Products
Thrombin inhibitors are commercially available in many countries in the form of infusion preparations and as capsules. The first oral thrombin inhibitor to be launched was ximelagatran (Exanta) in 2003. Due to its liver toxicity, sales had to be discontinued. Currently, the most widely used oral and direct thrombin inhibitor, dabigatran (Pradaxa), was approved in 2008.
Structure and properties
The older thrombin inhibitors are analogs of hirudin from the salivary glands of the leech, which consists of 65 amino acids. They are peptides that are not bioavailable perorally. The newer agents have a nonpeptidic structure, are small molecules, and can be taken orally.
Effects
Thrombin inhibitors have anticoagulant and antithrombotic properties. The effects are due to inhibition of the serine protease thrombin, which is central to blood clotting. Thrombin catalyzes the formation of fibrin from fibrinogen, activates various clotting factors, and additionally promotes platelet aggregation. Thrombin is formed from prothrombin by factor Xa.
Indications
The agents are approved for different indications:
- Deep vein thrombosis (prevention and treatment).
- Pulmonary embolism (prevention and treatment).
- Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation.
- In the setting of percutaneous coronary intervention (PCI).
- Anticoagulation in heparin-induced thrombocytopenia type II.
Dosage
According to the SmPC. Thrombin inhibitors are administered orally or parenterally.
Active Ingredients
Peptide thrombin inhibitors:
- Bivalirudin (Angiox, off label).
- Desirudin
- Hirudin (leech)
- Lepirudin (Refludan, out of commerce).
Non-peptide thrombin inhibitors:
- Argatroban (Argatra)
- Dabigatran (Pradaxa), antidote: idarucizumab (Praxbind).
- Ximelagatran (Exanta, out of commerce, liver toxic), prodrug of melagatran.
Contraindications
Contraindications include (selection):
- Hypersensitivity
- Bleeding, tendency to bleed
- Severe liver or kidney dysfunction (depending on the active substance).
For complete precautions, see the drug label.
Interactions
Other drugs that affect blood clotting may increase the risk of bleeding. Dabigatran is a substrate of P-glycoprotein.
Adverse Effects
The most common potential adverse effects include bleeding in various organs. The antibody fragment idarucizumab (Praxbind) is available as an antidote for dabigatran.
