Question 10

Outline the pharmacological properties of an ideal agent for sedating patients
undergoing mechanical ventilation in intensive care (50% of marks). Describe how
propofol compares to the ‘ideal’ agent (50% of marks).

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College Answer

Candidates can benefit by having a system by which they approach topics that involve a broad and general topic such as that of the pharmacology of a particular drug or ideal agent. A good answer included the following logical subheadings: Desirable pharmacology – long shelf life, stable when drawn up and on exposure to light, cheap, mixes well with other agents in the central line lumen. Bacteriostatic. Desirable pharmacokinetics – Low volume of distribution, rapid clearance (context-sensitive half-life), clearance not affected by either renal or hepatic dysfunction. Little inter-individual variation in pharmacokinetics. (Availability of an antagonist). Desirable pharmacodynamics – Affects only CNS. Reliable dose – effect curve with little inter-individual variation in effect. Anxiolysis. (Analgesic properties). No effect on cardiovascular performance. Does not depress respiratory drive.
Minimal side effects – No incidences of allergy / anaphylaxis. No idiosyncratic reactions. No tachyphylaxis.
As indicated, 50% of the marks were allocated to mentioning how well propofol reflects these properties. Mention of ‘propofol infusion syndrome’ characterised by cardiac failure which can occur when propofol is used at >4mg/Kg/Hr for more than 24 hours also attracted marks.

Syllabus: G2a 1&2
Reference Text: Pharmacology and Physiology in Anesthetic Practice / R K Stoelting

Discussion

	Propofol	Ideal anaesthetic agent
Pharmaceutics	Lipid-soluble, poorly water soluble; needs to be administered as an emulsion	Should be water soluble Should be stable chemically Should be chemically inert and non-interactive with circuits or giving sets
Routes of administration	IV only	Multiple routes of administration should be available
Absorption	Minimal oral bioavailability due to very high first-pass metabolism and high hepatic extraction ratio	Should be well absorbed orally, or from the lung (if inhaled)
Solubility	pKa 11; minimally soluble in water	Should be soluble in water, so that it may present as an aqueous solution without excipients
Distribution	VOD=2-10 L/Kg; 98% protein-bound	Should not be protein-bound (as this decreases availability). Should not accumulate with sustained use (eg. through compartment distribution)
Target receptor	GABA-A chloride channels, where propofol acts as a GABA-agonist	Molecular targets should be specific to produce sedation and anaesthesia with no other effects
Metabolism	Metabolism is by glucouronide and sulphate conjugation, which happens mainly in the liver.	Should undergo no metabolism, or be metabolised without reliance on any specific organ system. There should be no active metabolites.
Elimination	All the metabolites are inactive and excreted renally, which can give the urine a healthy green tinge.	Should be cleared without delay
Time course of action	Bolus half life = 120 seconds Half life from steady state = 5-12 hours	Should have a rapid onset of effect, as well as offset of effect. Should have minimal half-life.
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.	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.	There should be ONLY an anaesthetic effect, and no other effects. The drug should not produce any change in the patient's cardiovascular or respiratory performance. There should be no withdrawal or rebound effects. There should be minimal interindividual variation in dose requirements.
Single best reference for further information	Sahinovich et al (2018)	Dundee (1980)

References

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

Dundee, John. "THE IDEAL INTRAVENOUS ANAESTHETIC." г CLINICAL EVALUATION OF PROPOFOL (1980): 3.

Panahi, Yunes, et al. "Analgesic and sedative agents used in the intensive care unit: A review." Journal of cellular biochemistry 119.11 (2018): 8684-8693.

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