Paracetamol Poisoning Assistant Professor Dr. Shamil AL-Nuaimi M B ch B, M Sc, Ph D

Acetaminophen (Paracetamol) Overall, acetaminophen is involved in some 15 to 30% of deliberate self-poisonings Only a small minority of patients are at risk of severe liver damage and the liver has remarkable powers of regeneration.

HEPATOTOXICITY Most hepatotoxicity probably results from a toxic intermediary products causing hepatic necrosis. Alternate explanations of necrosis involve : 1. lipid peroxidation 2. oxidation of thiol groups

The liver metabolizes most therapeutic doses of acetaminophen by glucuronide and sulfate conjugation. Only small amounts of acetaminophen are converted to the highly reactive intermediate N-acetyl-p- benzoquinoneimine (NAPQI) by the cytochrome P450 mixed-function oxidase system. Glutathione rapidly detoxifies this intermediate to cysteine and mercapturate conjugates

One explanation of acetaminophen hepatotoxicity is the saturation of the sulfate pathway by the ingestion of an excessive acetaminophen dose When glutathione stores are depleted below a critical value (about 30% of normal stores), NAPQI binds covalently with hepatic cell macromolecules, producing tissue necrosis

Depletion of hepatocellular reduced glutathione alone does not account for acetaminophen-induced hepatotoxicity Age, diet, nutritional status, metabolic state, and concomitant drug ingestion apparently affect individual changes in cytochrome P450 mixed-function oxidase activity and susceptibility to hepatotoxicity Drugs that induce hepatic P450 enzymes (e.g. phenobarbital,) may enhance acetaminophen-induced hepatotoxicity

RISK FACTORS Risk factors include alcoholism and chronic ingestion of (agents that induce hepatic microsomal enzymes (e.g., isoniazid. Starvation depletes glutathione stores

TOXIC DOSE Toxic dose in adults 5-15 gm(15-45 tablets of 325 mg each) Lethal dose 13-25 gm (46-75 mg of 325 mg each)

NONHEPATIC TOXICITY RENAL FAILURE The kidney also metabolizes acetaminophen to a toxic intermediate, which binds to renal macromolecules, leading to cell death Oliguric renal failure may become apparent within 24 to 48 hours of acetaminophen overdose,

CARDIOTOXICITY Acetaminophen-induced cardiotoxicity is rarely clinically significant, but if ST/T-wave abnormalities or a dysrhythmia is present, treatment with N-acetylcysteine should be considered, probably irrespective of the plasma acetaminophen level or time lapse since ingestion

PANCREATIC TOXICITY Doses of acetaminophen as low as 9.75 g have been associated with pancreatitis Hyperamylasemia is often observed

HYPERSENSITIVITY REACTIONS Allergic reactions to acetaminophen are rare and usually involve the skin Bronchospasm and urticaria have been reported in adults Dose-dependent anaphylactoid reactions

CLINICAL PRESENTATION Consciousness is not depressed, even in the presence of high serum levels of acetaminophen, unless other drugs have also been taken or there is a very high plasma acetaminophen concentration on the order of 6.62 mmol/L (100 mg/L) with a metabolic acidosis

l II III IIII characteristics Time following ingestion stage Anorexia, nausea,vomitting,malaise,pallor ½-24 hr l Abd.pain,liver tenderness,elevated liver enzymes,oliguria 24-48 hr II Peak hepatic enzymes abn.,↑bilirubin,PT 72-96 hr III Resolution or progressive hep. failure 4 days-2 wk IIII

The Rumack-Matthew nomogram interprets the acetaminophen concentration (in micrograms per mL), in relation to time (in hours) after ingestion, and is predictive of possible hepatotoxicity after single, acute ingestions of acetaminophen .

NOMOGRAMS AND TREATMENT LINES Treatment lines have been suggested to offer a guide to the possibility of severe liver damage (plasma transaminase activity of 1000 IU/mL or more) when plasma acetaminophen concentrations are correlated with time after exposure. Limitations Their usefulness in young children and after 15 hours postingestion has never been validated..

Lines 200 line: Joins concentration of 200 µg/L at 4 hours and 30 µg/L at 15 hours on a semilogarithmic graph. 150 line: Joins 150 µg/L at 4 hours and 30 µg/L at 12 hours 300 line: Joins a semilogarithmic plot at 3 hours of 300 µg/L at 4 hours and 75 µg/L at 12 hours (fatal hepatic failure case, acute renal failure) 100 line: Joins 100 µg/L at 4 hours at 15 µg/L at 15 hours

LABORATORY BLOOD A serum acetaminophen level in all cases of drug overdose can be cost effective . The analytical performance of the TD x immunoassay is comparable to that of high-performance liquid chromatography and this method is simple and relatively free from interference

Prothrombin Time The prothrombin time is the best laboratory guide to the severity of hepatic encephalopathy. The development of an encephalopathy is likely when the prothrombin time exceeds 25 seconds at 48 hours postingestion or 40 seconds at 72 hours A peak prothrombin time exceeding 100 seconds or a prothrombin time that continues to increase 4 days after an overdose indicates a poor prognosis (<8% chance of survival) and suggests the need for a liver transplant

PHOSPHATE LEVELS Hypophosphatemia correlates with the degree of hepatic damage and is a recognized feature of acute liver failure RAPID TESTS A rapid acetaminophen assay on whole blood may be useful for bedside use . The process appears to be accurate over the concentration range 10 to 300 µg/mL.

ANCILLARY TESTS Patients hospitalized for serious ingestions of :acetaminophen should be monitored for 1.Renal function, 2.Hypoglycemia, and 3.Electrolyte imbalance.

Recommended serum studies (Summary): 1.Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST]), bilirubin [total and fractionated], alkaline phosphatase) 2.Prothrombin time (PT) with international normalized ratio (INR) 3.Glucose 4.Renal function studies (electrolytes, BUN, creatinine) 5.Lipase and amylase (in patients with abdominal pain) 6.Serum human chorionic gonadotropin (hCG) (in females of childbearing age) 7.Salicylate level (in patients with concern of co-ingestants) 8.Arterial blood gas and ammonia (in clinically compromised patients)

Additional recommended studies are as follows: 1.Urinalysis (to check for hematuria and proteinuria) 2.ECG (to detect additional clues for co- ingestants)

TREATMENT GUT DECONTAMINATION: ACTIVATED CHARCOAL Reduction of Acetaminophen Absorption Activated charcoal should be given within the first several hours of ingestion of acetaminophen. Activated charcoal may reduce the serum level of acetaminophen even after absorption is complete

if a patient presents within 1 to 2 hours of an acetaminophen overdose, emesis or activated charcoal therapy will probably reduce the availability of acetaminophen and result in lower blood levels

ELIMINATION Exchange Transfusion Exchange transfusion has been used in neonates following acetaminophen ingestion by the mother shortly before birth Arteriovenous Hemofiltration Arteriovenous hemofiltration has been employed for treatment of the associated hepatic encephalopathy

Hemodialysis The primary use of hemodialysis in overdoses of acetaminophen is for the treatment of renal failure..

ANTIDOTE Methionine Methionine is an oral antidote Methionine is much less expensive than NAC but may exacerbate hepatic encephalopathy when administered more than 1 hour postingestion

Methionine acts as a glutathione precursor and protects against acetaminophen-induced hepatic and renal toxicity, provided that it is administered within 8 to 10 hours of the overdose .Methionine is usually administered orally and it is therefore unsuitable for use in patients who are vomiting and for those in coma.

Oral methionine has been effective in protecting against severe liver damage, renal failure, and death after acetaminophen overdose when given within 10 hours of ingestion.

Indications Oral methionine is indicated for the treatment of acute acetaminophen poisoning. When 4 hours or more has elapsed after ingestion of an overdose, the plasma concentration of acetaminophen should be measured. Specific treatment with methionine is required if the plasma acetaminophen concentration falls above a line that on a semilog graph joins plots of 200 µg/L (1.32 mmol/L) at 4 hours and 30 µg/L (0.33 mmol/L) 15 hours after the overdose.

In cases where plasma concentrations of acetaminophen are not available, methionine should be given if more than 100 mg/kg acetaminophen is taken in a single dose . If the patient is either vomiting or unconscious, then it is more appropriate to give NAC by the intravenous route

Dose Methionine should be given orally in a dose of 2.5 g, followed by three further doses of 2.5 g at 4-hour intervals. If a patient is vomiting and is unable to tolerate oral methionine, intravenous NAC should be given.

N-Acetylcysteine Mechanism of Action N-Acetylcysteine is the N-acetyl derivative of L-cysteine, a naturally occurring amino acid . The oral bioavailability of NAC is low, probably as a result of extensive first-pass metabolism.

Indications N-Acetylcysteine is indicated in the treatment of acetaminophen poisoning if: . 1.Plasma acetaminophen levels taken between 4 and 12 hours postingestion fall above the "treatment line" . . 2.More than 100 mg/kg acetaminophen has been ingested in a single dose and plasma acetaminophen concentrations are not available. . 3. Acute acetaminophen-induced liver failure has developed or is likely to develop

NAC provides maximum protection against hepatotoxicity when administered within 8 to 10 hours of an acetaminophen overdose

Adverse Effects Intravenous Form. Anaphylactic reactions occur about 15 to 60 minutes after the initiation of intravenous NAC in about 3 to 9% of cases These reactions are serum concentration dependent and probably result from histamine release.

SUPPORTIVE MEASURES IN ACUTE OVERDOSE Baseline blood tests for hospitalized patients include a complete blood count, liver function tests, glucose, electrolytes, and creatinine. Repeat liver function tests daily for 3 days, then as indicated by the appearance of hepatic encephalopathy .

Watch for development of hypoglycemia . Watch for development of hypoglycemia. . Maintain normal hydration and electrolyte balance and avoid forced diuresis. Administer vitamin K1 for an elevated prothrombin time (1.5 × normal). Fresh-frozen plasma should be used for severe prolongation (3 × normal). Prophylactic cimetidine may decrease the incidence of gastrointestinal ulcers.

Regular lactulose and enemas assist the elimination of nitrogenous substances and endotoxins from the bowel in encephalopathic patients. . Cerebral edema is a major cause of death following the development of hepatic encephalopathy and may be treated with mannitol and fluid restriction.