Barbiturates metabolism/excretion

B arbitur ates are metabolized in the liver via hydroxylation and glucuronide conjugation. Short-acting barbiturates are excreted in the urine as metabolites for about one to four days, while long-acting barbiturates are excreted for two to three weeks. 

Table VI lists several drugs Inducing hepatic microsomal enzymes (5). These enzymes can metabolize the drug as well as other substrates. Barbiturates, grlseofulvln, and glutethlmlde Induce enzymes which metabolize coumarln and phenlndlone derivatives and thus reduce their anticoagulant activity. Dlphenylhydantoln and phenylbutazone stimulate cortisol hydroxylase activity and Increase the urinary excretion of B-hydroxy cortisol and decrease the concentration of cortisol In the plasma.

An alternative process that can lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excreted products. The role that metabolism plays in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates such as thiopental and pentobarbital would have extremely long half-lives if it were not for their metabolic conversion to more water-soluble compounds. 

The inactive metabolites are excreted in the urine. The administration of bicarbonate enhances the urinary excretion of barbiturates that have a pK of 7.4 (phenobarbital and thiopental). This generalization is not true of other barbiturates. The long-term administration of barbiturates activates the cytochrome P-450 drug-metabolizing system. 

Barbiturates are absorbed orally and distributed widely throughout the body. All barbiturates redistribute in the body from the brain to the splanchnic areas, to skeletal muscle, and finally to adipose tissue. This movement is important in causing the short duration of action of thiopental and similar short-acting derivatives (see p. 115). Barbiturates are metabolized in the liver, and inactive metabolites are excreted in the urine. 

Most of the common barbiturates contain a 5-ethyl substituent and some may contain 5,5-diethylbarb-ituric acid (barbitone) as an impurity. The presence of this compound at a concentration of only 1 to 2% can produce unexpected results. For example, if amylobarbitone containing 1% of barbitone as an impurity caused coma in an overdose complicated by renal failure, the barbitone would form a higher percentage in the blood. This is because amylobarbitone is removed by rapid metabolism in the liver, but barbitone is eliminated more slowly by renal excretion. In the case of coma with renal function being maintained, barbitone would be a major fraction of the barbiturate excreted in the urine in some cases the concentration has been so high that it has been regarded as a metabolite. 

Treatment involves sedating the patient and keeping them in a darkened room isolated from external stimuli. This is because the slightest noise or touch can be followed by a violent movement or convulsion. Sometimes an anaesthetic, such as ether or chloroform, was used to stop this reaction, but barbiturates seem more effective and are preferred. Helping the victim to survive the convulsions allows the body to metabolize and excrete the toxin. 

Succinylcholine is an ultra-short-acting depolarizing skeletal muscle relaxant. The neuromuscular block remains for as long as sufficient quantities of succinylcholine remain. After i.v. administration, the onset of action is typically within Imin and lasts for 2-3 min. Succinylcholine is metabolized by plasma cholinesterases to choline and the weakly active succinylmono-choline, which is primarily excreted in the urine (Plumb 1995). Succinylcholine should be administered i.v. at a dose rate of 0.088mg/kg (Plumb 1995). Succinylcholine can also be added to an overdose of barbiturate to produce euthanasia in horses. This is accompanied by a minimal amount of postmortem muscular contraction, making the addition of succinylcholine desirable for use during euthanasia when the client is present. 

Phenobarbital is absorbed rapidly and well after oral administration to horses, with bioavailability approaching 100% (Ravis et al 1987). It is distributed widely into the tissues but, because of its lower lipid solubility, does not distribute into the CNS as rapidly as other barbiturates. After i.v. administration, it may take 15-20 min before therapeutic concentrations of phenobarbital are reached in the CNS. Phenobarbital primarily undergoes hepatic metabolism and only 25% is excreted as unchanged drug. The half-lives reported in horses, around 18-24 h (Duran et al 1987, Knox et al 1982, Ravis et al 1987) and 12 h in foals (Spear et al 1984), are substantially shorter than in other species, meaning that steady-state concentrations can be achieved more rapidly. 

Medications can cross the placenta and have an adverse effect on the fetus. The fetus has an immature metabolism and a slow excretion rate that can cause a pooling of the medication. Depending on the physiological effect of the medication, the fetus can be addicted to the medication and go through withdrawal after birth. This can occur with alcohol, barbiturates, and narcotics. 

Oxidation of substituents attached to C5 is the most important pathway of metabolism for the barbiturates. The oxidative processes may yield alcohols, ketones, and carboxylic acids. For example, pentobarbital is oxidized to a hydroxy compound and a carboxylic acid (8) as shown in Fig. 5.2. The oxidative process may also yield phenols. If the barbiturate has a phenyl group attached to C5, by far the most important metabolic product is the p-hydroxyphenyl derivative, which has been shown to be formed through the intermediate epoxide (9). For example, phenobarbital is metabolized top-hydroxyphenobarbital (Fig. 5.3). The oxygenated metabolites (alcohols, phenols, ketones, and carboxylic acids) may be excreted in the urine in the free form or conjugated with glucuronic or sulfuric acid. 

Elimination. Barbiturates are eliminated from the body both by hepatic metabolism and by renal excretion. In the liver, phenobarbital is parahydroxylated and subsequently conjugated to glucuronic acid. 

Phenobarbital is metabolized by CyP 2C19 to p-hydroxy-phenobarbital, which is largely excreted as the glucuronide (by UGT). When renal and hepatic function are decreased, patients experience decreased clearance of the drug. Alcohol, carbamazepine, other barbiturates, and rifampin induce oxidative enzymes (CyP 2C19 and 2C9) this induction results in increased metabolism of phenytoin, reduced serum concentration of phenobarbital, and a reduced pharmaco-... 

The barbiturates undergo extensive hepatic metabolism in which the C5 substituents are transformed to alcohols, phenols, ketones, or carboxylic acids these metabolites may be excreted in urine in part as glucuronide conjugates. For some barbiturates (amobarbital and phenobarbital), N-glucosylation is an additional important metabolic trans-... 

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