IC3 Anticoagulants Flashcards
What are the 5 anticoagulants we need to know?
- warfarin
- dabigatran
- rivaroxaban
- heparin
- LMWHs
Which stage of hemostasis & thrombosis does anticoagulants act on?
secondary hemostasis (fibrin polymerization)
What is the general mechanism of action of anticoagulants?
Blocks activation of clotting factors
What drug class does warfarin belong to?
Vitamin K antagonist
Describe the MOA of warfarin
inhibits VKORC1 to inhibit synthesis of
* clotting factors 2, 7, 9, 10
* natural anticoagulants protein C and S
Explain the MOA of warfarin
- active vit K activates clotting factors 2, 7, 9, 10, and is reduced to inactive vit K in the process
- vit K reductase (VKORC1) reactivates inactivated vit K so that it can further activate more clotting factors
- warfarin is a vit K antagonist which inhibits VKORC1, preventing the reactivation of inactive vit K
- this reduces the activation of clotting factors 2/7/9/10 and protein C/S, resulting in anticoagulation
Warfarin PK
1. Duration of onset
2. Duration to peak plasma conc
3. Duration required to see full therapeutic effect
- 1-3 days
- 4h (uptodate)
- 5-7 days
how to rmbr: warfarin takes 1-3 days for effects to be seen, and 6-7 days for maximal effect. takes around 4h to reach peak plasma conc
Why does warfarin have such a long duration of onset?
Endogenous vit K reserves need to be depleted for effects to kick in
What is the main route of metabolism of warfarin?
Hepatic
What are the metabolizing enzymes of warfarin?
S-warfarin (more active): 2C9
R-warfarin: 1A1, 1A2, 3A4
Why is there such extensive interindividual variability in response to warfarin?
due to genetic polymorphisms of genes encoding for VKORC1 and 2C9
- VKORC1 polymorphism causes an increase in susceptibility of the enzyme to warfarin-induced inhibition –> lower dose required
- 2C9 polymorphism results in ↓ warfarin metabolism –> lower dose required
What are the side effects of warfarin?
- bleeding
- cutaneous necrosis in first 3-5 days
- hepatitis (in older men >60 within 1st month of therapy)
What is the reversal agent for warfarin?
vit K
What are the contraindications for warfarin?
- drug hypersensitivity
- active bleeding / risk of bleeding (eg. after surgery)
- severe/malignant HTN
- severe renal OR hepatic disease
- pregnancy (teratogenic)
- subacute bacterial endocarditis, pericarditis, pericardial effusion
What conditions must we be cautious of when using warfarin?
- breastfeeding
- diverticulitis, colitis
- mild-moderate HTN
- mild-moderate renal OR hepatic disease
- drainage tubes in any orifice
What is a common OTC medication that displays DDI with warfarin?
Paracetamol
* high dose >2g/day
* used >2 weeks
What is the effect of the DDI of warfarin with paracetamol?
↑ risk of bleeding
What are the drugs that ↑ risk of bleeding when used with warfarin?
- salicylates
- allopurinol
- PPI
- metronidazole (2C9 inhibitor)
- TCM/herbs/supplements (gingko, ginseng, cranberry juice)
What are the drugs that ↓ AP effect (ie. more likely to clot) when used with warfarin?
- barbiturates
- corticosteroids
- spironolactone
- thiazide diuretics
- TCM/herbs/supplements (vit K supplements, green tea)
What drug class does dabigatran and rivaroxaban belong to?
direct oral anticoagulants (DOAC)s / non-vit K antagonists
What clotting factor does dabigatran inhibit?
Factor IIa (thrombin)
What clotting factor does rivaroxaban inhibit?
Factor Xa
(how to rmbr: rivaroXAban)
What is the reversal agent for dabigatran?
Idarucizumab
What is the reversal agent for rivaroxaban?
Andexanet alfa
Describe the bioavailability of dabigatran VS rivaroxaban
rivaroxaban oral F > dabigatran
[80-100% VS 3-7%]
What are the side effects of dabigatran?
- bleeding
- GI symptoms
What are the side effects of rivaroxaban?
bleeding
Rivaroxaban is a substrate of … and …, therefore we need to be aware of DDI involving these two transporters.
Pgp
3A4
What is the route of administration of heparins?
parenteral
Describe the general mechanism of action of heparin
heparin potentiates the action of antithrombin III (ATIII), inactivating thrombin (factor IIa) and Xa
What clotting factors is UFH selective for?
2, 9, 10, 11, 12
factor IIa (thrombin) required to convert fibrinogen to fibrin. therefore, inhibition of factor 2 prevents clot formation
What clotting factors is LMWH selective for?
Xa
Why is LMWH preferred over heparin?
- higher bioavailability
- longer half life
- lower rate of thrombocytopenia (HIT is more a/w UFH; but there is cross-sensitivity with LMWH)
What are the side effects of heparin?
- bleeding
- ↑ risk of epidural/spinal hematoma & thus paralysis in pts receiving epidural/spinal anesthesia/spinal puncture
- heparin induced thrombocytopenia (HIT) (heparin > LMWH)
How does heparin cause thrombocytopenia?
heparin binds to platelet factor 4 (PF4) on activated platelet surface –> synthesis of IgG Ab against heparin-PF4 complex –> ↓ platelet count = thrombocytopenia
What is the reversal agent for heparin and LMWH?
protamine sulfate IV infusion
* complete reversal of heparin
* incomplete reversal of LMWH
What are the contraindications for heparin and LMWH?
- hypersensitivity to heparins or PORK PRODUCTS
- active major bleeding
- thrombocytopenia/antiplatelet Abs
Can heparin and LMWH be used in pregnancy?
yes
What conditions must we be cautious of when using heparins?
- elderly
- risk of bleeding (prosthetic heart valves, major surgery, regional/lumbar block anesthesia, blood disorders, recent childbirth, pericarditis/pericardial effusion)
- renal insufficiency (for LMWHs)
What are the drugs that will ↑ risk of bleeding when used with heparins?
- Antithrombotics, fibrinolytics
- NSAIDs
- SSRIs (eg. fluoxetine, paroxetine, sertraline)
- herbs (chamomile, fenugreek, garlic, ginger, gingko, ginseng)
