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
heparin
polymeric, highly sulfated glycosaminoclycan
30-50 saccharide units
binds to antithrombin
heparin-antithrombin complex inhibits FXa and thrombin equally
higher versus lower molecular weight heparin
lower mostly inhibits FXa, and higher inhibits thrombin and binds to platelets
all enhance the activity of antithrombin
heparin half-life
dose-dependent - 56 min after 100 U/kg and 156 min after 400 U/kg
reduced in patients with extensive thrombotic disease, and thrombin bound to fibrin is protected from heparin-antithrombin complex
unfractionated heparin
inactived if given orally
administered IV, subcutaneous
heparin-AT complex inhibits IXa, Xa, XIIa, VIIa-tissue factor as well as thrombin
inhibits smooth muscle proliferation, angiogenesis
metabolism of heparin
done in the liver and kidney
binds to endothelium, taken up by macrophages
30% inactivated by liver heparinase, and 70% excreted as uroheparin
neutralized by platelet factor 4
therapeutic uses of heparin
a. In the acute treatment of deep vein thrombosis, pulmonary thromboembolism, sudden arterial occlusion, consumption coagulopathy (DIC) associated with malignancy, and to prevent clotting in extracorporeal circuits (renal dialysis, heart-lung machine, etc.)
Complications: bleeding in approximately 20% of patients, especially women > 60. Contraindications (all relative): thrombocytopenia (platelet factor 4 neutralizes heparin), peptic ulcer, liver and renal disease. Antagonist: protamine sulfate - 5 mg for each 1000 u of heparin given.
b. Prophylaxis to prevent deep vein thrombosis and pulmonary embolism in patients on prolonged bed rest (post-operative, after myocardial infarction, etc.), or for chronic intravascular coagulation syndromes
Complication: osteoporosis and vertebral collapse when given for > 6 months.
c. In patients in whom warfarin is not appropriate (pregnant, non-compliant, etc.)
Heparin-induced thrombocytopenia
immunologic basis (antibodies to neoepitopes on platelet factor 4 induced by heparin-binding). Associated with paradoxical thromboses. When recognized, heparin must be discontinued immediately, and alternative anticoagulants started (direct thrombin inhibitors-discussed below)
monitoring of unfractionated heparin
aPTT monitoring
check after 4 hours and then every 6 hours
therapeutic range is dependent on aPTT reageant
alternative monitoring: anti-Xa levels
adverser reactions of unfractionated heparin
bleeding (more frequent in elderly and underweight) in wound/soft tissue, lungs, GI, GU, nasal, retroperitoneal region, CNS
rarely heparin induced thrombocytopenia
osteoporosis - enhances bone resorption, inhibits bone formation
mild inhibition of aldosterone increases potassium
advantages of unfractonated heparin
immediate effect
readily reversed by protamine
use in patients with renal insufficiency
disadvantages of unfractionated heparin
heterogenous mixture - only a fraction has anticoagulant activity
binds to a number of plasma proteins and vessel wall
neutralized by platelet factor
not effective in neutralizing clot-boud thrombin
minority of patients are therapeutic in the first 12 hours
heparin induced thrombocytopenia (HIT)
low molecular weight heparin
depolymerization of porcine heparin: 13-22 saccharide units
anti-Xa but little antithrombin activity
administered subcutaneously
advantages of low-molecular weight heparins
better bioavailability - less beinding to endothelium
predictable anticoagulant effect - less binding to plasma proteins
reliability of achieving therapeutic target
convenient dosint - based on weight
lower incidence of thrombocytopenia
routine lab monitoring unnecessary
lower bleeding rate - less inhibition of platelet function, less interference with platelet-vessel interaction, less binding to platelets and vWF
less osteoporosis
protamine sulfate
reverses the effect of heparin, but has only limited effect on LMWHs
three types of LMWHs
dalteparin, enoxaparin, tinzaparin
enoxaparin has the highest antiXa/antiIIa ratio and is the most bioavailable
all have renal clearance except enoxaparin which also has liver clearance
clinical use of LMWH
used for prophylaxis, superior to heparin in treatment of deep vein thrombosis/pulmonary embolism, unstable angina
can be used in pregnancy as it does not cross placenta or appear in breast milk
major adverse effects of LMWH
bleeding, often in the epidural space after epidural catheter placements
don’t give too soon after invasive procedures
fondaparinux
totally synthetic, consisting of the pentasaccharide sequence that serves as the binding site for antithrombin
enhances the ability of antithrombin to inhibit factor Xa, but has no anti-thrombin activity
advantages of fondaparinux
greater than 90% absorption from subcutaneous depots
very little binding to plasma proteins
half-life of 17-21 hours (once daily subcutaneous injection)
does not form complexes with platelet factor 4
uses of fondaparinux
somewhat more effective than LMWH for the prevention of thromboembolism
safe and effect for thromboembolism treatment
effective for pulmonary embolism and deep vein thrombosis
contraindications of fondaparinux
patients with renal failure because this drug is completely cleared by the kidneys
direct Xa inhibitors
oral anticoagulants
rivaroxaban - used for orthopedic prophylaxis, atrial fibrillation, and venous thrombosis
apixiban - used for othropedic prophylaxis and atrial fibrillation
direct thrombin inhibitors
thrombin has an exosite that binds to fibrinogen and a catalytic site that cleaves fibrinogin to fibrin
these inhibitors bind to one or both of these sites
parenteral direct thrombin inhibitors and their uses
desirudin - DVT prophylaxis in surgical patients
bivalirudin - thrombus prevention in coronary interventions
argatroban - approved for heparin-induced thrombocytopenia
dabigatran
oral direct thrombin inhibitor
prodrug, converted to dabigatran after absorption from the gut
approved for atrial fibrillation
eliminated by the kidneys
food has minimal effect on absorption
advantages of direct thrombin inhibitors
biophysical advantage over heparins
inactivate clot-bound thrombin in addition to soluble thrombin
inhibit thrombin directly, without requiring antithrombin as a cofactor
not activated by platelet factor 4 or heparinase
IV direct thrombin inhibitors
lepirudin - HIT
bivalirudin - coronary angioplasty
agratroban
argatroban
synthetic direct thrombin inhibitor
reversibly binds to catalytic site of thrombin
given IV for HIT
monitor with aPTT
conversion to warfarin problematic because argatroban also prolongs prothrombin time
