Compare and contrast dexmedetomidine and ketamine
The majority of candidates were able to describe the mechanism of action, uses, dose and some side effects of each drug. The better answers were in a table format. It is of course possible to include much of the relevant information without using a table; however without the visual prompt of a table it makes it likely sections will be omitted. When comparing two drugs it would be useful to note that though they both provide sedation with analgesia they are used in different circumstances. In ICU, dexmedetomidine is mainly used for sedation peri-extubation and may be continued post-extubation but this was not often mentioned. The pharmacodynamic effects often omitted the cardiovascular and respiratory effects of ketamine (particularly bronchodilation). The pharmacokinetic information required was not detailed but only minimal marks can be awarded for ‘administered IV with 100% bioavailability, liver metabolism and renal excretion’ which was a common answer. Noting dexmedetomidine is metabolised to inactive metabolites and ketamine is metabolised to norketamine gained marks, specific pathways were not required. Both drugs are licenced for administration intravenously (and ketamine may be administered IM); however other routes of administration are emerging in clinical
practice for both drugs.
|Routes of administration||IV is the usual route of administration, but it can also be given IM, buccally, intranasally, and intrathecally||Intravenous, intramuscular, subcutaneous, oral (rarely), buccal, transdermal and rectal|
|Absorption||16% oral bioavailability; undergoes extensive first-pass metabolism||17% oral bioavailability|
|Solubility||pKa 7.1; freely soluble in water, but also has excellent fat solubility.||pKa 7.5; relatively poor water solubility; 20-50% protein-bound|
|Distribution||VOD = 1.3-2.5L; highly protein-bound (96%)||1-3L/kg VOD; 20-50% protein-bound|
|Target receptor||Presynaptic α2 noradrenaline receptors, as well as imidazoline receptors||NMDA receptor|
|Metabolism||Mainly hepatic metabolism by N-glucuronidation and hydroxylation by CYP450.||Metabolised by CYP450 enzymes into multiple metabolites, of which only norketamine is mildly active.|
|Elimination||All the metabolites are inactive and excreted renally||Elimination half-life is 2.5 hrs, but redistribution (alpha) half-life is ~ 7-11 minutes|
|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||Onset of anaesthetic effect, following an anaesthetic dose (~2mg/kg), is within 15-30 seconds. Duration of useful anaesthesia/analgesia is about 15-30 minutes.|
|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
|Lodges in the pore of the NMDA cation channel, causing the receptor to become closed, and to stop binding glutamate. As a consequence, it prevents glutamate-simulated sodium and calcium influx into the cell, and potassium efflux. The result is a depressed excitatory neurotransmission|
|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.||Dissociative anaesthesia, analgesia, sialorrhoea, bronchorrhoea, bronchodilation, possible increased cerebral metabolic rate, reversal of opioid tolerance, and slightly increased skeletal muscle tone.
Haemodynamic effects are largely indirect, i.e. the result of sympathetic stimulation.
- Increased cardiac output
- Markedly increased heart rate
- Increased mean arterial pressure initially, which rapidly renormalises
- Decreased pulmonary vascular resistance
- Decreased peripheral vascular resistance
- Decreased CVP
Direct effects of ketamine on inotropy are negative
|Single best reference for further information||Weerink et al (2017)||the Australian PI from Interpharma.|
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.
Clements, J. A., W. S. Nimmo, and I. S. Grant. "Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans." Journal of pharmaceutical sciences 71.5 (1982): 539-542.
Wieber, J., et al. "Pharmacokinetics of ketamine in man." Der Anaesthesist 24.6 (1975): 260-263.
Sleigh, Jamie, et al. "Ketamine–More mechanisms of action than just NMDA blockade." Trends in anaesthesia and critical care 4.2-3 (2014): 76-81.