Dabigatran Etexilate

Mechanism

Mechanism of Action

Dabigatran is a direct, reversible and competitive inhibitor of thrombin (Factor IIa), the final effector enzyme of the coagulation cascade.

Molecular Mechanism of Direct Thrombin Blockade

1. Dabigatran etexilate is an inactive prodrug with a hydrophobic structure that requires enzymatic hydrolysis by plasma and hepatic esterases to convert into the active form: Dabigatran.
2. Active dabigatran binds directly and with high specificity to the active catalytic site of thrombin.
3. Unlike heparins, which only inhibit circulating free thrombin due to the steric hindrance of the heparin-AT-III complex, dabigatran is capable of inhibiting both free thrombin and thrombin bound to the fibrin clot, and also thrombin-induced platelet aggregation.
4. By inhibiting the conversion of soluble fibrinogen to insoluble fibrin polymers and preventing the thrombin-catalyzed feedback activation of factors V, VIII, and XI, dabigatran disrupts the propagation phase of coagulation in a concentration-dependent manner.

Pharmacokinetics

Pharmacokinetics

• Rout of administration: Oral. The capsules contain granules coated with a tartaric acid core to optimize gastric dissolution (independent of pH). They should not be opened or chewed, as this increases bioavailability by 75%, unacceptably increasing the risk of bleeding.
• Bioavailability (F): Very low, approx. 6.5%.
• Distribution: Moderate apparent volume of distribution (50 - 70 L). Weak binding to human plasma proteins (~35%), allowing its elimination by extrarenal dialysis in cases of acute overdose (unlike factor Xa inhibitors).
• Metabolism: Mainly by non-microsomal esterases that hydrolyze etexilate to free active dabigatran. Subsequent minor hepatic conjugation via glucuronidation to active isomers. It does not interact with CYP450 cytochromes.
• Excretion: Predominantly renal elimination (80 - 85% of the dose excreted as unchanged active drug in the urine). The rest is eliminated via the bile-fecal route.
• Half-life (t_1/2): Approximately 12 to 17 hours in healthy subjects; It is exponentially prolonged in renal failure (up to 28 - 35 hours in patients with Cl_Cr < 30 mL/min).

Indicators and dose

Indications

• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
• Treatment of DVT and PE after at least 5 days of initial concomitant parenteral anticoagulation.
• Primary prophylaxis of venous thromboembolism episodes in adults undergoing elective hip or knee replacement surgery.

Dosage and Renal Adjustment

• Standard FA dose: 150 mg orally twice daily.
• Dose of 110 mg twice daily recommended in: Patients over 80 years of age, patients receiving concomitant treatment with verapamil (moderate P-Gp inhibitor) and patients with high bleeding risk.
• Strict renal adjustment: Contraindicated if Cl_Cr < 30 mL/min. For patients with CrCl of 30 - 49 mL/min, use with extreme caution (consider a dose of 110 mg twice daily).

Pregnancy and Breastfeeding

FDA Category C. Contraindicated in pregnancy. It crosses the placenta and lacks safety data in humans. It is unknown if it is excreted in human milk; breast-feeding should be discontinued during treatment.

Security

Contraindications

Absolute

• Hypersensitivity to dabigatran or excipients.
• Severe active bleeding or predisposing active mucosal pathology.
• Severe renal failure with creatinine clearance Cl_Cr < 30 mL/min.
• Mechanical cardiac valve prostheses (the RE-ALIGN clinical study demonstrated a higher rate of valve thrombosis and bleeding with dabigatran versus warfarin).
• Simultaneous treatment with potent systemic P-Gp inhibitors (such as Ketoconazole, Cyclosporin, Itraconazole or Dronedarone).

Relative

• Active severe esophagitis or gastroesophageal reflux disease (the excipient tartaric acid exacerbates dyspepsia).
• Age over 75 years with borderline kidney function.
• Combination with dual antiplatelet agents.

Adverse Effects (ADR)

• Hemorrhage: Increased risk of gastrointestinal bleeding compared to warfarin, but lower overall risk of life-threatening intracranial bleeding.
• Dyspepsia and abdominal pain: Affects 10 - 15% of patients; It is due to the local release of tartaric acid in the gastric lumen to promote absorption. Frequent cause of treatment abandonment.
• Mild thrombocytopenia: Uncommon variation.

Interactions

Direct substrate of the efflux transporter P-Gp (P-glycoprotein). Systemic P-Gp inhibitors markedly increase the bioavailability and plasma concentrations of dabigatran. P-Gp inducers (e.g., Rifampicin) reduce its bioavailability, decreasing antithrombotic efficacy.