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.
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