IC3- Anticoagulants Flashcards
General MOA of anticoagulants?
Block activation of fibrin polymerization and secondary haemostasis
What are the types of anticoagulants and which agents are under them?
- Vit K antagonist (PO) (warfarin)
- DOACs (PO); (a) Thrombin inhibitors (dabigatran), (b) Coagulation factor Xa inhibitors (rivaroxabans)
- Heparins (Parenteral); (a) Heparin, (b) LMWH
Can Warfarin be used in pregnancy and lactation?
Contraindicated in pregnancy, caution in lactation
What is the reversal agent for Vit K antagonist? When do we use it?
Vit K (given if pt on warfarin starts to bleed uncontrollably/ if warfarin dose too high, resulting in bleeding)
MOA of Warfarin? Which clotting factors does it work on?
Warfarin competitively inhibits Vit K reductase enzyme (VKORC1) → prevents reactivation of oxidised vitamin K
Inhibits activation of clotting factors II, VII, IX and X
What is the onset, time to peak, DOA and full therapeutic effect of Warfarin?
Onset: 24 - 72h (2-3d) (takes time to deplete endogenous Vit K)
Time to peak, plasma: 2-8h
DOA: 2-5d (due to long t1/2 of factor II ~50h)
Full therapeutic effect: 5-7d
How is warfarin metabolised?
Hepatic, primarily via CYP2C9
Describe the elimination t1/2 of warfarin, why is it highly variable among individuals?
What other genetic polymorphism contributes to interindividual variability?
20-60h.
Due to genetic polymorphisms in CYP2C9 and VKORC1
How is warfarin excreted?
Urine and faeces
ADEs of warfarin? (3)
- *Haemorrhage/ bleeding (blood in urine, melena, excessive menstrual bleeding)
Rare but serious:
- Hepatitis (0.2-0.3%); greatest risk if > 60 years, male, on warfarin < 1m
- Cutaneous necrosis (1 in 10,000), infarction of breast, buttocks and extremities (typically 3-5d after Tx initiation)
Monitoring of warfarin?
Regular INR (🎯2-3) and PT → used to titrate dose
Contraindications of warfarin? (8)
- *Hypersensitivity
- *Active bleeding/ risk of pathologic bleeding, after recent major surgery
- *Severe/ malignant HTN
- *Severe renal/ hepatic disease
- Subacute bacterial endocarditis, pericarditis, pericardial effusion
- *Pregnancy (crosses placenta- teratogenic, causes severe birth defects in bone and CNS, and haemorrhagic disorders in fetus)
- Caution in lactation
- Caution in pts with diverticulitis, colitis, mild-moderate HTN, mild-moderate renal/ hepatic disease, drainage tubes in any orifice
DDIs of warfarin?
↑ bleeding 🩸:
- Paracetamol long-term Tx (> 2w) at high doses (> 2g/d)
- Allopurinol, NSAIDs, salicylates, PPIs, metronidazole
- TCM/ foods: gingko, ginseng, reishi mushrooms, cranberry juice
↓ warfarin efficacy:
- Barbiturates (antiseizure), corticosteroids, spironolactone, thiazide diuretics
- TCM herbs and supplements/ Vit K-rich foods (eg. green tea, kale, mustard greens, spinach 🥬)
What is the MOA of Dabigatran etexilate (prodrug)? (DOAC)
Competitive, REVERSIBLE thrombin (coagulation factor IIa) inhibitor → blocks conversion of fibrinogen to fibrin → inhibits platelet aggregation and fibrin clot formation
Reversal agent for Dabigatran etexilate (prodrug)? Indication?
Reversal agent: Idarucizumab (humanised mAB)
Indication- for reversal of dabigatran in emergency surgery/ urgent procedures and in life-threatening/ uncontrolled bleeding
Onset, bioavailability, peak action, t1/2 and excretion of Dabigatran?
Onset: rapid
F: 3-7%
Peak action: 3h
T1/2: 12-17h
E: urine
Describe the metabolism of Dabigatran etexilate (prodrug)
Dabigatran + its acyl glucuronide metabolites are competitive, reversible non-peptide antagonists of thrombin (factor IIa); largely excreted unchanged
note: parent prodrug is NOT active!
ADEs of Dabigatran? (2)
- Bleeding
- GI disturbances
DDIs of Dabigatran?
↑ risk of bleeding 🩸:
- Antiplatelets, anticoagulants, fibrinolytics, NSAIDs, ketoconazole
↓ dabigatran level:
- Rifampicin
What is the reversal agent of rivaroxaban?
Andexanet alfa
MOA of rivaroxaban?
Competitive REVERSIBLE antagonist of activated factor X (Xa) → inhibits conversion of prothrombin to thrombin → fibrinogen cannot convert to fibrin → inhibits platelet aggregation and fibrin clot formation
Onset, bioavailability, peak action, metabolism, t1/2 and excretion of rivaroxaban?
Onset: rapid
F: 80-100%
Peak action: 2.5-4h
M: hepatic, CYP3A4 (major)
T1/2: 5-9h
E: urine (66%), faeces (28%)
ADEs of rivaroxaban? (1)
Bleeding
DDIs of rivaroxaban?
↑ risk of bleeding 🩸:
- Antiplatelets, anticoagulants, NSAIDs, P-gp and CYP3A4 inhibitors
↓ rivaroxaban level:
- P-gp and CYP3A4 inducers
General MOA of Parenteral DOACs? (Heparins, LMWHs)
Active heparin molecules bind tightly to antithrombin III (AT III) → conformational change which exposes AT III’s active site for more interaction with proteases → potentiates action of AT III to inactivate thrombin → no conversion of fibrinogen to fibrin → no clot formation
What are the clotting factors inactivated by the Heparin-AT III complex?
LMWHs (enoxaparin) are more selective for a type of factor. What is it?
Thrombin (factor IIa) and factors IXa, Xa, XIa, XIIa (2, 9, 10, 11, 12)
LMWHs (enoxaparin) are more selective for factor Xa and less for factor IIa
Compare heparins and LMWHs.
- Which has higher molecular weight?
- Which has greater F?
- Which has longer t1/2?
- Which has renal excretion?
- Which has a lower incidence of thrombocytopenia (ADE)?
- Heparin
- LMWH (86-98%)
- LMWH (4h)
- LMWH
- LMWH (< 1%)
Longer t1/2 and higher bioavailability for LMWHs favours them over continuous heparin infusions.
ADEs of parenteral DOACs? (3)
- Bleeding (1-5% for IV)
- Heparin-induced thrombocytopenia (HIT) (up to 5%, lesser risk with LMWHs) (When heparin is administered, it binds to platelet factor 4 (PF4) on activated platelet surface
lgG Ab against heparin-PF4 complex) - ↑ risk of epidural/ spinal haematoma and paralysis in pts receiving epidural or spinal anaesthesia/ spinal puncture
Can heparins and LMWHs be used in pregnancy?
Yes
Contraindications of parenteral DOACs? (5)
- Hypersensitivity to heparin or pork products
- Active major bleeding
- Thrombocytopenia/ antiplatelet Ab
- Caution in elderly
- Caution in risk of bleeding (eg pts with prosthetic heart valves, major surgery, regional/ lumbar block anaesthesia, blood dyscrasias, recent childbirth, pericarditis/ pericardial effusion, *renal insufficiency (LMWH)
DDIs of parenteral DOACs?
↑ bleeding risk 🩸:
- (drugs) antiplatelets, anticoagulants, fibrinolytics, NSAIDs, *SSRIs
- (food) chamomile, fenugreek, garlic, ginger, ginkgo, ginseng
Reversal agent for heparin? How does it work?
Protamine sulfate (IV) (highly basic peptide stably binds negatively charged heparin → neutralises anticoagulant properties of heparin)
Good at blocking surface-contact triggered coagulation (intrinsic pathway)- used when collecting blood in tubes
Reversal agent for LMWHs? What must we take note of?
Protamine sulfate (IV) but PARTIAL REVERSAL → hence given in combination with andexanet alfa
