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Overview

  • Anticoagulants decrease the formation of fibrin clots
    • heparin
    • warfarin (coumadin)
    • bivalirudin
Heparin
  • Mechanism
    • catalyzes the binding of antithrombin III to multiple clotting factors  
    • inactivates several factors
      • IIa (thrombin)
      • Xa
      • IXa
      • XIa
      • XIIa
  • Clinical use
    • immediate anticoagulation
      • pulmonary embolism
      • acute coronary syndrome
      • stroke
      • MI
      • DVT
      • DIC
    • during pregnancy
      • does not cross placenta
  • Toxicity
    • bleeding
    • osteoporosis
    • heparin-induced thrombocytopenia (HIT)
      • heparin binds to platelet factor IV
      • antibodies bind to and activate platelets
      • leads to hypercoagulable state and thrombocytopenia
    • hypersensitivity
  • Pharmacology
    • IV delivery only for therapeutic anticoagulation
    • short half-life (2h)
    • large, water-soluble polysaccharide
    • low-molecular-weight heparins (e.g. enoxaparin) have advantages of
      • longer half-lives (2-4x)
      • less thrombocytopenia
      • enhanced activity against factor Xa
      • administered subcutaneously without laboratory (PTT) monitoring
      • not easily reversible
  • Monitoring
    • partial thromboplastin time (PTT)
  • Antagonist
    • protamine sulfate 
      • positively charged to bind negatively charged heparin
Warfarin (Coumadin)
  • Mechanism
    • ↓ hepatic synthesis of vitamin K-dependent clotting factors
      • prevents the reduction of vitamin K, a necessary step in the synthesis of clotting factors
        • vitamin K epoxide reductase is inhibited
        • γ-carboxylation of clotting factors cannot occur 
      • affected clotting factors include
        • II
        • VII
        • IX
        • X
        • protein C
        • protein S
    • no effect on clotting factors already present
    • affects the extrinsic pathway
  • Clinical use
    • chronic anticoagulation
      • DVT prophylaxis
      • post-STEMI
      • heart valve damage
      • atrial arrhythmias
  • Toxicity
    • transient hypercoagulability
      • transient protein C deficiency when beginning warfarin treatment
        • due to short half life of protein C
      • can lead to skin necrosis and dermal vascular thrombosis
      • give heparin as you begin warfarin treatment
    • bleeding
    • teratogenic
      • bone dysmorphogenesis
      • not used in pregnancy
    • drug interactions
      • P450 metabolism 
        • inducers → ↓ PT
          • increase in P450 degrades more warfarin and levels fall
          • mnemonics
            • Chronic Alcoholics Steal Phen-Phen and Never Refuse Greasy Carbs
              • Chronic
              • Alcohol
              • St. John’s wort
              • Phenytoin
              • Phenobarbital
              • Nevirapine
              • Rifampin
              • Griseofulvin
              • Carbamazepine
        • inhibitors → ↑ PT
          • decrease in P450 degrades less warfarin and levels rise
          • mnemonics
            • AAA RACKS In GQ Magazine
              • Acute Alcohol Abuse
              • Ritonavir
              • Amiodarone
              • Cimetidine/Ciprofloxacin
              • Ketoconazole
              • Sulfonamides
              • Isoniazid
              • Grapefruit juice
              • Quinidine
              • Macrolides
      • ASA, sulfonamides, and phenytoin
        • displace warfarin from plasma proteins, leading to increased free fraction → ↑ PT
      • cholestyramine
        • ↓ oral absorption
          • due to low pKa
  • Pharmacology
    • oral
    • long half life (>30 hr)
    • small, lipid-soluble
  • Monitoring
    • prothrombin time (PT)
    • INR
      • (tested PT / reference PT)^(calibration value)
  • Antagonist 
    • vitamin K (slow onset)
    • fresh frozen plasma (fast onset) 
Lepirudin and Bivalirudin
  • Mechanism
    • direct inhibtors of thrombin (IIa)
  • Clinical use
    • alternative to heparin during heparin-induced thrombocytopenia 
    • unstable angina during percutaneous transluminal coronary angioplasty
 

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