Clinical Pharmacology

"Adverse Drug Event of the month"

A patient with paracetamol (acetaminophen) poisoning.

Case report:
A 29-year-old male patient presented to Emergency Medical Services of this institute with drowsiness and vomiting. He had allegedly ingested 11 Crocin tablets (Paracetamol 500mg), 9 Saridon tablets (Paracetamol 250 mg, Propyphenazone 150 mg, Caffeine 50 mg) and 5 Triple Action tablets (Paracetamol 500 mg) i.e. 10.25 gm of paracetamol in total with an intention of deliberate self-harm.

He was initially treated with gastric lavage in Emergency Medical Services. His blood was sent for liver function test that included SGOT, SGPT and PTINR. He was then given N-acetylcysteine granules (140mg/kg i.e.7.7gm) diluted in 300 ml water through a nasogastric tube as his PTINR was high (1.7). Other treatment included injection ranitidine (50mg IV 8hrly), injection 25% dextrose (100cc 6hrly), injection vitamin K (10mg every day for three doses), tablet metronidazole (400mg thrice a day) and IV fluids. N-acetylcysteine was continued at a dose of 70mg/kg every 4 hours till 17 doses.

He was then shifted to general medical ward on day 3 where he continued to receive the same treatment until Day 7 and was then discharged after complete recovery.

His laboratory findings on Day1, the day of admission were as follows:

• Outcome
  
  The patient recovered completely and was discharged on Day 7.
  
  Discussion:
  Paracetamol is an effective, simple analgesic that is well tolerated by adults and children at therapeutic doses (analgesic and antipyretic- oral, 325 to 500 mg every three hours, 325 to 650 mg every four hours, 650 mg to 1 gram every six hours as needed, or 1300 mg every 8 hours)(maximum dose- for short-term therapy (up to ten days)-up to 4 grams daily, for long-term therapy -up to 2.6 grams daily, unless chronic treatment with higher doses is prescribed and monitored by a physician). In most countries it is available without prescription. Unfortunately, due to its ready availability is associated with episodes of poisoning that prompt 3.3% of inquiries to US regional poisons centres (1), 10% of inquiries to the UK National Poisons Information Service (2), and up to 43% of all admissions to hospital with self poisoning in the United Kingdom (3). In the United States paracetamol alone accounted for 4.1% of deaths from poisoning reported to American poisons centres in 1997 (1). Most deaths are associated with deliberate self-poisoning, but therapeutic misadventures do occur rarely, in both adults and children.
  
  Mechanism of poisoning:
  Most acetaminophen is metabolized by hepatic conjugation with sulfate and glucuronide to form nontoxic metabolites, with minor amounts being excreted unchanged or oxidized by hepatic cytochrome P450 enzymes (primarily CYP2E1) to form a highly reactive, electrophilic, and potentially toxic intermediary metabolite n-acetyl-p-benzoquinoneimine (NAPQI). After therapeutic doses, NAPQI is rapidly detoxified by conjugation with glutathione and excreted as cysteine and mercapturic acid conjugates. Following an acute ingestion of a dose of ³140 mg/kg body weight, sulfate and glucuronide pathways become saturated, resulting in an increased fraction and amount of acetaminophen metabolized to NAPQI and eventual glutathione depletion. When this occurs, free NAPQI binds covalently to hepatocytes and causes their lysis (centrilobular necrosis). Less often, hepatotoxicity develops following the chronic ingestion of therapeutic or slightly greater amounts in conditions associated with decreased glutathione reserves (e.g., alcoholism, childhood, acute starvation, chronic malnutrition) and possibly in conditions with enhanced P450 enzyme activity (e.g., anticonvulsant and antitubercular drug use).
  
  Clinical Toxicity:
  Early manifestations of poisoning are nonspecific and not predictive of subsequent hepatotoxicity. Within 2 to 4 h of acute overdose, nausea, vomiting, diaphoresis, and pallor may develop. CNS depression is typically absent unless massive doses are ingested. Within 24 to 48 h, hepatotoxicity is evidenced by right upper quadrant tenderness and mild hepatomegaly. Renal function may also be impaired. Laboratory evidence of hepatic toxicity includes prolongation of the prothrombin time and elevation of serum bilirubin and transaminase activity (aspartate transaminase, alanine transaminase). Severe poisoning may cause hepatic failure. Greater than twofold prolongation of prothrombin time, a serum bilirubin level >68 umol/L (4 mg/dL), pH <7.30, serum creatinine >3.3, and a high-grade encephalopathy indicate a poor prognosis. In patients who recover, liver function returns to normal within 1 week, and liver histology returns to normal within 3 months. Chronic poisoning is usually similar, but alcoholics may present with a syndrome of severe combined hepatic and renal insufficiency with dehydration, jaundice, coagulopathy, hypoglycemia, and acute tubular necrosis (4).
  
  Diagnostic Evaluation:
  A serum acetaminophen level should be obtained between 4 and 24 h after ingestion. Concentrations determined prior to 4 hours following ingestion are not reliable for assessing potential hepatotoxicity. A level above the lower line on the Rumack-Matthew nomogram indicates possible hepatotoxicity and the need for antidote
  Metoclopramide is a dopamine receptor antagonist. It acts as an antiemetic agent by blocking central D2 receptors. (1) Metoclopromide is mainly used for the treatment of motility disorders of upper gastrointestinal tract, particularly delayed gastric emptying and nausea and vomiting from causes other than motion sickness. Being a dopamine antagonist metoclopramide is known to cause extra-pyramidal symptoms like dystonia, dyskinesia and rarely Parkinsonism and tardive dyskinesia. Other adverse reactions with Metoclopramide include restlessness, drowsiness, dizziness, headache and bowel upset. There are isolated reports of dose related delirium, depression, and uncontrolled crying in patients treated with Metoclopramide. Neuroleptic malignant syndrome has also been reported after the use of the drug. (2) therapy (5). Few other nomograms are also available for the management of paracetamol poisoning (6,7). Liver function tests (serum aspartate aminotransferase [AST; SGOT], serum alanine aminotransferase [ALT; SGPT], prothrombin time, and bilirubin) should be performed at 24-hour intervals for at least 96 hours post ingestion if the plasma acetaminophen concentration indicates potential hepatotoxicity. If no abnormalities are detected within 96 hours, further determinations are not needed. In this patient liver function tests were done on Day 1 and Day 2 and were within normal limits. Renal and cardiac function should be monitored and appropriate therapy instituted if necessary.
  
  Treatment:
  
  Activated charcoal is recommended for patients who present within 4 h of ingestion. (Charcoal does not interfere significantly with acetylcysteine therapy.) Antidotal therapy consists of oral N-acetylcysteine (NAC), diluted 3:1 with a nonalcoholic, nondairy beverage. It is given at a loading dose of 140 mg/kg body weight, followed by a maintenance dose of 70 mg/kg body weight every 4 h for 17 additional doses. If initiation of treatment will not be delayed beyond 10 to 12 hours after ingestion of the overdose, acetylcysteine therapy may be withheld until the results of plasma acetaminophen determinations are available. Otherwise, an initial dose of acetylcysteine should be administered immediately, without awaiting for the results of acetaminophen determinations or other laboratory tests. If the level is subsequently shown to be nontoxic, therapy may be discontinued. Side effects of NAC include nausea, vomiting (acetylcysteine-induced vomiting may increase the risk of hemorrhage in peptic ulcer patients), and epigastric discomfort. The dose should be repeated if vomiting occurs within an hour of dosing. Antiemetics (metoclopramide, droperidol, ondansetron) may be necessary. Acetylcysteine solution must be diluted prior to administration because of its unpleasant odor and its irritating or sclerosing properties.
  
  Dilution may also reduce the risk of vomiting. Also, the medication may be tolerated better if the diluted solution is administered well chilled (over ice, if necessary) and sipped from a covered container through a drinking straw. If necessary, an antiemetic may be used concurrently or acetylcysteine can be given via nasogastric tube.
  
  Bronchospastic allergic reaction (shortness of breath, troubled breathing, tightness in chest, or wheezing); dermatitis, allergic skin rash or hives and facial edema are seen with intravenous NAC. Therefore lots of countries including US have not licensed its IV formulation though it is available in India. However, as up to three quarters of severely poisoned patients develop vomiting after a paracetamol overdose, intravenous N-acetylcysteine given over 20-25 hours is generally the agent of choice in the UK (6).
  
  Supportive treatment includes maintaining fluid and electrolyte balance, correcting hypoglycemia, and administering vitamin K 1 (if prothrombin time ratio exceeds 1.5) and fresh frozen plasma or clotting factor concentrate (if prothrombin time ratio exceeds 3).
  
  Additional therapy to treat mixed overdose with other agents (i.e., naloxone for an opioid analgesic) may be needed, especially if symptoms of central nervous system (CNS) depression occur within a few hours after ingestion of the overdose.
  
  Liver and renal function should be monitored during therapy. Patients with severe hepatotoxicity should be considered for liver transplantation.
  
  Mechanism of action/Effect:
  
  Acetylcysteine may protect against acetaminophen overdose-induced hepatotoxicity by maintaining or restoring hepatic concentrations of glutathione. Glutathione is required to inactivate an intermediate metabolite of acetaminophen that is thought to be hepatotoxic. Acetylcysteine may act by reducing the metabolite to the parent compound and/or by providing sulfhydryl for conjugation of the metabolite. Experimental evidence also suggests that a sulfhydryl-containing compound such as acetylcysteine may also directly inactivate the metabolite.
  
  Other conditions where N-acetylcysteine is used / has been tried:
  
  1. As a mucolytic Agent:
  
  

  • As a mucolytic in respiratory disorders associated with the production of viscous mucus such as acute and chronic bronchitis, and in the routine cleansing of tracheostomies.
    
    
  • In alveolar proteinosis to remove proteinaceous material by repeated lavage with heparin and n-acetylcysteine which may prolong survival upto 5 years.
    
    
  • During mechanical ventilation in premature infants to relieve severe recurrent atelectasis.
    
    
  • In adult respiratory distress syndrome n-acetylcysteine is given intravenously.

  
  2. As an antidote to poisoning:
  
  

  • Ratol poisoning. (Yellow Phosphorous Poisoning)
  • Carbon tetrachloride poisoning
    

  
  3. Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris:
  
  

  • N-acetylcysteine when administered with nitroglycerin augments the clinical efficacy of nitroglycerin, particularly by preventing acute myocardial infarction
  • Interaction of nitroglycerin and N-acetylcysteine may lead to the formation of S-nitroso-N-acetylcysteine, which strongly inhibits platelet aggregation.
  • N-acetylcysteine appears to be able to potentiate the peripheral and coronary effects of glyceryl trinitrate.
  • Thus, used as an adjunct to nitrate therapy in the treatment of cardiovascular disorders, especially in the management of unstable angina pectoris.
    
    
  4. In Colposcopy: To clean the cervix and to remove cervical mucus prior to colposcopy.
  
  5. As a therapeutic agent in AIDS:
  
  N-acetylcysteine inhibits the stimulation of viral production during latency by restoring Glutathione concentrations. Evidence suggests NAC enhances the immune response of peripheral blood T cells. Cell culture evidence also suggests NAC supplementation can protect hematopoietic progenitor cells from zidovudine (AZT)-induced toxicity.
  
  6. To prevent radiographic-contrast agent induced reduction in renal function.
  
  7.Influenza: Administration of NAC appears to reduce symptomatology associated with influenza and influenza-like episodes.
  
  8. Sjogren's syndrome: NAC may also have a beneficial therapeutic effect on ocular symptoms of Sjogren's syndrome.
  
  
  References
  1.Litovitz TL, Klein-Schwartz W, Dyer KS, Shannon M, Lee S, Powers M. 1997 Annual report of the American Association of Poison Control Centers toxic exposure surveillance system. Am J Emerg Med 1998;16:443-97.
  
  2.Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet 1995;346:547-52.
  
  3.Bialas MC, Reid P, Beck P, Lazarus JH, Smith PM, Scorer RC, et al. Changing patterns of poisoning in a UK health district between 1987-1988 and 1992-1993. Q J Med 1996;89:893-901.
  
  4.Linden CH, Burns MJ. Poisoning and drug overdosage. In:Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, et al, editors. Harrison's principles of internal medicine. 15th ed. NY: McGraw Hill, Health Professions Division; 1998. p.2595-616.
  
  5. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975;55:871­6.
  
  6. Prescott LF, Illingworth RN, Critchley JAJH, Proudfoot AT. Intravenous N-acetylcysteine: still the treatment of choice for paracetamol poisoning. BMJ 1980; 280: 46-7.
  
  7.Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: Analysis of the National Multicenter Study (1976 to 1985). N Engl J Med 1988; 319: 1557-62.
  
  
  
  
  
  

Department of Clinical Pharmacology*
and Medicine**
Seth G S medical College and KEM Hospital,
Parel,
Mumbai 400 012.