IC3 Anticoagulants Flashcards
Which step of hemostasis do Anticoagulants block?
- Secondary hemostasis
- Block activation of fibrin polymerization by preventing conversion of fibrinogen to fibrin
List & classify the Anticoagulants according to their route of administration
Oral
Warfarin
Dabigatran
Rivaroxaban
Parenteral
Heparin
LMWHs
Which oral Anticoagulants are antagonists of Vitamin K & which are not?
Vitamin K Antagonist
Warfarin
Non-Vitamin K Antagonist
Dabigatran
Rivaroxaban
What is the MOA of Warfarin?
- Active Vitamin K = reduced form
- Inactive Vitamin K = oxidised form
- Active Vitamin K is oxidised to inactive Vitamin K in a step that is coupled to the carboxylation of glutamic acid residues (on coagulation factors II, VII, IX & X)
- Carboxylation activates the factors II, VII, IX & X
- Warfarin inhibits Vitamin K reductase, the enzyme that reactivates the oxidized Vitamin K → Prevents activation of clotting factors
What is the reversal agent for Warfarin?
Vitamin K
What is the onset, time to peak plasma concentration & duration of action of Warfarin?
Onset
24 to 72h for oral, effects kick in when endogenous reserves of active vitamin K are depleted
Time to peak, plasma
2 to 8h for oral
Duration of action
2 to 5 days
How long is needed before full therapeutic effect can be achieved for Warfarin? Suggest why
- 5 to 7 days
- As some of the coagulation factors have a long half-life
e.g. Factor II (prothrombin) has T1/2 = 50 h
How well absorbed is Warfarin & how is it excreted?
Absorption
Rapid & complete oral absorption
Excretion
Urine & faeces
How is Warfarin metabolised & what is its half life elimination?
- Metabolised by liver, primarily via CYP2C9
- Half-life elimination is 20-60 hours, highly variable among individuals
Why does Warfarin have a variable response?
- Mostly due to genetic polymorphisms in 2 genes
CYP2C9 & Vit K reductase complex, subunit 1 or VKORC1
What are the 2 main parameters used to monitor & titrate Warfarin dose?
- International normalized ratio (INR)
- Prothrombin time (PT)
What is a common adverse effect of Warfarin?
Haemorrhage / bleeding 🩸
Signs include blood in stools or urine, melaena (sticky, tar-like stools), excessive bruising, petechiae, persistent oozing from superficial injuries, excessive menstrual bleeding
What are the rare adverse effects of Warfarin? State the risk factors if any
Hepatitis
Greatest risk if >60 y/o, male, on warfarin < 1 month
Cutaneous necrosis & infarction of breast, buttocks and extremities
Likely due to ↓ blood supply to adipose tissue
Typically occurs 3 to 5 days after initiation
What are the contraindications of Warfarin?
- Hypersensitivity to drug
- Bleeding associated: Active bleeding, risk of pathologic bleeding, after recent major surgery
- Severe or malignant hypertension
- Severe renal or hepatic disease
- Subacute bacterial endocarditis, pericarditis, or pericardial effusion
- Pregnancy (teratogenic: severe defects in bone & CNS, can cause haemorrhagic disorder in fetus)
In whom should cautions be taken for Warfarin?
- Breast-feeding women
- Diverticulitis, colitis
- Mild or moderate hypertension
- Mild or moderate renal / hepatic disease
- Drainage tubes in any orifice
What are the drugs that may increase bleeding risks when used concomitantly with Warfarin?
- Paracetamol (warn patients! can get OTC easily)
when used long term (>2 weeks) at high doses (> 2g/day) - CYP2C9 inhibitors (allopurinol, NSAIDs, salicylates, PPI, metronidazole)
- Other antiplatelets or anticoagulants
What are the traditional medicines/herbs/supplements/food that may increase bleeding risks when used concomitantly with Warfarin?
- Gingko 🍁
- Ginseng
- Reishi mushrooms 🍄
- Cranberry juice
What drugs may reduce the efficacy of Warfarin when used concomitantly?
CYP2C9 inducers
* Barbiturates
* Corticosteroids
* Spironolactone, thiazide (diuretics)
What are the traditional medicines/herbs/supplements/food that may reduce the efficacy of Warfarin when used concomitantly?
- Vitamin K containing supplements
- Vitamin K-rich foods (mustard greens, spinach)
Ask patients to avoid excess vitamin K intake - Green tea
What should we monitor for drug-drug or drug-food interactions that may reduce efficacy of Warfarin?
Regular INR monitoring to ensure appropriate anticoagulant control
Which DOAC is a prodrug?
Dabigatran etexilate
rapidly converted to dabigatran
What is the difference between the target(s) of Dabigatran vs Rivaroxaban?
- Dabigatran & its acyl glucuronide metabolites are competitive reversible non-peptide antagonists of thrombin (factor IIa) while
- Rivaroxaban is a competitive reversible antagonist of activated factor X (Xa)
Which drug is Idarucizumab used as a reversal agent? Explain what it is & when it is indicated
- Dabigatran
- Is a humanized mAb fragment that binds Dabigatran & its acyl glucuronide metabolites with higher affinity than Dabigatran to thrombin
- Indicated for
1. Emergency surgery or urgent procedures
2. Life-threatening or uncontrolled bleeding
Which drug is 🥨 Andexanet alfa used as a reversal agent? Explain what it is
- Rivaroxaban or other -xabans
- Off-label for LMWHs
- Is a recombinant modified human factor Xa decoy protein
What are the advantages of DOACs over Warfarin?
- Less drug, food interactions
- Less interindividual variability
But DOACs are more expensive
Does Dabigatran etexilate or Rivaroxaban take a shorter time for reversal?
- Rivaroxaban
- Takes 1-2 days as half life is shorter, at 5 to 9h
- vs Dabigatran etexilate whose reversal takes 3-5 days as half life is longer, at 12 to 17h
Compare the adverse effects of Dabigatran etexilate & Rivaroxaban
- Both may cause bleeding
- Dabigatran etexilate may also cause GI symptoms
Does Dabigatran etexilate or Rivaroxaban have better bioavailability?
- Rivaroxaban (80 to 100%)
- Dabigatran etexilate (3 to 7%…so administered as enteric coated formulation)
Compare the drugs that increase bleeding risks of Dabigatran etexilate & Rivaroxaban
Dabigatran etexilate
Antiplatelets, anticoagulants, NSAIDs, fibrinolytics & ketoconazole
Rivaroxaban
Antiplatelets, anticoagulants, NSAIDs, P-gp & CYP3A4 inhibitors
Compare the respective drugs that reduce the levels of Dabigatran etexilate & Rivaroxaban
Dabigatran etexilate
RifamPIn
Rivaroxaban
P-gp & CYP3A4 inducers
What is the MOA of Heparin & LMWHs?
- Potentiate the action of antithrombin III (AT III), thereby inactivating thrombin
- Thrombin is needed for conversion of fibrinogen to fibrin
- Without fibrin, clot formation is impeded
- Active heparin molecules bind tightly to AT III → cause a conformational change which exposes AT III’s active site for more rapid interaction with proteases → accelerate inactivation of coagulation factors
What are the factors inactivated by Heparin vs LMWHs?
Heparin
🥨 Heparin-AT III complex inactivates thrombin (Factor IIa), IXa, 🥨 Xa, XIa & XIIa
LMWHs e.g. enoxaparin
🥨 Factor Xa & to a lesser extent, IIa
Which parenteral anticoagulant is good at blocking surface contact triggered coagulation?
- Heparins (not LMWHs)
- Also used in tubes for blood samples
What are the features of LMWHs that make them favourable over Heparin?
- Longer half-life (4h vs 1h)
- Higher bioavailability (86 to 98% vs 30%)
- Less need for INR monitoring as response is more consistent
- Lower risk of heparin-induced thrombocytopenia
Parenteral anticoagulants are administered _______
IV, subcutaneously
How is LMWHs vs Heparin excreted?
LMWHs are excreted renally but Heparins are via nonrenal mechanisms
What are the adverse effects of parenteral anticoagulants?
1. Bleeding
(in 1-5 % of patients treated with IV heparin)
Anticoagulant effect disappears within hours of discontinuation
2. ↑ Risk of epidural or spinal haematoma & paralysis
in patients receiving epidural, spinal anaesthesia or spinal puncture
3. Heparin-induced thrombocytopenia
Binds to platelet factor 4 (PF4) on activated platelet surface, triggering formation of IgG antibody against the heparin-PF4 complex
Even after discontinuation, antibodies sometimes continue to attack platelets
(Lower risk with LMWHs)
How can effects of parenteral anticoagulants be reversed?
- IV infusion of 🥨 Protamine sulfate
- Mainly for heparin, incomplete reversal if used for LMWHs
- Is a highly basic peptide that binds stably to negatively charged heparin → neutralise anticoagulant properties of heparin
Are parenteral anticoagulants safe for use in pregnancy?
- Both Heparin & LMWH do not cross the placenta (unlike Warfarin)
- Not been a/w fetal malformations
What are the contraindications for parenteral anticoagulants?
- Hypersensitive to heparins or pork products (those hypersensitive to pork showed cross reactivity to heparins)
- Active major bleeding
- Thrombocytopenia or antiplatelet antibodies
In whom should caution be exercised for parenteral anticoagulants?
- Elderly patients
- Risk of bleeding
Including patients with prosthetic heart valves, major surgery, regional or lumbar block anaesthesia, blood dyscrasias, recent childbirth, pericarditis or pericardial effusion & (LMWHs) renal insufficiency
What are the drug/food/herb interactions with parenteral anticoagulants?
All ↑ risk of bleeding
Drugs
Antiplatelets, anticoagulants, fibrinolytics, NSAIDs, SSRIs
Herbs/foods
Chamomile, fenugreek, garlic, ginger, ginkgo & ginseng
