Anesthesia Pharmacology: Drugs that Influence Coagulation

 

Anticoagulant Drugs: Pharmacology

Heparin

• Composition

  • Sulfated mucopolysaccharides (heterogenous)

• Mechanism of Action:

  1. Binds to endothelial cell surface membrane.

  2. Heparin activity dependent on: plasma protease inhibitor antithrombin III

     • Antithrombin III -- inhibitor of clotting factors proteases (forming 1:1 stable complexes)

     • Complex forming reactions normally slow -- accelerated by three orders of magnitude (1000 times) by heparin

     • Acceleration mechanism: heparin binding induces a change in antithrombin III inhibitor form resulting in  increased complex formation activity

     • Following antithrombin-protease complex formation, heparin is released; available for binding to other antithrombin molecules

       •   A heparin high-molecular-weight (HMW) fraction has higher affinity for antithrombin compared to other fractions

       •   A heparin low-molecular-weight (LMW) fraction has a lower affinity for antithrombin but inhibits factor Xa (activated)

         • A low-molecular-weight fraction (LMW), enoxaparin (Lovenox) is FDA approved for primary prevention of deep venous thrombosis following hip replacement surgery.

         • Dalteparin and danaproid have been also approved for prevention of the venous thrombosis following hip replacement surgery

• Heparin (HMW): standardized by bioassay (units)

  • Obtained from:

    • Porcine intestinal mucosa

    • Bovine lung

  • Enoxaparin (Lovenox) -- same sources; amount specified in milligrams

  • Dalteparin (Fragmin)and danaproid (Orgaran)-- amounts specified in anti-factor Xa units

• Toxicity: heparin

  • Major adverse/toxic effect: bleeding

    • Risk managed by attention to:

      1. Patient selection

      2. Dosage control

      3. Monitoring of partial thromboplastin time (PTT)

    •  Factors predisposing to hemorrhage:

      • Elderly

      • Renal failure patients

  •  Long-term heparin use-- increased incidence of:

    • Osteoporosis

    • Spontaneous fractures

  • Transient thrombocytopenia: frequency = 25%

  • Severe thrombocytopenia: frequency = 5%

  • Paradoxical thromboembolism →heparin-induced platelet aggregation

  • Patients on heparin:

    • Thrombocytopenia that causes bleeding: probably due to heparin

    • New thrombus: may be due to heparin

    • If thromboembolic disease may be heparin-induced:→ discontinue heparin

• Contraindications: heparin

  •   Heparin hypersensitivity

  •   Hematologic disease:

    • Hemophilia, thrombocytopenia, purpura,

  •   Cardiovascular:

    • Severe hypertension, intracranial hemorrhage, infective endocarditis

  •   Active tuberculosis

  •   Gastrointestinal tract

    • Ulcerative lesions

    • Visceral carcinoma

  •   Advanced hepatic/renal dysfunction

  •   Threatened abortion

  •   Related to medical procedures:

    • After brain, spinal cord, or eye surgery

    • Lumbar puncture/regional anesthesia blocks

•  Reversal of Heparin Effects

  1. Drug discontinuation

  2. Use specific antagonist, e.g. protamine sulfate (note!- excess protamine also has an anticoagulant effect)

   

• Chemistry/Pharmacokinetics: Warfarin and Coumarin

• Warfarin and Coumarin Structures

  • Warfarin

    Coumarin

  • Coumarin: produces plasma prothrombin deficiency

  • Active agent --: bishydroxycoumarin (synthesis -- dicumarol)

  • Uses:

    • Rodenticide

    • Humans: antithrombotic agent

  • Oral anticoagulants:

    • Warfarin

    • High bioavailability; most bound to plasma albumin (99%)

    • Racemate-- equal amounts of two enantiomorphs

      • Levorotatory-S-warfarin: four times more potent than dextrorotatory- R-warfarin

• Mechanism of Action: coumarin anticoagulants

  • Blockade of γ-carboxylation of glutamate residues in:

    •   Prothrombin

    •   Factors: VII, IX, X

    •   Endogenous anticoagulant protein C

  • γ-carboxylation results in biologically inactive molecules

  • Carboxylation reaction is coupled with oxidative deactivation of vitamin K

    • Anticoagulant prevents reductive metabolism of inactive vitamin K epoxide regenerating active hydroquinone.

  • Anticoagulant effect dependent on two considerations

    1. Partially inhibited synthesis of the four vitamin K-dependent clotting factors and

    2. Unaltered degradation rates of these factors.

  • Higher initial doses (loading doses) speed onset by maximally inhibiting synthesis

•  Toxicity: coumarin anticoagulants

  •  Warfarin: crosses the placenta → hemorrhagic fetal disorder

    •   Fetal abnormal bone formation (Warfarin effects on fetal proteins with g-carboxylglutamate residues).

    •   Never administer Warfarin during pregnancy

  •  Other Adverse Effects:coumarin anticoagulants

    • Cutaneous necrosis related to reduced protein C activity

    • Rare: reduced protein C activity  →  breast, fatty tissues, intestine, extremity infarction

• Drug-Drug Interactions: oral anticoagulants

  • Pharmacokinetic effects include:

    •   Enzyme induction

    •   Enzyme induction

    •   Reduced plasma protein binding

  • Pharmacodynamic effects include:

    •   Synergistic interactions with warfarin

      • Impaired hemostasis, diminish clotting factor synthesis (e.g. hepatic disease)

    •   Competitive antagonism (vitamin K)

    •   Abnormal physiologic vitamin K control loop (hereditary oral anticoagulant resistance)

  •  Most serious interaction:-- interactions that increase anti-coagulation (promote bleeding risk)

    •  Most dangerous: pharmacokinetic interactions with:

      • Pyrazolones phenylbutazone and sulfinpyrazone-- effects: a

        1. Added hypoprothrombinemia

        2. Platelet function inhibition

        3. Promotion: peptic ulcer disease

    • Metronidazole, fluconazole, trimethoprim-sulfamethoxazole:

      • Stereoselective in addition of S-warfarin metabolism

    • Amiodarone, disulfram, cimetadine:

      • Inhibit metabolism of warfarin (both enantiomorphs)

    • Aspirin, hepatic disease, hypothyroidism -- enhance Warfarin effects (pharmacodynamic)

      • Aspirin:  effects on platelets

      • Hepatic disease/hypothyroidism: increasing clotting factors turnover rates

    • Third-generation cephalosporins --

      • Kill intestinal bacteria that produce vitamin K

      • Directly inhibit vitamin K epoxide reductase

  •  Decrease of anticoagulant action:

    • Barbiturates and rifampin: anticoagulant reduction by increasing liver enzymes that transform racemic Warfarin.

    • Cholestyramine: promotes intestinal Warfarin binding

  •  Pharmacodynamic-mediated reduction of anticoagulant effects:

    • Vitamin K -- (increased clotting factors synthesis)

    • Diuretics -- chlorthalidone, spironolactone (affect clotting factor concentration)

    • Genetics -- (molecular mutations of vitamin K reactivation cycle components)

    • Hypothyroidism -- (reduced clotting factors turnover rate)

•   Reversal of Warfarin anticoagulant effects:

  • Dscontinue drug administration

  • Administer vitamin K₁ (phytonadione) and fresh-frozen plasma or factor IX concentrates (Konyne-80 and Proplex which contained prothrombin complex)

  • Objective of intervention: establishing normal clotting factor activity

    • Serious bleeding: large amounts of vitamin K₁ (intravenous administration), factor IX concentrates, and possibly whole blood transfusion

• Other related agents:(seldom used due to unfavorable toxicity/pharmacologic properties)

  • Dicumarol -- incompletely absorbed; GI symptoms

  • Phenprocoumon:  extended half-life; adverse renal/hepatic effects.

Primary Reference: O'Reilly, R.A. Drugs Used in Disorders of Coagulation, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 916-940

Handlin, R.I. Bleeding and Thrombosis, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 339-344.

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