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IV induction agents

Propofol, thiopentone, etomidate and ketamine side by side — presentation, pharmacokinetics, organ effects, indications and the contraindications that get examined.

Propofol vs thiopentone

The two classic induction agents. Note the opposite pH: propofol is near-neutral, thiopentone is strongly alkaline — which explains most of its hazards.

	Propofol	Thiopentone
Class	Alkyl phenol	Thiobarbiturate
Presentation	White lipid emulsion — 10% soyabean oil, 2.25% glycerol, 1.2% purified egg phosphatide, sodium hydroxide, water	Pale yellow powder, 2.5% solution. Rubber-bunged bottle with nitrogen in it to prevent oxidation
pH	6–8.5	10.5 — strongly alkaline
pKa	11	7.6
Ionisation	Largely un-ionised at pH 7.4	99.9% ionised in the vial at pH 10.5; in blood at pH 7.4 about 61% is un-ionised and therefore lipid soluble
Induction dose	1.5–2 mg/kg	4–6 mg/kg
Infusion doses	4–12 mg/kg/h anaesthesia · 0.3–4 mg/kg/h sedation	Not used as an infusion (zero-order kinetics)
Protein binding	98%	80%
Onset	30 seconds	One arm–brain circulation — very rapid
Duration	About 10 minutes (redistribution)	5–10 minutes (redistribution)
Vd	4 L/kg	2.5 L/kg
Elimination t½	5–12 hours	6–15 hours
Clearance	30–60 ml/kg/min — exceeds hepatic blood flow, so there is extrahepatic metabolism	3.5 ml/kg/min
Metabolism	Hepatic oxidation and conjugation, plus extrahepatic	Hepatic oxidation
Excretion	Urine, <1% unchanged	Urine, <1% unchanged

Why thiopentone's chemistry matters

Replacing the oxygen with a sulphur atom (thio-) gives rapid onset, short duration and quick recovery, by markedly increasing lipid solubility.
It is 2× more lipid soluble than the barbiturate parent and crosses the blood–brain barrier readily.
Because it is un-ionised drug that is lipid soluble, and 61% is un-ionised at pH 7.4, acidosis increases the un-ionised fraction and deepens the effect.
The pH of 10.5 means extravasation or intra-arterial injection causes vasoconstriction, thrombosis and tissue necrosis.

Organ effects compared

CNS: Both reduce ICP, CMRO₂ and cerebral blood flow. Thiopentone is additionally anticonvulsant. Both reduce EEG activity.
Respiratory: Propofol causes marked respiratory depression and obtunds airway reflexes well. Thiopentone depresses respiration but is more likely to cause laryngospasm because reflexes are less well suppressed.
CVS: Both cause ↓BP, ↓SVR and ↓CO. Propofol produces bradycardia; thiopentone produces a compensatory tachycardia.
Renal: Propofol may cause green urine. Thiopentone reduces renal plasma flow, raises ADH and reduces urine output.
GI: Propofol is antiemetic. Thiopentone causes splanchnic vasoconstriction.
Obstetrics: Propofol has high placental transfer; thiopentone is considered safe and was long the agent of choice.

The safety headlines

Propofol is SAFE in malignant hyperthermia and in porphyria. This is a favourite exam point.
Thiopentone is CONTRAINDICATED in porphyria — barbiturates induce ALA synthase. It is also contraindicated where there is airway obstruction or a fixed cardiac output state.
Thiopentone is the agent of choice in thyrotoxicosis — it has antithyroid activity.
Propofol infusion syndrome (PRIS) occurs above about 4 mg/kg/h for more than 48 hours. Thiopentone does not cause it.
Propofol causes pain on injection; thiopentone causes tissue necrosis on extravasation.

Etomidate vs ketamine

The two agents reached for when the patient is unstable — but for opposite reasons and with opposite haemodynamic mechanisms.

	Etomidate	Ketamine
Class	Carboxylated imidazole	Phencyclidine derivative
Mechanism	GABA-A agonist	Non-competitive NMDA antagonist
Main effect	Hypnosis	Dissociative anaesthesia
pH	8.1	3.5–5.5
pKa	4.1 — largely un-ionised at pH 7.4	7.5
Dose IV	0.2–0.3 mg/kg	1–2 mg/kg
Dose IM	Not used	10 mg/kg
Onset	30–60 s	30 s IV · 2–8 min IM
Duration	3–5 min	5–10 min IV · 10–20 min IM
Protein binding	75%	25%
Vd	2.5–4.5 L/kg	3 L/kg
Metabolism	Hepatic and plasma esterases	Hepatic — norketamine is active, about 30% of parent potency
Elimination t½	2–5 hours	3 hours
CVS	Cardiovascularly stable — BP, HR and CO maintained	↑HR, ↑BP, ↑CO via sympathetic stimulation
Respiratory	Minimal respiratory depression	Minimal depression; airway reflexes PRESERVED; bronchodilator
Cerebral	↓CBF, ↓CMRO₂, ↓ICP	↑CBF, ↑CMRO₂, ↑ICP
Airway	Depressed	Preserved

	Etomidate — side effects	Ketamine — side effects
Myoclonus PONV (high incidence) Cough and hiccup Adrenal suppression — inhibits 11-β-hydroxylase Inhibits platelet function Venous thrombosis Porphyria	Pain on injection Emergence delirium Hallucinations ↑Salivation ↑PONV ↑Uterine tone ↑ICP and ↑IOP Hypertension and tachycardia

Indications and contraindications

Etomidate — indications: the haemodynamically unstable patient, cardiac patients, shock, raised ICP, and shunt (cardiac) cases. Also used for ECT, as it lowers the seizure threshold.
Etomidate — contraindications: porphyria and adrenal suppression. Avoid in septic shock, where adrenal suppression is most harmful.
Ketamine — indications: trauma, burns, asthma, and neuropathic pain. Also for the hypotensive or hypovolaemic patient.
Ketamine — contraindications: hypertension, raised ICP, and ischaemic heart disease (it increases myocardial oxygen demand).
S-ketamine is more potent than the racemic mixture — roughly twice the potency with fewer psychotomimetic effects.

Clonidine — the sedative that isn't an induction agent

α₂ agonist, highly lipid soluble, and crosses the blood–brain barrier readily — which is why it produces central sedation and analgesia.
Provides sedation and analgesia without significant respiratory depression, plus sympatholysis.
Presynaptic α₂ stimulation inhibits noradrenaline release — the mechanism behind the fall in heart rate and blood pressure.
Dexmedetomidine is the more selective modern equivalent and reduces ICU delirium compared with benzodiazepines.

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