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)