Mechanism of actions Molecular structure of S(+) and R(-) enantiomers of<unk>  The biological effects of<unk>  depend primarily on its ability to penetrate the central nervous system.<unk>  can potentiate GABAA receptors, like all barbiturates. It has been found over the years that the S(+) enantiomer of<unk>  potentiates GABAA receptors more effectively than its R(-) enantiomer. When GABA binds to the GABAA receptor, the chloride ion channels open such that chloride ions can flow into the neuron. This causes a hyperpolarization in the membrane potential of the neuron, which makes it less likely for the neuron to start an action potential. Therefore, this type of receptor is the major inhibitory neurotransmitter receptor in the mammalian central nervous system. As a GABAA receptor potentiator,<unk>  binds to the barbiturate binding site localized in the chloride ion channel, thereby increasing the binding of GABA and benzodiazepines to their respective binding site, allosterically. Moreover,<unk>  causes the chloride ion channel opening to their longest open state of 9 milli seconds, thereby causing the postsynaptic inhibitory effect to be extended. In contrast to GABA, glutamate is the major excitatory neurotransmitter in the mammalian brain. In addition to the inhibitory effect,<unk>  blocks, like all barbiturates, AMPA receptors, kainate receptors, neural acetylcholine receptors. And above all, barbiturates inhibit glutamate release by causing an open channel block on P/Q‐type high‐voltage activated calcium channels. All in all,<unk>  causes an CNS-depressant effect on the brain by inhibiting the glutamate release and potentiating the GABA-effect. Metabolism The hepatic metabolism of<unk>  <unk>  can be divided into different pathways all forming different metabolites. The S(+) enantiomer of<unk>  preferentially metabolizes into β-3'-hydroxyhexobarbital and the R(-) enantiomer preferentially metabolizes into α-3'-hydroxyhexobarbital, the reaction thus is stereoselective. Both enantiomers, however, form both α- and β-isomers. In total four enantiomers for 3'-hydroxyhexobarbital (3HHB) can be metabolized. This reaction is catalyzed by a cytochrome P450, CYP2B1. All 3HHB isomers formed can undergo further metabolism via glucuronidation or dehydrogenation. If 3HHB undergoes a glucuronidation reaction, via UDP-glucuronosyl transferases (UGTs), it is readily excreted. 3HHB can also undergo dehydrogenation, forming a reactive ketone, 3'-oxohexobarbital (3OHB). The biotransformation of 3HHB into 3OHB is via the enzyme 3HHB dehydrogenase (3HBD), a NAD(P)+ linked oxidation. This enzyme is part of the aldo-keto reductase (AKR) superfamily. In humans, 3HBD has a high preference for NAD+. These reactions are also stereospecific, the R(-) conformation preferentially forms 3OHB as 3HBD has the highest activity for this enantiomer in both alpha and beta form. New evidence proved the further metabolism of 3OHB into 1,5-dimethylbarbituric acid and a cyclohexenone glutathione adduct. This biotransformation step takes place via an epoxide-diol mechanism. The formation of an reactive epoxide, leads to the formation of the compounds mentioned. Experiments in man indicated the major metabolites to be 3HHB, 3OHB and 1,5-dimethylbarbituric acid. none Health effects in man Excretion The plasma half-life of<unk>  in man is estimated at 222±54 min. The clearance of<unk>  differs between the two enantiomers and the age of the human subject. The clearance of the R(-) enantiomer is almost 10-fold greater than the clearance of the S(+) enantiomer. Clearance on average in elderly people, compared to young subjects, is slower. Excretion is mainly via urine, for the three major metabolites. The cyclohexenone glutathione adduct is excreted in the bile. Symptoms An intoxication in man with<unk>  can result in sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgment, drowsiness or coma, shallow breathing and staggering. In some severe cases coma and death can be the result of an overdose. Effects on animals The following table presents the studies about the effects of<unk>  on animals, which are done in the 1900s. Most of these studies showed that<unk>  has short-term toxicity effects and that it can induce hypnotic effects in mice, rabbits and frogs. +Table 1: Effects of<unk>  on animals Organism Testtype Route Dose Effect Reference rat LD50 intraperitoneal 330 mg/kg (330 mg/kg) rat LDLo subcutaneous 400 mg/kg (400 mg/kg) mouse LD50 oral 468 mg/kg (468 mg/kg) Prolongation of sleeping time mouse LD50 intraperitoneal 270 mg/kg (270 mg/kg) Prolongation of sleeping time and immobility time, which are potentiated by L-asparagine mouse LDLo subcutaneous 250 mg/kg (250 mg/kg) mouse LD50 intravenous 133 mg/kg (133 mg/kg) Behavioural: somnolence (general depressed activity) Archives Internationales de Pharmacodynamie et de Therapie., 163(11), 1966 mouse LDLo intrapleural 340 mg/kg (340 mg/kg) Hypnotic effect, which is potentiated by 4,5-dihydro-6-methyl-22-(4-pyridyl)-ethyl-3-pyridazinone (U-320) mouse LD50 parenteral 160 mg/kg (160 mg/kg) Pharmacology and Toxicology. English translation of FATOAO., 20(569), 1957 rabbit LDLo oral 1200 mg/kg (1200 mg/kg) Ultra-short actors; hypnotic effect Minimal lethal dose: 1200 mg/kg Minimal hypnotic dose: 15 mg/kg rabbit LDLo intravenous 80 mg/kg (80 mg/kg) Ultra-short actors; hypnotic effect Minimal lethal dose: 80 mg/kg Minimal hypnotic dose: 15 mg/kg rabbit LDLo rectal 175 mg/kg (175 mg/kg) Ultra-short actors; hypnotic effect Minimal lethal dose: 175 mg/kg Minimal hypnotic dose: 15 mg/kg frog LDLo intraperitoneal 30 mg/kg (30 mg/kg) frog LD50 parenteral 148 mg/kg (148 mg/kg) Pharmacology and Toxicology. English translation of FATOAO., 20(569), 1957
Hexobarbital
Pentobarbital
Amobarbital
Secobarbital
Ethallobarbital
Heptobarbital
Butobarbital
Ketazolam