Anticoagulant Drugs: Pharmacology

Heparin

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  • 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

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  • Heparin (HMW): standardized by bioassay (units)
    • obtained from:
      • porcine intestinal mucosa
      • bovine lung
    • Enoxaparin (Lovenox) -- same sources; amount specified in milligrams
    • Dalteparin (Fragmin)& danaproid (Orgaran)-- amounts specified in anti-factor Xa units

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  • 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

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  • 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

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  •  Reversal of Heparin Effects:
    1. drug discontinuation
    2. Use specific antagonist, e.g. protamine sulfate (note!- excess protamine also has an anticoagulant effect)

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Warfarin & Coumarin

  • Chemistry/Pharmacokinetics:Warfarin & Coumarin
    • Coumarin: produces plasma prothrombin deficiency
    • active agent --: bishydroxycoumarin (synthesis -- dicumarol)
    • Uses:
      • rodenticide
      • humans: antithrombotic agent
    • Oral anticoagulants:
      • Warfarin -- agent in use
      •  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

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  • Mechanism of Action:coumarin anticoagulants
    • Blockade of g-carboxylation of glutamate residues in:
      •    prothrombin
      •   factors: VII, IX, X
      •   endogenous anticoagulant protein C
    •  g-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. naltered degradation rates of these factors.
    • Higher initial doses (loading doses) speed onset by maximally inhibiting synthesis

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  •  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

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  • 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)

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    •  Most serious interaction:-- interactions that increase anti-coagulation (promote bleeding risk)
      •  most dangerous: pharmacokinetic interactions with:
        • pyrazolones phenylbutazone & 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 & rifampin: anticoagulant reduction by increasing liver enzymes that transform racemic Warfarin.
      • Cholestyramine: promotes intestinal Warfarin binding

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    •  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}

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  •   Reversal of Warfarin anticoagulant effects:
    • discontinue drug administration
    • administer vitamin K1 (phytonadione) & 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

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  • Other related agents:(seldom used due to unfavorable toxicity/pharmacologic properties)
    • dicumarol -- incompletely absorbed; GI symptoms
    • Phenprocoumon:extended half-life; adverse renal/hepatic effects.

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Fibrolytic Drugs

  • Overview:fibrolytic drugs
    • Lyse thrombi by catalyzing plasmin (serine protease) formation from plasminogen (the zymogen precursor)
    • Lytic state induced following IV administration
    • Note: both target thromboemboli and hemostatic thrombi are dissolved

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  • Pharmacology:streptokinase, alteplase, tissue plasminogen activator, reteplase, urokinase
    • Streptokinase (Streptase, Kabikinase):(protein {not an enzyme} derived from streptococci)
      • combines with plasminogen (proactivator)
      • Enzymic complex catalyzes: plasminogen ® active plasmin
    • Urokinase (Abbokinase):(human enzyme; renal)
      • Catalyzes: plasminogen ® active plasmin
      • Note: Plasmin cannot be directly used because of endogenous inhibitors;
        • endogenous antiplasmins do not affect urokinase or streptokinase-proactivator complex
        •  Urokinase (and streptokinase-proactivator complex) promote plasmin formation inside the thrombus ® lyse thrombus from within.
    • Anistreplase (APSAC, Eminase) (anisoylated plasminogen streptokinase activator complex; APSAC)
      • purified human plasminogen - bacterial acylated streptokinase complex {upon administration deacylation activatesstreptokinase-proactivator complex}
      • rapid IV injection
      • enhanced clot selectivity -- more plasminogen activity clot-associated than associated with free blood plasminogen
      • more thrombolytic activity
    • Tissue Plasminogen Activators (t-PA)
      • Plasminogen activator
      • preferential activation of fibrin-bound plasminogen
      • Human t-PA: recombinant DNA technology
      • Alteplase: unmodified human t-PA
      • Reteplase: modified human t-PA

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  • Clinical Uses: Fibrolytic Drugs---
    • Multiple pulmonary emboli (not requiring surgery)
    • Central deep venous thrombosis
      •  superior vena caval syndrome
      •  ascending thrombophlebitis (iliofemoral vein)
    •  Intra-arterial use -- peripheral vascular disease
    • Acute Myocardial Infarction:
      • careful patient selection (early intervention)

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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.