Oral Anti-Coagulants

ORAL ANTI-COAGULANTS


ORAL ANTI-COAGULANTS

Drugs:

  • Warfarin
  • Bishydroxycoumarin (dicumarol)
  • Acenocoumarin
  • Phenindione.

MOA:

  • Acts by inhibiting activation of vitamin K dependent clotting factors (like clotting factors II, VII, IX, X & anti-clotting proteins (protein C & protein S).
  • Done by inhibiting VKOR à ultimately, preventing activation of vitamin-K dependent factors.

Steps:

  • Vitamin-K dependent clotting factors synthesized by liver & activated by gamma-carboxylation of glutamate residues.
  • Hydroquinone form of vitamin K à converted to epoxide form, by enzyme vitamin K epoxide reductase (VKOR).
  • Anticoagulants inhibit VKOR & thus vit.K dependent clotting factors.

Note:

  • Nil effect on pre-activated factors.
  • Also only inhibits factor activation & does not affect its synthesis.

Efficacy of oral anticoagulants:

  • Better monitoring test: INR (international normalized ratio), based on human brain thromboplastin.
  • PT is prolonged by oral anticoagulants.

Important individual drugs:

1. Warfarin:

  • Absorbed well from GIT.
  • Highly plasma protein bound (99%).
  • Kinetics changes from 1st order to zero order within therapeutic concentrations.
  • Racemic mixture of R & S isomers.
  • S-warfarin – More active & metabolized by CYP2C9.
  • CYP2C9 polymorphisms affect warfarin activity.

Dosage:

  • Prothrombin time used to adjust warfarin dose – 
    • As it mainly affects extrinsic coagulation pathway.

Drug interactions of warfarin:

  • Requires dose adjustment – Due to drug interactions.

Drugs increasing warfarin effect:

  • Broad-spectrum antibiotics
  • Cephalosporins (cefamandole, cefoperazone)
  • Moxalactam (cause hypoprothrombinemia)
  • Aspirin
  • Phenylbutazone
  • Microsomal enzyme inhibitors (erythromycin, cimetidine).

Drugs decreasing warfarin effect:

  • Enzyme inducers (like rifampicin, griseofulvin etc).
  • Oral contraceptives (increases clotting factors).

Drug effects:

  • 1st factor affected –  Protein C
    • Protein C – Shorter half-life than most clotting factors (8hrs).
    • Protein C deficiency – Results in dermal vascular necrosis & hypercoagulation.
    • Early signs (due to deficiency) – Within 3-10 days, after therapy initiation.
  • 1st factor to disappear – Factor VII (Half-life – 6 hours).
  • Last factor to disappear: Factor II (Half-life – 60 hours).
    • Hence, delayed oral anticoagulants effect, gradually over 1-3 days.

Uses:

  • Preferred in patients with:
    • Mechanical prosthetic valves.
    • Advanced kidney disease [CrCL<30mL/min].
    • Moderate or severe mitral stenosis.
  • Used for maintenance of anticoagulation rather than treatment initiation.

Adverse effect:

  • Bleeding (most common).

Disadvantages:

  • Crosses placenta on usage during pregnancy- 
    • Causes “fetal warfarin syndrome”/”Contradi syndrome”
    • Presents with growth retardation, stippled epiphyses, hypoplasia of nose & hand bones.
    • Hence, contra-indicated.
  • Not secreted in breast milk – Safe for lactating mothers.

Treatment for warfarin overdose:

  • Fresh frozen plasma – Replenishes deficient factors.
  • Specific antidote – Vitamin K/phytonadione

Criteria for warfarin overdose management:

  • INR < 5 but above therapeutic range:
    • Discontinue warfarin temporarily & restart at low dose.
  • INR 5-9:
    • Vitamin K (1mg oral)
  • INR > 9 but no bleeding:
    • Vitamin K (2-3mg oral)
  • INR > 20 or bleeding:
    • Fresh frozen plasma.

2. Phenindione:

  • Cause orange-colored urine.
  • Result in liver & kidney damage.

NEW ORAL ANTICOAGULANTS:

Target specific/direct oral anticoagulants:

  • Drugs: Dabigatran etexilate, rivaroxaban, edoxaban & apixaban.
  • Rivaroxaban – Maximum (80%)
  • Dabigatran etexilate – Minimum (6%) oral bioavailability.
  • Do not require monitoring.

1. Dabigatran etexilate:

  • Direct thrombin inhibitor
  • Prodrug.

2. Rivaroxaban, apixaban & edoxaban:

  • Are factor Xa inhibitors.

Uses:

  • Preferred over warfarin in atrial fibrillation by European guidelines.
  • Edoxaban
    • Specifically indicated to reduce risk of stroke & systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).
    • Indicated for DVT treatment & pulmonary embolism, following 5 to 10 days of initial therapy with parenteral anticoagulant.

Exam Important

  • Warfarin, Bishydroxycoumarin (dicumarol), Acenocoumarin & Phenindione are all oral anticoagulant drugs.
  • Oral anticoagulants act by inhibiting activation of vitamin K dependent clotting factors.
  • Vitamin-K dependent clotting factors include clotting factors II, VII, IX, X & anti-clotting proteins (protein C & protein S).
  • Vitamin-K dependent clotting factors synthesized by liver & activated by gamma-carboxylation of glutamate residues.
  • Hydroquinone form of vitamin K –> converted to epoxide form, by enzyme vitamin K epoxide reductase (VKOR).
  • Anticoagulants inhibit VKOR & thus vit.K dependent clotting factors.
  • INR is better monitoring test for efficacy of oral anticoagulants.
  • PT is prolonged by oral anticoagulants.
  • Warfarin is highly plasma protein bound (99%).
  • Warfarin changes in kinetics from 1st order to zero order within therapeutic concentrations.
  • Warfarin has racemic mixture of R & S isomers, S-warfarin is more active.
  • CYP2C9 polymorphisms affect warfarin activity.
  • Prothrombin time used to adjust warfarin dose, as it mainly affects extrinsic coagulation pathway.
  • Protein C is 1st factor affected, due to shorter half-life than most clotting factors.
  • Protein C deficiency is results in dermal vascular necrosis & hypercoagulation.
  • Factor VII (half-life – 6 hrs) is 1st factor to disappear during warfarin therapy.
  • The last factor to disappear is factor II with half-life is 60hrs.
  • Delayed oral anticoagulants effect, gradually over 1-3 days.
  • Warfarin preferred as patients with mechanical prosthetic valves, advanced kidney disease [CrCL<30mL/min] & moderate or severe mitral stenosis.
  • Warfarin crosses placenta on usage during pregnancy causes “fetal warfarin syndrome”/”Contradi syndrome”.
  • Fetal warfarin syndrome presents with growth retardation, stippled epiphyses, hypoplasia of nose & hand bones.
  • Warfarin is contra-indicated in pregnancy, due to fetal warfarin syndrome.
  • Warfarin is not secreted in breast milk, hence safe for lactating mothers.
  • Treatment for warfarin overdose fresh frozen plasma for replenishing deficient factors.
  • Specific antidote is Vit. K/phytonadione
  • With INR < 5 but above therapeutic range, discontinue warfarin temporarily & restart at low dose.
  • With INR 5-9, give vitamin K (1mg oral).
  • INR > 9 but no bleeding, give vitamin K (2-3mg oral).
  • INR > 20 or bleeding is fresh frozen plasma.
  • Phenindione causes orange-colored urine.
  • Target specific/direct oral anticoagulants includes Dabigatran etexilate, rivaroxaban, edoxaban & apixaban.
  • Dabigatran etexilate is direct thrombin inhibitor.
  • Dabigatran etexilate is a prodrug.
  • Rivaroxaban, apixaban & edoxaban are factor Xa inhibitors.
  • Edoxaban specifically indicated to reduce risk of stroke & systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).
  • Edoxaban indicated for DVT treatment & pulmonary embolism, following 5 to 10 days of initial therapy with parenteral anticoagulant.
Don’t Forget to Solve all the previous Year Question asked on ORAL ANTI-COAGULANTS

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