Question 14

Describe the pharmacology of propofol.

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College Answer

Those candidates who did poorly lacked any structure for answering a pharmacology question.
Pharmacokinetics was generally poorly handled and many answers revealed a lack of
knowledge about this drug. Adverse effects and mechanism of action were generally well
known. Doses of the drug were often incorrectly stated.
Important aspects such as dose or pharmacodynamics were often omitted and a structured
approach helps avoid this.

Discussion

Class	IV anaesthetic
Chemistry	Alkylphenol
Presentation	Oil emulsion. Vial contains: 1% propofol (10mg/ml) 10% soybean oil 1.2% purified egg phospholipid 2.25% glycerol, to adjust tonicity Sodium hydroxide to keep the pH between 6 and 8.5. Sodium EDTA as an antimicrobial additive
Dose	1-2mg/kg, more in young children, much less in hemodynamically unstable, elderly or already obtunded patients
Routes of administration	IV only
Absorption	Minimal oral bioavailability due to very high first-pass metabolism and high hepatic extraction ratio
Solubility	pKa 11; minimally soluble in water
Distribution	VOD=2-10 L/Kg; 98% protein-bound
Target receptor	GABA-A chloride channels, where propofol acts as a GABA-agonist
Metabolism	Metabolism is by glucouronide and sulphate conjugation, which happens mainly in the liver.
Elimination	All the metabolites are inactive and excreted renally, which can give the urine a healthy green tinge.
Time course of action	Bolus half life = 120 seconds Half life from steady state = 5-12 hours
Mechanism of action	Propofol binds to the β-subunit of the postsynaptic GABAA receptor, where it causes an inward directed chloride current that hyperpolarizes the postsynaptic membrane and inhibits neuronal depolarisation.
Clinical effects	Anaesthesia, respiratory depression, decreased CMRO2, depressed cardiovascular reflexes. Also antipruritic and antiemetic effects. Haemodynamic effects are largely indirect, i.e. the result of sympathetic depression. - Stable cardiac output - Decreased heart rate (blunted baroreceptor reflex) - Decreased mean arterial pressure, mainly due to increased unstressed volume and decreased MSFP - Decreased peripheral vascular resistance - Decreased CVP Direct effects of propofol on inotropy are minimal, at normal therapeutic doses.
Single best reference for further information	Sahinovich et al (2018)

References

Sahinovic, Marko M., Michel MRF Struys, and Anthony R. Absalom. "Clinical pharmacokinetics and pharmacodynamics of propofol." Clinical pharmacokinetics 57.12 (2018): 1539-1558.

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