Question 15

Describe the physiology of the NMDA (N-Methyl D-aspartate) receptor (40% of marks). Outline the pharmacology of ketamine (60% of marks).

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College Answer

The NMDA receptor is a ligand gated voltage dependent ion channel located on post synaptic membranes throughout the CNS, with glutamate, an excitatory neurotransmitter, its natural ligand. A brief description of its structure, roles of glycine and magnesium, ions conducted, result of activation, role in memory and learning and agonists/antagonists was expected. Detail on structure and functions of the receptor were a common omission. Ketamine, a phencyclidine derivative, is a non-competitive antagonist at the NMDA receptor. It is presented as a racemic mixture or as the single S(+) enantiomer (2-3 X potency). Administration routes and doses scored marks. Pharmacodynamics were generally well covered including CVS (direct and indirect effects), CNS (anaesthesia, analgesia, amnesia, delirium, effects on CBF and ICP) respiratory (bronchodilator with preservation of airway reflexes) GIT effects (salivation, N and V). Knowledge of specific pharmacokinetic parameters was less well covered, including low oral bioavailability and protein binding and active metabolite (norketamine).

Discussion

  • The NMDA receptor is a ligand-gated nonselective cation channel
  • It is a heterotrtamer transmembrane protein, consisting of four subunits
  • 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. 

Ketamine pharmacology:

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
- Decreased pulmonary vascular resistance
- Decreased peripheral vascular resistance
- Decreased CVP
Direct effects of ketamine on inotropy are negative.
Single best reference Domino (2010)

References

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.

Tyler, Marshall W., et al. "Classics in chemical neuroscience: ketamine." ACS Chemical Neuroscience 8.6 (2017): 1122-1134.

Peltoniemi, Marko A., et al. "Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy." Clinical pharmacokinetics 55.9 (2016): 1059-1077.

Blanke, Marie L., and Antonius MJ VanDongen. "13 Activation Mechanisms of the NMDA Receptor." Biology of the NMDA Receptor (2008): 283.