Racemic ketamine is an effective non-opioid anaesthetic/analgesic used in human anaesthesia and veterinary medicine. Its most clinically significant adverse effect is its hallucinogenic properties. Therefore it is normally administered together with sedatives like midazolam and/or propofol to control the prolonged period of post-anaesthesia hallucinations. To overcome this draw back we prepared a series of aliphatic esters of ketamine as shorter-acting analogues and evaluated them in an infused rat model, measuring the time after infusion to recover from both the anaesthetic (righting reflex) and analgesic (response to stimulus) effects. For Me, Et and i-Pr esters recovery from anaesthesia was 10-15 fold faster and for n-Pr esters was20-25 fold faster, than from ketamine.  There was no direct correlation between the potency of esters as sedatives and the ester chain length. Me, Et and i-Pr esters were the more dose potent (up to twofold less than ketamine), whereas n-Pr esters were less potent (from 2- to 6-fold less than ketamine). Pharmacokinetic studies in rabbits showed ultra-rapid metabolism to the corresponding (inactive) carboxylic acids in 1-2 min, yet an isopropyl ester analogue provided a duration of profound analgesia well beyond measured exposure of drug, and outlasting its sedative effect by more than three-fold in both rats and rabbits, suggesting alternative mechanisms downstream from the direct receptor effects. In summary, the data obtained from the study shows that it is indeed possible with the esters to reduce the hallucinogenic effect of ketamine without significantly reducing the anaesthetic potential.

Structure�activity relationships for ketamine esters as short-acting anaesthetics

248th National Meeting (2014)

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