186 Special Article Ketamine: an update on the first twenty-five years of clinical David L. Reich MD, George Silvay MD PhO experience Contents Ketamine is a dissociative anaesthetic agent that has Pharmacology acquired an unique place in clinical practice. Since the - Pharmacokinetics first published report of its clinical use ~an understanding - Pharmacodynamics of its anaesthetic, analgesic, and amnestic qualities has - Mechanism of action - N-methyl-aspartate receptor theory grown from extensive clinical and laboratory research. - Opiate receptor theory The initial experience with ketamine as a sole anaesthetic - Miscellaneous receptor theory agent led to the recognition of unpleasant emergence Central nervous system effects reactions and cardiovascular stimulant properties, which - Eleetroencephalographic effects limited its usefulness. However, supplementation with - lntracranial pressure other drugs such as the benzodiazepines have reduced - Emergence phenomena Cardiovascular effects these side effects. Previous reviewersz'J have detailed the - Mechanism early work on the pharmacology and clinical uses of - Effects on rhythm ketamine. This review encompasses the more recent - Prevention of cardiovascular stimulation research on ketamine, and emphasizes human data. - lschaemic heart disease Ketamine's role in clinical anaesthesia is changing as a - Cardiovascular effects in children and neona~s Respiratory effects result of the evolving concepts of its mechanism of action - Respiratory pattem and the advantages of alternative routes of administration. - Hypoxic pulmonary vasoconstriction - Bronchodilation - Airway maintenance Optical isomers Pharmacology Other pharmacologic effects Ketamine [KETALAR~, KETAJECT| is chemically - Neuromuscular blockade related to phencyclidine (PCP) and cyclohexamine, it - Endocrine/metabolic response has a molecular weight of 238 and a pKa of 7.5. Although Effects on intraocular pressure ketamine hydrochloride is water soluble, ketamine's lipid - Effects on coagulation Clinical uses solubility is ten times that of thiopentone. The molecular - Epidural and intrathecal ketamine structure (2-(O-chloropheny l)-2-methylamino cyclohex- - Oral and rectal ketamine anone) contains a chiral centre at the C-2 carbon of the - Obstetrics cyclohexanone ring so that two enantiomers of the Paediatrie radiation therapy and burn patients ketamine molecule exist: s(+)ketamine and r(-)keta- - Outpatient anaesthesia mine. Commercially available racemic ketamine prep- - Critically ill patients - Cardiac surgery arations contain equal concentrations of the two enan- - Miscellaneous topics tiomers. These enantiomers differ in anaesthetic potency, Summary in the responses of the electroencephalograph (EEG), in Key words effects on catecholamine reuptake, and possibly in the incidence of emergence reactions. ANAESTHETICS,INTRAVENOUS: ketamine. From the Department of Anacsthcsiology, Box 1010, Mount Pharmacokinetics Sinai Medical Center, One Gustavc L. Levy Place, New Ketamine has a high bioavailability following intravenous York, New York 10029 U.S.A. or intramuscular administration. First-pass metabolism Address correspondence to: Dr. D. L. Reich. and lower absorption necessitate higher dosages when CAN J ANAESTH 1989 ! 36:2 / pp 186-97 Reich and Silvay: KETAMINE, TWENTY-FIVE YEARS CLINICAL EXPERIENCE 187 ketamine is administered by the oral or rectal routes (vide high concentrations of ketamine for intravenous regional infra). Biotransformation takes place in the liver, and anaesthesia and subarachnoid block, m,~ multiple metabolites have been described. The most important pathway involves N-demethylation by cyto- Mechanism of action chrome P4so to norketamine, an active metabolite with The anaesthetic state produced by ketamine was original- an anaesthetic potency one third that of ketamine. Nor- ly described as a functional and electrophysiological ketamine (originally termed metabolite I in the earlier dissociation between the thalamoneocortical and limbic literature) is then hydroxylated and conjugated to water systems. Ketamine as the sole anaesthetic produces a soluble compounds that are excreted in the urine. The cataleptic state with nystagmus and intact corneal and cyclohexanone ring also undergoes oxidative metabo- light reflexes. Hypertonus, purposeful movements and lism. Earlier literature listed dehydronorketamine (meta- vocalization may occur. bolite I1) as an important breakdown product of ketamine, Ketamine is a potent analgesic at subanaesthetie plasma but this compound is most likely an artifact of the concentrations, and its analgesic and anaesthetic effects chromatographic analysis, and not an important meta- may be mediated by different mechanisms. The analgesia bolite in vivo. 4 may be due to an interaction between ketamine and central Ketamine pharmacokinetics follow a three-term or spinal opiate receptors. ~: exponential decline. In unpremedicated patients, distribu- tion half-life (h12~') was 24.1 seconds, redistribution half-life (h/2a) was 4.68 minutes, and elimination half- N-METHYL-ASPARTATE RECEPTOR THEORY life (h~213) was 2.17 hours. 5 Pharmacokinetics were sim- N-methyl-aspartate (NMA) is an excitatory amine, and its ilar in children, except that absorption was more rapid receptors in mammalian brain are blocked by PCP and following intramuscular administration, and higher con- ketamine, t3'~4 The NMA receptors may represent a centrations of norketamine were present. 6 Diazepam subgroup of the sigma opiate receptors ("the PCP site") seems to inhibit the hepatic metabolism of ketamine, but that block spinal nociceptive reflexes. IS Ketamlne also etomidate does not. 7 blocks NMA-induced seizures at high doses, and NMA- induced behavioural changes at lower doses in the rat model. Js Metaphit, a recently synthesized piperidine derivative, Pharmacodynamics The pharmacodynamic effect of ketamine in humans is blocks the action of NMA by acetylating the receptors. It apparently due to the CNS activity of the parent com- was hoped that metaphit might displace ketamine from pound. As CNS levels of ketaminc decline by redistribu- NMA receptors and reverse ketamine anaesthesia. How- tion to the peripheral compartment, the CNS effects ever, metaphit acts as an agonist/antagonist at the recep- subside, although not as rapidly as would be predicted tors, and does not reverse dissociative anaesthesia in fl~e rat model. ~7 from its high lipid solubility,s Decreased renal fnnction, and the presence of active metabolites, do not prolong the drug's action. Tolerance and hepatic enzyme induction OPIATE RECEPTOR THEORY have been reported following chronic administration. Ketamine's affinity for opiate receptors is controversial, Both halothane and diazepam prolong the clinical but this provides an attractive theory for its analgesic anaesthetic effect of ketamine. However, it is not clear activity at central and spinal sites. Smith et al. showed whether this is due to the synergistic effects of CNS that racemic ketamine displaced tritiated naloxone from depressant drugs, decreased ketamine clearance, or a rat brain opiate receptors in vitro, and that (+)ketamine combination of these factors. Diazepam causes an in- was about twice as potent as (-)ketamine for this crease in plasma ketamine levels, but also a prolongation purpose. 18 Finck and Ngai not only confirmed the above of tu2a and tlt213 in humans. study, but also found similar stereospecific opiate recep- Analgesia from ketamine is associated with a plasma tor binding by (+)ketamine in guinea pig ileum in vitro, t9 concentration of 0.15 ~g. ml-t following intramuscular Cross-tolerance between the opiates and ketamine would administration, and 0.04 v,g" ml-J following oral admin- also be expected if there is a common receptor. This has istration. The difference in the analgesic plasma concen- now been shown in two independent animal studies. 2~ trations might be explained by a higher norketamine The opiate receptor theory would gain more credence if concentration following oral administration (probably ketamine reversal by naloxone were proven in humans. from first-pass metabolism), which contributes to the Stella et al. reported that none of 68 adult patients analgesia. Awakening from ketamine anaesthesia takes premedicated with naloxone lost consciousness following place at plasma concentrations of 0.64-1.12 p,g- ml- ~.9 the administration of EDso doses of ketamine. 22 Amiot et Both sensory and motor block occur in humans using al. repeated the doses used in the above study, but in 188 CANADIAN JOURNAL OF ANAESTHESIA pregnant patients whose anaesthetic requirements may and found no further increase in ICP with 0.5 or 2.0 have been lower, and without a control group. They found mg.kg-~ of IV ketamine. 36 It was also hypothesized in no evidence of naloxone reversal of ketamine at a similar earlier studies, thai ketamine increased ICP due to a direct dosagefl 3 cerebral vasodilatory action. However, Schwedler et al. injected ketamine directly into cerebral vessels, and found MISCELLANEOUS RECEPTOR THEORY no effects on the vasculature. 37 Anterior fontanelle pres- Other neuronal systems may be involved in the antinoci- sure, an indirect monitor of ICP, declined by I 0 per cent ceptive action of ketamine, since blockade of noradrena- in mechanically ventilated preterm neonates following line and serotonin receptors attenuates the analgesic 2 mg "kg-~ of IV ketamine. 3s action of ketamine in animals. 2a Interaction of kctamine with sigma opiate