Medical Pharmacology Chapter 39: 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.

Disclaimer

This Web-based pharmacology and disease-based integrated teaching site is based on reference materials, that are believed reliable and consistent with standards accepted at the time of development. Possibility of human error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete. Users should confirm the information contained herein with other sources. This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site. Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals. Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.  Advertisements that appear on this site are not reviewed for content accuracy and it is the responsibility of users of this website to make individual assessments concerning this information.  Medical or other information  thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.