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. Intravenous barbiturates have been used for neurosurgery due to the reduction in cerebral metabolic rate of oxygen consumption. For individuals with severe traumatic brain injury (TBI), high-dose barbiturates may be a consideration but are not indicated for prophylactic administration. In a review of practice in five European countries, about 20% of patients received barbiturates. In the treatment of refractory status epilepticus, a Cochrane Review found that thiopental was equally effective as propofol for control of seizure activity.
Thiopental was introduced in 1934 for induction of anesthesia for general anesthesia. Thiopental was the predominant IV anesthetic induction agent until its replacement by propofol. Because of its use in lethal injection protocols, the major supplier of thiopental in the US elected to discontinue production in 2011.
Methohexital has demonstrated safety and effectiveness for procedural sedation of short duration for cardioversion, pediatric outpatient surgery, emergency department fracture reduction, and sedation for elective intubation in neonates. Methohexital has preferential use in electroconvulsive therapy due to its longer seizure duration.
Barbiturates are linked to postsynaptic enhancement of GABA, interacting with alpha and beta subunits of the GABA receptor. Barbiturates increase chloride ion flux which results in GABA-induced post-synaptic inhibition. Phenobarbital and pentobarbital affect the GABA receptors with a dose-dependent response. At higher micromolar concentrations associated with anesthetic levels, these drugs directly activate chloride channels. Both barbiturates and benzodiazepines interact with GABA receptors, but barbiturates are unique in that they potentiate GABA receptors while increasing chloride ion influx.
Barbiturate classification is according to the duration of their action, IV formulations of thiopental and methohexital are in the ultrashort-acting class. The short and intermediate-acting have an effect lasting 2 to 6 hours. This classification includes sleeping pills pentobarbital, secobarbital, amobarbital, and butabarbital. Long-acting barbiturates have an effect of longer than 6 hours and include barbital and phenobarbital.
The German chemist Adolf von Baeyer synthesized barbituric acid (malonylurea)in 1864. The date of this discovery was December 4, the feast day of Saint Barbara which was the inspiration for the compound’s name. Barbituric acid was the basis of many other formulations patented by the Bayer company. Barbituric acid had no innate central nervous system activity, due it's 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. Amylobarbitone became the first intravenous anesthetic used in 1928.
The formulation of parenteral dosage forms came with the addition of sodium at the C2 position. Lipophilicity was enhanced by Volviler and Tabern with the addition of a sulfur group while replacing an oxygen atom, creating the thiobarbiturates in 1934. 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.
The R(+) isomer of many barbiturates produces excitatory effects, while the S(-) isomers produce more depressant effects.
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. The elimination half-life for thiopental is about 5 hours. Metabolism plays an insignificant role in patient-awakening after a single bolus. In low doses of 5mg/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. Age-related changes have been demonstrated in pharmacokinetics due to slower intercompartment clearance in the elderly, resulting in higher serum concentrations with smaller drug doses. In children, a shorter elimination half-time occurs due to greater hepatic clearance.
Phenobarbital has frequent use in the pediatric population; half-lives range between 59 to 182 hours. 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 a loading dose IV, followed by IV or enteral administration.
Both methohexital and thiopental may be administered rectally in pediatrics, particularly if the child is unable to a cooperative in IV needle insertion. This method is best suited in procedures of short duration such as radiology or dentistry.
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.
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.
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 1A2, 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.
For women taking phenobarbital as monotherapy, the drug has correlations with congenital defects in exposed infants.
When given in IV anesthetics, barbiturates will produce a reduction in blood pressure and increase in heart rate. Respiratory depression and apnea may occur.
Thiopental and thiamylal have been shown to release histamine, while methohexital and pentobarbital have minimal histamine release.
Extravasation of thiopental (a vesicant) may cause severe tissue necrosis. If extravasation occurs, treatment measures include hyaluronidase and phentolamine. Case reports of successful treatment also include topical application of eutectic mixture of local anesthetics (EMLA) along with the local injection of lidocaine.
The placental transfer occurs within 1 minute of administration. 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; in mothers who received methohexital was found in breastmilk at the highest levels 1 to 2 hours after an IV dose and undetectable 24 to 48 hours after an IV dose. For thiopental when used for induction of anesthesia for cesarean section, the highest level of thiopental in breast milk was in the first nursing after anesthesia, about .9mg/L 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.
Absolute contraindications for any barbiturate include status asthmaticus and acute and intermittent variegate porphyria.
Due to the abuse potential of barbiturates, restricted access started with the passage of the Federal Comprehensive Drug Abuse and Control Act of 1970. Barbiturates classify as Schedule II-IV based on their abuse potential.
Development of Tolerance and Dependence.
Tolerance is a gradual loss of effectiveness such that the dose has to be increased to maintain the same effect. This effect is explainable in part from enzyme induction in the liver. Animal models have demonstrated tolerance.
Withdrawal symptoms may occur: nervousness, tremor, agitation, and hypotension may develop 2 to 8 days after the abrupt discontinuation of barbiturates. Additionally, the patient may develop delirium or grand mal seizures.
Phenobarbital has a narrow therapeutic range of 10 to 30 mg/L, with 80mg/L reported as being fatal. A Cochrane review found no clear evidence of a benefit to routine serum monitoring of drug levels for antiepileptic drugs. Dose titration to control of seizures was found to be effective.
Acute barbiturate toxicity may occur as the result of an intentional or unintentional overdose. Barbiturates have a history of abuse, New York City Health Department data showed 8469 cases of barbiturate poisoning in the period between 1957 through 1963. Overdosage of phenobarbital symptoms includes CNS depression, respiratory failure, and hemodynamic instability. No antidote exists. Treatment of an overdose includes supportive care, activated charcoal, and urinary alkalinization. Case reports exist of successful treatment of overdosage with hemodialysis.
Barbiturates have historically been a widely prescribed class of drugs both in and out of the hospital. Benzodiazepines have largely replaced them when used for anti-anxiety or insomnia. IV anesthetic uses of barbiturates are minimal for two reasons:
Phenobarbital continues to be used as a second-line antiepileptic drug in the US and has frequent use in low-resource countries as a first-line drug due to its low cost. All healthcare workers including nurse practitioners who prescribe these agents must be fully aware of the side effects, misuse, drug-drug interactions, and the potential to develop physical dependence. Given the potential for severe adverse events including death, a pharmacist should verify the dosing, and perform a thorough medication reconciliation to ensure there are no drug interactions, in particular, additive effects. Further, the healthcare worker must know how to resuscitate the patient in case of an overdose.
Barbiturates are controlled substances; thus all DEA prescriptive requirements must be met.
|||Brodie MJ,Kwan P, Current position of phenobarbital in epilepsy and its future. Epilepsia. 2012 Dec; [PubMed PMID: 23205961]|
|||Kadiyala PK,Kadiyala LD, Anaesthesia for electroconvulsive therapy: An overview with an update on its role in potentiating electroconvulsive therapy. Indian journal of anaesthesia. 2017 May; [PubMed PMID: 28584345]|
|||Haddad SH,Arabi YM, Critical care management of severe traumatic brain injury in adults. Scandinavian journal of trauma, resuscitation and emergency medicine. 2012 Feb 3; [PubMed PMID: 22304785]|
|||Majdan M,Mauritz W,Wilbacher I,Brazinova A,Rusnak M,Leitgeb J, Barbiturates use and its effects in patients with severe traumatic brain injury in five European countries. Journal of neurotrauma. 2013 Jan 1; [PubMed PMID: 22950895]|
|||Prabhakar H,Kalaivani M, Propofol versus thiopental sodium for the treatment of refractory status epilepticus. The Cochrane database of systematic reviews. 2017 Feb 3; [PubMed PMID: 28155226]|
|||Sneyd JR, Thiopental to desflurane - an anaesthetic journey. Where are we going next? British journal of anaesthesia. 2017 Dec 1; [PubMed PMID: 29161390]|
|||Brown TC, Thiopentone and its challengers. Paediatric anaesthesia. 2013 Oct; [PubMed PMID: 23216953]|
|||Ruble JH, The [PubMed PMID: 25121632]|
|||Wood J,Ferguson C, Best evidence topic report. Procedural sedation for cardioversion. Emergency medicine journal : EMJ. 2006 Dec; [PubMed PMID: 17130605]|
|||Jones NE,Kelleman MS,Simon HK,Stockwell JA,McCracken C,Mallory MD,Kamat PP, Evaluation of methohexital as an alternative to propofol in a high volume outpatient pediatric sedation service. The American journal of emergency medicine. 2017 Aug; [PubMed PMID: 28330689]|
|||Miner JR,Biros M,Krieg S,Johnson C,Heegaard W,Plummer D, Randomized clinical trial of propofol versus methohexital for procedural sedation during fracture and dislocation reduction in the emergency department. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2003 Sep; [PubMed PMID: 12957974]|
|||Naulaers G,Deloof E,Vanhole C,Kola E,Devlieger H, Use of methohexital for elective intubation in neonates. Archives of disease in childhood. Fetal and neonatal edition. 1997 Jul; [PubMed PMID: 9279186]|
|||Chau PL, New insights into the molecular mechanisms of general anaesthetics. British journal of pharmacology. 2010 Sep; [PubMed PMID: 20735416]|
|||Löscher W,Rogawski MA, How theories evolved concerning the mechanism of action of barbiturates. Epilepsia. 2012 Dec; [PubMed PMID: 23205959]|
|||Martone CH,Nagelhout J,Wolf SM, Methohexital: a practical review for outpatient dental anesthesia. Anesthesia progress. 1991 Nov-Dec; [PubMed PMID: 1842156]|
|||Devenyi P,Wilson M, Barbiturate abuse and addiction and their relationship to alcohol and alcoholism. Canadian Medical Association journal. 1971 Feb 6; [PubMed PMID: 4924250]|
|||Cozanitis DA, One hundred years of barbiturates and their saint. Journal of the Royal Society of Medicine. 2004 Dec; [PubMed PMID: 15574863]|
|||Ho IK,Harris RA, Mechanism of action of barbiturates. Annual review of pharmacology and toxicology. 1981; [PubMed PMID: 6263177]|
|||Sorbo S,Hudson RJ,Loomis JC, The pharmacokinetics of thiopental in pediatric surgical patients. Anesthesiology. 1984 Dec; [PubMed PMID: 6507924]|
|||Stanski DR,Maitre PO, Population pharmacokinetics and pharmacodynamics of thiopental: the effect of age revisited. Anesthesiology. 1990 Mar; [PubMed PMID: 2310020]|
|||Burch PG,Stanski DR, The role of metabolism and protein binding in thiopental anesthesia. Anesthesiology. 1983 Feb; [PubMed PMID: 6824168]|
|||Stanski DR,Mihm FG,Rosenthal MH,Kalman SM, Pharmacokinetics of high-dose thiopental used in cerebral resuscitation. Anesthesiology. 1980 Aug; [PubMed PMID: 7416528]|
|||Homer TD,Stanski DR, The effect of increasing age on thiopental disposition and anesthetic requirement. Anesthesiology. 1985 Jun; [PubMed PMID: 4003792]|
|||Jalling B, Plasma concentrations of phenobarbital in the treatment of seizures in newborns. Acta paediatrica Scandinavica. 1975 May; [PubMed PMID: 1155069]|
|||Moffett BS,Weingarten MM,Galati M,Placencia JL,Rodman EA,Riviello JJ,Kayyal SY, Phenobarbital population pharmacokinetics across the pediatric age spectrum. Epilepsia. 2018 Jul; [PubMed PMID: 29897629]|
|||Hunter MJ,Griswold JD,Rosenberg M, Administration of methohexital for pediatric outpatient dentistry. Anesthesia progress. 1990 Sep-Oct; [PubMed PMID: 2096749]|
|||Carrel R,Binns WH Jr, Rectal pentothal sedation for selected patients. Anesthesia progress. 1975 Sep-Oct; [PubMed PMID: 1060389]|
|||Coté CJ,Goudsouzian NG,Liu LM,Dedrick DF,Rosow CE, The dose response of intravenous thiopental for the induction of general anesthesia in unpremedicated children. Anesthesiology. 1981 Dec; [PubMed PMID: 7305061]|
|||Nevitt SJ,Sudell M,Weston J,Tudur Smith C,Marson AG, Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. The Cochrane database of systematic reviews. 2017 Jun 29; [PubMed PMID: 28661008]|
|||Brodie MJ,Mintzer S,Pack AM,Gidal BE,Vecht CJ,Schmidt D, Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia. 2013 Jan; [PubMed PMID: 23016553]|
|||Hirshman CA,Edelstein RA,Ebertz JM,Hanifin JM, Thiobarbiturate-induced histamine release in human skin mast cells. Anesthesiology. 1985 Oct; [PubMed PMID: 2412468]|
|||Le A,Patel S, Extravasation of Noncytotoxic Drugs: A Review of the Literature. The Annals of pharmacotherapy. 2014 Jul; [PubMed PMID: 24714850]|
|||Mao CC,Hsieh YC,Hseu SS,Tsai SK,Lee TY, EMLA cream and lidocaine local injection in the treatment of extravenous thiopental injection--a case report. Acta anaesthesiologica Sinica. 1997 Jun; [PubMed PMID: 9293651]|
|||Methohexital 2006; [PubMed PMID: 30000358]|
|||Thiopental 2006; [PubMed PMID: 30000360]|
|||Phenobarbital 2006; [PubMed PMID: 30000331]|
|||Gabay M, The federal controlled substances act: schedules and pharmacy registration. Hospital pharmacy. 2013 Jun; [PubMed PMID: 24421507]|
|||Hoyland K,Hoy M,Austin R,Wildman M, Successful use of haemodialysis to treat phenobarbital overdose. BMJ case reports. 2013 Nov 21; [PubMed PMID: 24265338]|
|||Tomson T,Dahl ML,Kimland E, Therapeutic monitoring of antiepileptic drugs for epilepsy. The Cochrane database of systematic reviews. 2007 Jan 24; [PubMed PMID: 17253477]|
|||BUCOVE A, MISUSE OF VALUABLE THERAPEUTIC AGENTS: BARBITURATES, TRANQUILIZERS, AND AMPHETAMINES. Bulletin of the New York Academy of Medicine. 1964 Dec; [PubMed PMID: 14232143]|