Ketamine pharmacology

Research continues to illuminate different aspects of ketamine pharmacology, some of it promising enough to indicate that new clinical uses (principally in the field of anesthesiology) for the drug will be approved. It is still used as a general anesthetic for children and geriatric patients because it is well tolerated. Benzodiazepine-based tranquilizers are used to keep the auditory and visual hallucinations to a minimum. 

Another injectable anesthetic widely used in feline and primate practice is ketamine hydrochloride [1867-66-9]. Ketamine, a derivative of phencychdine, can be chemically classified as a cyclohexamine and pharmacologically as a dissociative agent. Analgesia is produced along with a state that resembles anesthesia but in humans has been associated with hallucinations and confusion. For these reasons, ketamine is often combined with a tranquilizer. The product is safe when used in accordance with label directions, but the recovery period may be as long as 12—24 h. 

White PF, Way WE, Trevor AJ Ketamine its pharmacology and therapeutic uses. Anesthesiology 56 119—136, 1982... 

This laboratory has utilized two approaches to define further the anticonvulsant properties of PCP. One approach involved a relatively simple convulsant model, pentylenetetrazol-induced convulsions. In this model, the administration of ketamine alone, or in combination with several known anticonvulsants, was tested. Ketamine, as a structural analog of PCP, shares many of the pharmacological properties associated with PCP. The second approach involved a more complex model, hippocampal-kindled seizures. 

Although generally similar pharmacologic profiles were obtained for the phencyclinoids, subtle but perhaps important differences in these compounds were discernible depending upon the individual assay employed. For example, ketamine never produced behavioral convulsions and was least potent with respect to SLA and disruption of rotarod performance, but was more potent than PCPY, TCPY, TCP, and PCA in the assessment of analgesic activity. PCA, which was very effective in decreasing the severity of electroshock convulsions, was not particularly efficacious or potent in other assays. While PCE was equipotent with PCP in stimulating SLA, it was least efficacious of all compounds with respect to peak SLA achieved. 

The ion-channel blocking mechanism has been widely tested and found to be important in both pharmacology and physiology. Examples are the block of nerve and cardiac sodium channels by local anesthetics, or block of NMDA receptor channels by Mg2+ and the anesthetic ketamine. The channel-block mechanism was first used quantitatively to describe block of the squid axon K+ current by tetraethylammonium (TEA) ions. The effects of channel blockers on synaptic potentials and synaptic currents were investigated, particularly at the neuromuscular junction, and the development of the single-channel recording technique allowed channel blockages to be observed directly for the first time. 

Ketamine has analgesic activity that persists beyond the period of unconsciousness up to 1 h after injection. On regaining consciousness, the patient may experience a disconnection between outside reality and inner mental state (dissociative anesthesia). Frequently there is memory loss for the duration of the recovery period however, adults in particular complain about dis-Ltillmann, Color Atlas of Pharmacology... 

Ketamine and also tiletamine are structurally and pharmacologically related to phencyclidine. Its mechanism of action is not well understood. It has been suggested that it blocks the membrane effects of the excitatory neurotransmitter glutamic acid. Ketamine produces dissociative anesthesia, which means that the patient seems to be awake but there are no responses to sensory stimuli. Ketamine, which can be administered IV or IM, has strong analgesic activity. It is especially indicated for interventions of short duration without any need for skeletal... 

Ketamine is a cyclohexanone derivative whose pharmacological actions are quite different from those of the other IV anesthetics. The state of unconsciousness it produces is trancelike (i.e., eyes may remain open until deep anesthesia is obtained) and cataleptic it has frequently been characterized as dissociative (i.e., the patient may appear awake and reactive but does not respond to sensory stimuli). The term dissociative anesthesia is used to describe these qualities of profound analgesia, amnesia, and superficial level of sleep. 

Figure 10.1 Drug enforcement agents in the Phillipines surround confiscated bags and vials of ketamine after an apartment raid in May 2005. The drugs had an estimated street value of 150,000 U.S. dollars. In powdered form, ketamine has an appearance similar to cocaine but a vastly different pharmacology.

It is a new non-barbiturate anaesthetic agent and pharmacologically related to phencyclidine, a hallucinogen. Intravenous ketamine produces unconsciousness and analgesia within 30 seconds. It can be given by intramuscular route also. It acts on the cerebral cortex and subcortical areas. 

White PF, Way WL, Trevor AJ Ketamine—its pharmacology and therapeutic uses. Anesthesiology 1982 56 119. [PMID 6892475]... 

Ketamine, a weakly basic compound structurally and pharmacologically similar to phencyclidine, is utilized in the U.S. to induce anesthesia.1 It is available in solution for intravenous or intramuscular injection. Since the drug is pharmacologically similar to PCP it has the potential of producing hallucinogenic effects and, therefore, in recent years has become a drug of abuse. 

Both phencyclidine and ketamine bind with high affinity to a number of receptors in the brain, but it is now accepted that the primary target is the sigma-PCP receptor site located in the ion channel of the NMDA excitatory amino acid receptor complex. The precise function of this receptor in the brain is still the subject of debate. It is now known that there are two distinct sigma receptor sites in the mammalian brain (ctj and a2) which are not associated with the NMDA receptor complex. Haloperidol and the atypical neuroleptic remoxipride bind with high affinity to such sites, and it has been postulated that some typical and atypical neuroleptics may owe some of their pharmacological effects to their action on such receptors. 

The belladonna alkaloids are much more toxic than the indoles and phenethylamines. Furthermore, they are just plain dangerous, and the experiences they give are, at best, difficult to integrate with ordinary consciousness. Kava-kava seems to me more like alcohol than like the psychedelics, as does nitrous oxide, a general anesthetic with similar depressant qualities. PCP and ketamine are pharmacological curiosities, not related to other recreational drugs. Many users like the "dissociative" states they provide, but few find them truly psychedelic. Their toxicity and abuse potential are significant. 

Ketamine, more commonly known on the street as Special K and to the scientist as ketamine hydrochloride, is a unique drug with a combination of pharmacological effects. Although it is primarily used by veterinarians as an animal tranquilizer, it is available for limited uses in humans. Chemically, it is similar to phencyclidine (PCP or angel dust), a Schedule II drug that was the first of a new class of general anesthetics called dissociative anesthetics. As the name implies, dissociative anesthetics produce in patients a feeling of detachment and disconnection from pain and the environment. 

The pharmacological effects of the R- and 5-enantiomers of ketamine have been compared in 11 subjects who received //-ketamine 0.5 mg and then 5-ketamine 0.15 mg, separated by 1 week (432). Before and after each drug administration they were subjected to a painful stimulus using a nerve stimulator applied to the right central incisor tooth. Pain suppression was equal with the two drugs. The subjects reported more unpleasant psychotomimetic effects with 5-ketamine and more pleasant effects with //-ketamine. Seven of eleven subjects preferred //-ketamine, while none preferred 5-ketamine. These results suggest that the neuropsychiatric effect of ketamine may be predominantly due to the 5-enantiomer, and that //-ketamine may be a better alternative. This study is in direct distinction to earlier work suggesting that //-ketamine is responsible for most of the undesirable neuropsychiatric side effects of ketamine. 

Currently there is a trend toward the synthesis and large-scale production of a single active enantiomer in the pharmaceutical industry [61-63]. In addition, in some cases a racemic drug formulation may contain an enantiomer that will be more potent (pharmacologically active) than the other enantiomer(s). For example, carvedilol, a drug that interacts with adrenoceptors, has one chiral center yielding two enantiomers. The (-)-enantiomer is a potent beta-receptor blocker while the (-i-)-enantiomer is about 100-fold weaker at the beta-receptor. Ketamine is an intravenous anesthetic where the (+)-enantiomer is more potent and less toxic than the (-)-enantiomer. Furthermore, the possibility of in vivo chiral inversion—that is, prochiral chiral, chiral nonchiral, chiral diastereoisomer, and chiral chiral transformations—could create critical issues in the interpretation of the metabolism and pharmacokinetics of the drug. Therefore, selective analytical methods for separations of enantionmers and diastereomers, where applicable, are inherently important. 

The pharmacology of ketamine, including its adverse effects, has been reviewed (4), as has the use and adverse effects of 5-ketamine in the intensive care unit (5). 

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