Fever vs Hyperthermia & Paracetamol

Current · V5 (2025) → M1.iv 1 exam appearance

2026A Q17

Exam question

a) Compare and contrast fever and hyperthermia using the following headings: i) physiological mechanisms (30% of marks), ii) causes (30% of marks). With respect to paracetamol: i) outline the mechanism of action (15% of marks), ii) list the adverse effects (10% marks), iii) outline mechanism of toxicity. (15% of marks). Management of toxicity is NOT required.

CICMWrecks answer

Master answer

Open Paracetamol in the Pharmacopeia

a) Fever vs hyperthermia

i) Physiological mechanisms (30%)

Feature	Fever	Hyperthermia
Core mechanism	Raised hypothalamic set-point.	Set-point unchanged; heat gain exceeds heat loss.
Trigger	Exogenous/endogenous pyrogens → IL-1, IL-6, TNF → COX-2/PGE₂ signalling in hypothalamus.	Excess environmental heat, excessive metabolic heat production, or failed heat dissipation.
Thermoregulatory response	Body perceives itself as “cold” relative to the new set-point → vasoconstriction, shivering, behavioural heat seeking.	Normal heat-loss responses are activated → vasodilation and sweating, but are insufficient.
When temperature falls	When the set-point returns toward normal, vasodilation and sweating occur.	Falls only when heat production/exposure is reduced or heat loss improves.
Antipyretics	Effective because they reduce prostaglandin-mediated set-point elevation.	Generally ineffective because the hypothalamic set-point is already normal.

ii) Causes (30%)

Fever	Hyperthermia
Infection — bacterial, viral, fungal, parasitic. Inflammation / autoimmune disease. Malignancy. Drug fever / transfusion reactions. Tissue injury or other cytokine-mediated inflammatory states.	Environmental heat exposure / heat stroke. Excess muscle activity — seizures, severe agitation, exercise. Drug/toxin syndromes — sympathomimetics, serotonin syndrome, anticholinergic toxicity. Malignant hyperthermia / neuroleptic malignant syndrome. Endocrine/metabolic excess such as thyrotoxicosis.

b) Paracetamol

i) Mechanism of action (15%)

Mechanism is not completely defined.
Its antipyretic effect is mainly central: reduces prostaglandin E₂ synthesis/signalling in the hypothalamus, lowering the elevated febrile set-point toward normal.
Central cyclooxygenase/peroxidase inhibition contributes; analgesic effects also involve non-COX pathways including serotonergic and AM404/endocannabinoid–TRPV1 signalling.
It has little peripheral anti-inflammatory or antiplatelet effect compared with NSAIDs.

ii) Adverse effects (10%)

Usually well tolerated at therapeutic doses.
Hepatotoxicity with overdose or excessive cumulative dosing.
Hypersensitivity / serious skin reactions are rare.
Renal injury is uncommon but may occur, particularly with significant toxicity or prolonged excessive exposure.

iii) Mechanism of toxicity (15%)

Most paracetamol is normally conjugated by glucuronidation and sulfation.
A small fraction undergoes CYP-mediated oxidation, particularly via CYP2E1, to the reactive metabolite NAPQI.
At therapeutic doses NAPQI is rapidly detoxified by conjugation with glutathione.
In overdose, normal conjugation pathways become saturated and glutathione stores are depleted → NAPQI accumulates.
NAPQI binds covalently to hepatocyte proteins, particularly mitochondrial proteins → oxidative stress, mitochondrial dysfunction and centrilobular (zone 3) hepatocellular necrosis.

Exam focus

The key distinction is raised set-point in fever vs normal set-point in hyperthermia.
Do not omit pyrogens → cytokines → PGE₂ in fever.
For paracetamol toxicity, write the sequence NAPQI → glutathione depletion → oxidative hepatocyte injury.

Quick reference

Summary

Feature	High-yield point
Fever	Raised hypothalamic set-point via pyrogens/cytokines → PGE2
Hyperthermia	Set-point unchanged; heat production/gain exceeds heat loss
Paracetamol MOA	Central reduction of PGE2 signalling; analgesia also involves non-COX pathways
Toxicity	NAPQI accumulation after glutathione depletion → oxidative mitochondrial hepatocyte injury

Past papers

Exam appearances

1 appearance

Exam	Exact exam wording	Candidate success
2026A Q17	a) Compare and contrast fever and hyperthermia using the following headings: i) physiological mechanisms (30% of marks), ii) causes (30% of marks). With respect to paracetamol: i) outline the mechanism of action (15% of marks), ii) list the adverse effects (10% marks), iii) outline mechanism of toxicity. (15% of marks). Management of toxicity is NOT required.	16%