L36.Prophylaxis and Treatment of Thrombosis: ORAL Anticoagulants Flashcards
What is the most widely prescribed brand of ORAL anticoagulants?
- only coumarin derivatives are used in US.
- warfarin (Coumadin) brand of ORAL anticoagulant is most widely prescribed
What are the prophylactic and therapeutic uses of warfarin and the coumarin anticoagulants?
- prophylactic: prevention of thrombotic disorders (if you have risk factors or a pertinent history)
- therapeutic: tx of established thrombus (DVT)
What are the anticoag target sites of warfarin?
-warfarin decreases the functionality of coagulation factors 2, 7a (releases TPFI), 9, and 10
What are the anticoag target sites of heparins?
-heparins target Factors 9a, 7a (release TPFI), 10a, and 2a (thrombin)
What is the chemical structure of oral anticoagulants structurally similar to? Why is this important?
ORAL anticoagulants are structurally similar to vit K (analogues)
-imp. because of vit K and activation of coagulation parameters
Warfarin MOA
-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
What is the Vitamin K cycle?
- 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)
What is the time course of Vit K dependent factors after warfarin?
- 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
What is the dosing of warfarin?
day 1: 5-10 mg/d (initial dosing)
day 2: 5-7 mg/d (maintenance)
-pt wont be properly coagulated till 3-5 days
Warfarin-Route of Admin
- all well absorbed orally
- F=100%
Why do oral anticoagulants have long t1/2?
- due to binding to plasma albumin (warfarin is 97% bound)
- be careful if theres another drug with high protein binding
Warfarin Metabolism
- Dicumarol and warfarin are hydroxylated to inactive compounds by HEPATIC ER
- metabolism varies greatly in pts
Why is therapeutic monitoring of ORAL anticoagulant drugs necessary? What is used to monitor warfarin?
- 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
What levels of PT are considered therapeutic?
- 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
What is used in order to obtain uniform degrees of anticoagulation?
-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
What are the FIVE factors that affect warfarin dose?
- Nutrition
- Anemia
- Liver disease
- Biliary Obstruction
- Drugs
1/5 Nutrition
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
2/5 Anemia
plasma volume is much larger than their cells, so drugs will be more diluted
3/5 Liver Disease
liver=location of production for factors
4/5 Biliary Obstruction
decreased absorption of warfarin so decreased anti-coag effects
5/5 Drugs
- 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.
MORE drug interactions with warfarin–POTENTIATION
- -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
MORE drug interactions with warfarin–INHIBITION
- -drugs reported to cause inhibition of the anticoagulant action of warfarin by:…
a. decreasing warfarin absorption
b. enhancing warfarin metabolism
Which drugs INCREASE the effect on bleeding via warfarin interactions?
- antibiotics
- antifungal
- antidepressants
- antiplatelet drugs
- amidarone
- anti-inflammatory agents
- acetaminophen
- alternative remedies: gingko biloba, dong quai, chamomile, St. John’s wort
Which drugs DECREASE the effect on bleeding via warfarin interactions?
- alternative remedies: gingko biloba, dong quai, chamomile, St. John’s wort
- rafampin
What is the toxicity of warfarin?
- 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
Warfarin and pregnant patients-DONT DO IT
-NEVER perscribe warfarin to pregnant patients because it (and all oral anticoagulants) crosses the placental barrier and can form fetal bone malformation
What is the treatment of oral anticoagulant overdose?
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
Vit K-Function
- 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)
Vit K-Therapeutic Use
- drug-induced hypoprothrombinemia antidote
- intestinal disorders and surgery (gastrectomy)
- hypoprothrombinemias of newborn [coagulation proteins are lower in kids, doesnt normalize until ~9 yo]
Vit K-Toxicity
- -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
What are some new oral anticoagulants?
-Anti-Xa (10a) agents-all fixed and dont need coagulation monitoring >Rivaroxaban (Xarelto) >Apixiban >Edoxaban ---AND--- -Antithrombin (2a) agents >Dabigatran >Ximelagatran
Anti-10a: RIVAROXABAN
Target: 10a Dosing: fixed, 1x daily Coagulation monitoring: no Half life (h): 9h RENAL clearance (%): 65 Interactions: potent CYP3A4 inhibitors
Anti-10a: APIXIBAN
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--
Anti-10a: DABIGATRAN
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--
New vs. WARFARIN dd
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
