Fentanyl vs Ketamine

Current · V5 (2025) → H6.iii 1 exam appearance

2026A Q09

Exam question

Compare and contrast fentanyl and ketamine using the following headings:
a) mechanism of action (20% of marks),
b) pharmacokinetics relevant to the intravenous administration in intensive care (40% of marks),
c) pharmacodynamics and adverse effects (40% of marks).

CICMWrecks answer

Master answer

This question specifically asks about intravenous use in intensive care; non-IV routes and non-ICU detail are therefore omitted.

Compare Fentanyl & Ketamine in the Pharmacopeia

a) Mechanism of action (20%)

Feature	Fentanyl	Ketamine
Primary target	Potent μ-opioid receptor agonist	Predominantly a non-competitive NMDA receptor antagonist
Receptor / signalling	μ receptor is Gi/o-protein coupled → inhibits adenylyl cyclase → ↓ cAMP; opens postsynaptic K⁺ channels and inhibits presynaptic voltage-gated Ca²⁺ channels → hyperpolarisation and ↓ neurotransmitter release	Binds within the NMDA receptor ion channel (PCP site) → reduces glutamate-mediated Na⁺/Ca²⁺ influx and excitatory neurotransmission
Relevant secondary actions	Modulates nociceptive transmission in brain and spinal cord	Inhibits neuronal catecholamine reuptake, contributing to indirect sympathomimetic effects; additional interactions with opioid and monoaminergic systems
Clinical consequence	Potent analgesia and sedation	Dissociative anaesthesia, analgesia and amnesia

b) Pharmacokinetics relevant to IV administration in ICU (40%)

Feature	Fentanyl	Ketamine
IV onset	Almost immediate; rapid CNS penetration because of high lipid solubility	Very rapid, usually within ~30 seconds
Distribution	Three-compartment behaviour; rapid initial distribution and redistribution into muscle and fat	Rapid distribution from brain to peripheral tissues; initial distribution phase ~10–15 min
Volume of distribution	Large, about 4 L/kg	Large, approximately 1–3 L/kg
Protein binding	High, approximately 80–85%	Lower, approximately 20–50%
Metabolism	Predominantly hepatic, mainly CYP3A4, to inactive metabolites	Hepatic N-demethylation, mainly via CYP2B6 and CYP3A4, to active norketamine, followed by further hydroxylation/conjugation
Excretion	Mainly urine as metabolites; little unchanged fentanyl	Mainly renal excretion of metabolites; little unchanged ketamine
Terminal / elimination half-life	Approximately 3–4 h	Approximately 2–3 h
Context-sensitive behaviour	Markedly prolonged after long infusions because fentanyl accumulates in peripheral tissue compartments and redistributes back into plasma after cessation	Offset is initially dominated by redistribution and hepatic metabolism; context-sensitive prolongation is less marked than fentanyl, although prolonged infusion and active norketamine can still delay recovery
Critical illness relevance	Prolonged infusion may cause accumulation and delayed awakening/extubation. Hepatic dysfunction, reduced hepatic blood flow and CYP3A4 interactions may reduce clearance. No clinically important active metabolite, so renal failure has less effect than with morphine	Hepatic dysfunction may prolong parent-drug clearance. Active metabolites may contribute during prolonged use; renal dysfunction can reduce metabolite clearance. Rapid redistribution makes bolus offset relatively quick

c) Pharmacodynamics and adverse effects (40%)

System / effect	Fentanyl	Ketamine
Analgesia / sedation	Potent dose-dependent analgesia and sedation; no reliable amnesia when used alone	Profound analgesia with dissociative sedation/anaesthesia and amnesia
Cardiovascular	Usually relatively haemodynamically stable; may cause vagal bradycardia and hypotension, especially with other sedatives	Usually ↑ HR, BP and cardiac output via indirect sympathomimetic action. Has a direct myocardial depressant effect which may become apparent in catecholamine-depleted shock → hypotension/cardiovascular collapse
Respiratory	Dose-dependent respiratory depression and apnoea; reduced CO₂ responsiveness and cough reflex	Respiratory drive is relatively preserved at usual doses, but rapid/high-dose IV administration can still cause respiratory depression or apnoea
Airway / chest	High or rapidly administered doses can cause chest-wall / respiratory muscle rigidity	Bronchodilator; pharyngeal/laryngeal reflexes are relatively preserved, but increased secretions, laryngospasm and airway obstruction can occur
CNS	Sedation, miosis; tolerance, dependence and withdrawal with prolonged exposure	Dissociation, nystagmus, increased muscle tone/spontaneous movements; hallucinations and emergence delirium. May increase cerebral blood flow/ICP in some circumstances
GI	Nausea/vomiting, ↓ gastrointestinal motility and constipation	Nausea/vomiting; hypersalivation
Other important toxicity	Pruritus, urinary retention; serotonin syndrome with serotonergic drugs; opioid-induced hyperalgesia may occur with prolonged/high exposure	With repeated/prolonged exposure: hepatobiliary injury/cholangiopathy and cystitis have been described
Reversal	Effects can be antagonised with naloxone, although renarcotisation is possible if fentanyl outlasts naloxone	No specific pharmacological antagonist

ICU comparison — practical implications

Fentanyl: useful when potent titratable analgesia is required and relative cardiovascular stability is desirable, but prolonged infusions can accumulate and delay ventilator weaning; respiratory depression is a major limitation.
Ketamine: attractive when analgesia plus sedation is required in a patient with bronchospasm or where preservation of spontaneous ventilation is useful; however, sympathetic stimulation, emergence phenomena and the possibility of cardiovascular depression in catecholamine-depleted shock are important limitations.
Both: rapid-onset, lipophilic IV drugs with large volumes of distribution and predominantly hepatic metabolism, but their receptor targets, cardiorespiratory effects and behaviour during prolonged ICU infusion are substantially different.

Quick reference

Summary

Feature	Fentanyl	Ketamine
Primary target	μ-opioid agonist	NMDA antagonist
Vd	~4 L/kg	~1–3 L/kg
Protein binding	80–85%	20–50%
Metabolism	CYP3A4; inactive metabolites	CYP2B6/3A4 → active norketamine
Long infusion	Marked tissue accumulation / prolonged CSHT	Less marked accumulation; active metabolite contributes
Respiration	Respiratory depression	Relatively preserved; bronchodilation
CV	Usually stable; bradycardia	Usually ↑ HR/BP/CO; may depress myocardium if catecholamine depleted

Past papers

Exam appearances

1 appearance

Exam	Exact exam wording	Candidate success
2026A Q09	Compare and contrast fentanyl and ketamine using the following headings: a) mechanism of action (20% of marks), b) pharmacokinetics relevant to the intravenous administration in intensive care (40% of marks), c) pharmacodynamics and adverse effects (40% of marks).	51.8%