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Practical Toxicology Cases

Practical Toxicology Cases. Acetaminophen TOXICITY. Class. Acetaminophen is a non-narcotic analgesic, antipyretic, weak anti-inflammatory activity. Therapeutic mechanism of action. •  COX-3 in CNS   PGs ( brain)

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Practical Toxicology Cases

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  1. Practical Toxicology Cases Acetaminophen TOXICITY

  2. Class Acetaminophen is a non-narcotic analgesic, antipyretic, weak anti-inflammatory activity. Therapeutic mechanism of action •  COX-3 inCNS  PGs (brain) Pyrogen PG  temp. regulatory centres  hyperthermias. •  COX-1 & COX-2 in periphery (mild effect)

  3. Indications for preferential use of acetaminophen • Peptic ulcer. • Bronchial asthma. • Viral infection in children. (Aspirin may lead to Reye’s syndrome (hepatic encephalopathy)). Doses • Toxic dose: more than 7.5g as a single dose •Hepatotoxic dose: starts at 140 mg/kg

  4. Acetaminophen metabolism Mercapturic acid and cysteine conjugates GSH ROS Bind with macromolecules in liver cells (lipid, protein, DNA)  necrosis Chandok N , Watt K D S Mayo Clin Proc. 2010;85:451-458

  5. Stages of Toxicity • Stage I: (6-24 hrs) • Non specific symptoms: • a) Anorexia, malaise • b) Nausea, vomiting • c) Diaphoresis • Symptoms may persist for up to 24 hrs. • Stage II: (24-48 hrs) • State of well being • AST & ALTdisturbance in liver function. • Prolonged prothrombin time. • Patient may complain from right upper quadrant tenderness & the liver may be enlarged.

  6. Stages of Toxicity Stage III: (3-5 days)(Liver necrosis) Hypoglycaemia: glycogenolysis& gluconeogenesis Metabolic acidosis: lipolysis (TG FFA acetyl co A ketone bodies) Hyperbilirubinemia: Disturbance in uptake of bilirubin from blood to liver so in blood  secretion of conjugated bilirubin from liver to extra hepatic bile duct Lethargy Coma Coagulopathy: prothrombin time & bleeding. Renal failure: Formation of  NAPQI in kidney (rich in Cyt P450 ) depletion of GSH  NAPQI Renal injury Death is a result of complications associated with hepatic failure

  7. Stages of Toxicity • Stage IV: (7-8 days) • During this stage recovery occurs • The serum enzymes return to normal, but hepatic necrosis persist • In which stage the patient appear normal? (II,IV) • In which stage the liver disturbance starts? (II)

  8. Poor Prognosis Severe liver damage that might necessitate LIVER transplantation can be suspected in the following cases: Severe acidosis (pH <7.3) Prothrombin time > 50s (USA) or 100s (UK) Grade III/IV hepatic encephalopathy Serum creatinine > 3.3 mg/dL (300mM/L) Bilirubin > 4mg/dL

  9. Management • 1. Gut decontamination: (1-4 hrs after ingestion) • Emesis: but not used if vomiting, coma, permanent emesis • Gastric lavage: put the patient on his left side. • Activated charcoal: 1-2g/kg • 2. Antidote: (within 8-14 hrs) • Must be taken within 8 hrs to prevent liver necrosis • N-acetylcysteine: • Directly binds with NAPQI. • Source for GSH (GSH precursor) • (N-acetylcysteinecysteine GSH inhibit NAPQI)

  10. Management • N-acetylcysteine: (continued) • Types: I.V (Parvolex) - Oral (Mucomyst) • Parvolex is only allowed in UK as it may cause anaphylactic shock • Dose: • Loading dose: N-acetylcysteine is 140 mg/kg. It must be diluted to a 5% conc with Cola or fruit juice. After 1 hr give maintenance dose • Maintenance dose: 17 doses of 70 mg/kg every 4hrs • E.g.: 140mg/kg • 140 mg 1 kg • X mg  50 kg X = 7000mg = 7gm • 5 gm100ml • 7 gm Y Y= 140 ml

  11. Management • N-acetylcysteine: (continued) • In case of persistent vomiting: • The patient can’t receive oral antidotal treatment, so metoclopramide (1mg/kg I.V.) is given. If this failed, ondansetron (0.15mg/kg) is given to stop the vomiting before ttt with the antidote is ensued. • 3. Enhanced elimination: • This is done by exchange transfusion (complete blood replacement) • Successful in the following cases: • Patients who didn’t receive antidote within 15 hrs from intoxication • Patients at risk of severe liver damage • ALT/AST levels > 5000 U/L

  12. Assessment of Toxicity

  13. Keep in mind the following • How could you overcome the administration of giving antidote with activated charcoal? • Remove activated charcoal first by gastric lavage before administration of antidote. • dose of antidote by 30 - 40% • In some conditions, although the amount of acetaminophen in plasma is less than the toxic threshold in nomogram, the patient may suffer from hepatotoxicity, why? • Chronic alcoholism: CytP450 NAPQI • Malnutrition: GSH • Why is acetaminophen toxicity less likely to occur with children? • Acetaminophen overdose  induction vomiting. • Metabolic system is sulfation, (acetaminophen inactive) • Cyt P450 not well developed, turn over of GSH is very high

  14. Case Study W.R. is a 40-year old, 75 kg alcoholic male brought to the emergency department six hours after ingesting fifty 500 mg acetaminophen tablets. At home, he was given syrup of ipecac to induce emesis, but no undissolved tablets were seen. The patient’s only complaints were nausea, vomiting, and anorexia. He was given an oral dose of activated charcoal60gm and magnesium citrate300mL. Physical examination was unremarkable; a blood sample for measurement of the acetaminophen serum concentration was obtained.

  15. Case Study What are the symptoms of acetaminophen poisoning? Were W.R. symptoms consistent with an acute intoxication? • Symptoms: (see stages I-IV) • The symptoms are consistent with acute intoxication as the patient suffered from stage I symptoms (nausea, vomiting, and anorexia)

  16. Case Study Describe the mechanism(s) of acetaminophen-induced hepatotoxicity and assess W.R. risk for the development of this complication. • Mechanisms: (see NAPQI formation) • W.R. ingested 330 mg/kg of acetaminophen ((50 X 500)/75). • Ingestions of this magnitude are usually associated with hepatic necrosis, if antidotal treatment is not initiated or is delayed. • If W.R.’s serum concentration was less than 120 mg/ml four to six hours after ingestion, his risk for development of hepatic necrosis would be estimated as minimal by the nomogram. • However, hepatotoxicity has been reported in alcoholics after repeated therapeutic doses of acetaminophen and hepatotoxicity could occur in W.R.even with a reportedly “safe” serum concentration. • Alcoholics appear to be at increased risk for acetaminophen-induced hepatotoxicity, because an alcohol-induced cytochrome P450mixed-function oxidase system results in increased formation of the reactive intermediate. • Also, alcohol-associated malnutrition can result in decreased hepatic glutathione stores.

  17. Case Study The acetaminophen serum concentration obtained on admission was 295 mg/mL. What additional treatment is indicated for W R.? The patient should immediately receive an antidotal treatment and should be closely monitored for possible application of enhanced elimination techniques.

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