PRACTICAL TOXICOLOGY CASES

ACETAMINOPHENTOXICITY

Acetaminophen is a non-narcotic analgesic, antipyretic, weak anti-inflammatory activity.

Class

• COX-3 in CNS PGs (brain)Pyrogen PG temp. regulatory centres hyperthermias. • COX-1 & COX-2 in periphery (mild effect)

Therapeutic mechanism of action

• Peptic ulcer.• Bronchial asthma.• Viral infection in children. (Aspirin may lead to Reye’s

syndrome (hepatic encephalopathy)).

Indications for preferential use of acetaminophen

• Toxic dose: more than 7.5g as a single dose• Hepatotoxic dose: starts at 140 mg/kg

Doses

Acetaminophen metabolism

ROSBind with

macromolecules in liver cells (lipid, protein, DNA)

necrosisChandok N , Watt K D S Mayo Clin Proc. 2010;85:451-458

GSHMercapturic acid and cysteine conjugates

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.

Stages of Toxicity

STAGE III: (3-5 DAYS) (Liver necrosis)

1. Hypoglycaemia: glycogenolysis & gluconeogenesis2. Metabolic acidosis:

lipolysis (TG FFA acetyl co A ketone bodies)3. Hyperbilirubinemia:

a. Disturbance in uptake of bilirubin from blood to liver so in blood .b secretion of conjugated bilirubin from liver to extra hepatic bile

duct4. Lethargy5. Coma6. Coagulopathy: prothrombin time & bleeding.7. Renal failure:8. 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

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)

Stages of Toxicity

Severe liver damage that might necessitate LIVER transplantation can be suspected in the following cases:

1. Severe acidosis (pH <7.3)

2. Prothrombin time > 50s (USA) or 100s (UK)

3. Grade III/IV hepatic encephalopathy

4. Serum creatinine > 3.3 mg/dL (300mM/L)

5. Bilirubin > 4mg/dL

Poor Prognosis

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:

a. Directly binds with NAPQI.b. Source for GSH (GSH precursor)

(N-acetylcysteine cysteine GSH inhibit NAPQI)

Management

ManagementN-acetylcysteine: (continued)

• Types: I.V (Parvolex) - Oral (Mucomyst) Parvolex is only allowed in UK as it may cause anaphylactic shock

• Dose:a. 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

b. 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

ManagementN-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:1. Patients who didn’t receive antidote within 15 hrs from

intoxication2. Patients at risk of severe liver damage3. ALT/AST levels > 5000 U/L

Assessment of Toxicity

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: Cyt P450 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

Keep in mind the following

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 charcoal 60gm and

magnesium citrate 300mL. Physical examination was

unremarkable; a blood sample for measurement of the

acetaminophen serum concentration was obtained.

Case StudyWhat 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)

Case StudyDescribe 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 P450 mixed-function oxidase system results in increased formation of the reactive intermediate.

• Also, alcohol-associated malnutrition can result in decreased hepatic glutathione stores.

Case StudyThe 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.