Compare and contrast the pharmacology of dexmedetomidine and propofol.
A basic and fundamental pharmacology question which required candidates to present their answer in a coherent fashion (a table worked best) as well as demonstrate sufficient knowledge. The majority of candidates did so, and so scored well. Candidates tended to struggle with the pharmacokinetic properties of these drugs.
|Routes of administration||IV is the usual route of administration, but it can also be given IM, bucally, intranasally, and intrathecally||IV only|
|Absorption||16% oral bioavailability; undergoes extensive first-pass metabolism||Minimal oral bioavailability due to very high first-pass metabolism and high hepatic extraction ratio|
|Solubility||pKa 7.1; freely soluble in water, but also has excellent fat solubility.||pKa 11; minimally soluble in water|
|Distribution||VOD = 1.3-2.5L; highly protein-bound (96%)||VOD=2-10 L/Kg; 98% protein-bound|
|Target receptor||Presynaptic α2 noradrenaline receptors, as well as imidazoline receptors||GABA-A chloride channels, where propofol acts as a GABA-agonist|
|Metabolism||Mainly hepatic metabolism by N-glucuronidation and hydroxylation by CYP450.||Metabolism is by glucouronide and sulphate conjugation, which happens mainly in the liver.|
|Elimination||All the metabolites are inactive and excreted renally||All the metabolites are inactive and excreted renally, which can give the urine a healthy green tinge.|
|Time course of action||Redistribution half-life is 6 minutes; elimination half life coming off a high dose infusion after steady state is reached is usually 2.2-3.7 hrs in critically ill patients||Bolus half life = 120 seconds
Half life from steady state = 5-12 hours
|Mechanism of action||α2 receptor effects: by hyperpolarising the presynaptic membrane, α2 receptor activation creates negative feedback which suppresses further noradrenaline release from the presynaptic nerve terminal (responsible for some of the sedating and analgesic effects)
Imidazoline receptor effects are poorly understood, but are at least equally important to the analgesic haemodynamic and sedating effects
|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||Sedation (which resembles natural sleep) and a minor analgesic effect (likely related to opioid potentiation and anxiolysis). No effect on airway reflexes, apart from what is expected with normal sleep. No depression of the respiratory drive, even at high doses. Bradycardia and hypotension with decreased cardiac output, due to its sympatholytic 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||Weerink et al (2017)||Sahinovich et al (2018)|
Weerink, Maud AS, et al. "Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine." Clinical pharmacokinetics 56.8 (2017): 893-913.
Afonso, Joana, and Flávio Reis. "Dexmedetomidine: current role in anesthesia and intensive care." Revista brasileira de anestesiologia 62 (2012): 125-133.
Bousquet, Pascal, et al. "Imidazoline receptor system: the past, the present, and the future." Pharmacological reviews 72.1 (2020): 50-79.
Sahinovic, Marko M., Michel MRF Struys, and Anthony R. Absalom. "Clinical pharmacokinetics and pharmacodynamics of propofol." Clinical pharmacokinetics 57.12 (2018): 1539-1558.