K4ii / 22A11: Outline the structure and function of the N-methyl-D-aspartate (NMDA) receptor (25% marks). Discuss the pharmacology of ketamine (75% marks).

22A11: Exam Report

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

74% of candidates passed this question.

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.

K3iii / 22A11: Outline the structure and function of the N-methyl-D-aspartate (NMDA) receptor (25% marks). Discuss the pharmacology of ketamine (75% marks).

Structure

Type

  • Ligand-gated voltage-dependent ionotropic (cationic) receptor

Location

  • Spinal cord: Especially dorsal horn 2° nociceptive afferents

  • Brain: Especially hippocampus

    Both pre and post synaptic

Structure

  • Transmembrane

  • 2 x NR1 subunits (pore-forming)

  • 1 x NR2A subunit (binds glutamate)

  • 1 x NR2B (binds glycine)

Binding Sites

  • Orthosteric site: For glutamate

  • Coactivating site: Glycine

  • Phencyclidine site: Ketamine, PCP

  • Pore: Blocked by Mg2+

  • N2O and Xe: Site unknown (antagonists)

Activation Process

1. Priming

  • Activation of adjacent AMPA or NK-1 receptors

  • Partial depolarisation -> removal of MG2+ or Zinc plug

2. Coactivation

  • Binding of glycine

3. Activation

  • Binding of glutamate -> Opening

  • Ion flux (Ca2+ influx > Na+ influx = K+ efflux)

  • Cell-dependent downstream effect

Function

Ca2+ flux through NMDA receptors in particular is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory, due to proteins which bind to and are activated by Ca2+ ions.

 

Excessive influx of Ca2+ can lead to excitotoxicity which is implied to be involved in some neurodegenerative disorders

Ketamine

Ketamine

Chemical

Phencyclidine derivative, dissociative anaesthetic

Use

  1. Induction GA
  2. Conscious sedation
  3. Analgesia
  4. Severe asthma

Presentation

2mL vial → 200mg in 2mL, clear colourless solution

  • pKa 7.5 → 40% ionised at pH 7.4
  • H2O soluble → EXTREMELY LIPID SOLUBLE

ISOMERISM solution contains 50:50

  • Ketamine contains an asymmetrical carbon atom with 2 optical isomers (enantiomers)

S (+)

  • 3 x potent
  • Intense analgesia/anesthesia
  • Lower emergence reactions
  • More rapid metabolism/recovery
  • Less CVS stimulation

R (-) = more bronchodilation & psych SE

Dose

ANALGESIA: 0.1 – 0.2mg IV bolus → then 0.1 – 0.3mg/kg/hr thereafter

SEDATION: 0.3 – 0.5mg IV

GA: 1 – 2mg/kg IV

Route

IV/IM/PO/PR

↓

But poor OBA 16% due to high 1st pass metabolism

Onset

30 – 60sec IV → 3 – 8mins IM

DoA

Return of consciousness

10 – 20mins

MoA

  1. NMDA Antagonism
  2. Voltage sensitive Ca2+ channel inhibition
  3. Muscarinic antagonist
  4. Facilitates descending inhibitory monoaminergic pathways → inhibits reuptake of CA → INDIRECT SYMPATHOMIMETIC
  5. Weak opioid receptor agonism

PD

CNS

  • Dissociative anaesthesia with slow nystagmic gaze
    • Dissociates thalamus (relays sensory info from RAS to C. Cortex) from Limbic Cortex (awareness & sensation)
  • Amnesia → anterograde
  • Analgesia
  • Emergence delirium → visual, auditory, illusion & delirium
  • Cerebral protection → ↑CMRO2 & ↑CBF

(Directly dilates cerebral arteries)

RESP

  • ↑airway secretions → anticholinergic
  • Preserves laryngeal reflexes
  • Bronchodilation → ↑symp & Ca2+ channel inhibition
  • ↑PAP → ↑symp NS

CVS

  • ↑MAP, PAP, CVP, HR, CO, myocardial O2 requirements
    • Actually a Direct – ve Inotrope
    • But with ↑symp NS & adequate catecholamine stores, therefore CVS stimulating effects predominate

NB: can be unmasked in ICU patients with ↓catecholamine stores

GI

  • Salivation = antimuscarinic
  • ↑BSL = ↑symp

PK

A

Lipid soluble → absorbed, but poor poor OBA 16%

Due to high 1st pass metabolism

D

  • Large → 5L/kg
  • PPB small 12%
  • Rapidly crosses placenta
  • *HIGH LIPID SOLUBILITY *
  • Peak plasma 1 min post IV

↓

Rapidly distributed to VRG

Extreme lipid solubility & ↑CBF = rapid crosses BBB & ↑brain [   ]

↓

Subsequently redistributed from brain to less well perfused tissues

M

High hepatic ER

  • Clearance 18mL/kg/min
  • ∆HBF will alter clearance
  • DE-METHYLATION by CYP450 to NORKETAMINE (25% potency)

↓

HYDROXYLATION & CONJUGATION to inactive & glucuronide metabolites

E

H2O soluble metabolites excreted by kidney

<5% unchanged

Faecal excretion <5% dose

Adverse Effects

Tolerance (enzyme induction

IHD/HTN/CCF = Increases myocardial work

Increases ICP, CBF and CMRO2

Pregnancy = reduces uterine BF

Prolongs SUX activity

Unmasks myocardial depression when given w sympatholutic

Enhances NDMR block

Author: Henrique Mendes / Krisoula Zahariou