Question 4

Compare and contrast ketamine and midazolam

[Click here to toggle visibility of the answers]

College Answer

In addition to the key PK and PD properties of each drug, a clear comparison was required to score well (why choose one drug over the other?). When a table was used the addition of a comparison column was helpful.

A good answer covered the following: ketamine has analgesic properties whilst midazolam does not; ketamine preserves airway reflexes and does not cause respiratory depression unlike midazolam; whilst ketamine increases cerebral blood flow and CMRO2, midazolam decreases it; ketamine has a direct myocardial depressant effect which is often offset by an increase in sympathetic tone, whilst midazolam has no direct cardiac depressant effects but may reduce BP due to reduced SVR; midazolam has anticonvulsant properties, ketamine does not; ketamine is a bronchodilator; both drug effects are offset by redistribution; midazolam is lipophillic at body pH and will accumulate with prolonged infusions, ketamine will not; both are metabolised in the liver; midazolam can be reliably reversed by flumazenil, whereas there is no reliable complete reversal of ketamine; midazolam exhibits tolerance, dependence and withdrawal, whereas patients will only experience tolerance to the analgesic properties of ketamine. “

Drugs in Anaesthesia and Intensive care” chapters on midazolam and ketamine outline the key facts to include in this answer; interpretation and comparison of these facts will help achieve a good mark.

Discussion

Name Midazolam Ketamine
Class Sedative IV anaesthetic
Chemistry Benzodiazepine Cyclohexylamine
Routes of administration IV, IM, subcutaneously, intranasally buccaly and orally (though the oral dose required is about doubled) Intravenous, intramuscular, subcutaneous, oral (rarely), buccal, transdermal and rectal
Absorption 44% bioavauilability; well absorbed, but also undergoes significant first-pass metabolism 17% oral bioavailability
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 7.5; relatively poor water solubility; 20-50% protein bound
Distribution VOD = 0.8 to 1.5 L/kg; 96% protein bound 1-3L/kg VOD; 20-50% protein bound
Target receptor GABA-A channel (a separate binding site from GABA) NMDA receptor
Metabolism Hepatic metabolism to α-hydroxymidazolam (which is active), and then an inactive renally excreted glucouronide. α-hydroxymidazolam can accumulate in renal failure Metabolised by CYP450 enzymes into multiple metabolites, of which only norketamine is mildly active.
Elimination Both the active metabolite and the inactive glucouronide are renally excreted Elimination half-life is 2.5 hrs, but redistribution (alpha) half-life is ~ 7-11 minutes
Time course of action Redistribution half-life is 15 minutes; elimination half-life is 1.5-3.5 hours 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 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 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 calicum influx into the cell, and potassium efflux. The result is a depressed excitatory neurotransmission
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.
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.skeletal muscle tone
Single best reference for further information Okkola & Ahonen (2008) the Australian PI from Interpharma.

References

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.

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.