Pentobarbital toxicity

Death from overdose of barbiturates may occur and is more likely when more than 10 times the hypnotic dose is ingested. The barbiturates with high lipid solubility and short half-lives are the most toxic. Thus the lethal dose of phenobarbital is 6—10 g, whereas that of secobarbital, pentobarbital, or amo-barbital is 2-3 g. Symptoms of barbiturate poisoning include CNS depression, coma, depressed reflex activity, a positive Babinski reflex, contracted pupils (with hypoxia there may be paralytic dilation), altered respiration, hypothermia, depressed cardiac function, hypotension, shock, pulmonary complications, and renal failure. 

Barbiturates. The hrst barbiturate, barbital, was introduced in 1903 and was followed a few years later by phenobarbital. The barbiturates effectively relieve anxiety, but they are never used as anxiolytics today due to toxicity and abuse concerns. However, several barbiturates, including phenobarbital (Luminal), secobarbital (Seconal), and pentobarbital (Nembutal), remain available and are occasionally used to treat epilepsy and rarely to manage acute alcohol withdrawal. 

Before the introduction of the benzodiazepines, a number of drugs from different chemical and pharmacological classes were used in the treatment of anxiety and insomnia. However, these drugs are more toxic and produce more serious side effects than do the benzodiazepines. Many also have signihcant abuse potential. Consequently, most of these compounds are no longer widely used. These drugs include the barbiturates (e.g., pentobarbital, amobarbital), carbamates (e.g., meprobamate), piperidinediones (e.g., glutethimide), and alcohols (e.g., ethchlorvynol). 

Two mechanisms help protect the fetus from drugs in the maternal circulation (1) The placenta itself plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it. Several different types of aromatic oxidation reactions (eg, hydroxylation, /V-dealkylation, demethylation) have been shown to occur in placental tissue. Pentobarbital is oxidized in this way. Conversely, it is possible that the metabolic capacity of the placenta may lead to creation of toxic metabolites, and the placenta may therefore augment toxicity (eg, ethanol, benzpyrenes). (2) Drugs that have crossed the placenta enter the fetal circulation via the umbilical vein. 

The S enantiomer of hexobarbital possesses three- to fourfold greater hypnotic activity than its antipode (4). However, in the elderly population, the clearance of R-hexobarbital, but not that of S-hexobarbital, is substantially reduced (23). Administration of the S enantiomer, therefore, will produce a more predictable clearance than that of the racemate. Also, as the safety profile of the less active enanticaner is unknown, one cannot rule out the possibility of its involvement in the overall toxicity of hexobarbital. For a related barbiturate, pentobarbital, it has been suggested that despite its weaker pharmacological activities, sedation with the R enantiomer is accompanied by symptrans of hyperexcitability (24). 

LEE with chloroform from acidified serum is widely executedafter the method of Shiu and Nemoto. However, chloroform is of great toxicity and is not suitable for routine use. LLE with pentane at pH 6.4 was investigated for feasibility with seven barbiturates and was found to be specific for thiopental—an important barbiturate being used for anaesthetic medication and treatment of head trauma with severe brain injury. Comparing acetonitrile deproteinization with chloroform deproteinization, Shihabi demonstrated the feasibility of acetonitrile for extraction of pentobarbital. However, electropherograms obtained by extraction with chloroform are more sensitive and cleaner.Wu et al. used LLE with ether for extraction from serum, and chloroform for extraction from urine. They obtained recoveries of six barbiturates from 86.6% to 118%. 

The effect of proteins on pollutant toxicity includes both quantitative and qualitative aspects. Experiments show that animals fed proteins of low biological value exhibited a lowered microsomal oxidase activity when dietary proteins were supplemented with tryptophan, the enzyme activity was enhanced. Alteration of xenobiotic metabolism by protein deprivation may lead to enhanced or decreased toxicity, depending on whether metabolites are more or less toxic than the parent compound. For example, rats fed a protein-deficient diet show decreased metabolism but increased mortality with respect to pentobarbital, parathion, malathion, DDT, and toxaphene (Table 6.4). On the other hand, rats treated under the same conditions may show a decreased mortality with respect to heptachlor, CC14, and aflatoxin. It is known that, in the liver, heptachlor is metabolized to epoxide, which is more toxic than heptachlor itself, while CC14 is metabolized to CC13, a highly reactive free radical. As for aflatoxin, the decreased mortality is due to reduced binding of its metabolites to DNA. 

The low concentration of protein in the interstitial fluid has been suggested as another factor which may reduce the distribution of some substances in the central nervous system. Lipid soluble compounds, such as methyl mercury which is toxic to the central nervous system (see Chapter 7). can enter the brain readily, the facility being reflected by the partition coefficient. Another example which illustrates the importance of the lipophilicity in the tissue distribution and duration of action of a foreign compound is afforded by a comparison of the drugs thiopental and pentobarbital (figure 3,5). These drugs are very similar in structure, only differing by one atom. Their pKa values are similar and consequently the... 

Solaphyllidine (325) and desacetylsolaphyllidine (326) were examined for their biological effects in mice [686]. The two alkaloids exhibited comparable toxicity (LD50 = 14.5, 12 mg/kg). Both 325 and 326 decreased pentobarbital-induced sleeping time, while 325 increased locomotor activity [686]. 

The toxic action of cocaine can be combated by barbital curatively (143) or preventively (144), but this is scarcely seen to be effective in the clinic (145). Steinhaus and Tatum (146), however, stated that pentobarbital in doses of 15 mg./kg., when given intravenously, affords protection against 100 mg./kg. of cocaine injected subcutaneously. The toxicity of cocaine injected into the venous system depends upon the speed with which it is introduced into the organism. If this speed is great the cardiovascular system is affected before the respiration, but if it is slow the contrary is seen, as is the case for subcutaneous injections. 

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