K1vii / 19A15: NMDA receptor and Ketamine

19A15: Exam Report

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

49% of candidates passed this question.

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).

K1vii / 19A15: Describe the physiology of the NMDA receptor (40 marks). Outline the pharmacology of Ketamine (60 marks)

Nmda Receptor

Definition:  NMDA Receptors are ionotropic glutamate receptors

Structure

Heterotetramers

2 Glycine binding subunits

2 Glutamate binding subunits

Central pore

NMDA receptor

Located

Exclusively in neurons, widespread and expressed at post synaptic site

Function

Slow ESPS

Growth

Differentiation

Apoptosis

Synaptic Plasticity (Learning & Memory)

Excitotoxicity (ie pathophysiology of epilepsy, Alzheimer’s Disease)

Pain Sensitization:

  • Persistent pain will ↑[GLUTAMATE] & ↑signal transmission & causing Mg2+ dislodgement → NMDA receptor activates → CENTRAL SENSITISATION via 2nd messenger & further release of excitatory NT which ↑pain signal, even to benign stimuli
  • KA WIND UP

Endogenous Agonists

Glycine

Glutamate/Asparate (not as strong)

Ions Conducted

High Ca++ permeability

Na, K permeability

Result of Activation

  1. Binding GLUTAMATE
  2. Binding co-agonist GLYCINE
  3. Membrane depolarisation (partial by other receptors AMPA & NK on some neurons)

↓

Mg2+ block released

↓

Na+, Ca2+ influx/K+ outflow

↓

Activation of protein kinase & phosphorylating enzymes

Channel Blockers

Phencyclidine

Memantidine

Ketamine

Mg++

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