Anticoag - Medchem

Warfarin

• Structure:

  • Lactone, coumarin

  • Acidic 4-hydroxy group → acidic, ↑ solubility of drug 

  • (S)-warfarin more potent than ®

• PK: 100% bioavailability, peak plasma conc. in 3hr 

• DDI: Induction or inhibition of CYP2C9 → monitoring

Heparin-Based Anticoagulants

• Heparin

  • Structure: HMW polysaccharide

  • PK: administered IV/SC 

• Enoxaparin and Dalteparin

  • Structure: LMW polysaccharide 

  • Mechanism: more selective

• Fondaparinux

  • Structure: Synthetic polysaccharide

  • Mechanism: First selective Factor Xa Inhibitor

  • PK: Improved PK→ complete absorption, SC injection

  • Elimination half life 17 hrs

  • No monitoring 

• All have sulfated negatively charged acidic molecule

Direct Thrombin Inhibitors

• Hirudin, Lepirudin, Desirudin

  • Structure: small protein

  • Mechanism: irreversible inhibition of thrombin 

  • PK: short half life 

• Bivalirudin

  • Structure: peptide 

  • Mechanism: Reversible inhibitor → less risk of bleeding

• Argatroban

  • Structure: peptide-mimetic 

  • Mechanism: reversible inhibitor (binds selectively to the active site of thrombin)

• Dabigatran

  • Structure: Nonpeptide mimetic, prodrug 

  • Mechanism: Reversible inhibitor

  • PK: orally active, low bioavailability

  • Does not require coagulation monitoring 

Thrombolytic Drugs

• Streptokinase

  • Structure: Serine protease

• Alteplase

  • Structure: Serine protease 

  • Mechanism: selective → high affinity for plasminogen bound to fibrin 

  • PK: short half-life (5 mins)

• Tenecteplase

  • Structure: serine protease, three point mutations → improved specificity and prolonged half life (17 mins)