Describe the ideal sedative agent for an Intensive Care patient (50% of marks). How
does midazolam compare to this (50% of marks)?
Candidates who had a structured approach (i.e. pharmaceutical, pharmacokinetic,
pharmacodynamic) provided more content and scored higher. Candidates who also
approached pharmacodynamic effects in an organ system based approach scored higher.
Relating a pharmacokinetic property of midazolam (e.g. volume of distribution or half-life) to a
un/desirable attribute e.g. offset of action and accumulation displayed a greater understanding
of the question. For many candidates, the description of an ideal drug contained more detail
and candidates were not able to adequately state how midazolam compares.
|Name||Midazolam||Ideal anaesthetic agent|
|Pharmaceutics||Presents as aqueous solution
Shelf-stable at room temperature
Nonvolatile and chemically inert
Does have a tendency to absorb into giving sets and PVC circuits (eg. ECMO circuit)
|Should be water soluble
Should be stable chemically
Should be chemically inert and non-interactive with circuits or giving sets
|Routes of administration||IV, IM, subcutaneously, intranasally buccaly and orally (though the oral dose required is about doubled)||Multiple routes of administration should be available|
|Absorption||44% bioavauilability; well absorbed, but also undergoes significant first-pass metabolism||Should be well absorbed orally, or from the lung (if inhaled)|
|Solubility||pKa 6.7; good water solubility at pH <4 (as a hydrochloride salt) -0 when injected, it becomes lipid-soluble at physiologic pH||Should be soluble in water, so that it may present as an aqueous solution without excipients|
|Distribution||VOD = 0.8 to 1.5 L/kg; 96% 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 channel (a separate binding site from GABA)||Molecular targets should be specific to produce sedation and anaesthesia with no other effects|
|Metabolism||Hepatic metabolism to α-hydroxymidazolam (which is active), and then an inactive renally excreted glucouronide. α-hydroxymidazolam can accumulate in renal failure||Should undergo no metabolism, or be metabolised without reliance on any specific organ system.
There should be no active metabolites.
|Elimination||Both the active metabolite and the inactive glucouronide are renally excreted||Should be cleared without delay|
|Time course of action||Redistribution half-life is 15 minutes; elimination half-life is 1.5-3.5 hours||Should have a rapid onset of effect, as well as offset of effect.
Should have minimal half-life.
|Mechanism of action||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||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, 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.
There is significant individual variability with dose.
There is a well-known withdrawal effect after sustained use.
|There should be ONLY an anaesthetic effect, and no other effects.
The drug should not produce any change in the patient;s cardiovascular performance.
There should be no withdrawal or rebound effects.
There should be minimal interindividual variation in dose requirements.
|Single best reference for further information||Okkola & Ahonen (2008)||Dundee (1980)|