Barbiturates

Barbiturates are a group of sedative-hypnotic medications used for the treatment of seizure disorder, neonatal withdrawal, insomnia, preoperative anxiety, induction of coma for increased intracranial pressure. They are also useful for inducing anesthesia.

Phenobarbital has extensive use as an antiepileptic drug in the neonatal and pediatric population. It is the most cost-effective drug treatment for epilepsy in adults in low resource countries.[1] Intravenous barbiturates have been used for neurosurgery due to the reduction in cerebral metabolic rate of oxygen consumption.[2] For individuals with severe traumatic brain injury (TBI), high-dose barbiturates may be a consideration but are not indicated for prophylactic administration.[3]  In a review of practice in five European countries, about 20% of patients received barbiturates.[4] In the treatment of refractory status epilepticus, a Cochrane Review found that thiopental was equally effective as propofol for control of seizure activity.[5]

Thiopental was introduced in 1934 for induction of anesthesia for general anesthesia.[6] Thiopental was the predominant IV anesthetic induction agent until its replacement by propofol.[7] Because of its use in lethal injection protocols, the major supplier of thiopental in the US elected to discontinue production in 2011, and thus it is not available in the USA.[8]

Methohexital has demonstrated safety and effectiveness for procedural sedation of short duration for cardioversion,[9] pediatric outpatient surgery,[10] emergency department fracture reduction,[11] and sedation for elective intubation in neonates.[12] Methohexital has preferential use in electroconvulsive therapy due to its longer seizure duration.[2]

Barbiturates cause postsynaptic enhancement of GABA, interacting with alpha and beta subunits of the GABA-A receptor.[13]  Barbiturates increase chloride ion flux which results in GABA-induced post-synaptic inhibition. Phenobarbital and pentobarbital affect the GABA-A receptors with a dose-dependent response.   At higher micromolar concentrations associated with anesthetic levels, these drugs directly activate chloride channels.[14] Both barbiturates and benzodiazepines interact with GABA-A receptors, but barbiturates are unique in that they potentiate GABA-A receptors while increasing chloride ion influx even with very low concentrations of the GABA neurotransmitter.[15]

Barbiturate classification is according to the duration of their action, IV formulations of thiopental and methohexital are in the ultra short-acting class.  The short and intermediate-acting have an effect lasting 2 to 6 hours.  This classification includes sleeping medications pentobarbital, secobarbital, amobarbital, and butabarbital.  Long-acting barbiturates have an effect of longer than 6 hours and include barbital and phenobarbital.[16]

Structure-Activity Relationships

The German chemist Adolf von Baeyer synthesized barbituric acid (malonylurea)in 1864.[14]  The date of this discovery was December 4, the feast day of Saint Barbara which was the inspiration for the compound’s name.[17]  Barbituric acid was the basis of many other formulations patented by the Bayer company. Barbituric acid had no innate central nervous system activity, due to its lack of lipophilicity. A lipophilic derivative of barbituric acid was developed (barbital: 5,5-diethylbarbituric acid) and was successfully used to induce sleep in dogs.[14] Amylobarbitone became the first intravenous anesthetic used in 1928.[17]

The formulation of parenteral dosage forms came with the addition of sodium at the C2 position.[17] Lipophilicity was enhanced by Volviler and Tabern with the addition of a sulfur group while replacing an oxygen atom, creating the thiobarbiturates in 1934.[17]  In 1957 Methohexital was created by Stoelting with the addition of an aliphatic side chain at carbon 5, along with methylation of the nitrogen atom.[15]

The R(+) isomer of many barbiturates produces excitatory effects, while the S(-) isomers produce more depressant effects.[18]

Pharmacokinetics

Ultrashort-acting IV Barbiturates

Terminating the effect of a single bolus IV injection of thiopental occurs by redistribution from the central compartment to peripheral compartments and takes about 2 to 4 minutes.[19]  The elimination half-life for thiopental is about 5 hours.[20] Metabolism plays an insignificant role in patient-awakening after a single bolus.[21] In low doses of 5 mg/kg boluses, thiopental observes first-order kinetics.  In high-dose or prolonged infusions, non-linear kinetics will occur due to the progressive saturation of enzyme systems.[22] Age-related changes have been demonstrated in pharmacokinetics due to slower intercompartment clearance in the elderly[21], resulting in higher serum concentrations with smaller drug doses.[23]  In children, a shorter elimination half-time occurs due to greater hepatic clearance.[19]

Phenobarbital has frequent use in the pediatric population; half-lives range between 59 to 182 hours.[24] With organ maturation, variations may occur in clearance, so that frequent determinations of drug concentration are necessary.

When administered as an antiepileptic drug for pediatric patients, phenobarbital may be given as an IV loading dose, followed by IV or oral administration.[25]

Both methohexital and thiopental may be administered rectally in pediatrics, particularly if the child is unable to cooperate with IV needle administration. This method is best suited in procedures of short duration such as radiology or dentistry.[26][27]

When using the IV route of administration in pediatrics wide variation in the required dose has been noted.  Cote recommended a higher dose range for unpremeditated children.[28]

The indication for use typically determines the route of administration for adults. Maintenance therapy for antiepileptic drugs in adults is typically the oral route; other first-line drugs have replaced phenobarbital.[29]

Barbiturates administered for the induction of anesthesia in adults are most commonly given as an IV bolus for a rapid and pleasant loss of consciousness.

Drug interactions with oral barbiturates have been a frequent topic of research. Phenobarbital is known to be an inducer of the cytochrome enzyme system, specifically the CYP1A2, 2B6, 2C9 and 3A4/5 isozymes that will reduce the efficacy of warfarin, steroids, oral contraceptives, psychoactive, immunosuppressants. Phenobarbital will also lower the plasma concentrations other antiepileptic drugs such as lamotrigine, oxcarbazepine, phenytoin, tiagabine, valproate.[30]

For women taking phenobarbital as monotherapy, the drug has correlations with congenital defects in exposed infants.[1]

When given in IV anesthetics, barbiturates will produce a reduction in blood pressure and an increase in heart rate. Respiratory depression and apnea may occur.[15]

Thiopental and thiamylal have been shown to release histamine, while methohexital and pentobarbital have minimal histamine release.[31]

Extravasation of thiopental (a vesicant) may cause severe tissue necrosis. If extravasation occurs, treatment measures include hyaluronidase and phentolamine.[32] Case reports of successful treatment also include topical application of a eutectic mixture of local anesthetics (EMLA) along with the local injection of lidocaine.[33]

The placental transfer occurs within 1 minute of administration.[15] Neonatal depression may occur if used as an induction agent for cesarean section.

Breastfeeding concerns: Limited data is available.  Concerning the short-acting IV barbiturates; mothers who received methohexital were found in breastmilk at the highest concentrations 1 to 2 hours after an IV dose and undetectable 24 to 48 hours after an IV dose.[34]  For thiopental when used for induction of anesthesia for cesarean section, the highest concentration of thiopental in breast milk was in the first nursing after anesthesia, about 0.9 mg/L[35] Data on the effects of phenobarbital show that there is inter and intrapatient variability of excretion into breastmilk. In a series of breastfeeding infants, for each mg/kg of phenobarbital taken by mothers, the infant’s serum concentration increased by 2 to 5 mg/L.  Several case reports exist of infant sedation occurring in mothers treated with phenobarbital.[36]

Absolute contraindications for any barbiturate include status asthmaticus and acute and intermittent variegate porphyria.[15]