N-acetyl-P-aminophenol Acetaminophen N-acetyl-P-aminophenol (APAP)

Paracetamol Overdose -Most common drug taken in overdose -As little as 12g can be fatal (therapeutic dose = 2.6 gm/24 hour) -It is a hepatic and renal toxin (Centrolobular necrosis) -More toxic if liver enzymes are induced or with reduced ability to conjugate toxin (alcoholics, phenytoin, phenobarbitone) -The safety of acetaminophen depends on the availability of electron donors such as reduced glutathione (GSH) and other thiol-containing substances required to detoxify NAPQI.

Met pathways of APAP 1- Hepatic glucuronide conjugation(40-65%) Hepatic sulfat conjugation(20 - 45%) 90% inactive metabolites excreted in the urine. 2- Excretion of unchanged APAP in the urine (5%). 3- Oxidation by P450 cytochromes to NAPQI (5-15%)  GSH combines with NAPQI  nontoxic cysteine/mercaptate conjugates  excreted in urine. Hepatic glucuronide conjugation(40-65%) Hepatic sulfat conjugation(20 - 45%)

Mechanism of Toxicity: The ingested APAP undergo oxidative metabolism by CYP- 450 to reactive intermediate metabolite (N-acetyl –P-benzoquinone imine=NAPQI) which is rapidly bounded to glutathion ,detoxified through conjugation pathway ,and excreted. In the presence of adequate GSH stores , there is no fear from any toxicity. However, overdose of APAP saturate the conjugation pathways and NAPQI overwhelms the GSH detoxifi-cation mechanism , finally leading to liver necrosis and may be death.

Paracetamol Metabolism

What happens to APAP metabolism in an OD situation? 1-Saturation of glucuronidation and sulfation pathways 2-Amount of APAP metabolized by p450 cytochromes to NAPQI increases. 3-Normally NAPQI is detoxified by reduced GSH (glutathione) and thiol containing substances. 4-In OD: rate and quantity of NAPQI formation overwhelms GSH supply and regeneration:  elimination of NAPQI prolonged  free NAPQI binds critical intracellular proteins with sulfhydryl groups  cellular dysfunction and cell death.

Factors which adversely affect APAP metabolism 1-Upregulation (i.e. induction) of CYP 2E1 enzyme activity: smoking, barbituates, rifampin, carbamazepine, phenytoin, ethanol 2-Decreased glutathione stores (malnutrition) 3-Frequent dosing interval of APAP. 4-Prolonged duration of excessive dosing.

GSH stores Glutathione stores are determined by: -Age -Diet -Liver disease -Fasting prior ingestion -Chronic malnutrition -Anorexia -Gastroenteritis -Chronic alcoholism -HIV Glutathione replacement by sulfhydryl compounds: -Eating -NAC

Renal toxicity Organ dysfunction results everywhere where local oxidative metabolism (via p450) creates NAPQI that cannot be detoxified  direct toxicity: cytochrome P-450 enzymes produce NAPQI in the renal tubules  NAPQI binds cellular macromolecules  acute tubular necrosis. (25% of hepatotoxic cases) Hepatorenal Syndrome &Volume depletion

Other organs damaged Heart  myocarditis Pancreas  pancreatitis It is controversial whether these entities are part of multisystem organ failure (MSOF) from fulminant hepatic failure (FHF) or from the local accumulation of toxic metabolites.

Clinical presentation Phase 1 (few hrs after ingestion up to 24 hr) : Malaise , nausea , vomiting and diaphoresis. Phase 2 (24-72 hrs after ingestion) : Increase in liver enzymes, serum bilirubin , prothrombin time , and pain in the right upper abdominal quadrant. Phase 3 (72-96 hrs after ingestion) : Peak in the liver function, altered consciousness, hypoglycemia, jaundice , and coagulation abnormalities. Hepatic failure can develops in 4th or in the 5th day if hepatic damage is sever. Myocardial necrosis, pancreatitis , heamolytic anemia and skin rashes may develop but are rare. Phase 4 (7-10 days after ingestion) : Liver enzymes abnormalities reaching resolution. If hepatic damage is massively sever sepsis and death may occure at 7-10 days

Laboratory analysis 1-Determination of plasma APAP level. 2-Monitoring liver profile including serum ALT, AST , bilirubin , glucose , prothrombin time, platelet count…etc 3- Determination of kideny functions by measuring plasma creatinine and BUN. 4-ECG for assessment of myocardial injury. 5- Urine analysis.

Management Steps: General measures -Gastric lavage (if the patient is presented to ER within 4 hrs of ingestion -Gastric lavage -Activated charcoal ,cathartics (saline sulfate are prefered to enhance sulfate metabolic pathway). glucose, bicarbonate, Vit K for elevated prothrombin time <8 hours -Take level of APAP after four hours (Peak concentration at 4 hrs then hepatic metabolism) -Start N-aceylcysteine (antidote) if APAP concentration is high =APAP is on or above nomogram tx line. -Patients should be advised to return to hospital if vomiting or abdominal pain develop or reoccur.

Nomogram

Management 2 >8 hours Urgent action required because the efficacy of NAC declines progressively from 8 hours after the overdose Therefore, if > 150mg/kg or > 12g (whichever is the smaller) has been ingested, start NAC immediately, without waiting for the result of the plasma paracetamol concentration >24 hours Still benefit from starting NAC

N-acetylcysteine (Antidote) Supplies glutathione precursor (cysteine) Dosage for NAC infusion (1) 150mg/kg IV infusion in 200ml 5% dextrose over 15 minutes, then (2) 50mg/kg IV infusion in 500ml 5% dextrose over 4 hours, then (3) 100mg/kg IV infusion in 1000ml 5% dextrose over 16 hours Side-effects Flushing, hypotension, wheezing, anaphylactoid reaction -Alternative is methionine PO , it increase GSH synthesis. -Hemodialysis and hemoperfusion can be considered in extremly elevated APAP level.