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

List:

· Physicochemical

· Pharmacokinetic

· Pharmacodynamic

Pharmaceutics:

· 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)

Pharmacokinetics:

Administration	· 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%
Distribution	· 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
Metabolism	· 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
Excretion	· Active and inactive metabolites renally excreted

Analgesia:

Mechanisms	· 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
Effects	· ↓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:

CNS	· 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)