2008B04 Briefly outline the pharmacology of ketamine with reference to its use as an analgesic agent in the post-operative period.



·      Physicochemical

·      Pharmacokinetic

·      Pharmacodynamic



·         Stable in solution

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

·         Low risk of bacterial growth (suitable for slow infusion in single syringe)

·         No precipitation

·         Low risk anaphylaxis

·         Not painful on injection (suitable for peripheral IV)




·   Common routes for analgesia (not just post-op…)

o IV bolus 0.1-0.3mg/kg (e.g. rescue in PACU, fracture manipulation in A&E)

o IV infusion 0.1-0.2mg/kg/h (e.g. days 1-2 post-op)

§ Useful if NBM

§ Titratable

§ Avoids peaks/troughs hence toxicity e.g. delirium

o Sublingual PRN: 0.3mg/kg q5min (e.g. dressing changes)

o PO: 0.5mg/kg tds (e.g. on ward)

o IN 0.5-1mg/kg q15mins (e.g. procedural sedation in children)

Time course

·   IV: onset 30 seconds, peak 90 seconds, duration varies

·   SL: onset 10-30 mins, duration 2-4 hours

·   PO: onset 30 mins, duration 2-4 hours

Absorption (bioav)

·   PO: 16% (first pass ++)

·   SL ~30%

·   IN 50%

·   PR 25%


·   Rapid effect site equilibration (t1/2ke0 0.5 mins)

o Highly lipid soluble (5-10x thiopentone) – crosses placenta

o Low plasma protein binding (25%)

o Hence suitable for small rescue bolus in PACU

·   Large VDSS 3L/kg and rapid distribution

o Hence intra-operative loading dose recommended


·   Hepatic phase 1, CYP3A4 N-demethylation > other

·   Active metabolite norketamine (30% as active)

o May prolong duration

o Inactivated by hydroxylation then conjugation

o t1/2β 4 hours

·   Rapid Clearance 17mL/kg/min, short t1/2b 2 hours

o Suitable for infusion

·   Risk of hepatotoxicity if infused

o Check LFTs second daily


·   Active and inactive metabolites renally excreted




·   Primary: non-competitive NMDA antagonist at PCP site

o Post-synaptic inhibition at dorsal horn

o Short term: ↓excitability, ↓wind-up

o Long term: ↓synaptic reinforcement, ↓long-term potentiation

·   Secondary: ↓Monoamine reuptake, ↓VDNaC, ↑mu opioid

·   S-ketamine 2-4x more potent than R-ketamine


·   ↓Acute and chronic pain

·   ↓Somatic and neuropathic pain

·   ↓Hyperalgaesia and allodynia

·   Risk of chronic pain, phantom pain

·   ↓Opioid requirement

·   “Re-set” opioid sensitivity in opioid-induced hyperalgaesia


Side effects:


·   Delirium: nightmares, hallucinations

o Dose-dependent

o May be attenuated by midazolam (e.g. 1mg with 200mg ketamine)

o High risk of psychiatric illness

o R-ketamine > S-ketamine

·   ↑CMRO2, ↑CBF, +/- ICP (contraindicated if CNS bleed, tumour with ↑ICP)

·   Dependence, addiction

Uncommon at analgesic dose

·   CNS: dissociative anaesthesia, nausea/vomiting

·   CVS: SNS stimulation, direct negative inotropy, vasodilation (R > S-ketamine)

·   Resp: mild ↓minute ventilation, ↑airway secretions, bronchodilation
(bronchodilation R > S-ketamine)



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