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PR3154 > IC3- Anticoagulants > Flashcards

IC3- Anticoagulants Flashcards

1
Q

General MOA of anticoagulants?

A

Block activation of fibrin polymerization and secondary haemostasis

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2
Q

What are the types of anticoagulants and which agents are under them?

A
  1. Vit K antagonist (PO) (warfarin)
  2. DOACs (PO); (a) Thrombin inhibitors (dabigatran), (b) Coagulation factor Xa inhibitors (rivaroxabans)
  3. Heparins (Parenteral); (a) Heparin, (b) LMWH
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3
Q

Can Warfarin be used in pregnancy and lactation?

A

Contraindicated in pregnancy, caution in lactation

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4
Q

What is the reversal agent for Vit K antagonist? When do we use it?

A

Vit K (given if pt on warfarin starts to bleed uncontrollably/ if warfarin dose too high, resulting in bleeding)

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5
Q

MOA of Warfarin? Which clotting factors does it work on?

A

Warfarin competitively inhibits Vit K reductase enzyme (VKORC1) → prevents reactivation of oxidised vitamin K

Inhibits activation of clotting factors II, VII, IX and X

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6
Q

What is the onset, time to peak, DOA and full therapeutic effect of Warfarin?

A

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

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7
Q

How is warfarin metabolised?

A

Hepatic, primarily via CYP2C9

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8
Q

Describe the elimination t1/2 of warfarin, why is it highly variable among individuals?

What other genetic polymorphism contributes to interindividual variability?

A

20-60h.

Due to genetic polymorphisms in CYP2C9 and VKORC1

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9
Q

How is warfarin excreted?

A

Urine and faeces

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10
Q

ADEs of warfarin? (3)

A
  • *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)

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11
Q

Monitoring of warfarin?

A

Regular INR (🎯2-3) and PT → used to titrate dose

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12
Q

Contraindications of warfarin? (8)

A
  • *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
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13
Q

DDIs of warfarin?

A

↑ 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 🥬)

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14
Q

What is the MOA of Dabigatran etexilate (prodrug)? (DOAC)

A

Competitive, REVERSIBLE thrombin (coagulation factor IIa) inhibitor → blocks conversion of fibrinogen to fibrin → inhibits platelet aggregation and fibrin clot formation

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15
Q

Reversal agent for Dabigatran etexilate (prodrug)? Indication?

A

Reversal agent: Idarucizumab (humanised mAB)

Indication- for reversal of dabigatran in emergency surgery/ urgent procedures and in life-threatening/ uncontrolled bleeding

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16
Q

Onset, bioavailability, peak action, t1/2 and excretion of Dabigatran?

A

Onset: rapid
F: 3-7%
Peak action: 3h
T1/2: 12-17h
E: urine

17
Q

Describe the metabolism of Dabigatran etexilate (prodrug)

A

Dabigatran + its acyl glucuronide metabolites are competitive, reversible non-peptide antagonists of thrombin (factor IIa); largely excreted unchanged

note: parent prodrug is NOT active!

18
Q

ADEs of Dabigatran? (2)

A
  • Bleeding
  • GI disturbances
19
Q

DDIs of Dabigatran?

A

↑ risk of bleeding 🩸:
- Antiplatelets, anticoagulants, fibrinolytics, NSAIDs, ketoconazole

↓ dabigatran level:
- Rifampicin

20
Q

What is the reversal agent of rivaroxaban?

A

Andexanet alfa

21
Q

MOA of rivaroxaban?

A

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

22
Q

Onset, bioavailability, peak action, metabolism, t1/2 and excretion of rivaroxaban?

A

Onset: rapid
F: 80-100%
Peak action: 2.5-4h
M: hepatic, CYP3A4 (major)
T1/2: 5-9h
E: urine (66%), faeces (28%)

23
Q

ADEs of rivaroxaban? (1)

A

Bleeding

24
Q

DDIs of rivaroxaban?

A

↑ risk of bleeding 🩸:
- Antiplatelets, anticoagulants, NSAIDs, P-gp and CYP3A4 inhibitors

↓ rivaroxaban level:
- P-gp and CYP3A4 inducers

25
Q

General MOA of Parenteral DOACs? (Heparins, LMWHs)

A

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

26
Q

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?

A

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

27
Q

Compare heparins and LMWHs.

  1. Which has higher molecular weight?
  2. Which has greater F?
  3. Which has longer t1/2?
  4. Which has renal excretion?
  5. Which has a lower incidence of thrombocytopenia (ADE)?
A
  1. Heparin
  2. LMWH (86-98%)
  3. LMWH (4h)
  4. LMWH
  5. LMWH (< 1%)

Longer t1/2 and higher bioavailability for LMWHs favours them over continuous heparin infusions.

28
Q

ADEs of parenteral DOACs? (3)

A
  • 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
29
Q

Can heparins and LMWHs be used in pregnancy?

A

Yes

30
Q

Contraindications of parenteral DOACs? (5)

A
  • 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)
31
Q

DDIs of parenteral DOACs?

A

↑ bleeding risk 🩸:
- (drugs) antiplatelets, anticoagulants, fibrinolytics, NSAIDs, *SSRIs
- (food) chamomile, fenugreek, garlic, ginger, ginkgo, ginseng

32
Q

Reversal agent for heparin? How does it work?

A

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

33
Q

Reversal agent for LMWHs? What must we take note of?

A

Protamine sulfate (IV) but PARTIAL REVERSAL → hence given in combination with andexanet alfa

PR3154 (11 decks)

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