Action of Barbiturates

In general, the hypnotics may act in two different ways, namely first by exerting their action on the sensory eortex raising the threshold at which it responds to afferent stimuli secondly, they may interfere with the passage of impulses from the subsidiary centre or eentres in the hypothalamus to the cortex. In other words, barbiturates act on the central synaptic transmission process of the reticular 

In normal human being the cerebral electrical activity is directly proportional to anxiety, emotional excitement, or administration of a potent central nervous system stimulant e.g., caffeine, dexamphetamine, lysergic acid diethylamide LSD to name a few). At this juneture the administration of a reasonably overdose of barbiturates would cause a calming effect, which could be measured demonstrably with the help of an electroencephalogram, (EEG). Thus, barbiturates depress the reticular activating system by impairing the synaptic transmission. 

The pharmacological effects of the barbiturates is invariably marked by a decrease with regard to the normal functional activities in the brain. It has been duly observed that at the prevailing therapeutic dose levels in vivo the barbiturates cause a distinct marked enhancement of the GABAergic inhibitory response, in a mechanism very much akin to that shown by the benzodiazepines, that is, by influencing conductance at the site of chloride channel. It is pertinent to mention here that at comparatively higher concentration barbiturates would display six marked and pronounced pharmacological actions  

Barbiturates, also eflfeet the transportation of carbohydrates, and are observed to enhanee the activity of liver microsomal enzymes, responsible for the regulatory mode of several drug substanees via biotransformation. 

In short, it has been advocated, though not yet proven experimentally, that the BZ2 subclass of the benzodiazepines is solely responsible for attributing the sedative-hypnotic activity whereas the BZj subclass specific compounds would be non sedative in character.  

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The purpose of this paper is to give some of the results obtained in a study of the antidotal action of barbiturates in chlordan poisoning, and of the metabolic fate of chlordan. 

Table 1. Antidotal Action of Barbiturates in Chlordan Poisoning in Rabbits...

By far, the biggest class of hypnotic drugs are derivatives of barbituric acid. The action of barbiturates is reliable and reprodueible, they are easy to administer and offer a wide range of activity. 

Hypnotics fall into different categories, including the benzodiazepines (e.g., triazolam, temazepam, clotiaze-pam, nitrazepam), barbiturates (e.g., hexobarbital, pentobarbital), chloral hydrate, and Hi-antihistamines with sedative activity (p. 114). Benzodiazepines act at specific receptors (p. 226). The site and mechanism of action of barbiturates, antihistamines, and chloral hydrate are incompletely understood. 

Ian Oswald is to be considered a pioneer in this field of research, having taken up sleep polygraphic investigations of the action of barbiturates, amphetamines, antidepressants, benzodiazepines and other substances in the early 1960s (Oswald, 1968). He and others found that almost all psychotropic... 

Similar to serotonin, the Rauwolfia alkaloids potentiate the action of barbiturates and alcohol. This potentiating action is mediated through serotonin. The alkaloids also exert an antiveratrinic and antiarrhythmic action on the isolated heart. 

The barbiturates were used extensively in the past as hypnotic sedatives, but have been replaced by the much safer benzodiazepine derivatives. They do continue to be used as anesthetics and as anticonvulsants. The primary mechanism of action of barbiturates is to increase inhibition through the GABA system. Anesthetic barbiturates also decrease excitation via a decrease in calcium conductance. 

In addition, the sleep-producing action of barbiturates is used to relax and partially anesthetize patients before some surgical procedures. Before some major brain surgeries, barbiturates (usually pentobarbital or thiopental) are used to temporarily induce coma in an effort to protect the brain these drugs can reduce the metabolic rate of brain tissue and control cerebral blood flow. 

Smith AG and Margolis G (1954) Camphor poisoning Anatomical and pharmacologic study report of a fatal case experimental investigation of protective action of barbiturate. American Journal of Pathology 30 857-868. 

A study of the effects of highly purified optical isomers of several barbiturates (hexobar-bital, pentobarbital, and thiopental) showed the S-enantiomers to be about two to four times more potent than the R-enantiomers in the potentiation of GABA-induced ion currents (134). These results support a direct action of barbiturates at the receptor level as opposed to non-specific effects on membranes. 

Structural features of the barbiturate molecule which are required for its hypnotic, convulsant, and/or anticonvulsant properties have been summarized by Vida and Gerry,381 and numerous studies were devoted to physiological effects and pharmacological mechanisms of action of barbiturates in relation to chemical and stereochemical factors. Some recent articles and reviews are suggested on this fascinating and still incompletely elucidated subject.382 Clearly, the history of barbiturates383 has many paragraphs yet to be written. 

Amobarbital, a barbiturate, is used as a sedative to treat insomnia and as a preanesthetic medication. The barbiturates were used extensively in the past as hypnotic-sedatives but have been replaced by the much safer benzodiazepine derivatives (see Table 9). They do continue to be used as anesthetics (e.g., thiopental) and anticonvulsants (e.g., phenobarbital). The primary mechanism of action of barbiturates is to increase inhibition through the gamma-aminobutyric acid (GABA) system (see Figure 50). Anesthetic barbiturates also decrease excitation via a decrease in calcium conductance. The most commonly used barbiturates are thiopental (Pentothal), methohexital (Brevital), secobarbital (Seconal), pentobarbital (Nembutal), amobarbital (Amytal), and phenobarbital (Luminal). 

Barbiturates bind to barbiturate receptors on the chloride channel (see Figure, question 5). Activation of the receptor potentiates the effects of GABA, and increases chloride flux across the neuronal membrane, causing partial hyperpolarization of the neuronal membrane, and decreased conduction. Because the barbiturate receptor is adjacent to both the benzodiazepine receptor and GABA receptor on the channel, the action of barbiturates enhances not only the binding of GABA to its receptor, but the receptor binding of benzodiazepines as well. 

Knoll R. Selective actions of barbiturates on synaptic transmission. In Lipton MA, DiMascio A, Killam AF, eds. Psychopharmacology A Generation of Progress. New York Raven Press, 1978 1337-1348. 

Although the action of barbiturates on the biosynthetic chain to at least two phospholipids is apparently at a point subsequent to the phosphorylation of the base, an investigation of later stages (Fig. 2) proved difficult because of the low concentration of the cytidine nucleotides in the brain (Nelson and Barnum, 1960 Ansell and Bayliss, 1961). This investigation should be possible in vitro and has been carried out for chlorpromazine (Section III, B). Although no experiments have apparently been carried out on the effect of barbiturates on the biosynthesis of cytidine nucleotides in vitro, studies have been made on the transfer of P 2-orthophosphate to phospholipids. This transfer presumably involves cytidine nucleotides for certain phospholipids. Strickland (1954) found that 4 X 10 M Chloretone (l,l,l-trichloro-2-methyl-2-pro-... 

Good relationships between the retention in MLC and some biological activities of local anesthetics (bupivacaine, lidocaine, mepiva-caine, prilocaine, procaine and tetracaine), such as anesthetic potency, concentration of compound that produces an effect similar to a reference concentration of cocaine, duration of the action, toxicity and time taken to eliminate half the drug present in the body, have also b n reported [24]. Some anesthetic actions of barbiturates also correlated well with the retention minimum effective hypnotic dose in rabbits, molar drug concentration necessary to reduce cell division, and molar drug concentration required to reduce 50% the inhibition of oxygen respiration on the brain of a rat in vitro [25],... 

N. B. Bromide of 2-amino-3-(l-adamantylcarb-onylmethyl)-l-methylbenzimidazolium, that manifests the psycho-stimulating, anti-cataleptic activity and possessing the ability to shorten the soporific action of barbiturates. USSR Claim JV° 1108737, JV 3570487/23-04, 31.03.83, published. 15.11.90. bulletin. 42. 

From time to time, attempts have been made to find some individuality in the hypnotic action of barbiturates, such as would exclude them from the class of general depressants. However, no acceptable evidence has been presented that would separate them from the general class. The small amount of ionization of which they are capable actually hinders their action a little (Mautner and Clemson, 1970 3 Hansch and Anderson, 1967)-... 

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