Propofol

Core facts (what to say first in a viva)

Intravenous hypnotic agent used for induction and maintenance of anaesthesia and for sedation (including TIVA).
Highly lipid soluble; formulated as an oil-in-water emulsion; rapid onset and rapid recovery due to redistribution and high clearance.
Main mechanism: potentiation of inhibitory neurotransmission at GABAA receptor (positive allosteric modulator; at higher concentrations can directly gate the channel).
Key physiological effects: dose-dependent CNS depression; cardiovascular depression (↓SVR, ↓BP, some negative inotropy); respiratory depression/apnoea; antiemetic; anticonvulsant (but can cause excitatory movements).

Typical doses (adult)

Induction: ~1.5–2.5 mg/kg IV (lower in elderly, hypovolaemia, shocked, co-administered opioids/benzodiazepines).
Maintenance (TIVA): commonly ~4–12 mg/kg/h (≈ 70–200 microg/kg/min), titrated to effect/TCI model.
Sedation: lower infusion rates (e.g. ~0.5–4 mg/kg/h depending on target depth and setting); avoid deep sedation without airway-skilled supervision.

Chemical class and formulation

Chemical: 2,6-diisopropylphenol; weak acid; very low water solubility → requires lipid emulsion.
Formulation: oil-in-water emulsion (commonly soybean oil + egg lecithin/phosphatide + glycerol) giving a milky appearance; typically 1% (10 mg/mL) and 2% (20 mg/mL).
Aqueous phase contains free propofol responsible for onset; emulsion supports rapid delivery and contributes to pain on injection and infection risk.
Preservatives: some preparations contain EDTA or metabisulfite; preservative reduces microbial growth but does not eliminate contamination risk.
Allergy: egg/soy allergy rarely clinically relevant because lecithin is highly purified; true anaphylaxis to propofol is possible (phenol structure).

Mechanism of action (PD)

GABAA receptor: increases chloride conductance via positive allosteric modulation; at higher concentrations can directly activate the receptor.
Additional actions (less central for FRCA but useful): effects on glycine receptors; inhibition of NMDA receptor activity; modulation of endocannabinoid system and sodium channels proposed.
Produces hypnosis and amnesia; no analgesia (may reduce pain perception but clinically not an analgesic).

Pharmacokinetics (PK): distribution, metabolism, elimination

Onset: rapid (loss of consciousness typically within ~30–45 s) due to high lipid solubility and high cerebral blood flow delivery.
Distribution: extensive; high protein binding (~95–99%); large volume of distribution; rapid redistribution from vessel-rich group to muscle/fat explains short clinical duration after bolus.
Metabolism: mainly hepatic conjugation (glucuronidation) and hydroxylation to inactive metabolites; significant extrahepatic metabolism (e.g. lungs) contributes to high clearance.
Clearance: high (often exceeds hepatic blood flow → supports extrahepatic metabolism).
Elimination: metabolites excreted in urine; terminal elimination half-life is long due to slow release from peripheral compartments, but this does not reflect clinical recovery after short infusions.
Context-sensitive half-time: relatively short compared with many agents; increases with duration of infusion but remains favourable for many clinical durations (key concept for TIVA).

PK/PD concepts relevant to TCI

Effect-site equilibration is relatively fast (short ke0) → rapid onset/offset when changing target concentrations.
Common TCI models: Marsh (weight-based; often used for adults) and Schnider (incorporates age, height, lean body mass; different predicted concentrations).
Clinical implication: elderly and frail require lower targets; co-administered opioids reduce hypnotic requirement (synergy).

Central nervous system effects

Hypnosis and amnesia; reduces cerebral metabolic rate (CMRO2), cerebral blood flow (CBF) and intracranial pressure (ICP) while maintaining coupling (CBF falls with CMRO2).
EEG: dose-dependent slowing; burst suppression at high doses.
Anticonvulsant properties; can terminate status epilepticus; may cause myoclonus/excitatory movements that are not necessarily epileptic.
Reduces intraocular pressure.

Cardiovascular effects

Dose-dependent hypotension: mainly via decreased systemic vascular resistance (vasodilation) and reduced preload (venodilation); also some negative inotropy.
Blunts baroreflex → less compensatory tachycardia; heart rate may remain unchanged or fall.
Reduces myocardial oxygen consumption; can be problematic in hypovolaemia, severe aortic stenosis, cardiogenic shock.
May cause bradycardia and rarely asystole, especially with vagotonic stimuli or co-administration of opioids/anticholinesterases without antimuscarinic.

Respiratory effects

Dose-dependent respiratory depression: reduced tidal volume and respiratory rate; apnoea common after induction bolus.
Blunts ventilatory responses to CO2 and hypoxia.
Reduces upper airway tone → airway obstruction risk during sedation.
Bronchodilation: can reduce airway resistance; useful in reactive airways (but hypotension may limit).

Other system effects

Antiemetic effect at subhypnotic doses (reduced PONV compared with volatile agents).
No trigger for malignant hyperthermia; does not cause porphyria exacerbation (generally considered safe in acute porphyrias).
Endocrine: does not suppress adrenal steroidogenesis (contrast etomidate).

Adverse effects and practical issues

Pain on injection: common; worse in small veins and with cold propofol; reduced by large vein, lidocaine, prior opioid, or mixing with lidocaine (within local policy).
- Mechanisms: irritation of endothelium; activation of kallikrein–kinin system; free aqueous propofol fraction contributes.
Hypotension and apnoea: major dose-limiting effects; increased in elderly, hypovolaemia, cardiac disease, co-induction with opioids/benzodiazepines.
Infection risk: lipid emulsion supports bacterial growth; strict asepsis; follow local guidance on vial/syringe handling and disposal times.
Hypertriglyceridaemia and pancreatitis risk with prolonged high-dose infusions (especially ICU sedation).
Green urine: benign, due to phenolic metabolites (rare).
Anaphylaxis: rare but important; can occur on first exposure; manage as per anaphylaxis guidelines and refer for investigation.

Propofol infusion syndrome (PRIS)

Rare but life-threatening syndrome associated with prolonged high-dose propofol infusions (classically ICU sedation).
Risk factors: high dose and long duration (often cited >4 mg/kg/h for >48 h), critical illness (sepsis, head injury), catecholamines, corticosteroids, low carbohydrate intake, mitochondrial disease.
Features: metabolic (often lactic) acidosis, rhabdomyolysis, hyperkalaemia, acute kidney injury, cardiac failure, arrhythmias (bradyarrhythmias), hepatomegaly, lipaemia.
Proposed mechanism: impaired mitochondrial fatty acid oxidation and electron transport → energy failure in cardiac/skeletal muscle.
Management: stop propofol immediately; supportive ICU care; treat arrhythmias and hyperkalaemia; consider renal replacement therapy/ECMO in severe cases; provide alternative sedation and adequate carbohydrate.

Drug interactions and co-induction

Synergy with opioids, benzodiazepines, alpha-2 agonists and volatile agents → reduced propofol dose requirement but increased risk of hypotension/apnoea.
Neuromuscular blockers: no direct blockade; facilitates intubation by deep hypnosis; can reduce airway reflexes.
Local anaesthetic lidocaine reduces injection pain; be mindful of maximum lidocaine dose if repeated.

Special populations

Elderly: increased sensitivity and reduced central compartment volume → lower induction dose and lower TCI targets; greater hypotension risk.
Obesity: dosing depends on context—bolus induction often closer to lean body weight; maintenance/infusion may relate to total body weight initially but titrate to effect; TCI model choice matters.
Pregnancy: crosses placenta; used for induction (e.g. RSI) but neonatal depression possible with high doses; maternal hypotension reduces uteroplacental perfusion.
Hepatic/renal impairment: clearance may be relatively preserved due to extrahepatic metabolism; nevertheless increased sensitivity and altered protein binding may require dose reduction.
Paediatrics: used widely; dosing differs; PRIS risk emphasised with prolonged infusions; avoid prolonged high-dose sedation.

Describe propofol, including its formulation and why it is formulated that way.

Aim: define the drug, its physical properties, and implications of the emulsion.

Propofol is 2,6-diisopropylphenol, an IV hypnotic with very low water solubility.
Formulated as an oil-in-water lipid emulsion (milky) to allow IV administration; commonly 1% (10 mg/mL) and 2% (20 mg/mL).
Emulsion components typically include soybean oil, egg lecithin/phosphatide and glycerol; some preparations contain EDTA or metabisulfite.
Clinical implications: pain on injection, risk of bacterial growth/contamination, hypertriglyceridaemia with prolonged infusion.

Explain the mechanism of action of propofol at the receptor level and the clinical effects that follow.

Link receptor action to hypnosis, cardiorespiratory depression, and antiemesis.

Primary action: positive allosteric modulation of the GABAA receptor → increased chloride influx → neuronal hyperpolarisation.
At higher concentrations can directly activate (gate) the GABAA channel.
Clinical effects: hypnosis and amnesia (no analgesia), dose-dependent respiratory depression/apnoea, cardiovascular depression (↓SVR, ↓BP), antiemetic effect, anticonvulsant properties.

Outline the pharmacokinetics of propofol and explain why recovery is rapid after a bolus dose.

Examiners want redistribution vs elimination, and the concept of context-sensitive half-time.

Rapid onset due to high lipid solubility and delivery to the brain (vessel-rich group).
Short duration after bolus mainly due to redistribution from brain to muscle/fat, not metabolism.
High protein binding and large Vd; high clearance (often exceeding hepatic blood flow) due to hepatic and extrahepatic metabolism.
Context-sensitive half-time is relatively short compared with many sedatives; increases with infusion duration but remains favourable for many anaesthetic durations.

Compare the cardiovascular effects of propofol with thiopentone (or etomidate) for induction.

A common FRCA comparison: haemodynamics, baroreflex, and suitability in shock.

Propofol commonly causes more hypotension than thiopentone due to marked ↓SVR and venodilation plus some negative inotropy; blunts baroreflex so tachycardia is limited.
Thiopentone also reduces BP (venodilation and myocardial depression) but often with more reflex tachycardia; overall haemodynamic depression is typically less than propofol at equipotent doses.
Etomidate is relatively cardiovascularly stable (minimal change in SVR/contractility) but causes adrenal suppression; hence preferred in haemodynamic compromise when appropriate.

What are the respiratory effects of propofol and what are the practical implications during sedation?

Focus on apnoea, loss of airway tone, and blunted ventilatory responses.

Dose-dependent respiratory depression; apnoea is common after induction bolus.
Blunts ventilatory responses to CO2 and hypoxia.
Reduces upper airway muscle tone → obstruction risk; requires vigilant airway positioning, oxygenation, and readiness to ventilate/intubate.
Can cause bronchodilation and reduce airway resistance.

Discuss pain on injection with propofol: incidence, mechanisms, and methods to reduce it.

This has appeared repeatedly in FRCA-style pharmacology questions.

Common adverse effect; more frequent with small peripheral veins and cold propofol.
Mechanisms include endothelial irritation and activation of the kallikrein–kinin system; the free aqueous fraction contributes.
Reduction strategies: use a large vein (antecubital), pretreat with lidocaine (with/without venous occlusion), co-induction opioid, warm the drug, slower injection.

What is propofol infusion syndrome (PRIS)? Give risk factors, features, and management.

High-yield ICU pharmacology and safety topic.

A rare but potentially fatal syndrome associated with prolonged high-dose propofol infusions, especially in critically ill patients.
Risk factors: high dose/long duration (often quoted >4 mg/kg/h for >48 h), critical illness (sepsis, head injury), catecholamines, corticosteroids, low carbohydrate intake, mitochondrial disease.
Features: lactic metabolic acidosis, rhabdomyolysis, hyperkalaemia, AKI, cardiac failure and arrhythmias (often bradyarrhythmias), hepatomegaly, lipaemia.
Management: stop propofol; supportive care; treat metabolic derangements; consider RRT/ECMO in severe cases; switch to alternative sedative and ensure adequate carbohydrate.

Explain why propofol is associated with a lower incidence of postoperative nausea and vomiting (PONV).

Often asked as a short viva add-on.

Propofol has intrinsic antiemetic properties at subhypnotic concentrations and avoids emetogenic volatile agents and nitrous oxide when used for TIVA.
Likely mechanisms include GABAergic modulation and reduced serotonergic activity in chemoreceptor trigger pathways (mechanism not fully defined).

How does propofol affect cerebral physiology and why might it be chosen in neuroanaesthesia?

Key points: CMRO2, CBF, ICP, and coupling.

Reduces CMRO2 and CBF with preserved flow–metabolism coupling, leading to reduced ICP.
Can produce burst suppression at high doses; may be used to control refractory intracranial hypertension or seizures in selected settings.
Caution: hypotension can reduce cerebral perfusion pressure; must support MAP.

Describe the key practical handling and safety considerations with propofol syringes/vials.

Focus on contamination risk and aseptic technique.

Lipid emulsion supports bacterial growth; strict asepsis during drawing up and administration is essential.
Use single-patient use vials/ampoules; label syringes; discard according to local policy/time limits; avoid reusing giving sets/syringes between patients.
Be aware of preservative-containing vs preservative-free preparations (relevant to contamination risk and some allergy considerations).

What are the common target-controlled infusion (TCI) models for propofol and how do they differ clinically?

A frequent primary FRCA viva topic when discussing TIVA.

Marsh model: weight-based; commonly used; tends to produce different predicted plasma/effect-site concentrations compared with Schnider for the same clinical effect.
Schnider model: incorporates age, height, lean body mass; often results in lower infusion rates in older patients for a given target.
Clinical approach: choose a model used locally, understand that targets are model-specific, and titrate to effect with appropriate monitoring (e.g. clinical signs ± processed EEG).