Compare and contrast the pharmacology of propofol and midazolam.
Highlighting important similarities and differences between the drugs scored higher marks than listing the pharmacology of each drug separately. More pharmacokinetic information was required than simply stating both drugs “are metabolized in the liver and excreted by the kidney”.
|Routes of administration||IV, IM, subcutaneously, intranasally buccaly and orally (though the oral dose required is about doubled)||IV only|
|Absorption||44% bioavauilability; well absorbed, but also undergoes significant first-pass metabolism||Minimal oral bioavailability due to very high first-pass metabolism and high hepatic extraction ratio|
|Solubility||pKa 6.7; good water solubility at pH <4 (as a hydrochloride salt) -0 when injected, it becomes lipid-soluble at physiologic pH||pKa 11; minimally soluble in water|
|Distribution||VOD = 0.8 to 1.5 L/kg; 96% protein bound||VOD=2-10 L/Kg; 98% protein-bound|
|Target receptor||GABA-A channel (a separate binding site from GABA)||GABA-A chloride channels, where propofol acts as a GABA-agonist|
|Metabolism||Hepatic metabolism to α-hydroxymidazolam (which is active), and then an inactive renally excreted glucouronide. α-hydroxymidazolam can accumulate in renal failure||Metabolism is by glucouronide and sulphate conjugation, which happens mainly in the liver.|
|Elimination||Both the active metabolite and the inactive glucouronide are renally excreted||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 15 minutes; elimination half-life is 1.5-3.5 hours||Bolus half life = 120 seconds
Half life from steady state = 5-12 hours
|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. These are less pronounced than those of propofol.
|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||Okkola & Ahonen (2008)||Sahinovich et al (2018)|
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.
Sahinovic, Marko M., Michel MRF Struys, and Anthony R. Absalom. "Clinical pharmacokinetics and pharmacodynamics of propofol." Clinical pharmacokinetics 57.12 (2018): 1539-1558.