Efectos No Analgésicos del Clorhidrato de Ketamina. Nuevas Indicaciones.

El clorhidrato de ketamina (CKTM) es un agente anestésico disociativo, con un lugar único en la práctica anestésica. Fue descrito por primera vez en la literatura en 1965, y aprobado por la Food and Drug Adminstration (FDA) en 1970, siendo introducido comercialmente con la descripción del fabricante como la de un "anestésico general no barbitúrico de acción rápida". Este fármaco se considera como el único anestésico completo, ya que brinda una anestesia real que incluye hipnosis, analgesia y protección neuroendocrina, además de amnesia considerable. Además, las respuestas inadecuadas que durante un tiempo conllevaron su mínimo uso podían ser minimizadas o abolidas con el uso de fármacos adyuvantes como las benzodiazepinas y las butirofenonas. Este fármaco ha contribuido de manera notable al conocimiento anestésico-analgésico, así como de los cuadros depresivos y esquizofrénicos. Hoy en día continúa arrojando luz sobre las bases moleculares del dolor, hipnosis y la fisiopatología de los diferentes trastornos neuropsiquiátricos. Por sus propiedades farmacológicas y clínicas únicas, así como por sus nuevas indicaciones descubiertas recientemente, el CKTM actualmente tiene una amplia variedad de aplicaciones clínicas. Tanto los efectos neuroprotectores, antiinflamatorios y antitumorales descubiertos en los últimos años, como los hallazgos sobre la utilidad de los regímenes de dosis bajas de CKTM, han contribuido a ampliar el perfil de aplicación clínica de este medicamento. El importante papel que juega en la actualidad, se corrobora por las miles de citas bibliográficas que continúan apareciendo en la literatura médica mundial. Esta revisión presenta las principales indicaciones off label, excluyendo aquellas de la esfera del dolor agudo y crónico, como son su empleo en cuadros de depresión resistente a tratamiento, trastornos obsesivos compulsivos, estrés postraumático, suicidio, insomnio, terapia electroconvulsiva, migraña, disquinesia de la enfermedad de Parkinson, asma bronquial, sedoanalgesia del paciente crítico, disfunción cognitiva postoperatoria, terapia antitumoral y traumática, etc. En resumen, se ratifica su versatilidad, tanto en las múltiples vías de administración, como en los conceptos de protector cerebral y potenciador de analgesia perioperatoria en analgesia preventiva. Por el contrario, se ha informado de la presencia de tolerancia, inducción enzimática hepática, así como múltiples y diversos eventos adversos con su administración crónica. ABSTRACT Ketamine hydrochloride (CKTM) is a dissociative anesthetic agent, with a unique position in the anesthetic practice. It was first described in the literature in 1965 and approved by the Food and Drug Administration (FDA) in 1970, being introduced commercially with the manufacturers description as that of a "general anesthesia non-barbiturate of rapid action.” This drug is considered as the only complete anesthetic, since it provides a real anesthesia that includes hypnosis, analgesia and neuroendocrine protection, in addition to considerable amnesia. In addition, inadequate responses that for a time carried out its minimum use, could be minimized or avoided with the use of adjuvant drugs such as benzodiazepines and butyrophenones.This drug has contributed significantly to the anesthetic-analgesic knowledge, as well as depressive and schizophrenic symptoms. Today, it continues to shed light on the molecular basis of pain, hypnosis and the physiopathology of different neuropsychiatric disorders. Because of its unique pharmacological and clinical properties, as well as its newly discovered indications, CKTM currently has a wide variety of clinical applications. Both the neuroprotective, antiinflammatory and antitumor effects discovered in recent years, as well as the findings on the use of low dose regimens of CKTM, have helped to broaden the profile of clinical application of this drug. The important role it plays today is corroborated by the thousands of bibliographic quotes that continue to appear in the world medical literature.This review presents the main off label indications, excluding those of acute and chronic pain, such as its use in treatment-resistant depression, obsessive-compulsive disorders, posttraumatic stress, suicide, insomnia, electroconvulsive therapy, migraine, Parkinson's disease dyskinesia, bronchial asthma, sedoanalgesia of the critical patient, postoperative cognitive dysfunction, antitumor and traumatic therapy, etc. In summary, its versatility is confirmed, both in the multiple administration routes, as well as in the concepts of brain protector and perioperative analgesia enhancer in preventive analgesia. On the contrary, the presence of tolerance, hepatic enzymatic induction, as well as multiple and diverse adverse events have been reported with its chronic administration.

A Fresh Insight into the Interaction of Natural Products with Pregnane X Receptor

The discovery that various drugs (e.g., phenobarbital) stimulate their own metabolism through a mechanism coined as enzymatic induction opened up a fascinating road that eventually led to the accurate biochemical characterization of the pregnane X receptor. After numerous studies, researchers have concluded that this receptor is activated by different endogenous steroids and a number of foreign lipophile ligands. Once activated, it induces the synthesis of oxygenases and conjugating enzymes. The activating ligands identified to date include many synthetic drugs, along with a number of natural products. The present review summarizes the data relating to the origin, chemistry, and pharmacological activity of the newest natural products that have been found to interact with the pregnane X receptor.

Phenobarbital influence on neuromuscular block produced by rocuronium in rats

PURPOSE: To evaluate in vitro and in vivo neuromuscular blockade produced by rocuronium in rats treated with Phenobarbital and to determine cytochrome P450 and cytochrome b5 concentrations in hepatic microsomes. METHODS: Thirty rats were included in the study and distributed into 6 groups of 5 animals each. Rats were treated for seven days with phenobarbital (20 mg/kg) and the following parameters were evaluated: 1) the amplitude of muscle response in the preparation of rats exposed to phenobarbital; 2) rocuronium effect on rat preparation exposed or not to phenobarbital; 3) concentrations of cytochrome P450 and cytochrome b5 in hepatic microsomes isolated from rats exposed or not to phenobarbital. The concentration and dose of rocuronium used in vitro and in vivo experiments were 4 µg/mL and 0,6 mg/kg, respectively. RESULTS: Phenobarbital in vitro and in vivo did not alter the amplitude of muscle response. The neuromuscular blockade in vitro produced by rocuronium was significantly different (p=0.019) between exposed (20%) and not exposed (60%) rats; the blockade in vivo was significantly greater (p=0.0081) in treated rats (93.4%). The enzymatic concentrations were significantly greater in rats exposed to phenobarbital. CONCLUSIONS: Phenobarbital alone did not compromise neuromuscular transmission. It produced enzymatic induction, and neuromuscular blockade in vivo produced by rocuronium was potentiated by phenobarbital.

Cytochrome P450 Monooxygenases and Interactions of Psychotropic Drugs: A Five-Year Update

Objective: This article is a five-year update on a previous review article ( International Journal of Psychiatry in Medicine, 21:47–56, 1991) on cytochrome P450 monooxygenases and interactions of psychotropic drugs. Method: In the literature review, the recent committee work on nomenclature of the P450 superfamily are highlighted. Then, the author reviewed gene clusters of three human cytochrome P450s— CYP1A2, CYP2D6, and CYP3A4 with the focus on the changes of serum levels of the coadministered psychotropic drugs in the context of enzymatic induction and inhibition of these three hepatic enzymes. Results: As indicated in one table, the author stratified probes, inducers, inhibitors, chemical reactions, and substrates under these three gene clusters. As shown in another simple table, the author compared the hepatic enzymatic inhibitions of four selective serotonin reuptake inhibitors and pointed out the inhibition potentials of fluvoxamine at CYP1A2, fluoxetine and paroxetine at CYP2D6, and fluoxetine and fluvoxamine at CYP3A4 if these two SSRIs have higher serum concentrations. Conclusion: The author suggests that with these systematic approaches, this rapidly adding knowledge can help psychiatrists better understand psychotropic drug interactions and maximize the benefits of patients' psychopharmacotherapy.

Transient Hepatic Dysfunction in an Infant of an Epileptic Mother Treated with Carbamazepine during Pregnancy and Breastfeeding

OBJECTIVE: A case is reported of a carbamazepine (CBZ)-treated epileptic mother whose newborn presented with transient hepatic dysfunction characterized by direct hyperbilirubinemia and high concentrations of gamma-glutamyltransferase (GGT). DATA SOURCES: Information was obtained from case reports, clinical trials, and relevant bibliographic laboratory studies. DATA EXTRACTION: Data from case reports were evaluated and compared with those from our patient. The hepatotoxic reactions together with the microsomal enzymatic induction of CBZ were reviewed. DATA SYNTHESIS: A female infant bom to an epileptic mother treated with CBZ throughout pregnancy and breastfeeding presented with transient direct hyperbilirubinemia and high concentrations of GGT. The characteristics of her transient hepatic dysfunction were: early appearance (during the first day of life); discrepancy between the normal liver enzymes and high GGT concentrations; slow decrease of GGT, which nevertheless remained at above-normal concentrations even after the complete disappearance of direct hyperbilirubinemia; and spontaneous resolution in spite of only occasional breastfeeding. The possible explanations of this transient hepatic dysfunction (like enzymatic induction) are discussed. CONCLUSIONS: CBZ-induced hepatic dysfunction in neonates appears to have different clinical expressions. Infants of epileptic mothers treated with CBZ throughout pregnancy and breastfeeding should be carefully monitored for possible adverse effects.