APAP TOXICITY

Anthony CiorciariAssociate ProfessorEmergency Medicine

Albert Einstein College of Medicine

N-ACETYL-PARA-AMINOPHENOL

SALICYLIC ACID

ACETYLSALICYLIC ACID

APAP

• First used in the US in 1950

• Over 100K cases reported to US poison Control centers each year

• More admissions that any other common pharmaceutical agent

• In the US, most common cause of acute hepatic failure

APAP

• Analgesic

• Antipyretic

• Weak peripheral anti-inflammatory

APAP PHARMACOKINETICS

• Immediate release-peaks in 45 minutes (liquid about 30 minutes)

• Extended release: peaks in 1-2 hours with most absorbed in 4-5 hours

• Total protein binding is about 10-30%– Does not change in overdose

APAP METABOLISM

• First pass about 25% of dose

• Once absorbed– Hepatic conjugation (90%)– Oxidized by CYP2E1

• This results in NAPQI• Glutathione (GSH) quickly combines with NAPQI• Results in non-toxic cysteine or mercaptate

conjugates (eliminated in urine)

APAP TOXICITY

• Glucuronidation and sulfaction are exceeded (saturated)

• There is an increase in NAPQI– GSH supply diminished

• NAPQI binds to hepatocytes (acrylates cell proteins)– Cell death (GSH < 30%)– Secondary inflammation

                                                                                                                                                                                                                                                                                                                 

 

N-ACETYLCYSTEINE (NAC)

NAC

• Regenerates GSH

• May enhance sulfate conjugation

• Anti-inflammatory properties

• Anti-oxidant

• Increases NO– Vasodilatory effect

FACTORS FOR HEPATOTOXICITY

• Increased dosing

• Duration of excessive dosing

• Increase in CYP2E1

• Decrease in GSH

• Decrease glucuronidation and sulfaction

OTHER ORGAN INJURY

• Renal: occurs in about 25% with significant hepatic enzyme elevation

• Other areas rarely reported

• If there are alterations in mitochondrial function:– Anion-gap acidosis– Elevation of lactate

STAGES

STAGE I

• No hepatic injury yet

• May be a subclinical rise in AST

• Nausea, vomiting, malaise, pallor diaphoresis

STAGE II

• Onset of liver injury

• 24-72 hours (may be earlier in the severely poisoned)

• RUQ pain

• Looks like infectious hepatitis

• Continued rise in AST

• Could be a deterioration in renal function– BUN may be normal

STAGE III

• Time of maximal hepatotoxicity

• 72-96 hours

• Fulminant hepatic failure– Encephalopathy– Coma– Hemorrhage

• AST and ALT > 10,000

STAGE IV

• Survivors of Stage III

• Recovery phase

• Hepatic regeneration is complete

• No chronic hepatic dysfunction

• Recovery will occur 5-7 after the overdose, but it may take weeks

THE ACUTE INGESTION

• > 7.5 g in adults

• > 150 mg/kg in a child

• Unknown amount

• You are very confident about the time the medication was taken

• Look at the nomogram

RUMACK-MATTHEW

NOMOGRAM

TREATMENT/ACUTE

• Activated Charcoal– Will decrease number of patients above

treatment line– Most effective 1-2 hours after ingestion– Reasonable to give it within 4 hours– No evidence that AC and NAC interaction is

clinically significant– If repeated AC dosing is needed, better to use

IV NAC

IV VS. PO NAC

• Mostly they are equivalent• Oral has fewer side effects• Oral costs less• IV has shorter course• Old days: Oral was given IV

– Had an excellent safety profile– No published bad outcomes– Not generally recommended– But if pushed to the wall. . .

NAC PROTOCOLS

• 72 hour oral protocol

• 20 hour IV protocol

SPECIFIC INDICATIONS FOR IV NAC

• Hepatic failure

• Cerebral edema

• Cant tolerate PO

• Pregnancy

WHAT ABOUT:

• Acute OD and ETOH?• OD and INH, phenobarbital, rifampin?• APAP < 4 hours?• Extended release?• Don’t have a time window, or > 24 hours?

– Get APAP and LFTs– If LFTs elevated: treat– If APAP elevated: prudent to treat– If LFTs and APAP normal: no treatment

REPEATED/CHRONIC EXCESSIVE APAP DOSING

• Presence or signs of hepatotoxicity

• Usually symptomatic for > 24 hours prior to diagnosis

• If not symptomatic and ingested more than 4 g in a day– Do lab studies

LAB STUDIES

• AST– If the AST is normal the patient may still be at risk if

APAP is elevated– The peak APAP should be

• < 10 4-6 hours after ingestion• < 30 30-90 minutes after ingestion

• Remember the high risk patients– Chronic ETOH– Malnutrition– Anorexia nervosa

RISK STRATIFICATION

• High risk (NAC)– AST > 2X normal– AST elevated, APAP > 10– APAP is higher than expected

• Moderate risk (follow-up)– Asymptomatic, less than expected APAP,

normal AST– Asymptomatic, APAP < 10, AST < 2X normal

RISK STRATIFICATION

• Minimal risk (instruction)– APAP < 10– Normal AST