What is the mechanism of action acetaminophen?
- Analgesic - inhibits COX-3 in CNS
- Competitive central inhibition of COX-3 decreases production of prostaglandin E2 in CNS
- Very weak anti-inflammatory activity due to weak inhibition of peripheral tissue COX-1, COX-2
- Does not cause GI ulceration or inhibit platelet aggregation like aspirin - Antipyretic
- Direct effect on heat-regulating centres of the hypothalamus, leading to increased heat dissipation through vasodilation and sweating
How is APAP metabolized?
- Acetaminophen is metabolized into N-Acetyl-p-benzoquinoeimine (NAPQI) by CYP2E1
- Acetaminophen is metabolized into sulfate-acetaminophen (20-46%)
- Acetaminophen is metabolized into glucuronide-acetominophen (40-67%)
How does APAP overdose cause liver injury?
Up to 45% of APAP is converted into NAPQI by P450 2E1 (a.k.a CYP2E1).
Usually, glutathione (GSH) converts NAPQI into cysteinyl conjugate.
But if GSH is > 70% depleted, then excess NAPQI binds to SH groups in cellular proteins and causes cell injury which results in centrilobular hepatic necrosis.
What causes APAP toxicity?
- Induction of liver CYP2E1 or CYP3A4 isoenzymes
- Results in increased formation of NAPQI - Depletion of glutathione (GSH)
- Decreased detoxification of NAPQI
What are the clinical conditions that may cause the induction of liver CYP2E1 or CYP3A4 isoenzymes?
- Long term treatment with enzyme inducing drugs
- Carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, rifabutin, efavirenz, nevirapine, and St John’s wart - Regular consumption of ethanol in excess of recommended amounts
What are the clinical conditions that may cause the depletion of GSH?
- Malnourished
- Eating disorders
- Cystic fibrosis in children
- AIDS
- Alcoholism
What are the stages of acetaminophen poisoning with their associated times?
Stage I (0.5-24 h)
Stage II (18-48 h)
Stage III (72-96 h)
Stage IV (5d - 3w)
What are the symptoms of Stage I acetaminophen poisoning?
GI irritation
- Anorexia, nausea, vomiting
- Liver function tests normal
What are the symptoms of Stage II acetaminophen poisoning?
Latent period (onset of liver injury)
- Transient resolution of GI symptoms
- Right upper quadrant (RUQ) abdominal pain
- AST/ALT increased
- Prothrombin time/bilirubin sometimes elevated if severe
What are the symptoms of Stage III acetaminophen poisoning?
Maximal hepatotoxicity
- Symptoms of hepatotoxicity - vomiting reappears
- Fulminant hepatic failure may develop: liver tenderness, jaundice, hepatic encephalopathy & hemorrage
- AST/ALT > 10000 IU/L, bilirubin peak
- Sometimes renal failure or pancreatitis
What are the symptoms of Stage IV acetaminophen poisoning?
Recovery or death
- Resolution of hepatotoxicity
- AST ALT return to normal (5-7 days)
OR progression to multiple organ failure (sometimes fatal)
What test for APAP poisoning?
Plasma acetaminophen level:
4 hours post ingestion - to determine probability of liver damage
What is the antidote for APAP poisoning? When is it used?
N-acetylcysteine (NAC, Mucomyst)
Decision of antidote treatment is based on timed plasma acetaminophen concentration - Rumack-Matthew nomogram
What are the Nomogram commandments?
- Only for single acute ingestion
- APAP blood levels NOT obtained < 4 h after ingestion
- Period of 4 h after ingestion was chosen to assume complete absorption & a peak plasma APAP level - Unreliable when ingestion > 24 h
- APAP levels may be undetectable even if significant hepatotoxicity
When is the APAP nomogram not applicable?
- Time of ingestion unknown
- Extended-release APAP
- Staggered overdose
- Chronic overdose exposure
What is the mechanism of NAC?
- NAC increases synthesis and availability of GSH
- Acts as intracellular GSH substitute by directly binding to NAPQI and detox
- Provides substrate for sulfation, which increases percentage of non-toxic detoxification
- Enhances reduction of NAPQI to APAP
