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Anesthesia and the Patient with Epilepsy
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
Samantha L. Mullis, A. Donald Finek
The barbiturate family of drugs, including sodium thiopental (Fentothal), methohexital (Brevital), and thiamylal (Surital), have been used extensively by anesthesiologists for the induction of general anesthesia and in the production of a sedative and hypnotic state. In general, the barbiturates produce various degrees of CNS depression depending upon the dose utilized (40). Those drugs possessing a 5-phenyl substitution (i.e., phenobarbital) have an additional advantage of having anticonvulsant properties. Indeed, anesthetic doses of barbiturates, including pentobarbital and thiopental, have been effective in the treatment of status epilepticus and produce prompt cessation of both motor and EEG seizure activity (41).
Surgical Facilities, Peri-Operative Care, Anesthesia, and Surgical Techniques
Published in Yuehuei H. An, Richard J. Friedman, Animal Models in Orthopaedic Research, 2020
Alison C. Smith, M. Michael Swindle
Barbiturate anesthesia is used in all species. However, it requires iv access for most species. They may be administered as an ip injection for rodents. The barbiturates are potent cardiorespiratory depressants which are dose dependent in their activity. In large animals, they are best administered as iv infusion protocols. Pentobarbital is relatively long acting in most animals and may provide 30-45 min. of anesthetic activity following a single iv injection. It requires hepatic metabolism and excretion for biodegradation. Thiobarbiturates, such as thiopental and thiamylal, are primarily excreted by the kidneys and have much shorter anesthetic times of 5-20 min. The dosage of barbiturates are reduced 1/3-1/2 by administration of tranquilizers or other preanesthetic agents.11-16
Disposition and Metabolism of Drugs of Dependence
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
It has been customary to classify barbiturates into long, intermediate, short, and ultrashort-acting types on the basis of their duration of action in experimental animals. This classification can be highly misleading288 as species differences289–291 in response to barbiturates prevent indiscriminate application to man of data received from experimental animals. The rates of metabolism of clinically available barbiturates fall into two groups, one ranging from 10 to 70% per day (long and medium-acting ones) and the other 0.5 to 20% per hour (anesthetic and short-acting ones). On the basis of clinical experience, the original classification could be supplanted by a simple more accurate designation of sedative-hypnotic drugs and anesthetic barbiturates and the drug, dosage, and route of administration could be left to the physician based on familiarity and experience.288 Phenobarbital, mephobarbital, and metharbital (long-acting barbiturates) are usually employed as sedative-hypnotics and antiepileptic agents; amobarbital, aprobarbital, butabarbital, pentobarbital, secobarbital, and vinbarbital (short to intermediate-acting barbiturates) as sedative-hypnotics and methohexital, thiopental, and thiamylal (ultrashort-acting types) as intravenous anesthetic agents.
Induction of human cytochrome P450 3A4 by the irreversible myeloperoxidase inactivator PF-06282999 is mediated by the pregnane X receptor
Published in Xenobiotica, 2018
Jamie E. Moscovitz, Zhiwu Lin, Nathaniel Johnson, Meihua Tu, Theunis C. Goosen, Yan Weng, Amit S. Kalgutkar
In retrospect, the activation of PXR by PF-06282999 is not altogether surprising when one considers the structural resemblance of PF-06282999 to previously characterized PXR agonists such as barbiturate (e.g. phenobarbital and mephobarbital) and hydantoin (e.g. phenytoin and mephenytoin) derivatives (Kobayashi et al., 2004), and in particular thiamylal, which is a thiobarbiturate analog of secobarbital (Figure 6) (Shukla et al., 2011). From a drug discovery perspective, several publications have outlined SAR trends towards elimination of PXR activation (and CYP3A4 induction) liability in a chemical series (Fotsch et al., 2008; Gao et al., 2007; Harper et al., 2005; Kaizerman et al., 2010; Sinz, 2015; Rew et al., 2009; Zimmermann et al., 2010). Strategies to attenuate binding to the PXR LBD domain primarily hinge on destabilizing ligand-receptor interaction (Gao et al., 2007) via introduction of polarity (to disrupt hydrophobic interactions), steric hindrance (disruption of specific binding interactions with the LBD) and elimination of key hydrogen bond acceptors that ion pair with specific residues in the PXR LBD. Based on the information gained in our present studies, PXR transactivation assays in tandem with CYP3A4 induction studies in human hepatocytes have been implemented in the design of the next generation of selective thiouracil-based MPO inactivators that do not induce CYP3A4. These efforts leading to the discovery of a back-up clinical candidate devoid of CYP3A4 induction will be disclosed in due course.
Sedation in cardiac arrhythmias management
Published in Expert Review of Cardiovascular Therapy, 2018
Federico Guerra, Giulia Stronati, Alessandro Capucci
Dexmedetomidine was proposed as a viable alternative in two randomized controlled trials. The first one randomized dexmedetomidine and remifentanil versus midazolam and remifentanil in targeting moderate to deep sedation during AF ablation [56]. Dexmedetomidine was associated with a lower incidence of respiratory depression (33% vs. 2%), a deeper level of sedation despite a lower mean dose of remifentanil, and higher satisfaction score as reported by the electrophysiologist. Dexmedetomidine was associated with a nonsignificant trend toward a higher rate of hypotension (11% vs. 0%), and transient bradycardia, both mediated by the well-known biphasic hemodynamic response to α-2-mediated sympatholytic action. The other trial compared dexmedetomidine with the barbiturate thiamylal, reporting a similar incidence of bradycardia and hypotension but fewer body movements and apneic events [57].