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Flashcards in Anticoagulants Deck (46):
1

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

2

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

3

coagulation proteins affected by warfarin

FVII

FIX

FX

prothrombin

Protein C

Protein Z

Protein S

4

Describe the Vitamin K cycle

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monitoring of warfarin effect

prothrombin time, which is sensitive to factors II, VII, and X

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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

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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)

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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

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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.

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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

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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

12

adverse reactions of warfarin

increased risk of bleading

teratogenic

necrosis/gangrene

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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

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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

15

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

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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)

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contraindications of warfarin

pregnancy, especially 1st and 3rd trimester

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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

19

heparin

polymeric, highly sulfated glycosaminoclycan

30-50 saccharide units

binds to antithrombin

heparin-antithrombin complex inhibits FXa and thrombin equally

20

higher versus lower molecular weight heparin

lower mostly inhibits FXa, and higher inhibits thrombin and binds to platelets

all enhance the activity of antithrombin

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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

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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

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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

24

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.)

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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)

26

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

27

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

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advantages of unfractonated heparin

immediate effect

readily reversed by protamine

use in patients with renal insufficiency

29

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)

30

low molecular weight heparin

depolymerization of porcine heparin: 13-22 saccharide units

anti-Xa but little antithrombin activity

administered subcutaneously

31

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

32

protamine sulfate

reverses the effect of heparin, but has only limited effect on LMWHs

33

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

34

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

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major adverse effects of LMWH

bleeding, often in the epidural space after epidural catheter placements

don't give too soon after invasive procedures

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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

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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

38

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

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contraindications of fondaparinux

patients with renal failure because this drug is completely cleared by the kidneys

40

direct Xa inhibitors

oral anticoagulants

rivaroxaban - used for orthopedic prophylaxis, atrial fibrillation, and venous thrombosis

apixiban - used for othropedic prophylaxis and atrial fibrillation

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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

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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

43

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

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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

45

IV direct thrombin inhibitors

lepirudin - HIT

bivalirudin - coronary angioplasty

agratroban

46

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