Pharm II finished - Hefnawy

Question 1

warfarin action

Answer 1

• inhibits vit. K epoxide reductase complex 1 (VKORC1) enzyme–> interferes with synthesis/carboxylation of vit. K dependent factors 2,7,9,10* (and protein C) in liver*
• fail to recycle vit. K when taking warfarin
• mutations in VKORC1 –> warfarin resistant**

Question 2

VKORC1

Answer 2

-vit. K dependent
-produces factors 2,7,9,10, and protein C (anticoagulant) in liver by carboxylation
-

Question 3

what can lead to vit. K deficiency?

Answer 3

• taking antibiotics –> destroy bacteria that produce vit. K
• removing terminal ileum problems or fat malabsorption syndrome –> problems with bile salt and fat absorption
• also problems with Vit. K and warfarin absorption*

comes from gut flora or foliage

Question 4

what do you need to monitor with someone on warfarin?

Answer 4

• extrinsic pathway due to factor 7**

- PT/INR**

Question 5

which 2 are the most sensitive to vit. K deficiency?

Answer 5

• factor 7 and protein C (anticoagulant)** –> have very short half-lives
• protein C and S shorter half-life than factor 7*
• reason for warfarin inhibiting protein C before the others* –> hypercoagulation

Question 6

what leads to hyper coagulation of warfarin?

Answer 6

• protein C –> very vit. K dependent
• warfarin inhibits vit. K recycling –> inhibits protein C (anticoagulant) –> hyerpercoagulation***
• seen with INITIAL treatment of warfarin*
• decreases anticoagulant before pro-coagulants**
• give LOW dose warfarin or give bridge therapy with heparin before to prevent**

Question 7

pharmacokinetics of warfarin

Answer 7

• orally - 100% bioavailability
• 99% bound to proteins (albumin) –> no renal excretion**
• excreted/metabolized in liver by CYP2C9 (can have mutations)**
• give mixture of S and R forms bc metabolism is variable (S-warfarin 4x potent/stronger**)
• dependent on vit. K intake/absorption*

Question 8

difference between S and R warfarin

Answer 8

• R warfarin –> enzymes CYP2C19, 3A4, 1A2
• S warfarin –> enzymes CYP2C9**

many drugs affect these enzymes leading to increased excretion rate or toxicity from decreased metabolism

Question 9

indications of warfarin

Answer 9

• # 1 for prosthetic heart valves**
• chronic Afib*
• prophylaxis/treatment of DVT or PE*
• does not dissolve DVT, but prevents spreading**

-don’t try to dissolve uncomplicated clot in DVT with fibrinolytics** - give heparin or warfarin instead to prevent spread

Question 10

contraindications of warfarin

Answer 10

• pregnancy* (teratogen)
• HTN –> cause bursting in capillaries
• CYP mutations* –> changes in metabolism
• fat malabsorption syndrome* –> mess with vit. K absorption

Question 11

warfarin side effects

Answer 11

-hypercoagulation –> reduce the anti-coagulants before the pro-coagulants

reverse effects by giving fresh frozen plasma (contains coagulation factors)**
-Vit. K would take too long

Question 12

interactions of warfarin

Answer 12

• vit. K absorption*
• don’t take other NSAIDs
• antimicrobials –> inducers/inhibitors of CYP
• GI drugs
• lipid-lowering drugs

Question 13

antimicrobials that interfere with warfarin

Answer 13

1. erythromycin** –> inhibitors of CYP/metabolism of warfarin –> toxicity –> severe bleeding**
2. rifampin* –> inducer of CYP/metabolism of warfarin –> faster excretion

Question 14

GI drugs that interact with warfarin

Answer 14

-cimetidine and omezaprole*** (OTC drugs) –> inhibit the metabolism of warfarin –> toxicity

Question 15

lipid lowering drugs of warfarin

Answer 15

-cholestyramine** –> impair vit. K and warfarin absorption

Question 16

comparing warfarin and rivaroxaban**

Answer 16

1. warfarin
   - monitor with PT/INR
   - takes 1-2 days to be active
   - hypercoagulation
   - dependent on vit. K
2. rivaroxaban
   - fast acting
   - no monitoring with aPTT
   - no hyper coagulation
   - not dependent on vit. K