Paracetamol

How to use it peri-operatively

• Use as a baseline analgesic in multimodal regimens to reduce opioid requirement and opioid-related adverse effects.
  • Particularly useful when NSAIDs are contraindicated (e.g. renal impairment, peptic ulcer disease, bleeding risk).
• Routes: oral, IV, rectal (variable absorption).
  • IV is helpful when enteral route unavailable or rapid onset desired; ensure correct dose and infusion time.
• Typical adult dosing (UK): 1 g every 6 hours (max 4 g/24 h) if ≥50 kg and no risk factors.
  • If <50 kg or risk factors for hepatotoxicity: use reduced maximum daily dose (commonly 60 mg/kg/day; do not exceed 3 g/day in many hospital policies).
• IV administration: infuse over 15 minutes (standard adult 1 g in 100 mL).
  • Avoid dosing errors: paediatric concentrations and weight-based dosing are common sources of harm.
• In liver disease/malnutrition/alcohol excess: reduce dose and increase vigilance; avoid repeated supratherapeutic dosing.
  • Acute severe hepatitis or acute liver failure: avoid unless specialist advice.

Overdose: immediate approach (anaesthetic/critical care relevance)

• Assess time of ingestion, dose, formulation (immediate vs modified release), co-ingestants, risk factors (chronic alcohol, malnutrition, enzyme inducers).
  • Staggered ingestion or unknown time: treat as high risk and discuss urgently with toxicology/NPIS.
• Check paracetamol level at ≥4 hours post-ingestion (or immediately if presentation is late) and LFTs, INR, U&Es, glucose, VBG/ABG ± lactate.
  • Early metabolic acidosis and raised lactate can suggest massive overdose and mitochondrial toxicity.
• Antidote: N-acetylcysteine (NAC) according to current UK guidance; do not delay if indicated.
  • Indications depend on nomogram (single acute ingestion with known time) or clinical scenario (staggered/late/unknown). Follow local protocol and NPIS/TOXBASE.
• Consider activated charcoal within 1 hour of large ingestion (longer window may apply for modified-release or massive ingestion per toxicology advice).
  • Airway protection is paramount if reduced consciousness or co-ingestants.
• Escalate early to ICU/liver unit if evolving hepatic failure (INR rising, encephalopathy, hypoglycaemia, acidosis, renal failure).
  • Transplant criteria are specialist-led; anaesthetists may be involved in transfer, organ support, and peri-transplant care.

Drug class and core properties

• Non-opioid analgesic and antipyretic with minimal peripheral anti-inflammatory activity at therapeutic doses.
• Does not inhibit platelet function and has minimal effect on gastric mucosa compared with NSAIDs.
• Useful across age groups; dosing must be weight-based in children and in adults <50 kg.

Mechanism of action (exam-level)

• Predominantly central analgesic action: reduces prostaglandin synthesis within CNS (functional COX inhibition in low peroxide environments).
  • Likely acts on COX-1/COX-2 pathways centrally rather than being a classic peripheral COX inhibitor.
• Enhances descending serotonergic inhibitory pathways (5-HT) contributing to analgesia.
• Metabolite pathway: AM404 (from p-aminophenol) may modulate endocannabinoid system (CB1) and TRPV1, contributing to analgesia.
• Antipyresis: acts at hypothalamus to reduce PGE2-mediated set point.

Pharmacokinetics

• Absorption: oral rapid (Tmax ~30–60 min); rectal slower and unpredictable; IV immediate systemic availability.
• Distribution: Vd ~0.9 L/kg; low protein binding at therapeutic concentrations (increases in overdose).
• Metabolism (hepatic): mainly glucuronidation (~50–60%) and sulfation (~25–35%).
  • Small fraction oxidised via CYP2E1 (also 1A2, 3A4) to NAPQI (toxic).
  • NAPQI normally detoxified by glutathione conjugation; glutathione depletion → hepatocellular necrosis.
• Elimination: renal excretion of conjugates; t1/2 ~2 hours (prolonged in overdose and hepatic failure).

Pharmacodynamics and clinical effects

• Analgesic ceiling: moderate analgesia; best for mild–moderate pain and as an adjunct for severe pain.
• Opioid-sparing effect can reduce PONV, sedation, ileus, respiratory depression risk.
• Minimal haemodynamic effects at therapeutic dose; IV formulation can cause hypotension in some patients (multifactorial: vasodilation, fluid status, critical illness).

Indications

• Post-operative pain (baseline analgesic), trauma pain, headache, musculoskeletal pain, fever.
• Peri-operative use in enhanced recovery pathways; useful when NSAIDs avoided.

Contraindications and cautions

• Absolute: hypersensitivity (rare).
• Caution: chronic liver disease, chronic alcohol excess, malnutrition/low body weight, dehydration, sepsis/critical illness, enzyme-inducing drugs (e.g. carbamazepine, phenytoin, rifampicin), repeated high dosing.
• Renal impairment: generally safe at therapeutic doses; avoid chronic high-dose use; consider longer dosing interval in severe renal failure per local policy.

Adverse effects

• Therapeutic dosing: usually well tolerated; occasional rash/urticaria; very rare serious skin reactions (SJS/TEN).
• Hepatotoxicity: dose-dependent; can occur with acute overdose or repeated supratherapeutic ingestion, especially with risk factors.
• IV-related: hypotension (notably in critically ill), infusion-related discomfort; dosing errors (10-fold) are a key safety issue.

Drug interactions (high-yield)

• Enzyme inducers (carbamazepine, phenytoin, phenobarbital, rifampicin, St John’s wort): increase NAPQI formation and risk of hepatotoxicity (especially with high/repeated dosing).
• Chronic alcohol excess: induces CYP2E1 and reduces glutathione stores → higher risk.
• Warfarin: prolonged regular paracetamol use can increase INR (mechanism unclear; likely reduced vitamin K cycle/altered metabolism). Monitor INR if prolonged use.
• Cholestyramine reduces absorption (separate dosing); metoclopramide/domperidone can increase rate of absorption.

Special populations

• Pregnancy: widely used; considered safe at therapeutic doses; avoid prolonged high-dose use without indication.
• Breastfeeding: compatible; small amounts in breast milk.
• Paediatrics: dose by weight; ensure correct formulation and maximum daily dose; rectal route has variable bioavailability.
• Elderly/frail/low body weight: increased risk of dosing above mg/kg thresholds; reduce total daily dose and document weight.

Overdose and toxicity (key facts)

• Toxic metabolite: NAPQI causes centrilobular (zone 3) hepatic necrosis when glutathione depleted.
• Clinical phases: early (0–24 h) nausea/vomiting/diaphoresis; 24–72 h RUQ pain, rising transaminases; 72–96 h peak hepatic failure; recovery or multi-organ failure/death.
• NAC replenishes glutathione and improves outcomes even when given late; also improves microcirculatory blood flow and acts as antioxidant.
• Modified-release preparations and co-ingestion with opioids/antimuscarinics can delay absorption; may need repeated levels and prolonged treatment per toxicology advice.