Compare and contrast the pharmacology of midazolam and dexmedetomidine when used for sedation.
This question was also well suited to be answered in a preset format. For example a tabular format that had headings such as mechanism of action, preparations, dosing, pharmacokinetics, metabolism and excretion, pharmacodynamics, drug interactions and side effects.
A good answer was expected to include the following points. Under mechanism of action, mention that both drugs produce sedation by hyperpolarizing CNS nerve membranes and act on different receptors (Midazolam binds the benzodiazepine receptor and dexmedetomidine being selective for the a2 receptor). Also mention of other effects for each drug, eg anxiolytic, anticonvulsunt, analgesia, etc. A similar approach would be required for other key
areas such as metabolism and excretion,(including alterations with age, organ failure, disease, etc), drug interactions, pharmacodynamics, particularly in relation to important physiological effects (eg CNS and CVS effects). A brief summary of the similarities and differences which influence the clinical use of these agents gained more marks and showed the candidate had applied knowledge of these drugs. The common omissions were lack of explanation of mechanism of action and failure to mention pharmacodynamic effects, drug interactions and specific advantages for each agent.
It must be said without any sort of smirk that "lack of explanation of mechanism of action" is a problem of the international literature on dexmedetomidine, and not unique to junior CICM registrars - as the exact molecular pathways of its effect on the CNS are still being investigated.
|Routes of administration||IV is the usual route of administration, but it can also be given IM, buccally, intranasally, and intrathecally||IV, IM, subcutaneously, intranasally buccally and orally (though the oral dose required is about doubled)|
|Absorption||16% oral bioavailability; undergoes extensive first-pass metabolism||44% bioavailability; well absorbed, but also undergoes significant first-pass metabolism|
|Solubility||pKa 7.1; freely soluble in water, but also has excellent fat solubility.||pKa 6.7; good water solubility at pH <4 (as a hydrochloride salt) -0 when injected, it becomes lipid-soluble at physiologic pH|
|Distribution||VOD = 1.3-2.5L; highly protein-bound (96%)||VOD = 0.8 to 1.5 L/kg; 96% protein-bound|
|Target receptor||Presynaptic α2 noradrenaline receptors, as well as imidazoline receptors||GABA-A channel (a separate binding site from GABA)|
|Metabolism||N-glucuronidation and hydroxylation by CYP450.||Hepatic metabolism to α-hydroxymidazolam (which is active), and then an inactive renally excreted glucouronide. α-hydroxymidazolam can accumulate in renal failure|
|Elimination||All the metabolites are inactive and excreted renally, which can give the urine a healthy green tinge.||Both the active metabolite and the inactive glucouronide are renally excreted|
|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||Redistribution half-life is 15 minutes; elimination half-life is 1.5-3.5 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
|Allosteric modulator of the GABA-A receptor: acts on GABA-A chloride channels, where it binds to a site distinct from the GABA binding site, and potentiates the effects of GABA, this increasing the chloride current and hyperpolarising the cell membrane of the neuron|
|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.||Sedation, amnesia, anticonvulsant effect, mild decrease in cerebral oxygen demand, no effect on ICP.
Respiratory response to raised CO2 is flattened, but respiratory drive is not as suppressed as it would be with opioids. Airway reflexes are depressed.
Haemodynamic effects (decreased blood pressure and heart rate) are related to its suppression of the sympathetic nervous system. These are less pronounced than those of propofol.
|Single best reference for further information||Weerink et al (2017)||Okkola & Ahonen (2008)|
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.
Dundee, J. W., et al. "Midazolam." Drugs 28.6 (1984): 519-543.
Olkkola, Klaus Tapio, and Jouni Ahonen. "Midazolam and other benzodiazepines." Modern anesthetics (2008): 335-360.
Gerecke, M. "Chemical structure and properties of midazolam compared with other benzodiazepines." British journal of clinical pharmacology 16.S1 (1983): 11S-16S.