Acenocoumarol (DB01418): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Acenocoumarol is a potent, orally administered anticoagulant belonging to the 4-hydroxycoumarin class of Vitamin K antagonists (VKAs). Structurally a nitro-derivative of warfarin, it functions through the competitive inhibition of the Vitamin K epoxide reductase complex subunit 1 (VKORC1), thereby impairing the synthesis of active coagulation factors II, VII, IX, and X, as well as the anticoagulant proteins C and S. This monograph provides an exhaustive analysis of its chemical properties, pharmacology, pharmacokinetics, clinical applications, and safety profile.

Characterized by rapid absorption and a short elimination half-life of 8 to 11 hours, Acenocoumarol presents a distinct pharmacokinetic profile compared to other VKAs, notably warfarin. Its administration as a racemic mixture of R(+) and S(-) enantiomers, which undergo highly stereoselective metabolism primarily via the cytochrome P450 2C9 (CYP2C9) enzyme, introduces significant complexity. This metabolic pathway is the foundation for its narrow therapeutic index and the substantial inter-individual variability in dose response. This variability is largely attributable to common genetic polymorphisms in the CYP2C9 and VKORC1 genes, which profoundly alter drug clearance and sensitivity, respectively, and form a strong basis for pharmacogenomic-guided dosing strategies to mitigate the high risk of hemorrhagic complications.

Clinical management of Acenocoumarol therapy is critically dependent on frequent and regular monitoring of the International Normalized Ratio (INR) to maintain the delicate balance between therapeutic efficacy and the risk of bleeding. The primary adverse effect is hemorrhage, which can range from minor to life-threatening. The drug is contraindicated in pregnancy due to established teratogenicity.