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EDUCATIONAL OBJECTIVE: Readers will recognize and appropriately manage war arin re sistance in patients who need higher-than-expected doses o this drug An algorithm for managing warfarin resistance AbstrAct

Some patients need higher-than-expected doses o war arin (Coumadin) to get their international normalized ratio (INR) into the therapeutic range. The cause o war arin resistance can be either acquired (eg, poor compliance, drug interactions, dietary interactions) or hereditary, but the genetic mechanisms o war arin resistance are not well understood. This review o ers an algorithm or the evaluation o patients with suspected war arin resistance. Key Points

The most common cause o war arin resistance is noncompliance. Others include poor absorption, high vitamin K intake, hypersensitivity to vitamin K, and rapid drug deactivation. Patient education is necessary to improve compliance and to mitigate adverse e ects o war arin therapy, regardless o the dose. In time, it may be possible to individualize anticoagulant dosing on the basis o genetic testing or patients with war arin resistance, although currently such tests are not routinely advocated and are usually done only in specialized laboratories. In true hereditary war arin resistance, there are two approaches to treatment: increase the war arin dosage (perhaps to as high as 100 mg/day or more), or switch to another anticoagulant. W ar arin (coumadin) the F gs e s s ge ble e eq s t st e t h eve e - t es e the eq pe t e e s e t v es g e

th t the el

the , the e s

y p t e ts wh

lly h gh

ses

See related patient information at http://my.clevelandclinic.org/drugs/Coumadin/hic_ Understanding_Coumadin.aspx W I the p , g e phs th t v t ve st sy - thes ze ses 1948, w s st ll the es st e ly l h w t t e

ll w, we ev ew the

WHAT IS WArfArIn reSISTAnce? Res st s the H weve , reVieW doi:10.3949/ccjm.76a.09062 CREDIT CME Olusegun OsinbOwale, MD, Mba, RPVi Department o Cardiology, Section o Noninvasive e t w l h s bee es be - b t e se the te t l lze

b l ty t p h ghe w

g the p th eq e e t

Cardiology, Ochsner Clinic Foundation, New Orleans, LA MOnzR al Malki, MD Biotherapeutics Department Laboratory, Division o Surgical Research, Boston University School o Medicine, Roger Williams Medical Center, Providence, RI anDRew schaDe, MD, P D Division o Pathology and Laboratory Medicine, Department o Clinical Pathology, Cleveland Clinic JOhn R. baRthOlOMew, MD Department o Cardiovascular

Medicine, Head, Section o Vascular Medicine, Cleveland Clinic 724 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 NUMBER 12 DECEMBER 2009

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 NUMBER 12 DECEMBER 20097 2 5 osinboWAle And colleAgues es The W A p t ge es st t t h tsel est bl sh the lly e e te s st e e e e t th w g s s ly w es st w es st e. The p ev le ses t l e, wh h s e e ee t s h s e the w - pe t

weekly w

ew th lle

- b

e s th t p t e ts

ses

WHAT cAUSeS WArfArIn reSISTAnce? W t l te es st s s q e be l ss e t y, p e h st te s s ph k et vs ph

e vs he e sista

A qui d vs h H lse4 q e teg

dita y zes w he e t y.

es st

e s e the

Acquired resistance t w : P se) H gh De e se bs pt w s pt v t K p t e t pl e (the st

es lt

 I warfarin is metabolized by P450 enzymes D g table 1).12,13 Hereditary resistance h s bee p st l te t be se by ge et e h t le t s th t s s ly w es lt e - the , ste et b l s the g ( te t s ( th s p ge511) e se le e (see

H weve , the ge et es st Pa > 15 m / a h wa a a e e

e st

Warfarin is metabolized by P450 enzymes W e s e t e s ( e the p le t-h e S-e s p te t s the xt e RSge s e s), wh h te y et b l s .5,6 The t e s th ee t ve t es ght-h e R-e t e .

H weve , w s hep t lly et b l ze by the yt h e P450 plex, lth gh the S- s e s e p te t, the R- s e h s l ge h l -l e. Th s s be se S-w s et b l ze ste (v 7-hy xyl t by CYP2C9) th R-w (wh h s et b l ze v 10-hy xyl t by CYP1A1, CYP1A2, CYP3A4).7 E e t vely, S-w ts 60% t 70% the ve ll t g l t esp se, wh le the R-e t e s esp s ble pp x tely 30% t 40%.8 The ste y-st te s e t t w te -

e te by the se, by CYP2C9- e et b l s the S-e t e , by el

t hy xyl et b l tes, by g st test l bs pt ( she by he v t g), by -CYP2C9 et b l s , by the p t e ts t t l st te et, by te t s.9 s p ly bs be the test l t t te l st b v l b l ty 100%,10,11 ts t s s lly see w th 60 t 90 It ls be g ve t ve sly g lly. W

g st t , w th pe k bs ptes. s bl -

W s h ghly (97%99%) b t pl s p te s, p ly t lb , w th v l e st b t 0.12 t 0.13 L/kg.10 Its e h l -l e s 44 h s ( ge 2060).

726 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 NUMBER 12 DECEMBER 2009 WArfArin resistAnce esp te seve Pha ma Ph The e h ki k et s l ti se ep ts he e t y e- s st e e by s l p tte s

es

sista es st e se t e w es lt le lt pl e h s she t bee bs pt el e se el e te , lth gh the t ll w

Genetic factors. D pl

t yt 9 ex st th t

h e

e P450 e zy e ge es h s bee ss te w th h ghe -th y , le sh te y p e se the g t pl s x es st l e h ee e tes e.15

es l

be s t b t g t phe type t v ty, g ve th t the e e lleles

Hypoalbuminemia t le e w

h l -l lly e v ls

Hyperalbuminemia t b te t w

g b

g.Hyperlipidemia. Seve th t l we Diuretics w TABLe 1 d p P t a a tiat pp m h wa a i ha by g se

bse ve s h ve ly t gly e es, e ses the se s t v ty t w

l p s, p esp se t v l

y e e se the e g the pl s

e, w th

s bseq e t

e se

l tt

t v

wa a

Acetaminophen (Tylenol) Alcohol Allopurinol (Zyloprim) Amiodarone (Cordarone) Amoxicillin-clavulanate (Augmentin) Aspirin Celecoxib (Celebrex) Cipro oxacin (Cipro) Erythromycin Fenofbrate (Tricor) Fluconazole (Di ucan) Fluvastatin (Lescol) Garlic Gingko Levo oxacin (Levaquin) Levothyroxine (Synthroid) Nonsteroidal anti-in ammatory drugs Omeprazole (Prilosec) Paclitaxel (Taxol) Propa enone (Rythmol) Ritonavir (Norvir) Tramadol (Ultram) Trimethoprim-sul amethoxazole (Bactrim) Vitamin E I hibit wa a i

Azathioprine (Imuran)

Barbiturates Bosentan (Tracleer) Carbamazepine (Tegretol) Cholestyramine Cortisone Dicloxacillin Etodolac (Lodine) Ginseng Haloperidol (Haldol) Mercaptopurine (Purinethol) Multivitamins Na cillin (Unipen) Oral contraceptives Parenteral and enteral nutritional supplements Ribavirin (Rebetol) Ri ampin (Ri adin) Ritonavir (Norvir) Spironolactone (Aldactone) Trazodone (Desyrel) Vitamin C Vitamin K Wa a a pa m h ma v v wa a am K h -

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EDUCATIONAL OBJECTIVE: Readers will recognize and appropriately manage war arin re sistance in patients

who need higher-than-expected doses o this drug An algorithm for managing warfarin resistance AbstrAct

Some patients need higher-than-expected doses o war arin (Coumadin) to get their international normalized ratio (INR) into the therapeutic range. The cause o war arin resistance can be either acquired (eg, poor compliance, drug interactions, dietary interactions) or hereditary, but the genetic mechanisms o war arin resistance are not well understood. This review o ers an algorithm or the evaluation o patients with suspected war arin resistance. Key Points

The most common cause o war arin resistance is noncompliance. Others include poor absorption, high vitamin K intake, hypersensitivity to vitamin K, and rapid drug deactivation. Patient education is necessary to improve compliance and to mitigate adverse e ects o war arin therapy, regardless o the dose. In time, it may be possible to individualize anticoagulant dosing on the basis o genetic testing or patients with war arin resistance, although currently such tests are not routinely advocated and are usually done only in specialized laboratories. In true hereditary war arin resistance, there are two approaches to treatment: increase the war arin dosage (perhaps to as high as 100 mg/day or more), or switch to another anticoagulant. W ar arin (coumadin) the F gs e s s ge ble e eq s t st e t h eve e - t es e the eq pe t e e s e t v es g e

th t the el

the , the e s

y p t e ts wh

lly h gh

ses

See related patient information at http://my.clevelandclinic.org/drugs/Coumadin/hic_ Understanding_Coumadin.aspx W I the p , g e phs th t v t ve st sy - thes ze ses 1948, w s st ll the es st e ly l h w t t e

ll w, we ev ew the

WHAT IS WArfArIn reSISTAnce? Res st s the H weve , reVieW doi:10.3949/ccjm.76a.09062 CREDIT CME Olusegun OsinbOwale, MD, Mba, RPVi Department o Cardiology, Section o Noninvasive e t w l h s bee es be - b t e se the te t l lze

b l ty t p h ghe w

g the p th eq e e t

Cardiology, Ochsner Clinic Foundation, New Orleans, LA MOnzR al Malki, MD Biotherapeutics Department Laboratory, Division o Surgical Research, Boston University School o Medicine, Roger Williams Medical Center, Providence, RI anDRew schaDe, MD, P D Division o Pathology and Laboratory Medicine, Department o Clinical Pathology, Cleveland Clinic JOhn R. baRthOlOMew, MD Department o Cardiovascular

Medicine, Head, Section o Vascular Medicine, Cleveland Clinic 724 CLEVELAND CLINIC JOURNAL OF MEDICINE

VOLUME 76 NUMBER 12 DECEMBER 2009

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 NUMBER 12 DECEMBER 20097 2 5 osinboWAle And colleAgues es The W A p t ge es st t t h tsel est bl sh the lly e e te s st e e e e t th w g s s ly w es st w es st e. The p ev le ses t l e, wh h s e e ee t s h s e the w - pe t

weekly w

ew th lle

- b

e s th t p t e ts

ses

WHAT cAUSeS WArfArIn reSISTAnce? W t l te es st s s q e be l ss e t y, p e h st te s s ph k et vs ph

e vs he e sista

A qui d vs h H lse4 q e teg

dita y zes w he e t y.

es st

e s e the

Acquired resistance t w : P p t e t pl e (the st

es lt

 se) H gh De I warfarin is metabolized by P450 enzymes D g table 1).12,13 Hereditary resistance h s bee p st l te t be se by ge et e h t le t s th t s s ly w es lt e - the , ste et b l s the g ( te t s ( th s p ge511) e se le e (see e se bs pt w s pt v t K

H weve , the ge et es st Pa > 15 m / a h wa a a e e

e st

Warfarin is metabolized by P450 enzymes W e s e t e s ( e the p le t-h e S-e s p te t s the xt e RSge s e s), wh h te y et b l s .5,6 The t e s th ee t ve t es ght-h e R-e t e .

H weve , w s hep t lly et b l ze by the yt h e P450 plex, lth gh the S- s e s e p te t, the R- s e h s l ge h l -l e. Th s s be se S-w s et b l ze ste (v 7-hy xyl t by CYP2C9) th R-w (wh h s et b l ze v 10-hy xyl t by CYP1A1, CYP1A2, CYP3A4).7 E e t vely, S-w -

t s

ts 60% t 70% the ve ll g l t esp se, wh le the R-e t e esp s ble pp x tely 30% t 40%.8 e t t w

The ste y-st te e te et b l s t hy t l bs v t g), p t e ts te t W s

by the se, by CYP2C9- e te the S-e t e , by el xyl et b l tes, by g st tespt ( she by he by -CYP2C9 et b l s , by the t t l st te et, by s.9

s p ly bs be the test l t t te l st b v l b l ty 100%,10,11 ts t s s lly see w th 60 t 90 It ls be g ve t ve sly g lly.

g st t , w th pe k bs ptes. s bl -

W s h ghly (97%99%) b t pl s p te s, p ly t lb , w th v l e st b t 0.12 t 0.13 L/kg.10 Its e h l -l e s 44 h s ( ge 2060).

726 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 NUMBER 12 DECEMBER 2009 WArfArin resistAnce esp te seve l se ep ts he e t y e- s st e e by s l p tte s

es

Pha ma Ph The e h

ki k et s

ti

sista es st e se t e w es lt le lt pl es l be s t b t g t phe type t v ty, g ve th t the e e lleles e h s she t bee bs pt el e se el e te , lth gh the t ll w

Genetic factors. D pl t yt 9 ex st th t h e

e P450 e zy e ge es h s bee ss te w th h ghe -th y , le sh te y p e se the g t pl s x es st l e h ee e tes e.15

Hypoalbuminemia t le e w

h l -l lly e v ls

Hyperalbuminemia t b te t w

g b

g.Hyperlipidemia. Seve th t l we Diuretics w TABLe 1 d p P t a a tiat pp m h wa a i ha by g se

bse ve s h ve ly t gly e es, e ses the se s t v ty t w

l p s, p esp se t v l

y e e se the e g the pl s

e, w th

s bseq e t

e se

l tt

t v

wa a

Acetaminophen (Tylenol) Alcohol Allopurinol (Zyloprim) Amiodarone (Cordarone) Amoxicillin-clavulanate (Augmentin) Aspirin Celecoxib (Celebrex) Cipro oxacin (Cipro) Erythromycin Fenofbrate (Tricor) Fluconazole (Di ucan) Fluvastatin (Lescol) Garlic Gingko Levo oxacin (Levaquin) Levothyroxine (Synthroid) Nonsteroidal anti-in ammatory drugs Omeprazole (Prilosec) Paclitaxel (Taxol) Propa enone (Rythmol)

Ritonavir (Norvir) Tramadol (Ultram) Trimethoprim-sul amethoxazole (Bactrim) Vitamin E I hibit wa a i

Azathioprine (Imuran) Barbiturates Bosentan (Tracleer) Carbamazepine (Tegretol) Cholestyramine Cortisone Dicloxacillin Etodolac (Lodine) Ginseng Haloperidol (Haldol) Mercaptopurine (Purinethol) Multivitamins Na cillin (Unipen) Oral contraceptives Parenteral and enteral nutritional supplements Ribavirin (Rebetol) Ri ampin (Ri adin) Ritonavir (Norvir) Spironolactone (Aldactone) Trazodone (Desyrel) Vitamin C Vitamin K Wa a a pa m h ma v v wa a am K h -

Warfarin Resistance

Download this Document for FreePrintMobileCollectionsReport Document

..

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. Follow Aom Phatchareewan..

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PreviousNext

p.

p.

p.

p.

p.

p.

p.

p.

p.

p.

p.

p.

p.

p.

p. .

More from this user

PreviousNext

141 p.

9 p.

10 p.

7 p. .

Add a Comment

. .

. ..

Upload a Document Search Documents Follow Us! scribd.com/scribd twitter.com/scribd facebook.com/scribd About Press Blog Partners Scribd 101 Web Stuff Scribd Store Support FAQ Developers / API Jobs Terms Copyright Privacy .

Copyright 2011 Scribd Inc. Language: English.