Anticoagulants Flashcards
warfarin (coumadin)
a vitamin K antagonist
Mechanism: Inhibits the enzymatic reduction of vitamin K epoxide. Vitamin K (in the reduced state) is the coenzyme of a carboxylase responsible for the carboxylation of glutamic acid residues on factors II, VII, IX, X, and proteins C, S, and Z.
slow-acting anticoagulant because the depetion of carboxylated factors from the circulation is a function of their half-life
warfarin and reductase
principle modulator of warfarin response
mutations either increase sensitivity to warfarin or cause hereditary warfarin resistance
Vitamin K Epoxide Reductase is the main regulator of the carboxylation reaction
coagulation proteins affected by warfarin
FVII
FIX
FX
prothrombin
Protein C
Protein Z
Protein S
Describe the Vitamin K cycle
monitoring of warfarin effect
prothrombin time, which is sensitive to factors II, VII, and X
warfarin metabolism
metabolized by P450
SNPs in CYP2C9 effect the rate of warfarin metabolism
SNPs in VKORC1 leads to resistance and higher doses are required
When does warfarin treatment become effective?
warfarin becomes effective when levels of factor IX and X are down to below 20-30%
thsi requires at least 5 days of dosing to achieve therapeutic effect
and INR between 2-3 is therapeutic (8+ indicates too much drug)
International Normalization Ratio (INR)
derived from PT
ratio of patient PT to control PT, raised to ISI (international sensitivity index) power
INR = (patient PT/control PT)ISI
ISI is specific for each thromboplastin reagent
value is used to determine level of warfarin anticoagulation
factors that potentiate warfarin therapy
a. **poor oral intake of vitamin K **(patients on restricted diets, anorexic, diarrhea, destruction of bowel flora (a source of vitamin K)
b. polymorphisms of the reductase (VKORC1) are common
c. drugs inhibiting metabolic clearance (CYP 2C9) such as erythromycin, fluconazole, anti-inflammatory agents, H2-blockers
d. liver disease & CYP 2C9 polymorphisms (impaired metabolism)
e. unknown mechanism-other antibiotics, anti-arrhythmic drugs such as amiodarone, some herbals, etc.
factors that antagonize warfarin therapy
recent vitamin K therapy, anticonvulsants, and certain antibiotics (enhance CYP 2C9). Foods (broccoli, greens, etc.) rich in vitamin K have minimal effect and should not be restricted from the diet
warfarin necrosis
Heterozygotes for Protein C or S deficiency, or persons with low levels of Protein C/S due to poor diet and relative deficiency of vitamin K, may suffer massive skin and subcutaneous fat necrosis if suddenly exposed to full doses of warfarin. This is due to a disproportionate decline in Protein C or S as compared to factors IX, X, and prothrombin
adverse reactions of warfarin
increased risk of bleading
teratogenic
necrosis/gangrene
factors that increase risk of bleeding while a patient is on warfarin
vitamin K deficiency
drug interactions that alter warfarin binding, metabolism, or elimination
liver disease - decreased synthesis of clotting factors
polymorphisms in metabolism of warfarin
older age - increased risk of trauma or vascular problems
interaction with other medications that increase risk such as aspirin or NSAIDs
treatment of elevated INR in cases of no bleeding when on warfarin
hold warfarin
give oral (2.5 or 5 mg) vitamin K
if can’t eat or INR > 9, give vitamin K by injection
treatment of elevated INR in cases of bleeding when on warfarin
hold warfarin
give vik K oral or IV (slowly)
fresh frozen plasma (FFP), 20 ml/kg, transiently shortens PT by providing infusion of clotting factors
if bleeding is life-threatening, rVIIa or prothrombin complex concentrates (activated clotting factors
indicatsions for warfarin therapy
chronic anticoagulation of patients with thromboses
artificial heart valves
atrial fibrillation (to prevent embolization)
and other conditions predisposing to thrombosis (antithrombin, Protein C or S deficiency)
contraindications of warfarin
pregnancy, especially 1st and 3rd trimester
drugs given concurrently with warfarin
unfractionated or low molecular weight heparin
fondparinux
argatroban
**this is necessary because of the lag time before warfarin takes effect
**patients may be hypercoagulable to start because protein C and S levels fall first before many of the other clotting factors