1. Paracetamol Toxicity

2. Outline
Introduction
MOA
Indications
Dosage
Contraindications
Paracetamol toxicity

3. Paracetamol - Introduction
- Paracetamol , also known as acetaminophen or
APAP (N- acetyl-p-aminophenol).
- It was first introduced in the UK in 1955.
- It's the most widely used analgesic-antipyretic in
the US and Worldwide.
- It has no anti-inflammatory activity.
- The MOA of acetaminophen is not very well
understood. One of the proposed the mechanisms
is that APAPs inhibit COX2,
decreasing prostaglandin levels.

4. Paracetamol - MOA
- To date, the MOA is not completely
understood.
- The main mechanism proposed is
the inhibition of cyclooxygenase
(COX) and recent findings suggest
that it is highly selective for COX2.
- APA are poor inhibitor of
prostaglandin synthesis in the
peripheral tissues but a potent COX
inhibitor in the brain.
APAP

5. Paracetamol - Indications
- Mild to moderate pain
e.g. Headaches, menstrual periods, toothaches, backaches, osteoarthritis,
cold/flu aches and pain.
- Fever
- Patent ductus arteriosus
Acetaminophen is a suitable substitute to NSAIDs for patients
with gastric complaints/ risks, in those whom a prolongation of
bleeding time is not desirable, as well as those who do not require the
anti-inflammatory action of NSAIDs

6. Paracetamol - Dosage
Route of Administration
Oral, IV or Rectal
Therapeutic Dose
- In children; 10-15 mg/kg per dose every 4-6 h.
Maximum recommended dose 80 mg/kg per day
- In adults; 325-1000 per dose every 4-6 h.
Maximum recommended dose 4g per day

7. Paracetamol - Contraindications
- Injection
Hypersensitivity to acetaminophen or any component of the
formulation.
Severe hepatic impairment or severe active liver disease.
- OTC
Using other drug products containing acetaminophen.
Allergic to acetaminophen or any of the inactive ingredients.

8. Paracetamol - Contraindications
Acetaminophen should be used with caution in the following cases:
- G6PD deficiency
- Hepatic impairment
- Hypovolemia
- Alcoholism
- Warfarin

9. Paracetamol Toxicity

10. Paracetamol Toxicity
- It's a major cause of overdose and overdose-related liver failure and
death.
- It's one of the most reported products causing drug-induced liver
injury and is the most common cause of acute liver failure in the US,
accounting for 50 percent of all reported cases
- If overdose is identified early enough, mortality rates are extremely
low. However, once acute liver failure has developed, mortality is
approximately 28 percent, and a third of patients require liver
transplantation.

11. Paracetamol Toxicity
Minimum toxic doses of acetaminophen for a single ingestion, posing
significant risk of severe hepatotoxicity, are as follows:
Adults: 7.5-10 g
Children: 150 mg/kg; 200 mg/kg in healthy children aged 1-6 years

22. Paracetamol can induce hepatotoxicity even at therapeutic
doses in a very small percentage of population, WHY?

37. Mechanisms that Increase Risk of
Hepatotoxicity
• Excessive intake of Acetaminophen (most important)
• Delay between Acetaminophen ingestion and N-Acetylcystine (NAC)
therapy
• Excessive cytochrome P450 activity
• Decreased capacity for glucuronidation or sulfation
• Depletion of glutathione stores

38. Clinical Presentation
Phase 1 (0 to 24
hours):
loss of appetite,
nausea, vomiting,
general malaise.
1
Phase 2 (24 to 72
hours):
abdominal pain,
increased liver
enzymes.
2
Phase 3 (72 to 96
hours):
liver necrosis, jaundice,
encephalopathy, renal
failure, death.
3
Phase 4 (>4 days to 2
weeks):
complete resolution of
symptoms and organ
failure.
4

40. Approach to Paracetamol Toxicity
• ABCDE
• History
Dose, time of ingestion, intent of use, presence of comorbidities
• Physical Examination
• Investigations
CBC, LFT, PT/INR, Blood Glucose, Platelet count, urine output, KFT
electrolytes.
Plasma Paracetamol level
In suicidal attempts, toxic screening of blood and urine for other
ingested drugs should be performed

42. Paracetamol Toxicity Treatment
- Activated Charcoal
Given if patient presents within 1 hour of ingestion and is mentally and clinically
stable stable
- N-Acetylcysteine
- NAC is nearly 100% hepatoprotective when it is given within 8 hours after an
acute acetaminophen ingestion.
- NAC should be given even if the history is unclear but a potential toxicity is
suspected.
- Given for pregnant women and if the patient presents close to, or later than, 8
hours after an acute ingestion.
- If there is possible/probable toxicity according to the Rumack-Matthew
nomogram.

47. How Does N-
Acetylcysteine
work ?

54. Oral N-Acetylcysteine
The oral formulation of NAC (Mucomyst) is the drug of choice for the
treatment of acetaminophen overdose.
It is safe and effective for as long as 24 hours after a toxic ingestion.
The FDA-approved dosage regimen for oral NAC starts with a loading
dose of 140 mg/kg, followed by 17 doses, each at 70 mg/kg, given
every 4 hours. The total duration of the treatment course is 72 hours.

55. IV N-Acetylcysteine
Indicated in the following:
- Altered mental status
- GI bleeding and/or obstruction
- A history of caustic ingestion
- Potential acetaminophen toxicity in a pregnant woman
- Inability to tolerate oral NAC because of emesis refractory to proper
use of antiemetics

56. IV N-Acetylcysteine
• Loading dose: 150 mg/kg IV; mix in 200 mL of 5% dextrose in water
(D5W) and infuse over 1 h
Dose 2: 50 mg/kg IV in 500 mL D5W over 4 h
Dose 3: 100 mg/kg IV in 1000 mL D5W over 16 h
• loading dose of 150 mg/kg, given over 60 minutes, followed by a
maintenance infusion of 15 mg/kg/hr.
Continued until the serum acetaminophen concentration measures
less than 10 mg/L and the liver enzyme concentrations remain normal
or are trending downward.

57. N-Acetylcysteine
• If a patient presents 8-24 hours or later after an acute ingestion,
initiate NAC therapy immediately and evaluate for laboratory
evidence of hepatotoxicity.
• At the end of treatment, check INR, Creatinine and ALT.
If any of them is abnormal or the patient is symptomatic
further monitoring will be needed.

58. N-Acetylcysteine Side Effects
• Vomiting
• Anaphylactoid reaction
• Urticaria
• Angioedema
• Hypotension
• Bronchospasm
May be managed by discontinuation or anti-histamine

59. Paracetamol Toxicity Treatment
- 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 acidosis, unresponsive to resuscitation
• Kidney failure
• Coagulopathy
• Encephalopathy