5. Oral Anticoagulants

Question 1

What is the MOA of warfarin?

Answer 1

inhibits the synthesis of vitamin-K dependent coagulation factors by interfering with the cyclic interconversion of Vit K epoxide to the active form of Vit K

Question 2

What are the vitamin-K dependent coagulation factors?

Answer 2

• prothrombin
• VII
• IX
• X

Question 3

________ is a cofactor for the carboxylation of glutamate residues to gamma-carboxyglutamic acid.

Answer 3

Vit K

Question 4

What process allows the coagulation proteins to undergo a conformational change that is necessary for their activation?

Answer 4

carboxylation

Question 5

Warfarin depletes the _______ form of Vitamin K.

Answer 5

reduced

Question 6

What is the reduced form of Vitamin K?

Answer 6

vitamin KH2

Question 7

Therapeutic doses of warfarin decrease the total amount of active Vit K-dependent clotting factors by _____%

Answer 7

30-50%

Question 8

Warfarin affects the activity of already synthesized coagulation factors. (T/F)

Answer 8

False: does not affect the activity of already synthesized clotting factors

Question 9

What is the degradation half-life of prothrombin?

Answer 9

60 hours

Question 10

What is the degradation half-life of factor VII?

Answer 10

4-6 hours

Question 11

What is the degradation half-life of factor IX?

Answer 11

24 hours

Question 12

What is the degradation half-life of factor X?

Answer 12

48-72 hours

Question 13

How many days of warfarin therapy are required before a clinical response occurs?

Answer 13

~ 5 days

Question 14

Warfarin reduces the activity of anticoagulant proteins __ and __.

Answer 14

C and S

Question 15

What is the half-life of protein C?

Answer 15

8 hours

Question 16

What is the half-life of protein S?

Answer 16

30 hours

Question 17

___________ may be induced after treatment with warfarin is started.

Answer 17

hyper-coagulation

Question 18

Why can hyper-coagulation occur at the initiation of warfarin therapy?

Answer 18

The rapid loss of protein C temporarily shifts the balance in favor of clotting until sufficient time has passed for warfarin to decrease the activity of the clotting factors.

Question 19

PT is prolonged by ______.

Answer 19

warfarin

Question 20

Factors reduced by warfarin at a rate proportional to their ________.

Answer 20

half-life

Question 21

During the first few days of warfarin therapy, the PT primarily reflects the depression of factor ____.

Answer 21

VII

Question 22

With subsequent warfarin treatment, the PT is prolonged by depression of _______ and _______.

Answer 22

prothrombin and factor X

Question 23

PT is a reliable measure of anticoagulation throughout the duration of warfarin therapy. (T/F)

Answer 23

False: not reliable in the early course

Question 24

What is the route of administration of warfarin?

Answer 24

oral

Question 25

Orally administered warfarin is well absorbed from the GI tract. (T/F)

Answer 25

True

Question 26

The effect of warfarin is greatly amplified when administered IV compared to oral. (T/F)

Answer 26

False: no difference

Question 27

Plasma concentrations of warfarin are detectable within ______ of administration.

Answer 27

1 hour

Question 28

The clinical effects of warfarin can be seen in _______.

Answer 28

5-7 days

Question 29

A loading dose of 25 mg of warfarin is recommended to achieve clinical effects more quickly. (T/F)

Answer 29

False: loading doses > 10 mg do not provide quicker effects and may be associated with hyper-coagulation

Question 30

Warfarin is ______ protein bound.

Answer 30

highly

Question 31

Where is warfarin eliminated?

Answer 31

hepatic metabolism (CYP450)

Question 32

Name 3 drugs that increase warfarin levels.

Answer 32

- erythromycin : abx - isoniazid : abx - fluconazole : antifungal - cimetidine : H2RA - amiodarone : antiarrhythmic - clofibrate : lipid-lowering - propranolol : β blocker

Question 33

Name 3 drugs that decrease warfarin levels.

Answer 33

- cholestyramine : lipid-lowering - barbiturates : CNS depressant - rifampin : abx - sucralfate : GI protectant

Question 34

What does INR stand for?

Answer 34

international normalized ratio

Question 35

Why is INR used?

Answer 35

normalization of results using different commercial sources of tissue factor

Question 36

What is ISI?

Answer 36

international sensitivity index: sensitivity of each particular thromboplastin to warfarin

Question 37

What is the formula for INR?

Answer 37

INR = (PT patient/ PT mean normal) ^ISI

Question 38

Thromboplastin with higher ISI values are more sensitive to anticoagulation effects. (T/F)

Answer 38

False: lower ISI = more sensitive

Question 39

For most indications what is the target INR for warfarin therapy?

Answer 39

2.0 – 3.0

Question 40

What is the target INR for mechanical heart valves?

Answer 40

2.5 – 3.5

Question 41

What is the usual starting dose for warfarin?

Answer 41

5 – 10 mg

Question 42

How is anticoagulation therapy managed for an established thrombosis or high risk for thrombosis?

Answer 42

- initial treatment: rapid acting parenteral anticoagulant (heparin or LMWH) - long-term: warfarin with INR determined q4 weeks

Question 43

What are the direct factor Xa inhibitors?

Answer 43

- rivaroxaban (Xarelto) - edoxaban (Savaysa) - apixaban (Eliquis)

Question 44

What are the direct thrombin inhibitors?

Answer 44

dabigatran (Pradaxa)

Question 45

Dabigatran is a prodrug. (T/F)

Answer 45

True

Question 46

Dabigatran is an irreversible competitive inhibitor of thrombin. (T/F)

Answer 46

False: reversible

Question 47

Dabigatran inhibits free or clot-bound thrombin?

Answer 47

both free and clot-bound

Question 48

Dabigatran inhibits thrombin's activation of ________.

Answer 48

platelets

Question 49

How is dabigatran eliminated?

Answer 49

primarily unchanged in urine | substrate of P-glycoprotein

Question 50

Dabigatran is an inducer of CYP450 enzymes. (T/F)

Answer 50

False

Question 51

Dabigatran is a substrate of CYP450 enzymes. (T/F)

Answer 51

False

Question 52

Dabigatran is not an inhibitor of CYP450 enzymes. (T/F)

Answer 52

True

Question 53

What drug will reduce the plasma concentrations of dabigatran?

Answer 53

P-glycoprotein inducers: rifampin

Question 54

Dabigatran shows linear PK. (T/F)

Answer 54

True

Question 55

What is the dose of dabigatran?

Answer 55

150 mg BID (may reduce for ↓ CrCl)

Question 56

What is dabigatran approved for?

Answer 56

reduction in risk of stroke and systemic embolism in non-valvular a.fib

Question 57

What is the "antidote" for reversing anticoagulation with dabigatran?

Answer 57

idarucizumab

Question 58

How is rivaroxaban dosed?

Answer 58

once or twice daily depending on indication and CrCl

Question 59

What is the onset of action of rivaroxaban?

Answer 59

3 hours

Question 60

Rivaroxaban requires no lab monitoring. (T/F)

Answer 60

True

Question 61

How is rivaroxaban eliminated?

Answer 61

metabolized by CYP3A4 and excreted unchanged in urine

Question 62

What is the onset of action of edoxaban?

Answer 62

~ 3 hours

Question 63

INR must be monitored with edoxaban therapy. (T/F)

Answer 63

False: no lab monitoring

Question 64

Edoxaban undergoes minimal liver metabolism. (T/F)

Answer 64

True

Question 65

How is edoxaban primarily eliminated?

Answer 65

unchanged by the kidneys

Question 66

What is the black box warning with edoxaban?

Answer 66

Do not administer to non-valvular atrial fibrillation patients with CrCl > 95 mL/min

Question 67

What is the onset of action of apixaban?

Answer 67

~ 3 hours

Question 68

Apixaban does not require lab monitoring. (T/F)

Answer 68

True

Question 69

What is the metabolism of apixaban?

Answer 69

- Hepatic: primarily by CYP3A4/5 | - ~27% unchanged in urine

Question 70

What are the advantages of using direct thrombin/Xa inhibitors vs. warfarin?

Answer 70

- similar efficacy in preventing clots - rapid onset of action - less drug interactions / no food interactions - wide therapeutic index - no lab monitoring

Question 71

What are the disadvantages of using direct thrombin/Xa inhibitors vs. warfarin?

Answer 71

- high cost - lack of antidotes - difficulty with renal impairment - not approved for preventing embolism following MI