2012A07 Discuss the suitability of ketamine as an intravenous anaesthetic agent.

 

List:

·      Intro

·      PC

·      PK

·      PD

 

Intro:

·         Used as a sole agent in 3rd world and field anaesthesia

·         Anaesthetic: for induction (bolus) and maintenance (infusion or repeat boluses)

·         Analgesic

·         Relatively safe cardiovascular and respiratory profile

·         Cheap

 

Pharmaceutics:

·         Stable in solution

·         No toxic additives (benzethonium chloride: theoretical risk neurotoxicity)

·         Low risk of bacterial growth

·         No bacterial growth

·         No histamine release

·         No anaphylaxis

·         No pain on IV injection

·         Suitable for IM injection of IV access lost

 

Pharmacokinetics:

Administration

·   Many routes: IV, IM, SC, intranasal, PO

·   Used for oral premedication in children

·   For IM sedation of patients without IV access

Time course

·   Fast onset (30 seconds)

·   Fast peak (90 seconds)

·   Duration highly dependent upon dose

Absorption

N/A

Distribution

·   Very high lipid solubility (5-10x that of thiopentone)

·   Very fast effect site equilibration (t1/2ke0 0.5 minutes)

o Suitable for induction

·   Large VDSS 3L/kg

·   Rapid distribution

o Can be rapid offset after a bolus

Metabolism

·   Hepatic, phase 1, CYP3A4 N-demethylation > other

·   High hepatic extraction ratio, flow-dependent clearance

·   Subject to induction and inhibition

·   Active metabolite norketamine (30% as active)

o May increase duration of effect

o Inactivated by hydroxylation then conjugation

o t1/2β 4 hours

·   Rapid clearance 17mL/kg/min and short t1/2β 2 hours

o Suitable for maintenance infusion

·   Can be hepatotoxic

Excretion

·   Active metabolite renally excreted; accumulates in renal failure

 

CNS effect:

Mechanisms

·   Principal: non-competitive NMDA antagonist at PCP site

·   Other ↑: 2PK/5HT3/mu opioid

·   Other ↓: VDNaC, VdCC, monoamine reuptake, nnAChR

Anaesthesia

·   Thalamocortical dissocation (amnesia, sedation, hypnosis, immobility; not anxiolytic)

·   Atypical effect on EEG; not suitable for BIS or entropy monitoring

·   S-ketamine more potent than R-ketamine

Other beneficial effects

·   Analgesia:

o Multiple mechanisms (↓NMDA, ↑monoamines, ↑↓opioids, VDNaC)

o ↓Acute and chronic pain

o ↓Somatic and neuropathic

o ↓Hyperalgaesia and allodynia

o Opioid-sparing

·   Anaesthesia + analgesia allows use as a sole agent (e.g. field anaesthesia, 3rd world)

Side effects

·   Emergence delirium:

o R-ketamine > S-ketamine

o Hallucinations, nightmares in 30%

o Higher risk if psychiatric illness

o ?Attenuated by midazolam

·   Emetogenic

·   ↑CMRO2, ↑CBF +/- ↑ICP

o Contraindicated if CNS bleed or tumour with ↑ICP

Unclear effects

·   Both pro- and anti-convulsant

·   Neurotoxic to the developing brain; but may attenuate excitotoxicity in HIBI

 

Cardiovascular:

Direct effects

·   R-ketamine > S-ketamine

·   Negative inotropy, venodilatation, vasodilatation

Indirect effect

·   ↑SNS output from medulla

o ↑HR, ↑contractility, ↑SVR

o ↑MVO2 -> risk myocardial ischaemia

o ↑PVR -> ↑RV strain (avoid ↓PaO2, ↑PaCO2)

·   Direct effects balance indirect effects in health

·   Negative inotropy may be unmasked if maximal SNS activity or high dose vasoactives

·   Baroreceptor reflex relatively preserved

 

Respiratory:

 

·   Thalamocortical dissociation with relative preservation of vital medullary activity

·   ↑SNS output and ↓L-Ca2+ -> smooth muscle relaxation

Beneficial effects

·   Preserved ventilation (↔RR, TV), airway reflexes and pharyngeal dilator tone

·   Preserved airway reflexes

·   Preserved pharyngeal dilator tone

·   R-ketamine-> bronchodilation (suitable induction agent in status asthmaticus)

·   Ideal for field anaesthesia or if limited resources

·   May be inadequate alone for airway instrumentation

Side effects

·   ↑Airway secretion (may need anti-sialogogue)

 

 

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