KETAMINE HYDROCHLORIDE SELECTIVE NMDA AN TAGO

Absorption

Ketamine absorption is very rapid and the bioavailability is around 93%. After the first pass metabolism, only 17% of the administered dose is absorbed. It distributes very rapidly and presents a distribution half-life of 1.95 min. The Cmax levels at peak reach 0.75 mcg/ml in plasma and 0.2 mcg/ml in cerebrospinal fluid.

Toxicity

Preclinical studies related to the blocking of NMDA receptors have shown an increase in apoptosis in the developing brain which results in cognitive deficits when used for longer than 3 hours. Toxicity studies regarding carcinogenesis have not been performed. Regarding mutagenesis and fertility, ketamine showed to be clastogenic and to not have effects on fertility.

Originator

Ketanest,Parke Davis,W. Germany,1969

The Uses of KETAMINE HYDROCHLORIDE SELECTIVE NMDA AN TAGO

Anesthetic.

Background

Ketamine is an NMDA receptor antagonist with a potent anesthetic effect. It was developed in 1963 as a replacement for phencyclidine (PCP) by Calvin Stevens at Parke Davis Laboratories. It started being used for veterinary purposes in Belgium and in 1964 was proven that compared to PCP, it produced minor hallucinogenic effects and shorter psychotomimetic effects. It was FDA approved in 1970, and from there, it has been used as an anesthetic for children or patients undergoing minor surgeries but mainly for veterinary purposes.

Indications

Ketamine is indicated as an anesthetic agent for recommended diagnostic and surgical procedures. If skeletal muscle relaxation is needed, it should be combined with a muscle relaxant. If the surgical procedure involves visceral pain, it should be supplemented with an agent that obtunds visceral pain. Ketamine can be used for induction of anesthesia prior other general anesthetic agents and as a supplement of low potency agents.
Reports have indicated a potential use of ketamine as a therapeutic tool for the management of depression when administered in lower doses. These reports have increased the interest for ketamine in this area and several clinical trials are launched for this indication.

Definition

ChEBI: Ketamine is a member of the class of cyclohexanones in which one of the hydrogens at position 2 is substituted by a 2-chlorophenyl group, while the other is substituted by a methylamino group. It has a role as an intravenous anaesthetic, a NMDA receptor antagonist, an analgesic, a neurotoxin, an environmental contaminant and a xenobiotic. It is a member of cyclohexanones, a secondary amino compound and a member of monochlorobenzenes.

Manufacturing Process

The 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine used as an intermediate is prepared as follows. To the Grignard reagent prepared from 119.0 g of cyclopentyl bromide and 19.4 g of magnesium is added 55.2 g of o-chlorobenzonitrile. The reaction mixture is stirred for 3 days and thereafter hydrolyzed in the usual manner. From the hydrolysis there is obtained ochlorophenylcyclopentylketone, BP 96° to 97°C (0.3 mm), nD251.5452. To 21.0 g of the ketone is added 10.0 g of bromine in 80 ml of carbon tetrachloride.
1-Bromocyclopentyl-(o-chlorophenyl)-ketone, BP 111° to 114°C (0.1 mm) is isolated in the usual manner. Since it is unstable, it must be used immediately. The bromoketone (29.0 g) is dissolved in 50 ml of liquid methylamine. After one hour, the excess liquid methylamine is allowed to evaporate. The organic residue is dissolved in pentane, and upon evaporation of the solvent, 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine, MP 62°C, is isolated.
1-Hydroxycyclopentyl-(o-chlorophenyl)-ketone N-methylimine (2.0 g) is dissolved in 15 ml of Decalin and refluxed for 2,5 hours. After evaporation of the Decalin under reduced pressure, the residue is extracted with dilute hydrochloric acid, the solution treated with decolorizing charcoal, and the resulting acidic solution is made basic. The liberated product, 2-methylamino- 2-(o-chlorophenyl)-cyclohexanone, after crystallization from pentane-ether, has MP 92° to 93°C. The hydrochloride of this compound has MP 262° to 263°C.

brand name

Ketalar (Parkdale).

Therapeutic Function

Anesthetic

Mechanism of action

The mode of action of ketamine differs from that of the barbiturates. It suppresses the activities of the cerebral cortex (consciousness) and the thalamic pain pathways (analgesia). Parts of the upper brainstem and the limbic system are not affected (so-called dissociative analgesia). The patient exhibits a characteristic superficial sleep with complete elimination of pain. Because of the psychomotor side effects, combination with neuroleptics and tranquilizers is necessary. Ketamine is used especially in pediatrics. The usual preparations are 0.1 % and 0.5 % solutions.

Pharmacokinetics

Ketamine is a rapid-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression. The anesthetic state produced by Ketamine has been termed as "dissociative anesthesia" in that it appears to selectively interrupt association pathways of the brain before producing somesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems).
Ketamine enhances descending inhibiting serotoninergic pathways and can exert antidepressive effects. These effects are seen in concentrations ten times lower than the needed concentration for anesthetic proposes. The effect of ketamine can be described as analgesic by the prevention of central sensitization in dorsal horn neurons as well as by the inhibition on the synthesis of nitric oxide. Ketamine can present cardiovascular changes and bronchodilatation.

Clinical Use

Ketamine is a short-acting anesthetic effective for 5 – 30 min, depending on the amount injected. It is suitable for diagnostic purposes and for surgical procedures that do not require muscle relaxation. The occasional hallucinations that occur during anesthesia suggest a chemical relationship to phencyclidine, which was used as a short-acting anesthetic until identified as a dangerous drug of abuse.

Synthesis

It is prepared by bromination of o-chlorophenyl cyclopentyl ketone, which is then reacted with methylamine to give the methylimino alcohol. Thermolysis of the imino hydrochloride yields ketamine by ring expansion :

Metabolism

Ketamine presents a mainly hepatic metabolism and its major metabolite is norketamine. The biotransformation of ketamine corresponds to N-dealkylation, hydroxylation of the cyclohexone ring, conjugation to glucuronic acid and dehydration of the hydroxylated metabolites for the formation of cyclohexene derivatives.