apap toxicity
DESCRIPTION
APAP TOXICITY. Anthony Ciorciari Associate Professor Emergency Medicine Albert Einstein College of Medicine. N- ACET YL-PARA- AMINOPHEN OL. SALICYLIC ACID. ACETYLSALICYLIC ACID. APAP. First used in the US in 1950 Over 100K cases reported to US poison Control centers each year - PowerPoint PPT PresentationTRANSCRIPT
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