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E4.PHARM > L36.Prophylaxis and Treatment of Thrombosis: ORAL Anticoagulants > Flashcards

L36.Prophylaxis and Treatment of Thrombosis: ORAL Anticoagulants Flashcards

1
Q

What is the most widely prescribed brand of ORAL anticoagulants?

A
  • only coumarin derivatives are used in US.

- warfarin (Coumadin) brand of ORAL anticoagulant is most widely prescribed

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2
Q

What are the prophylactic and therapeutic uses of warfarin and the coumarin anticoagulants?

A
  • prophylactic: prevention of thrombotic disorders (if you have risk factors or a pertinent history)
  • therapeutic: tx of established thrombus (DVT)
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3
Q

What are the anticoag target sites of warfarin?

A

-warfarin decreases the functionality of coagulation factors 2, 7a (releases TPFI), 9, and 10

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4
Q

What are the anticoag target sites of heparins?

A

-heparins target Factors 9a, 7a (release TPFI), 10a, and 2a (thrombin)

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5
Q

What is the chemical structure of oral anticoagulants structurally similar to? Why is this important?

A

ORAL anticoagulants are structurally similar to vit K (analogues)
-imp. because of vit K and activation of coagulation parameters

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6
Q

Warfarin MOA

A

-all agents depress formation of functional forms of Factors 2 (prothrombin), 7, 9, and 10 by inhibiting the carboxylation of glutamic acid in these proteins which is essential for Ca2+ binding

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7
Q

What is the Vitamin K cycle?

A
  • reduced vit K is converted into oxidized vit K by gamma-glutamyl carboxylase. this reduction is linked to the conversion of non-fxnl prozymogens to fxnl zymogens
  • warfarin blocks epoxide reductase so blocks vit K synthesis (all coag factors are produced in the liver)
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8
Q

What is the time course of Vit K dependent factors after warfarin?

A
  • long onset of action
  • this drug wont help immediately, thats why you need hep
  • factor 2=last one to come down
  • as factors decrease, INR ration increases
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9
Q

What is the dosing of warfarin?

A

day 1: 5-10 mg/d (initial dosing)
day 2: 5-7 mg/d (maintenance)
-pt wont be properly coagulated till 3-5 days

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10
Q

Warfarin-Route of Admin

A
  • all well absorbed orally

- F=100%

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11
Q

Why do oral anticoagulants have long t1/2?

A
  • due to binding to plasma albumin (warfarin is 97% bound)

- be careful if theres another drug with high protein binding

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12
Q

Warfarin Metabolism

A
  • Dicumarol and warfarin are hydroxylated to inactive compounds by HEPATIC ER
  • metabolism varies greatly in pts
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13
Q

Why is therapeutic monitoring of ORAL anticoagulant drugs necessary? What is used to monitor warfarin?

A
  • very narrow therapeutic index
  • warfarin impairs the blood coagulation in the extrinsic pathway
  • prothrombin time (PT)/INR is used to monitor warfarin anti-coag effects
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14
Q

What levels of PT are considered therapeutic?

A
  • 1.5 time prolongation of the PT from the baseline=therapeutic
  • Ex: if pts baseline is 12s, considered in therapeutic range at 18s.
  • a pt with a lesser prolongation than 1.5 times the baseline is subtherapeutic and a dose increase may be necessary
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15
Q

What is used in order to obtain uniform degrees of anticoagulation?

A

-INR (international normalized ratio
INR= PT(sec) patient/PT(sec) mean nml control
-ISI =internal sensitivity index
-INR universally used to adjust the level of anticoag in a given pt thus helping in dosage optimization

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16
Q

What are the FIVE factors that affect warfarin dose?

A
  1. Nutrition
  2. Anemia
  3. Liver disease
  4. Biliary Obstruction
  5. Drugs
17
Q

1/5 Nutrition

A

green leafy veggies with vit K, may have decrease in oral anticoag effects on the drugs because warfarin inhibits synthesis of vit K, so vit K which antagonizes pts who are od on warfarin

18
Q

2/5 Anemia

A

plasma volume is much larger than their cells, so drugs will be more diluted

19
Q

3/5 Liver Disease

A

liver=location of production for factors

20
Q

4/5 Biliary Obstruction

A

decreased absorption of warfarin so decreased anti-coag effects

21
Q

5/5 Drugs

A
  • aspirin will cause a lower INR
  • aspirin is high protein bound, displaces warfarin which is now circulating as a free drug and will have a much higher effect diuretics-dilution effect will decrease the work of warfarin.
22
Q

MORE drug interactions with warfarin–POTENTIATION

A
  • -drugs cause warfarin potentiation by:…
    a. causing vit K deficiency-pts on antibiotics will decrease natural flora of the gut and wont be able to produce vit K
    b. displacing warfarin from protein binding sites
    c. decreasing clotting-factor synthesis
    d. by suppressing or competing for microsomal enzymes–>takes longer for drug to be broken up
    e. by having antiplatelet aggregating properties–>dbl edged sword, more prone to bleeding
23
Q

MORE drug interactions with warfarin–INHIBITION

A
  • -drugs reported to cause inhibition of the anticoagulant action of warfarin by:…
    a. decreasing warfarin absorption
    b. enhancing warfarin metabolism
24
Q

Which drugs INCREASE the effect on bleeding via warfarin interactions?

A
  1. antibiotics
  2. antifungal
  3. antidepressants
  4. antiplatelet drugs
  5. amidarone
  6. anti-inflammatory agents
  7. acetaminophen
  8. alternative remedies: gingko biloba, dong quai, chamomile, St. John’s wort
25
Q

Which drugs DECREASE the effect on bleeding via warfarin interactions?

A
  1. alternative remedies: gingko biloba, dong quai, chamomile, St. John’s wort
  2. rafampin
26
Q

What is the toxicity of warfarin?

A
  • principal toxicity is marked hypoprothombinemia resulting in ecchymosis, purpura, hematuria, hemorrhage, or bloody noses
  • produces necrosis (coumadin induced necrosis; more common is -obese- women than men) which is due to the impairment of the functionality of protein C (also vit K dependent)–this protein also required gamma-carboxylation of glutamic acid for functionality
27
Q

Warfarin and pregnant patients-DONT DO IT

A

-NEVER perscribe warfarin to pregnant patients because it (and all oral anticoagulants) crosses the placental barrier and can form fetal bone malformation

28
Q

What is the treatment of oral anticoagulant overdose?

A

a. replacement of 4 factors (2,7,9,10) via infusion of whole fresh blood or frozen plasma
b. recombinant Factor VIIa (novo 7)
c. Vitamin K

29
Q

Vit K-Function

A
  • essential to the attachment of a calcium binding functional group to prothrombin protein (preence of gamma-carboxyglutamic acid)
  • required for the synthesis of clottable coagulation factors (2,7,9,10)
30
Q

Vit K-Therapeutic Use

A
  • drug-induced hypoprothrombinemia antidote
  • intestinal disorders and surgery (gastrectomy)
  • hypoprothrombinemias of newborn [coagulation proteins are lower in kids, doesnt normalize until ~9 yo]
31
Q

Vit K-Toxicity

A
  • -remarkably NON-toxic–
  • high doses sometimes cause hemolysis in infants (mainly water soluble vit K)
  • certain individuals who are sensitive to primaquine may develop hemolysis
32
Q

What are some new oral anticoagulants?

A 
-Anti-Xa (10a) agents-all fixed and dont need coagulation monitoring
>Rivaroxaban (Xarelto)
>Apixiban
>Edoxaban
---AND---
-Antithrombin (2a) agents 
>Dabigatran
>Ximelagatran
33
Q

Anti-10a: RIVAROXABAN

A 
Target: 10a
Dosing: fixed, 1x daily
Coagulation monitoring: no
Half life (h): 9h
RENAL clearance (%): 65
Interactions: potent CYP3A4 inhibitors
34
Q

Anti-10a: APIXIBAN

A 
Target: 10a
Dosing: fixed, TWICE daily
Coagulation monitoring: no
Half life (h): 9-14h
RENAL clearance (%): 25
Interactions: potent CYP3A4 inhibitors
--less bleeding than other drugs--
35
Q

Anti-10a: DABIGATRAN

A 
Target: 2a (thrombin)
Dosing: fixed, TWICE daily
Coagulation monitoring: no
Half life (h): 14-17h
RENAL clearance (%): 100
Interactions: proton pump inhibitors
--dont give to elderly with impaired renal clearance--
36
Q

New vs. WARFARIN dd

A 
Target: Vit K epoxide reductase
Dosing: variable, 1x daily
Coagulation monitoring: YES
Half life (h): 40
RENAL clearance (%): NONE
Interactions: multiple drugs, dietary vit K

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