ACETAMINOPHEN POISONING By : Dr. Hafsah Salameh Supervised by : Dr . Abdalqader battah

ACETAMINOPHENS CHEMISTRY Molecular formula: C8-H9-N-O2Molecular weight: 151.16Odor: odorlessTaste: slightly bitter taste

ACETAMINOPHENS PHARMACEUTICAL CLASSES Classification chemical name,N-acetyl-p-aminophenol (APAP)

MECHANISM OF ACTION OF ACETAMINOPHEN Selectively reduces cyclooxygenase products in the CNS and PNS Principally prostaglandins (PG) E2 As well as other prostaglandins Thromboxane Prostacyclin

MECHANISM OF TOXICITY Oral acetaminophen is rapidly absorbed from the stomach and small intestine. The serum concentration peaks 1-2 hours post ingestionPeak plasma levels occur within 4 hours after ingestion of an overdose of an immediate-release preparation. Co-ingestion with drugs that delay gastric emptying ( opiates) or ingestion of an acetaminophen extended-release formulation may result in peak serum levels to be achieved more than 4 hours post ingestion.

the elimination half-life of acetaminophen is 2 hours In patients with underlying hepatic dysfunction, the half-life can last as long as 17 hours post ingestionAcetaminophen is primarily metabolized by conjugation in the liver to nontoxic, water-soluble compounds that are eliminated in the urine

ACETAMINOPHEN MECHANISM OF TOXICITY In acute overdose or when the maximum daily dose is exceeded over a prolonged period, metabolism by conjugation becomes saturated, and excess APAP is oxidatively metabolized by the CYP enzymes (CYP2E1, 1A2, 2A6, and 3A4) to the hepatotoxic reactive metabolite , N-acetyl-p-benzoquinone mine (NAPQI).

ACETAMINOPHEN MECHANISM OF TOXICITY NAPQI has an extremely short half-life and is rapidly conjugated with glutathione and is then renal excretion Under conditions of excessive NAPQI formation or a reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteine sulfhydryl groups of hepatocellular proteins, forming NAPQI-protein adducts

This causes an ensuing cascade of oxidative damage and mitochondrial dysfunction . Necrosis primarily occurs in the centrilobular (zone III) regionSimilar enzymatic reactions occur in extra hepatic organs, such as the kidney

the maximum recommended daily dose of APAP is 75 mg/kg for children and 4 g for adults. The minimum hepatotoxic dose of APAP as a single acute ingestion is 150 mg/kg for a child and 7.5-10 g for an adult.

ACETAMINOPHEN METABOLISM

ACETAMINOPHENS INDICATIONAnalgesic, non-narcotic Relives mild to moderate pain Reduces feverProvides only symptomatic relief Minimum anti-inflammatory activity Does not relieve redness, swelling, or stiffness due to arthritis

ROUTES OF EXPOSURE Most common Ingestion as tablets , elixirs ,suspension RectalIv Other routes Inhalation and dermal contact Usually by workers that work at places that APAP is produced or used

SYMPTOMSIn phase 1 (0.5-24 hours after ingestion) patients may be asymptomatic or report anorexia, nausea or vomiting, and malaise. Physical examination may reveal pallor, diaphoresis, malaise, and fatigue.

PHASE 2 (18-72 h after ingestion), patients generally develop right upper quadrant abdominal pain, anorexia, nausea, and vomiting. Tachycardia and hypotension indicate ongoing volume losses. Some patients may report decreased urinary output (oliguria)

PHASE 3 (72-96 h after ingestion), is also called the hepatic phase.Hepatic necrosis and dysfunction are associated with jaundice, coagulopathy, hypoglycemia, and hepatic encephalopathy. Acute renal failure develops in some critically ill patients. Death from multiorgan failure may occur

PHASE 4 the recovery phase (4 d to 3 wk. after ingestion). Patients who survive critical illness in phase 3 have complete resolution of symptoms and resolution of organ failure. Clinical recovery may take up to 21 days; however, complete hepatic histologic recovery requires several months

The serum acetaminophen (APAP) concentration is the basis for diagnosis and treatment, even in the absence of symptoms, because of the delay in onset of clinical manifestations of toxicity. An APAP level 4 hours post ingestion of greater than 150 mcg/ml reflects possible toxicity.

The Rumack-Matthew nomogram uses the serum acetaminophen level, correlated with time after ingestion, to assess hepatotoxicity risk for single acute ingestions of acetaminophen. It should not be used to evaluate chronic or repeated exposures

For example 400 after 12 hours

LAB VALUES ( LFT ) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels begin to rise within 24 hours after an acute ingestion and peak at about 72 hours In severe overdose, transaminase elevation can be detected as early as 12-16 hours post-ingestion. Toxicity is defined as serum AST or ALT levels greater than 1000 IU/L. Include bilirubin and alkaline phosphatase levels.

Prothrombin time (PT) and international normalized ratio (INR) should be measured and followed closely if hepatic dysfunction and liver failure develop, as they indicate impaired hepatic synthetic function. Abnormalities means high mortality rate.

Renal function tests ( electrolyte, blood urea nitrogen [BUN], and creatinine levels) can reveal evidence of renal failureAn elevated serum creatinine level is also a predictor of mortality. Urinalysis to check for proteinuria and hematuria helps in diagnosing acute tubular necrosis. Renal injury becomes apparent 2-3 days after an acute acetaminophen ingestion (phase 2

Assess for pancreatic injury by obtaining lipase and amylase levels, especially if the patient has evidence of clinically significant hepatotoxicity and complaints of severe abdominal pain.Abdominal ultrasonography

Acetaminophen crosses the placenta, and the fetal liver is able to elaborate the hepatotoxic metabolite of APAP,N-acetyl-p-benzoquinone imine (NAPQI) by 14 weeks gestation. Delayed antidotal treatment in pregnant women has been associated with fetal loss.

TREATMENTABCsExclude other life- threatening co-ingestion like salicylates Administer activated charcoal (AC) if the patient has a stable mental and clinical status and presents to the emergency department within 1 hour of ingestion.

Draw a 4-hour serum acetaminophen concentration to determine the risk for hepatotoxicity, plot this value using the Rumack-Matthew nomogramAdmit patients with acetaminophen plasma levels above the possible line on the Rumack-Matthew nomogram for treatment withoral N-acetyl cysteine (NAC).

Treat patients with evidence of hepatic failure, metabolic acidosis, coagulopathy, and/or encephalopathy in an intensive care unit (ICU). Transfer patients with evidence of clinically significant hepatotoxicity to a medical facility with intensive care support and organ transplant services

Surgical evaluation for possible liver transplantation is indicated for patients who have severe hepatotoxicity and potential to progress to hepatic failure. Criteria for liver transplantation include the following:Metabolic acidosisRenal failureCoagulopathyEncephalopathy

indications for IV administration of NAC also include the following:Altered mental statusGI bleeding and/or obstructionPotential fetal acetaminophen toxicity in a pregnant womanInability to tolerate oral NAC because of emesis refractory to proper use of antiemetic's

PROGNOSIS With aggressive supportive care and antidotal therapy, the mortality rate associated with acetaminophen hepatotoxicity is less than 2%. fewer than 4% of patients who suffer severe hepatotoxicity develop hepatic failure; fatalities or the need for liver transplantation occurs in less than half of these patients

RISK FACTORS FOR WORSE PROGNOSISOlder ageRestricted dietUnderlying hepatic or renal diseaseCompromised nutritional status (eg from prolonged fasting, eating disorders , cystic fibrosis,gastroenteritis, chronic alcoholism, or HIV disease)Because they decrease the storage of glutathione

AT AUTOPSY Centrilobular necrosis :

ACUTE TUBULAR NECROSIS

*Point out pka to show that it can irritate the stomach and it can be enteric coated *PGE2 are mediators of fever, pain, and inflammation *Basically there really is not any major ways that the general population may be exposed to APAP other then ingesting it. We have to remember that this is a drug and it usually comes in oral form. What causes it to be so significant is the rate of exposure that is seen in the general population. Since as we said before it is something that is a common OTC drug, most household do have it in their homes at all time. *Tenderness and abdominal pain, enlarged liver*Jaundice, GI bleeding, edemas, multi organ failures*No apparently physical symptoms but heavy liver damage or coma or death.- Stage 4 patients have hepatic histological changes such as increased CYP2E1 enzymes which may last for up to 3 months

*Now the lab values are really according to who the patient is and this will be further explained and explored as we talk about the individual cases. *