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