Pharmacodynamics Mechanism of action Antagonism of the NMDA receptor is responsible for the anesthetic, analgesic, and psychotomimetic effects of<unk> . NMDA receptor antagonism results in analgesia by preventing central sensitization in dorsal horn neurons; in other words,<unk> 's actions interfere with pain transmission in the spinal cord. The mechanism of antidepressant action of<unk>  is uncertain. It is not clear whether NMDA receptor is solely responsible for this action or interactions with other receptors are also necessary. It is not clear whether<unk>  alone is sufficient for the antidepressive action or its metabolites also are important. In any case, it has been elucidated that acute blockade of NMDA receptors in the brain results in an activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA receptors), which in turn modulate a variety of downstream signaling pathways to influence neurotransmission in the limbic system and mediate antidepressant effects of NMDA receptor antagonists like<unk> . Such downstream actions of this activation of AMPA receptors include upregulation of brain-derived neurotrophic factor (BDNF) and activation of its signaling receptor tropomyosin receptor kinase B (TrkB), activation of the mammalian target of rapamycin (mTOR) pathway, deactivation of glycogen synthase kinase 3 (GSK-3), and inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase. In addition to blockade of the NMDA receptor, the active metabolite of<unk>  hydroxynorketamine, which does not interact importantly with the NMDA receptor, but nonetheless indirectly activates AMPA receptors similarly, may also or alternatively be involved in the rapid-onset antidepressant effects of<unk> . Recent research has elucidated that an acute inhibition of the lateral habenula, a part of the brain in the limbic system that has been referred to as the "anti-reward center" (projecting to and inhibiting the mesolimbic reward pathway and modulating other limbic areas), may be involved in the antidepressant effects of<unk> .<unk>  is a mixture of equal amounts of two enantiomers: esketamine and arketamine. Esketamine is a more potent NMDA receptor antagonist and dissociative hallucinogen than arketamine. Because of the hypothesis that NMDA receptor antagonism underlies the antidepressant effects of<unk> , esketamine was developed as an antidepressant. However, multiple other NMDA receptor antagonists, including memantine, lanicemine, rislenemdaz, rapastinel, and 4-chlorokynurenine, thus far have failed to demonstrate sufficient effectiveness for depression. Furthermore, animal research indicates that arketamine, the enantiomer with a weaker NMDA receptor antagonism, as well as (2R,6R)-hydroxynorketamine, the metabolite with negligible affinity for the NMDA receptor, but a potent alpha-7 nicotinic receptor antagonist may have antidepressive action. It is now argued that NMDA receptor antagonism may not be responsible for the antidepressant effects of<unk> . Molecular targets +<unk>  and biological targets (with Ki below 100 μM) Site Value (μM) Type Action Species Ref 0.25–0.66 Ki Antagonist Human 42 Ki Antagonist Human 12.1 Ki Antagonist Human 2825 KiKi AntagonistAgonist Human σ2 26 Ki Rat D2 0.5>10 KiKi Agonist Human M1 45 Ki Human 92 IC50 Antagonist Human 29 IC50 Antagonist Human α3β2 50 IC50 Antagonist Human α3β4 9.5 IC50 Antagonist Human α4β2 72 IC50 Antagonist Human α4β4 18 IC50 Antagonist Human α7 3.1 IC50 Antagonist Rat 0.34 Ki Human 82–291 IC50 Inhibitor Human 63 Ki Inhibitor Rat 8–16 EC50 Inhibitor Mouse The smaller the value, the stronger the interaction with the site.<unk>  principally acts as an antagonist of the NMDA receptor, an ionotropic glutamate receptor. The S(+) and R(–) stereoisomers of<unk>  bind to the dizocilpine site of the NMDA receptor with different affinities, the former showing approximately 3- to 4- fold greater affinity for the receptor than the latter. As a result, the S isomer is a more potent anesthetic and analgesic than its R counterpart.<unk>  may interact with and inhibit the NMDAR via another allosteric site on the receptor. With a couple of exceptions<unk>  actions at other receptors are far weaker than<unk> 's antagonism of the NMDA receptor (see the activity table to the right). Although<unk>  is a very weak ligand of the monoamine transporters (Ki > 60 μM), it has been suggested that it may interact with allosteric sites on the monoamine transporters to produce monoamine reuptake inhibition. However, no functional inhibition (IC50) of the human monoamine transporters has been observed with<unk>  or its metabolites at concentrations of up to 10,000 nM. Moreover, animal studies and at least three human case reports have found no interaction between<unk>  and the monoamine oxidase inhibitor (MAOI) tranylcypromine, which is of importance as the combination of a monoamine reuptake inhibitor with an MAOI can produce severe toxicity such as serotonin syndrome or hypertensive crisis. Collectively, these findings shed doubt on the involvement of monoamine reuptake inhibition in the effects of<unk>  in humans.<unk>  has been found to increase dopaminergic neurotransmission in the brain, but instead of being due to dopamine reuptake inhibition, this may be via indirect/downstream mechanisms, namely through antagonism of the NMDA receptor. Whether<unk>  is an agonist of D2 receptors is controversial. Early research by the Philip Seeman group found<unk>  to be a D2 partial agonist with the potency similar to that of its NMDA receptor antagonism. However, later studies by different researchers found the affinity of<unk>  of >10 μM for the regular human and rat D2 receptors, Moreover, whereas D2 receptor agonists such as bromocriptine are able to rapidly and powerfully suppress prolactin secretion, subanesthetic doses of<unk>  have not been found to do this in humans and in fact, have been found to dose-dependently increase prolactin levels. Imaging studies have shown mixed results on inhibition of striatal 11C raclopride binding by<unk>  in humans, with some studies finding a significant decrease and others finding no such effect. However, changes in 11C raclopride binding may be due to changes in dopamine concentrations induced by<unk>  rather than binding of<unk>  to the D2 receptor. Relationships between levels and effects Dissociation and psychotomimetic effects are reported in patients treated with<unk>  at plasma concentrations of approximately 100 to 250 ng/mL (0.42–1.1 μM). The typical intravenous antidepressant dosage of<unk>  used to treat depression is low and results in maximal plasma concentrations of 70 to 200 ng/mL (0.29–0.84 μM). At similar plasma concentrations (70 to 160 ng/mL; 0.29–0.67 μM) it also shows analgesic effects. In 1–5 minutes after inducing anesthesia by a rapid intravenous injection of<unk> , its plasma concentration reaches as high as 60–110 μM. When the anesthesia was maintained using nitrous oxide together with continuous injection of<unk> , the<unk>  concentration stabilized at approximately 9.3 μM. In an experiment with purely<unk>  anesthesia, patients began to awaken once the plasma level of<unk>  decreased to about 2,600 ng/mL (11 μM) and became oriented in place and time when the level was down to 1,000 ng/mL (4 μM). In a single-case study, the concentration of<unk>  in cerebrospinal fluid, a proxy for the brain concentration, during anesthesia varied between 2.8 and 6.5 μM and was approximately 40% lower than in plasma. Pharmacokinetics<unk>  can be absorbed by many different routes due to both its water and lipid solubility. Intravenous<unk>  bioavailability is 100% by definition, intramuscular injection bioavailability is slightly lower at 93%, and epidural bioavailability is 77%. Subcutaneous bioavailability has never been measured, but is presumed to be high. Among the less invasive routes, the intranasal route has the highest bioavailability (45–50%) and oral – the lowest (16–20%). Sublingual and rectal bioavailabilities are intermediate at approximately 25–50%. After absorption<unk>  is rapidly distributed into the brain and other tissues. The plasma protein binding of<unk>  is variable at 23 to 47%. Major routes of<unk>  metabolism. In the body<unk>  undergoes extensive metabolism. It is biotransformed by CYP3A4 and CYP2B6 isoenzymes into norketamine, which, in turn, is converted by CYP2A6 and CYP2B6 into hydroxynorketamine and dehydronorketamine. Low oral bioavailability of<unk>  is due to the first-pass effect and, possibly,<unk>  intestinal metabolism by CYP3A4. As a result, norketamine plasma levels are several-fold higher than<unk>  following oral administration, and norketamine may play a role in anesthetic and analgesic action of oral<unk> . This also explains why oral<unk>  levels are independent of CYP2B6 activity, unlike subcutaneous<unk>  levels. After an intravenous injection of tritium-labelled<unk> , 91% of the radioactivity is recovered from urine and 3% from the feces. The medication is excreted mostly in the form of metabolites, with only 2% remaining unchanged. Conjugated hydroxylated derivatives of<unk>  (80%) followed by dehydronorketamine (16%) are the most prevalent metabolites detected in urine.
Ketamine
Propofol
Remifentanil
Alfentanil
Fentanyl
Etomidate
Esketamine
Sevoflurane