Paracetamol (Acetaminophen)

Overview

Paracetamol (also called acetaminophen or APAP) is one of the most widely used analgesic and antipyretic agents globally. It is available over-the-counter and forms the basis of countless combination products.

Mechanism of Action

The exact mechanism remains incompletely understood, but is thought to be primarily central in nature. Leading hypotheses include:

COX inhibition — Produces analgesic and antipyretic effects similar to NSAIDs, but without anti-inflammatory or anticoagulant properties.
L-arginine–nitric oxide pathway inhibition and reinforcement of descending inhibitory serotonergic pain pathways.
Cannabinoid receptor modulation via active metabolites.

(Clinical Management of Arboviral Diseases, p. 44)

Key Properties

Property	Detail
Drug class	Non-opioid analgesic / Antipyretic
Route	Oral, rectal, IV
Onset (oral)	~30–60 min
Duration	4–6 hours
Protein binding	~10–25%
Metabolism	Hepatic (glucuronidation, sulfation; minor CYP2E1 pathway produces toxic NAPQI)
Excretion	Renal

Indications

Pain: Mild to moderate pain (headache, musculoskeletal pain, post-operative pain, dental pain)
Fever: Antipyretic of choice in adults and children
Preferred over NSAIDs in: pregnancy (especially 1st/2nd trimester), peptic ulcer disease, renal impairment, anticoagulated patients

Dosing

Population	Standard Dose	Max Daily Dose
Adults	500–1000 mg every 4–6 h	4000 mg/day (3000 mg/day in elderly or chronic alcohol use)
Children	10–15 mg/kg every 4–6 h	60–75 mg/kg/day

Toxicity & Overdose

Paracetamol is the leading cause of drug-induced liver injury (DILI) and acute liver failure (ALF) in the US and many Western countries. (Acute Liver Failure, p. 12)

Toxic threshold

Single intentional overdose: >10–15 g (often a suicide attempt)
Unintentional overdose: >10 g over several days (e.g., using multiple APAP-containing products simultaneously)

Risk factors for enhanced toxicity

Fasting
Chronic alcohol use
CYP2E1 inducers (e.g., isoniazid, rifampicin)

Pathophysiology

At toxic doses, glucuronidation and sulfation pathways become saturated → excess APAP shunted to CYP2E1 → produces NAPQI (N-acetyl-p-benzoquinone imine), a reactive metabolite → depletes hepatic glutathione → hepatocellular necrosis (centrilobular pattern).

Stages of toxicity

Stage	Time	Features
I (0–24 h)	Nausea, vomiting, malaise	Liver enzymes may still be normal
II (24–72 h)	Hepatic necrosis begins	↑ AST/ALT, ↑ PT, RUQ pain
III (72–96 h)	Peak hepatotoxicity	Jaundice, coagulopathy, encephalopathy, possible ALF
IV (4 days–2 weeks)	Recovery or death

Management

Activated charcoal — if within 1–2 hours of ingestion
N-acetylcysteine (NAC) — cornerstone of treatment; replenishes glutathione; most effective within 8–10 hours, but may be given up to 24 hours or beyond
- IV protocol: 150 mg/kg over 1 h → 50 mg/kg over 4 h → 100 mg/kg over 16 h
- Oral protocol: 140 mg/kg loading, then 70 mg/kg every 4 h × 17 doses
Rumack–Matthew nomogram — use serum paracetamol level at 4 hours post-ingestion to guide NAC therapy
Liver transplant — for fulminant hepatic failure (King's College Criteria used for listing)

Contraindications / Cautions

Hepatic impairment — use with caution; reduce dose
Chronic alcohol use — lower daily maximum (2000–3000 mg/day)
G6PD deficiency — rare risk of hemolytic anemia
Caution with warfarin — regular high-dose use can potentiate anticoagulation

Comparison: Paracetamol vs NSAIDs

Feature	Paracetamol	NSAIDs
Analgesia	Mild–moderate	Mild–moderate to strong
Antipyretic	Yes	Yes
Anti-inflammatory	No	Yes
GI toxicity	Low	Higher
Renal toxicity	Low (usual doses)	Yes
Hepatotoxicity risk	Yes (overdose)	Low
Use in pregnancy	Preferred	Avoid (3rd trimester)

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