Pentobarbital

Phenobarbital is a barbiturate used mainly for its antiepileptic properties. It is given by mouth or parenterally, as the base or the sodium salt. It induces liver enzymes and alters the metabolism of a number of other drugs. Sedation is common but tends to become less of a problem as phenobarbital antiepileptic treatment continues.

Phenobarbital acts as a nonselective depressant of the central nervous system capable of producing all levels of CNS mood alteration from excitation to mild sedation, hypnosis and deep coma. In sufficiently high doses, barbiturates induce anaesthesia.

Recent studies have suggested that the sedative-hypnotic and anticonvulsant effects of barbiturates may be related to their ability to enhance and/or mimic the inhibitory synaptic action of gamma-aminobutyric acid (GABA).

Sedative-hypnotic: Barbiturates depress the sensory cortex, decrease motor activity, alter cerebral function, and produce drowsiness, sedation and hypnosis. Although the mechanism of action has not been completely established, the barbiturates appear to have a particular effect at the level of the thalamus where they inhibit ascending conduction in the reticular formation, thus interfering with the transmission of impulse to the cortex.

Anticonvulsant: Barbiturates are believed to act by depressing monosynaptic and polysynaptic transmission in the CNS. They also increase the threshold for electrical stimulation of the motor cortex.

Antihyperbilirubinemic: Phenobarbital lowers serum bilirubin concentrations probably by induction of glucuronyl transferase, the enzyme which conjugates bilirubin.

Other actions/effects

Barbiturates have little analgesic action at sub-anesthetic doses and may increase reaction to painful stimuli.

Although Phenobarbital, mephobarbital, and metharbital are the only barbiturates effective as anticonvulsants in sub-hypnotic doses, all of the barbiturates exhibit anticonvulsant activity in anesthetic doses.

Barbiturates are respiratory depressants; the degree of respiratory depression is dosedependent.

Barbiturates have been shown to reduce the rapid eye movement (REM) phase of sleep or dreaming stage. Also, Stages III and IV sleep (slow-wave sleep, SWS) are decreased.

Animal studies have shown that barbiturates cause reduction in the tone and contractility of the uterus, ureters, and urinary bladder; however, concentrations required to produce this effect in humans are not attained with sedative-hypnotic doses.

Barbiturates have been shown to induce liver microsomal enzymes, thereby increasing and altering the metabolism of other medications or compounds.

Absorption

Phenobarbital is readily absorbed from the gastro-intestinal tract, although it is relatively lipid-insoluble and may require and hour or longer to achieve effective concentrations. Phenobarbital is about 45% bound to plasma proteins and is only partly metabolised in the liver. About 25% of a dose is excreted in the urine unchanged at normal urinary pH. The plasma half-life is about 90 to 100 hours in adults but is greatly prolonged in neonates, and shorter (about 65 to 70 hours) in children. There is considerable inter-individual variation in Phenobarbital kinetics.

Monitoring of plasma concentrations has been performed as an aid in assessing control and the therapeutic range of plasma-Phenobarbital is usually quoted as being 10 to 40 mcg per ml (43 to 172 micromoles per litre)

Phenobarbital crosses the placental barrier and small amounts are excreted in breast milk.

The rate of absorption is increased if barbiturates are taken well diluted or on an empty stomach.

Distribution

Rapidly distributed to all tissues and fluids with high concentrations in the brain, liver, and kidneys.

Lipid solubility is the primary factor in distribution within the body. The more lipid soluble the barbiturate, the more rapidly it penetrates all tissues of the body; phenobarbital has the lowest lipid solubility and secobarbital the highest.

Biotransformation

Hepatic, primarily by the hepatic microsomal enzyme system. About 75% of a single oral dose of mephobarbital is metabolized to Phenobarbital in 24 hours.

Metharbital is metabolized to barbital.

Onset of action

Oral – Varies from 20 to 60 minutes.

Therapeutic serum concentration

Anticonvulsant – Phenobarbital: 10 to 40 mcg per mL (43 to 172 micromoles/L).

Note: The optimal blood Phenobarbital concentration should be determined by response in seizure control and the appearance of toxic effects.

To achieve blood concentrations considered therapeutic in children, higher-per-kg dosages of Phenobarbital and most other anticonvulsants generally are required.

Animal toxicology and/or pharmacology

Published studies in animals demonstrate that the use of anaesthetic and sedative agents during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of an anaesthetic regimen that produced a light surgical plane of anaesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

In a published study conducted on rhesus monkeys, administration of an anaesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the foetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring of rhesus macaques. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits. Healthcare providers should balance the benefits of appropriate anaesthesia in pregnant women, neonates and young children who require procedures with the potential risks suggested by the nonclinical data.