molecule direct thrombin inhibitor that binds rapidly to the catalytic site/a polar region of both circulating (free) and clot-bound thrombin.

ArgatrobanArgatroban• Inhibition of thrombin prevents various steps in the

coagulation process (e.g., activation of factors V, VIII, and XIII and of protein C; conversion of fibrinogen to fibrin; platelet activation and aggregation).

• At infusion rates up to 40 mcg/kg per minute, argatroban produces dose-dependent increases inactivated partial thromboplastin time (aPTT) and several other coagulation assays (activated clotting time [ACT], prothrombin time [PT], and thrombin time [TT]).

• Metabolized principally by the liver via hydroxylation and aromatization.

• Does not induce antibody formation to itself nor does it interact with heparin-induced antibodies.

• Administered by continuous IV infusion.

• Before administering argatroban, all parenteral anticoagulants must be discontinued and a baseline activated partial thromboplastin time (aPTT) obtained.

Supplied, as a concentrated drug (100 mg/ml), which must be diluted 100-fold prior to infusion. Should not be mixed with other drugs prior to dilution in a suitable intravenous fluid.

ArgatrobanArgatroban