Warfarin Sodium / Acenocoumarol

Mechanism

Mechanism of Action

VKAs are oral anticoagulants that act by indirectly interfering with the hepatic synthesis of biologically active coagulation factors.

Cell Physiology: Inhibition of Carboxylation of Factors

1. Coagulation factors II (Thrombin), VII, IX and This reaction is the γ-carboxylation of specific glutamic acid (Glu) residues to γ-carboxyglutamic acid (Gla) in their amino-terminal domains.
2. γ-Carboxylation is catalyzed by a hepatic carboxylase that requires the reduced form of vitamin K (Vitamin K hydroquinone) as an obligate cofactor.
3. During the reaction, reduced vitamin K is oxidized to vitamin K epoxide. To keep the cycle active, the enzyme Vitamin K Epoxide Reductase (VKORC1) must catalyze the reduction of vitamin K epoxide back to its active form.
4. Enzymatic inhibition: Warfarin and Acenocoumarol competitively inhibit subunit 1 of the VKORC1 complex. This depletes the reserves of reduced intracellular vitamin K, causing hepatic secretion of non-functional (de-gamma-carboxylated) factors known as PIVKAs (Proteins Induced by Vitamin K Absence), incapable of binding to phospholipid surfaces by calcium ions.

• Rout of administration: Oral (rapid and complete absorption).
• Bioavailability (F): > 95%. Maximum plasma concentration achieved in 4 hours for Warfarin.
• Distribution: Small apparent volume of distribution (approx. 0.14 L/kg). Highly bound to plasma proteins (mainly albumin, 99%), which makes it susceptible to interactions due to pharmacological displacement.
• Metabolism: Mainly hepatic. Warfarin is a racemic mixture of R and S enantiomers. S-warfarin is 3 to 5 times more potent than R-warfarin and is selectively metabolized in the liver by the cytochrome P450 enzyme CYP2C9. The R enantiomer is metabolized by CYP1A2 and CYP3A4.
• Excretion: Almost exclusive elimination through the kidneys in the form of inactive metabolites derived from hepatic metabolism.
• Half-life (t_1/2): Warfarin approx. 36 to 42 hours; Acenocoumarol is an agent with a significantly shorter half-life, between 8 and 12 hours.

Indicators and dose

Indications

• Treatment and secondary prevention of DVT and PE.
• Prevention of systemic thromboembolic events in patients with nonvalvular or valvular atrial fibrillation.
• Mandatory treatment of choice in patients with prosthetic mechanical heart valves of any location.
• Prevention of recurrent embolism in patients with acute myocardial infarction complicated by left ventricular mural thrombus.

Security

Contraindications

Absolute

• Confirmed pregnancy (except in high-risk mechanical valve carriers in specific weeks under monitoring).
• Clinically relevant active hemorrhagic diathesis.
• Recent major CNS, spinal cord or eye surgery.
• Lack of compliance or inability of the patient to undergo periodic laboratory monitoring (INR).
• Uncontrolled malignant arterial hypertension.

Relative

• Advanced liver disease with prolongation of basal hemostasis.
• High risk of repetitive traumatic falls (elderly, dementia).
• Chronic concomitant use of potent NSAIDs.

Adverse Effects (ADR)

Interactions

• Warfarin enhancers (Increase in INR and risk of bleeding): Inhibitors of CYP2C9 metabolism (Amiodarone, Metronidazole, Fluconazole, Sulfamethoxazole-Trimethoprim, Ciprofloxacin), albumin binding displacement (NSAIDs, salicylates), decrease in intestinal bacterial synthesis of vitamin K (broad antibiotics spectrum as third generation cephalosporins).
• Inhibitors of the effect (Decrease in INR and risk of thrombosis): Enzymatic inducers of hepatic clearance (Rifampicin, Carbamazepine, Phenytoin, St. John's Wort) and increased exogenous dietary intake of vitamin K (dark green leafy vegetables such as kale, spinach and broccoli).

Dosing and Monitoring

The dosage of VKAs is individualized and requires fine adjustment based on the International Normalized Ratio (INR), which measures the prolongation of prothrombin time.

• Standard therapeutic INR target: 2.0 to 3.0 for most indications (e.g. AF, DVT).
• Goal for mechanical valves: 2.5 to 3.5 in mitral position or older generation valves.
• Warfarin starting dose: Typically 5 mg per day orally in healthy adults. Massive loading doses (> 10 mg) are not recommended due to increased risk of inducing skin necrosis due to acute protein C depletion.

Clinical

Clinical Pearl: Pre-treatment Genotyping

The variability in warfarin dose response is largely determined by single nucleotide polymorphisms (SNP) in the CYP2C9 genes (*2 and *3 alleles that associate slowed clearance) and VKORC1 (haplotype A that confers hypersensitivity to inhibition). Patients carrying non-wild-type variants of CYP2C9 require drastic reductions in the maintenance dose (up to 50-70% of the standard dose) to avoid initial catastrophic overdose.

Pregnancy and Breastfeeding

FDA Category X. It is highly teratogenic. It easily crosses the placenta and produces warfarin embryopathy syndrome if administered during the first trimester (weeks 6 to 12), characterized by nasal hypoplasia, calcified chondrodysplasia punctata, mental retardation and CNS malformations. It can induce fetal cerebral hemorrhage in utero in the third trimester. Totally contraindicated in pregnancy, except in exceptional situations of very high-risk mitral mechanical valves where the maternal benefit outweighs the extreme fetal risk (weeks 14 to 34 only). Compatible with breastfeeding; warfarin is not actively excreted in human milk and does not induce alterations in the infant's coagulation levels.