1

6 . 10400

January-March 2011 Vol.19, No.1

.........................................................................

warfarin (drug interaction of warfarin)....................

Warfarin and intracranial haemorrhage........................................................
Phenytoin/Fosphenytoin....................................................................................

4
6
7

ToxCase Conference
Acetaminophen induced nephrotoxicity........................................... 10

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( 24 )
1.



Internet
2.

3.

4.

5. (Poison and Drug

Information Bulletin)
3

page 2

....................................................................................................
. ................................................................................................
..............................................................................................
/ ........................................................
. ........................................ ....................................
:
{ 1 100
{ 2 150
{ 3 250

.

026-4-01398-4

................

()

P&D Information Bulletin / Vol. 19 No. 1, 2011

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..

French Medical Societies

The French National Authority for Health (Haute Autorite
Sant HAS)
1979 2007 766
HAS
website 2008
(vitamin K
antagonists : VKA warfarin )
3
1.

24

INR (International Normalized Ratio)
INR
- INR 3-4 (
INR > 4 )
- INR 4-6 1 INR 2-3 (
1 INR 1-2 24 )
- INR 6-10 INR
2 ( INR > 6
1 INR 24
)
- INR >10 5

2.

1 5
1.
2. systolic BP < 90 mmHg
40 mmHg, MAP <65 mmHg,
shock

3. surgery,
interventional radiology, endoscopy
4. PRC transfusion
5.
: intracranial, intraspinal, intraocular,
retroorbital, hemothorax, hemoretroperitoneum, hemopericardium,
deep muscle, GI bleeding, hemarthrosis

- INR < 1.5

- Resuscitation
-
- surgical, endoscopic
endovascular procedure
- antidote
1. Prothrombin Complex Concentrate (PCC) dose 25-50
unit/kg of factor IX intravascular rate 4 ml/min bolus dose
Fresh Frozen Plasma (FFP)
PCC
2. Vitamin K 10 mg, intravenously
anaphylactic reaction
3. recombinant activated factor VII (rFVIIa,
NovoSeven)
VKA
INR

24
brain CT scan
4-6

page 3

 VKA
VKA 48-72
VKA endoscopic, endovascular procedure intracranial hemorrhage
1-2
bridging therapy [ enoxaparin warfarin]
VKA

VKA
- VKA (mechanical heart
valve) atrial fibrillation perioperative bridging
therapy 3
1.) Therapeutic subcutaneously low-molecular weight
heparin (LMWH)
2.) Therapeutic intravenously unfractionated heparin (UFH)
3.) Therapeutic subcutaneously UFH

venous thromboembolism (VTE)

1
1-3 preoperative
vena cava filter bridging therapy LMWH
UFH
24-48 bridging
therapy therapeutic heparin doses INR

INR < 1.5 <1.2 neurosurgery

skin surgery, cataract surgery,
rheumato procedures with low risk of bleeding, some dental
procedures, some GI endoscopic INR 2-3
VKA

1. Pernod G, Godie'r A, Gozalo C, Tremey B, Sie' P. French clinical

practice guidelines on the management of patients on vitamin K
antagonists in at-risk situations (overdose, risk of bleeding, and
active bleeding). Thromb Res 2010 Sep;126(3):167-74.

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warfarin (drug Interaction of warfarin)

.
..

Warfarin

3 .
99

coagulation factor

coagulation factor

factor VII 5 .
INR
factor VII 25% 15 (3

page 4

factor VII)
warfarin 20-60
5 6

warfarin racemic form 2

isomers R warfarin S warfarin S isomer
R isomer
R warfarin P450 enzyme CYP 1A2
3A4 S warfarin
CYP 2C9 S warfarin
R warfarin

P&D Information Bulletin / Vol. 19 No. 1, 2011

Cytochrome P450 CYP

mitochondria endoplasmic reticulum

CYP
,
- CYP

bilirubin
- CYP 2C9 ( 1A2 3A4)
warfarin
CYP warfarin

CYP warfarin
( 1 2)
1 CYP
1A2
cimetidine
FQs

2C9
fluconazole
amiodarone
isoniazid

3A4,5,7
indinavir
nelfinavir
ritonavir
clarithromycin
itraconazole
etoconazole
erythromycin
grapefruit
verapamil
diltiazem
cimetidine
amiodarone
NOT azithromycin

2 CYP
1A2
tobacco

2C9
rifampin

3A4,5,7
carbamazepine
phenobarbital
phenytoin
pioglitazone
rifampin
troglitazone

CYP warfarin

- albumin warfarin
- warfarin cholestylamine
- cyclic interconversion
second third generation
cephalosporins
- coagulation factor thyroxine
- flora
sulfonamide, broad spectrum
-
NSIADs, high dose penicillin ( 3)

( 12)

3 warfarin

acetaminophen, NSAIDs, allopurinol,

miodarone, quinidine,
clarithromycin, cephalosporins, erythromycin,
metronidazole, quinolones, TMP-SMX,
tetracycline, fluconazole, isoniazid,
ketoconazole, anabolic steroids,
chloral hydrate, cimetidine, clofibrate,
cyclic antidepressants, disulfiram, ethanol,
statins, omeprazole, phenytoin, sulfonylureas,
tamoxifen, thyroxine, vitamin E
cranberry, gingko, green tea, omega3

antacids, barbiturates, carbamazepine,

cholestyramine, olestipol, corticosteroids,
griseofulvin, oral contraceptives, phenytoin,
rifampin, vitamin K
dicloxacillin, Q10

page 5

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Warfarin and intracranial haemorrhage

..

warfarin
1-5%

8-10
warfarin
warfarin 3
1. embolism
atrial fibrillation
2.
3.
warfarin

warfarin

warfarin , INR
, > 80 , Glasgow Coma Score (GSC),
, intraventicular hemorrhage

Pathogenesis



warfarin
INR

Immediate management
pathogenesis warfarin
warfarin
vitamin K cofactor
prothrombin, factor VII, IX, X
coagulation factor
4 vitamin K, FFP, PCC,
recombinant activated factor VII

1 Options for reversal in warfarin associated intracerebral haemorrhage

Appelboam, R. and E.O. Thomas, Warfarin and intracranial haemorrhage. Blood Rev, 2009. 23(1): p. 5.

page 6

P&D Information Bulletin / Vol. 19 No. 1, 2011

Vitamin K
vitamin K ,

Fresh frozen plasma
coagulation factor

CYP1A2

Prothrombin complex concentrated
coagulation factor

FFP

Recombinant activated factor VIII
hemophilia

vitamin K PCC
PCC FFP
warfarin
bridging therapy

warfarin
(European Society
of Cardiologist/Stroke) 7-14

1. Appelboam R, Thomas EO. Warfarin and intracranial

haemorrhage. Blood Rev 2009; 23(1): 1-9.
2. Aguilar MI, Hart RG, Kase CS, Freeman WD, Hoeben MBJ,
Garci'a RC, et al. Treatment of Warfarin-Associated Intracerebral
Hemorrhage: Literature Review and Expert Opinion. Mayo
Clin Proc 2007;82(1):82-92.

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Phenytoin/Fosphenytoin

.

..

Phenytoin : ..1938

- (block of sodium
(alcohol channels)
withdrawal syndrome )
- (inhibit calcium
Fosphenytoin : .. 1997 channels)
phenytoin

- Na+/K+ ATPase pump

Phenytoin or 5,5-diphenyl-2,4-imidazolidinedione
barbiturates five membered ring
Fosphenytoin disodium phosphate ester of phenytoin phenytoin phosphatases
,
1 phenytoin fosphenytoin

page 7


albumin 90%
(volume of distribution ,Vd) 0.6 L/Kg
(free drug) 10%
albumin
albumin free drug
15% free drug 50%
metabolized
free drug distribution free
drug peripheral tissue free drug
drug interaction
albumin total form
bound form albumin
phenytoin

Phenytoin conc = observed concentration (mg/L)

(mg/L)

[0.2 x serum albumin (g/dl)] + 0.1

free drug
- free drug
-Neonate
-Elderly
-Hypoalbuminemia
-Hyperbilirubinemia
-Uremic patient
-Combination therapy with VPA,salicylates,
sulfonamides
-Metabolized primarily by CYP450
2C9 parahydroxylphenyl derivative secondarily
by CYP450 2C19 5% phenytoin
(inhibit) CYP450 2C9
amiodarone, fluconazole, fluoxetine, metronidazole or
zafirlukast phenytoin
(inducer) CYP450 2C9
phenobabital, rifampicin

page 8

CYP450 2C19 cimetidine,

felbamate, fluvoxamine, ketoconazole, lanzoprazole,
omeprazole, paroxetine, ticlopidine
phenytoin CYP450 2C19
carbamazepine rifampicin
metabolism phenytoin dose dependent
concentration 10 mg/L: first order elimination
metabolism half life
6-24 concentration metabolism
saturated (elimination) zero
order
half life
20-60
-Fosphenytoin : phenytoin
equivalents 1.5 mg fosphenytoin 1 mg phenytoin
phenytoin 6-16
IV (intravenous) 150 mgPE/min

Acute phenytoin toxicity [overdose]

cerebellar vestibular

15 mg/L nystagmus, 30 mg/L

ataxia, 50 mg/L
pyramidal extrapyramidal

chorea opisthotonic posturing
cardiovascular
Chronic phenytoin toxicity

zero order,
free drug ,
hepatic metabolism
Adverse effect

gingival hyperplasia, folic acid deficiency,
agranulocytosis, anticonvulsant hypersensitivity syndrome (AHS)
AHS : aromatic anticonvulsant phenytoin,
carbamazepine, phenobarbital, primidone
2
toxic arene oxide metabolites

P&D Information Bulletin / Vol. 19 No. 1, 2011

 multiorgan involvement
hepatitis, leukocytosis (atypical lymphocytes, eosinophils)
, admit, methylprednisolone 0.5-1 mg/kg/d
6

-Serum phenytoin concentration
zero
elimination
Therapeutic serum concentration : 10-20 mg/L
-Free phenytoin fraction
gas chromatography enzyme-multiplied
immunoassay technique (EMIT)
Therapeutic free phenytoin concentration : 1-2 mg/L

- (supportive care)
- 1
(NG lavage)
-Multiple-dose-activated charcoal (MDAC) half
life
-Hemodialysis or hemoperfusion
(90%)
- IV benzodiazepine,
barbiturate
admit ICU
-
- (coingestion)
-Coma
- ataxia

discharge ICU
-
-No coma
-
phenytoin
- 3-5
- 100 mg 1.2
mg/L
- propylene glycol (40%)
ethanol (10%) propylene glycol
(depress myocardial tissue)

(decrease peripheral vascular

resistance) ,
,
(EKG) show increase PR interval, widened QRS
interval, ST-T wave change
(Intramuscular;IM) hematoma,
sterile abscess, myonecrosis
(Extravasation) purple hand syndrome edema, erythema,
vesicle, bullae, local tissue ischemia, gangrene, compartment
syndrome, rhabdomyolysis, death

- 50 : 4-10
mg /ml NSS 50 mg/ml
- 50 : 4 mg/
ml NSS 25 mg/ml
- cardiac monitoring
-
- Marked bradycardia
- Second or third degree heart block
- Severe arteriosclerotic heart disease
- Hypotension
30-60
bolus 0.9%NSS 250-500 ml, atropine,
temporary cardiac pacing if symptomatic bradycardia

vascular or soft tissue injury
orthopedic plastic surgeon

1. LoVecchio F. Phenytoin. In: Brent J, Wallance KL, Burkhart

KK, Philips SD, Donovan JW. Critical care toxicology : diagnosis and management of critical poisoned patient. Philadelphia: Mosby;2005.p.553-8.
2. Goldfrank LR, Flomenbaum N, Hoffman RS, Howland MA,
Lewin NA, Nelson LS. Anticonvulsants. In: Goldfrank's manual
of toxicologic. New York: McGraw Hill;2007. p.403-13.

page 9

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CYP2E1

CYP3A4,5,7

Acetaminophen induced nephrotoxicity

.
..

47 .
: 1
: 1-2 (500 .) 10 4-6

: A Thai female with marked icteric sclera

:
Liver function test: AST 21,960 U/L ALT 5,415 U/L
ALP 122 U/L TB/DB 10.9/5.7 mg/dl
BUN 27.8 mg/dl Cr 2.8 mg/dl

AST 21,960 U/L, ALT 5,415 U/L transaminase enzyme
1,000 U/L
1. viral hepatitis
2. shock liver, ischemic hepatitis
3. toxin or drug induced hepatotoxicity

5 / 2030 /

fulminant hepatitis

acetaminophen induced hepatotoxicity


creatinine (2.8 mg/dl)
(nephrotoxicity)

Acetaminophen induced nephrotoxicity

acetaminophen (APAP)
(extrahepatic tissue) extrahepatic tissue renal function
abnormality (1,2) renal insufficiency

page 10

12 % APAP overdose (2)

25% significant hepatotoxicity
(3,4) 50% hepartic failure (5,6)
retrospective case series
APAP nephrotoxicity (7)
APAP-induced nephrotoxicity
8.9% APAP (7)
prospective study 275
encephalopathy coagulopathy APAPinduced fulminant
hepatic failure 43-57% creatininine > 2 mg/dl (8)
APAP-induced fulminant hepatic
failure
hepatic failure (6) APAP
overdose renal damage hepatoxicity
(9 11)
Pathophysiology
Primary toxicity APAP drug metabolism
(12) 1%

P&D Information Bulletin / Vol. 19 No. 1, 2011


toxic intermediate, N-acetylimidoquinone
cytochrome P450 pathway cellular
macromolecules cell injury cell death
cytochrome P450 activity phenobarbital, phenytoin
APAP-induced nephotoxicity (13)
Acute kidney injury:

1. Renal impairment 2%
2. 5%
3. 10 %
4. 53 % fulminant hepatic failure (14-15)
Histopathology
histopathology acute tubular necrosis
(ATN) (16) urinary analysis APAP
induced nephrotoxicity renal insufficiency
hepatorenal syndrome (HRS) prerenal azotemia
1 (14,17)
1 Urinalysis Findings Acute Renal Failure (14,17)
Parameter

ATN

Prerenal Azotemia

Sediment

Granular casts +/-cells None

Osmolality

Same as plasma

HRS
None

Greater than plasma Greater than plasma

Urine sodium >20 mmol/L

<10 mmol/L

< 10 mmol/L

Urine output Variable

Fluid responsive

Non-Fluid responsive

Recovery

Poor

Prognosis

Recovery

Key: ATN-acute tubular necrosis, HRS-hepatorenal syndrome

Manifestation


glutathione starvation,
alcoholism cytochrome P450 enzyme
intermediate
metabolite (18)
renal insufficiency
1-8 2-5
creatinine 7
316 renal function
1 1%
multisystem

organ failure medical comorbidity

renal dyfunction (17)
Management and the role of N-Acetylcysteine (NAC)


BUN, Cr renal
insufficiency ATN
prerenal azotemia hepatorenal syndrome
1
NAC APAP -induced liver
necrosis APAP-induced nephrotoxicity
NAC
NAC (24,25)
NAC NAC isolated
renal function NAC
peritoneum APAP
(26)
NAC
(22)
Summary
APAP induced nephropathy
APAP
isolated renal
toxicity multisystem organ failure
APAP induced nephropathy recover
NAC

APAP
NAC
supportive care, serial monitoring of urine output, blood
pressure markers of glomerular filtration


NAC 24 .
AST ALT creatinine
3.9 mg/dl BUN 38.5 mg/dl
AST 900 U/L , ALT
841 U/L, DB 8.7 mg/dl, PT with INR=1.4, BUN 41.7 mg/dl,
creatinine 2.3 mg/dl

page 11


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P&D Information Bulletin / Vol. 19 No. 1, 2011