Ketamine (1998)

Ketamine has a special position among anesthetic drugs. It was introduced into clinical practice >30 yr ago with the hope that it would function as a "monoanesthetic" drug: inducing analgesia, amnesia, loss of consciousness, and immobility. This dream was not fulfilled because significant side effects were soon reported. With the introduction of other IV anesthetic drugs, ketamine's role diminished rapidly. However, it is still used clinically for indications such as induction of anesthesia in patients in hemodynamic shock; induction of anesthesia in patients with active asthmatic disease; IM sedation of uncooperative patients, particularly children; supplementation of incomplete regional or local anesthesia; sedation in the intensive care setting; and short, painful procedures, such as dressing changes in burn patients. However, recent insights into ketamine's anesthetic mechanism of action and its neuronal effects, as well as a reevaluation of its profound analgesic properties, offer the potential of expanding this range of indications. In addition, studies with the S(+) ketamine isomer suggest that its use may be associated with fewer side effects than the racemic mixture. In this article, we review the mechanism of action of ketamine anesthesia, the pharmacologic properties of its stereoisomers, and the potential uses of ketamine for preemptive analgesia and neuroprotection. Several aspects discussed herein have been reviewed previously [1-4]. Clinical Pharmacology Commercial ketamine is a racemic mixture consisting of two optical enantiomers, R(-) and S(+) (Figure 1), and the preservative benzethonium chloride. Pharmacokinetically, ketamine has relatively short distribution and elimination half-lives: the alpha-elimination phase lasts only a few minutes, and the beta-elimination half life is 2-3 h. The compound is metabolized extensively by the hepatic cytochrome p450 system; its primary metabolite norketamine is only one-third to one-fifth as potent as the original compound but may be involved in the prolonged analgesic actions of ketamine. The metabolites of norketamine are excreted by the kidneys.Figure 1: Structural formulas of the two enantiomers of ketamine.Classic ketamine anesthetic effects are best described as a dose-dependent central nervous system (CNS) depression that leads to a so-called dissociative state, characterized by profound analgesia and amnesia but not necessarily loss of consciousness. Although not asleep, the subject seems completely unaware of the environment. Suggested mechanisms for this form of catalepsy include electrophysiologic inhibition of thalamocortical pathways and stimulation of the limbic system. Ketamine has other effects besides analgesia and amnesia. Effects on the respiratory system are generally beneficial: it is a well documented bronchodilator [5], it causes minimal respiratory depression with only mild hypercapnia [6] in clinically relevant doses, and protective airway reflexes are more likely to be preserved than with other IV anesthetics. However, increased oral secretions can occur. Ketamine often produces significant increases in blood pressure and heart rate [7], and increases in pulmonary artery pressure have been reported, especially in patients with preexisting heart disease [8,9]. These effects are due to sympathetic stimulation; ketamine's direct effect on the heart is depressant, S(+) less than R(-) [10]. Recovery time is dose-dependent, and emergence is, at times, complicated by psychotomimetic reactions (hallucinations, vivid dreams), which can be highly unpleasant. The manufacturer lists the presence of uncontrolled arterial hypertension or hypersensitivity to the drug as contraindications to the use of ketamine. However, caution has also been suggested when the drug is used in patients with coronary artery disease [11] or right heart failure [12]. Mechanisms of Action Ketamine's neuropharmacology is complex. The compound interacts with multiple binding sites, including N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic, and monoaminergic and opioid receptors. In addition, interactions with voltage-dependent ion channels such as Na and L-type Ca channels have been described. Inhibition of neuronal Na channels provides a modest local anesthetic effect of the compound, whereas Ca channel blockade may be responsible for cerebral vasodilation [13]. All of these interactions may play a role in ketamine's pharmacological and clinical properties. However, NMDA receptor antagonism accounts for most of the analgesic, amnestic, psychotomimetic, and neuroprotective effects of the compound. NMDA Glutamate Receptors The NMDA receptor is an ionotropic receptor (ligandgated ion channel) that is activated by glutamate, the most abundant excitatory neurotransmitter in the CNS (Figure 2). The channel is permeable to Ca and, to a lesser degree, to Na and K. It requires glycine as an obligatory co-agonist and is inhibited by Mg in a voltage-dependent manner. NMDA receptors are, among many other functions, involved in the so called wind-up phenomenon [14], which plays a major role in the development of chronic pain.Figure 2: The N-methyl-D-aspartate (NMDA) receptor. Schematic diagram of the molecular structure of the NMDA glutamate receptor/channel complex. The receptor consists of five subunits surrounding a central ion channel permeable to Ca, K, and Na. Binding sites for the agonist glutamate and the obligatory co-agonist glycine are indicated. Competitive glutamate and glycine antagonists act on these sites. One of the subunits has been removed to allow a view inside the ion channel, in which binding sites for ketamine and Mg are located. These compounds block NMDA receptor functioning noncompetitively. PCP = phencyclidine.The NMDA receptor is the postsynaptic site of action in ketamine's reduction of polysynaptic stimulation in the CNS [15-17]. Ketamine binds to the phencyclidine receptor in the NMDA channel and thus inhibits glutamate activation of the channel in a noncompetitive manner. The phencyclidine binding site partly overlaps with a binding site for Mg. The blockade is time-, concentration- and stimulation frequency-dependent (use-dependent) [18]. The S(+) enantiomer has a three-to fourfold greater affinity for the receptor than the R(-) form, as reflected in the observed differences in their analgesic and anesthetic [19,20] potencies. Although the precise interactions between ketamine and NMDA receptors are still being elucidated [21], enough evidence suggests a relation between ketamine's analgesic and anesthetic properties and NMDA channel blockade [21-23] to consider the NMDA receptor ketamine's primary site of anesthetic action. However, there are interactions with other systems that may also be relevant. Non-NMDA Glutamate Receptors Non-NMDA glutamate receptors exist in several classes, which are activated selectively by the agonists quisqualate, AMPA, or kainate. These receptors were previously thought not to interact with ketamine, but this was disproved in recent animal studies [24], which demonstrated inhibition by ketamine. The effects are probably mediated through the glutamate/NO/cGMP system. Not only NMDA receptor activation stimulates NO synthesis (which then increases intracellular cGMP production) [25], but non-NMDA receptor activation does so as well [26,27]. Besides playing a possible role in ketamine's neuroprotective and sympathetic activating actions, ketamine-induced NO synthase inhibition may be involved in its analgesic effects [28]. NO is known to play a role as a neurotransmitter, centrally as well as peripherally, and pain perception and NO are connected at least at the spinal level. In an animal model, the intrathecal administration of the NO-synthase inhibitor L-N-monomethylarginine induced a dose-dependent antinociceptive response. Other analgesic substances (acetaminophen and other nonsteroidal antiinflammatory drugs) similarly interact with NO metabolism [29]. These findings may partly explain some properties of ketamine not caused by NMDA interaction alone. Opioid Receptors Agonist actions of ketamine on opioid receptors, members of the G-protein-coupled receptor class, seem to play a minor role in its analgesic effects [30]. However, the psychotomimetic side effects of ketamine may be explained by the interaction with kappa opioid receptors, because kappa-agonists induce similar effects. Several investigations show likely interactions between ketamine and opioid receptors [31,32]. Its affinity for these receptors ranks [micro sign] > kappa > delta [32]. S(+) ketamine binds approximately two- to fourfold stronger to [micro sign] and kappa-receptors than does R(-). Still, the affinity of ketamine for these receptors is 10 ([micro sign]) to 20 (kappa) times less than for the NMDA channel, which suggests that the interaction is not of major clinical importance. This is confirmed by findings that naloxone does not reverse the analgesic effect of ketamine in humans [30]. However, in an animal study, ketamine-induced small bowel smooth muscle contraction could be partially reversed by naloxone [33]. Cholinergic and Adrenergic Signaling Both nicotinic and muscarinic acetylcholine receptors are affected by ketamine [34], and, in clinical concentrations, ketamine inhibits NMDA receptor-mediated acetylcholine release. The postsynaptic inhibitory effect of ketamine on nicotinic acetylcholine receptors in skeletal muscle is not necessarily noticeable clinically, as ketamine increases muscle tone by central mechanisms. However, the additional administration of muscle relaxants can uncover this ketamine effect [34]. Muscarinic receptors are also inhibited [35]. S(+) ketamine shows a twofold greater affinity for the muscarinic receptor than does R(-) [30], although this was not confirmed in functional studies [36]. Overall, however, affinity for the muscarinic receptor is 10- to 20-fold less than NMDA receptor binding [37]. Emergence side effects may be partly related to inhibition of cholinergic transmission. R(-) ketamine inhibits the neuronal uptake of norepinephrine, and S(+) ketamine additionally inhibits extraneural uptake, thus inducing a prolonged synaptic response and increased transfer of norepinephrine into the systemic circulation [34]. The uptake of dopamine and 5-HT is inhibited similarly [38], which could lead to an increase in central dopaminergic activity. The 5-HT antagonist methysergide antagonizes the analgesic effects of intrathecal ketamine, implicating serotonergic mechanisms in ketamine analgesia [39]. These mechanisms may also be involved in ketamine-related emesis, as ondansetron inhibits ketamine-induced currents through 5-HT receptors. Thus, influences of ketamine on monoaminergic transmission seem very likely, although their role in the clinical effects of the compound are not yet clear. GABAA Signaling GABA is the most common inhibitory neurotransmitter in the CNS, and GABA signaling neurons account for approximately 30% of all synaptic connections in the CNS. Investigations using GABAA receptors expressed recombinantly in Xenopus laevis oocytes revealed a significant increase of GABA-induced Cl current after ketamine application [40]. Similar effects were observed in olfactory cortex and hippocampal slices [41]. Although an effect of ketamine on GABA signaling seems established [42], the concentrations used were higher than those used clinically. Based on current knowledge, this interaction seems to be of minor importance for clinical practice [34]. S(+) Ketamine In 1992, the Food and Drug Administration stated that separation of stereoisomers had not received appropriate attention in commercial drug development and that, despite technical difficulties and high cost, focusing on this issue could open new horizons in therapeutics. The isomers of ketamine are a good example. It has been known since the late 1970s that the ketamine enantiomers exhibit pharmacologic and clinical differences. Receptor studies in animal models show that S(+) ketamine has approximately fourfold greater affinity at phencyclidine binding sites on the NMDA receptor than does R(-) ketamine. Not all of ketamine's effects are stereoselective. Norepinephrine release is inhibited in a nonstereoselective manner at clinically relevant concentrations. However, its uptake is influenced stereoselectively: both isomers inhibit neuronal uptake, whereas S(+) ketamine additionally inhibits extraneuronal uptake. Muscarinic receptors [36] and Ca channels [43] are inhibited nonstereoselectively. Interestingly, serotonin transport is inhibited twofold more potently by R(-) ketamine. Animal studies have not revealed significant pharmacokinetic differences between the enantiomers and the racemic mixture. After subcutaneous application, similar plasma and brain concentration curves have been found. In a clinical study, however, a significantly higher elimination rate was observed for S(+) ketamine compared with the racemate [44]. The increased inhibitory potency at the NMDA receptor combined with similar pharmacokinetics suggest that S(+) ketamine may be an interesting clinical drug, and its pharmacological properties have been studied in some detail. Table 1 summarizes the clinically relevant differences between the isomers.Table 1: Effects of S(+) and R(-) KetamineAnesthetic/Hypnotic/Analgesic Effects In rats and mice, S(+) ketamine exhibits 1.5- to 3-fold greater hypnotic and 3-fold greater analgesic potency than the R(-) compound. Compared with the racemic mixture, S(+) ketamine is twice as potent. The calculated therapeutic index of S(+) ketamine seems to be 2.5-fold greater than that of the mixture or R(-) alone [45]. A double-blind study with 60 patients [20] reinforced these findings: S(+) ketamine was 3.4-fold more potent an anesthetic than R(-) and 2-fold more potent than the racemate. Studies in rats and mice show that S(+) ketamine induces less spontaneous movement than does R(-) ketamine in comparable anesthetic doses. An explanation may be that, whereas plasma levels are equal after administration of S(+) or R(-) ketamine, cerebral levels of R(-) norketamine are two- to threefold greater than those of S(+) norketamine. In mice, R(-) induces more prominent CNS stimulation than does S(+) ketamine, thus making spontaneous movements more likely. As to hemodynamic response, no significant differences between the compounds could be demonstrated, despite the fact that catecholamine plasma levels are significantly lower after S(+) than R(-) ketamine anesthesia [46,47]. Emergence from Anesthesia and Psychotomimetic Effects S(+) ketamine and R(-) ketamine have a clinical potency ratio of approximately 2:1. Thus, only one-half the dose of S(+) ketamine should suffice for the induction of anesthesia, possibly affecting recovery time. Several clinical studies have assessed the duration of recovery after administration of the racemic mixture or S(+) ketamine. R(-) was excluded because its clinical potency is insufficient [44]. In virtually every study, the recovery phase was clearly shortened when S(+) ketamine was used compared with racemic ketamine. This was true regardless of whether the compounds were administered as a single IV bolus, as a bolus followed by continuous infusion, or by IM injection [46,48,49]. Classical side effects after ketamine anesthesia (amnesia, altered short-term memory, decreased ability to concentrate, decreased vigilance, altered cognitive performance, hallucinations, nightmares, nausea and vomiting) were observed with similar incidence after S(+) or racemic mixture administration [19]. At least for the racemic mixture, it was found that the incidence of these effects is clearly related to the ketamine plasma concentration [50], making psychedelic effects less likely (although still possible) at lower drug concentrations. Convincing evidence for a lower incidence of psychotomimetic side effects after S(+) ketamine administration could not be documented. Nonetheless, the patients felt more comfortable after S(+) ketamine [49], and a larger proportion of patients would be willing to have a repeat anesthetic with S(+)compared with the racemic mixture (85% vs 65%), mainly because of decreased agitation, disorientation, and anxiety [19]. The additional administration of a benzodiazepine provided both drugs with a significantly higher rate of acceptance, but the duration of recovery also increased significantly with this regimen. Taken together, these data suggest that S(+) ketamine allows the use of significantly smaller doses, with a resultant faster recovery and (possibly) some diminution in side effects. As a result, the compound has been approved for clinical use in Europe; therefore, additional clinical experience will soon be available. Ketamine and Preemptive Analgesia At small doses (0.1-0.5 mg/kg), ketamine has a noticeable analgesic action, which can be used to supplement regional or local anesthesia. A number of studies have suggested that administration of ketamine before the noxious stimulus occurs is even more effective [51-53]. This effect is referred to as preemptive analgesia. The goal of preemptive analgesia is to prevent or reduce the development of a "memory" of the pain stimulus in the nervous system [54,55], thereby lessening postoperative analgesic requirements. When a massive barrage of afferent nociceptive impulses reaches the spinal cord, a hyperexcitable state of CNS sensitization known as wind-up results [55]. NMDA receptors seem to be responsible for pain memory (as they are responsible for other forms of memory), and their blockade can contribute significantly to the prevention of pain [56]. NMDA antagonists prevent the induction of central sensitization and even abolish hypersensitivity once it is established [56]. Ketamine is the only NMDA antagonist approved by the Food and Drug Administration (although magnesium also has significant NMDA receptor-blocking properties), and several studies have demonstrated the effect of preemptive administration of small doses of ketamine postoperative pain, measured as a reduction in opioid requirements [57,58]. These effects require remarkably small doses of the drug and last for a relatively prolonged period of time (>or=to6 h). For example, patients undergoing gallbladder surgery who received ketamine were found to have diminished analgesic requirements after a single dose of 0.25 mg/kg IV ketamine versus patients who did not receive ketamine [58]. When presurgery versus postsurgery administration was compared, ketamine administered before skin incision (0.5 mg/kg bolus followed by continuous rate of 10 [micro sign]g [center dot] kg-1 [center dot] min-1) provided better pain control than ketamine given after wound closure [57]. Although the administration schedule and dose varies among studies, preoperatively (preemptively) administered ketamine seems to reduce the amount of narcotics required postoperatively for pain control. Opioid requirements were reduced 40%-60% on average [57,58]. Whether this translates to a lower incidence of opioid-related adverse effects is as yet unknown, although it seems likely. Psychotomimetic responses to these small ketamine doses have not been found troublesome. The role of S(+) ketamine in preemptive analgesia has not yet been studied. Ketamine and Neurosurgery Historically, ketamine has been felt to be contraindicated in patients at risk of increases in intracranial pressure (ICP). However, reports about its neuroprotective actions have led to a reevaluation of this issue. Effects on ICP ICP can increase after the administration of racemic ketamine (no data are available yet for S(+) ketamine). This is especially true when the ICP is already increased before ketamine administration and when the drug is given at doses >1 mg/kg IV. Two reasons are provided for the effect on ICP: cerebral blood volume may increase passively, caused by increased arterial pressure during a period of impaired cerebrovascular autoregulation; and (probably more important) increases in arterial PCO2, due to ketamine-induced ventilatory depression, may contribute [59]. It could be shown that, independent of the preexisting ICP, ketamine administration (0.5-5 mg/kg) did not increase ICP when normocapnia was maintained with controlled ventilation [60]. Although some studies show an ICP increase during normocapnia after the administration of 2 mg/kg ketamine, this increase could be avoided by mild hyperventilation or the administration of benzodiazepines. This is not different from the situation with most volatile drugs, which are used routinely in patients with increased ICP. It has been shown that neither 1.5, 3, nor 5 mg/kg IV ketamine increased ICP in patients with head trauma during controlled ventilation and sedation with propofol; the ICP decreased after ketamine administration Effects on Studies in have shown that racemic ketamine increases cerebral blood in the presence of the cerebral In other animal studies using as a anesthetic a in after ketamine This suggests that the cerebrovascular effects of ketamine are related to the preexisting cerebrovascular When ventilation is not of the effect may from increased However, ICP can increase even when the is and stimulation of cerebral rate by ketamine has been suggested to explain the increase in Ketamine inhibits cerebral and stimulates at the changes which are reflected as decreased in with reduced metabolism and increased in with higher metabolism The of these the effect on In addition, ketamine in as a Ca channel antagonist and increases blood by direct In racemic ketamine can increase on preexisting The mechanisms most likely stimulation and inhibition of cerebral and direct vasodilation by Ca channel The response of the cerebral to racemic ketamine has not been studied but S(+) ketamine does not this It also has been that ketamine does not more likely, by NMDA receptor and a that leads to and and neuronal (Figure In this the activation of NMDA and non-NMDA receptors plays an these receptors are by very high levels of glutamate or the resultant and intracellular of Na and Ca leads to and activation of inducing In NMDA receptor antagonists have received attention as neuroprotective drugs, although neuronal more with the distribution of than of NMDA receptors, and antagonists prevent the at least as as NMDA In animal studies, ketamine, given in doses before the and reduced the In bolus application or administration after the did not show an However, in a study using a head trauma in it was shown that the administration of ketamine mg/kg can reduce and when given 2 The protective properties of S(+) ketamine have been studied in a of incomplete cerebral S(+) ketamine in doses [center dot] kg-1 [center dot] min-1) to a greater than did smaller doses [center dot] kg-1 [center dot] min-1) and was also more protective than The and with the plasma levels of dopamine and The on the subject is because of differences in doses, duration of and other virtually hippocampal after with ketamine has been other investigations show that ketamine can neuronal during very and a effect only after prolonged found ketamine to an effect in found effects Ketamine can be in the cerebral cortex of rats were found to be after phencyclidine or ketamine however, could be by the administration of drugs, or is a that anesthesia with inhibits the protective effect of ketamine on hippocampal after application of the NMDA agonist The neuronal Schematic and diagram of the neuronal The after neuronal is an increase in intracellular This is about by several of leads to This induces of Ca channels and Ca the even also voltage-dependent Mg block from the N-methyl-D-aspartate (NMDA) which leads to Ca and when by The increased intracellular Ca has a number of effects. there is a increased intracellular Ca induces release of glutamate from in NMDA receptors. Ca a number of intracellular to the of to which by the are to and which induce of by Ca induces of increased Ca levels in inhibit their thus and lead to additional The at which ketamine can inhibit this is ketamine during cerebral is with current clinical and with the that is the of cerebral However, studies profound protective effects of very small in have on the on the role of glutamate signaling in the neuronal and suggests that ketamine may be appropriate in patients with cerebral However, it is to it for clinical The suggest that S(+) ketamine especially may have properties. neurons significantly increased and in rats when with S(+) ketamine, and the involved in neuronal was expressed at significantly increased levels compared with an control The indications for ketamine may have to be on current The separation of the enantiomers S(+) and R(-) has revealed the S(+) enantiomer to be a drug for IV anesthesia. S(+) ketamine has been found to be a very potent and effective anesthetic with less prominent side effects emergence from anesthesia and fewer psychotomimetic emergence than racemic ketamine. Its recent commercial introduction on the may lead to use and will into its pharmacological properties and indications Ketamine may have neuroprotective and even effects are or even the results thus more and even new indications Although many as time of administration and to be the of evidence a neuroprotective action. among studies probably from the of the after brain It seems likely that neither racemic nor S(+) ketamine will be clinically used as only when used in with other drugs and can be It seems confirmed that ketamine does not increase ICP when the blood pressure is controlled and mild is Thus, the for ketamine use in patients is only a and when and clinical studies a neuroprotective effect of the compound, ketamine and, more likely, S(+) ketamine may well a in the drug the analgesic properties of ketamine have been data suggest that the preemptive administration of ketamine can have profound effects on postoperative analgesic requirements with minimal risk and side effects. This provides the anesthesia with in the of for review of the