barbiturate(s) 化学特性,用途語,生産方法
生物学の機能
The effects of barbiturates on the sleep pattern are comparable to those of benzodiazepines. In short-term
studies, the barbiturates are equally effective as the benzodiazepines. Again, the importance of the
pharmacokinetic properties of the barbiturates determines their usefulness as hypnotics. The barbiturates that are slowly eliminated are capable of producing hangover and persistent
psychomotor impairment. For example, amobarbital was once extensively used as a hypnotic but is no longer
commercially available for oral dosing as a hypnotic (although it remains available in Tuinal, a combination of
amobarbital and secobarbital) because of excessive daytime sedation. Even amobarbital, however, still finds
clinical application as a parenteral formulation when used in the “ intracarotid amobarbital procedure” to
determine lateralization of language and memory before surgery.
一般的な説明
The barbiturates were used extensively as sedative–hypnoticdrugs. Except for a few specialized uses, they have beenreplaced largely by the much safer benzodiazepine.Barbiturates act throughout the CNS. However, they exertmost of their characteristic CNS effects mainly by bindingto an allosteric recognition site on GABA
A receptors thatpositively modulates the effect of the GABAA receptor—GABA binding. Unlike benzodiazepines, they bind at differentbinding sites and appear to increase the duration of theGABA-gated chloride channel openings. In addition, bybinding to the barbiturate modulatory site, barbiturates canalso increase chloride ion flux without GABA attaching toits receptor site on GABAA. This has been termed a GABAmimetic effect. It is thought to be related to the profoundCNS depression that barbiturates can produce.
The barbiturates are 5,5-disubstituted barbituric acids.Consideration of the structure of 5,5-disubstituted barbituricacids reveals their acidic character. Those without methylsubstituents on the nitrogen have pK
a’s of about 7.6; thosewith a methyl substituent have pK
a’s of about 8.4. The freeacids have poor water solubility and good lipid solubility(the latter largely a function of the two hydrocarbon substituentson the 5-position, although in the 2-thiobarbiturates,the sulfur atom increases lipid solubility).
作用機序
The effects of the barbiturates is marked by a decrease in functional activities in the brain. At therapeutic
doses, the barbiturates enhance the GABAergic inhibitory response in a mechanism similar to that of the benzodiazepines (i.e., by influencing conductance at the chloride channel). At higher concentrations, the
barbiturates can potentiate the GABAA-mediated chloride ion conductance and enhance both GABA and
benzodiazepine binding. Therefore, the barbiturates and benzodiazepines display cross-tolerance, and this can
be seen with the barbiturates exhibiting weak anxiolytics and muscle relaxant properties. The barbiturate
binding site is different from the benzodiazepines and is believed to occur at the picrotoxin binding site on the
chloride channel. These drugs affect the transport of sugars and are noted for their ability to induce liver
microsomal enzymes that lead to an increased rate of biotransformation of many commonly used drugs,
including the barbiturates. The biochemical effects of these drugs have been summarized elsewhere.
Barbiturates lose their activities through metabolic transformations and redistribution. The metabolism of the
barbiturates takes place primarily in the liver, in the endoplasmic reticulum. After metabolism, the lipophilic
character of barbiturates decreases, and this is associated with a loss in depressant activity. Although not used
as a hypnotic, the metabolic pathway for mephobarbital is representative of the metabolic pathway
for the barbiturates. T
臨床応用
The barbiturates have a different pharmacological and binding profile from that of the benzodiazepines. They exert a depressant effect on the cerebrospinal axis and depress neuronal activity as well as skeletal muscle, smooth muscle, and cardiac muscle activity. Depending on the compound, dose, and route of administration, the barbiturates can produce different degrees of CNS depression and have found use as sedatives, hypnotics, anticonvulsants, or anesthetics. Currently, the barbiturates get minimal use as sedatives and hypnotics (especially compared to the benzodiazepines) because of higher toxicity. This is associated with their ability to cause greater CNS depression and their ability to induce many of the liver drug-metabolizing enzymes. In addition, the barbiturates cause tolerance and, often, dependence. Even with all these disadvantages, the barbiturates continue to find occasional clinical applications as sedatives and hypnotics. Their primary use, however, is as general anesthetics and as antiseizure drugs.
The barbiturates also cause a physical dependence different from the opioid narcotics. In an individual addicted
to barbiturates, the barbiturates should not be withdrawn abruptly but, rather, tapered slowly. Sudden
withdrawal of the barbiturates can precipitate extreme agitation and grand mal seizures. This can lead to a
spasm of the respiratory musculature, producing impaired respiration, cyanosis, and possibly, death. As a
rule, drug dependence is followed by tolerance, in which increasing doses are required to obtain the same
pharmacological effect. Because barbiturates cause tolerance and, often, dependence, their use as a hypnotic
rarely is justified.
barbiturate(s) 上流と下流の製品情報
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