Question 11

Outline the structure and function of the N-methyl-D-aspartate (NMDA) receptor (25% marks). Discuss the pharmacology of ketamine (75% marks).

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College Answer

The first part of this question required a description of both the receptor structure and its function. This includes, but is not limited to, its location, the natural ligand, how the channel may be regulated and the results of receptor stimulation. The second part of this question related to ketamine. Marks lost here often related to vague statements and incorrect facts. The examiners also commented that some candidates got confused between the R and S enantiomers. Few candidates commented on the nature of the metabolites and generally the PD section was vaguely answered.


The NMDA receptor, 

  • The NMDA receptor is a ligand-gated nonselective cation channel
  • The ligands are the neurotransmitters glycine and glutamate, both of which have to bind in order to activate the receptor
  • Opening of the receptor channel permits the flow of:
    • potassium (out of the cell)
    • sodium (into the cell)
    • calcium (into the cell)
  • The sodium and potassium movements can depolarise the cell, i.e. the receptor can serve a synaptic function, allowing the propagation of an action potential. However, these receptors are not critically important for synaptic transmission (Blanke et al, 2008). 
  • The inward flow calcium is responsible for interesting intracellular second messenger effects, including neuromodulation, as well as excitotoxicity. 

Now, as for ketamine:

Name Ketamine
Class IV anaesthetic
Chemistry Cyclohexylamine
Routes of administration Intravenous, intramuscular, subcutaneous, oral (rarely), buccal, transdermal and rectal
Absorption 17% oral bioavailability
Solubility pKa 7.5; relatively poor water solubility; 20-50% protein bound
Distribution 1-3L/kg
Target receptor NMDA receptor
Mechanism of action 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
Metabolism Metabolised by CYP450 enzymes into multiple metabolites, of which only norketamine is mildly active.
Elimination Elimination half-life is 2.5 hrs, but redistribution (alpha) half-life is ~ 7-11 minutes
Time course of action 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.
Clinical 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
- Unchanged peripheral vascular resistance
Direct effects of ketamine on inotropy are negative.
Single best reference Domino (2010)


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.

Bolshakov, K. V., et al. "Determinants of trapping block of N‐methyl‐d‐aspartate receptor channels." Journal of neurochemistry 87.1 (2003): 56-65.

Domino, Edward F. "Taming the ketamine tiger." Anesthesiology: The Journal of the American Society of Anesthesiologists 113.3 (2010): 678-684.