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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Barbiturates

Last Update: October 3, 2021.

OVERVIEW

Introduction

Barbiturates are structurally related compounds with sedative and hypnotic activities, some of which (phenobarbital and mephobarital) are also used as anticonvulsants. Phenobarbital has been clearly linked to cases of idiosyncratic acute liver injury, resembling the immunoallergic hepatotoxicity of other aromatic anticonvulsants such as phenytoin and carbamazepine. In contrast, the other conventional sedative barbiturates have not been linked to serum enzyme elevations during therapy and clinically apparent acute liver injury due to the sedative barbiturates is extremely rare, if it occurs at all.

Background

Barbiturates are a family of compounds that have sedative and hypnotic activities and act as nonselective central nervous system (CNS) depressants. The barbiturates were introduced into medical practice in the early 20th century, used as a sleeping aid and in treatment of schizophrenia. However, with chronic use they often cause psychological and physical dependence and have serious adverse effects, including agitation, respiratory depression and daytime somnolence. Phenobarbital (fee" noe bar' bi tal) given in lower doses was found to have anticonvulsant activity and has been used extensively as an anticonvulsant, particularly in children. Phenobarbital appears to act by suppression of spread of seizure activity by enhancing the effect of gamma aminobutyric acid (GABA). Phenobarbital has been linked to instances of acute liver injury and is discussed separately as an anticonvulsant. The barbiturates that are used as sedatives and hypnotics, in contrast, have not been linked to cases of acute or chronic liver injury and are discussed together below.

Amobarbital, pentobarbital and secobarbital are used as sedatives and hypnotics and not as anticonvulsants. These and many other synthetic barbiturates were introduced into medical use in the United States in the early part of the 20th century as sedatives, hypnotics (short term treatment of insomnia) and preanesthetic agents. They are now rarely used, having been replaced by more effective and better tolerated sedatives and hypnotics such as the benzodiazepines and benzodiazepine receptor agonists. Amobarbital (am" oh bar' bi tal) and pentobarbital (pen” toe bar’ bi tal) are currently available, but only as solutions for parenteral administration, being used largely as preanesthetic agents. Secobarbital is available as a 100 mg capsule generically and under the brand name Seconal. Current indications for the barbiturates include short term treatment of insomnia and as a preanesthetic agent or sedative for a minor procedure or imaging study. The recommended dose of secobarbital in adults is 100 mg at bedtime or 200 to 300 mg 1 to 2 hours before surgery. Barbiturates that are no longer available in the United States include butalbital, butabarbital, mephobarbital, methohexital, and thiopental. Secobarbital, amobarbital and pentobarbital are classified as a Schedule II substances, indicating that they have definite potential for physical and psychological dependence and abuse. Frequent side effects include drowsiness, sedation, impairment of mental and physical abilities, hypotension, bradycardia, syncope, nausea, vomiting, headache, and skin rash. When given chronically, the barbiturates can cause psychological and physical dependence and their withdrawal can be associated with agitation, irritability, confusion, insomnia, and vivid dreams.

Hepatotoxicity

Despite wide scale previous use, there is little evidence that the conventional barbiturates used as sedatives or preanesthetic agents can cause liver injury, either serum enzyme elevations during therapy or clinically apparent acute liver disease. There have been no reports of liver injury associated with secobarbital, butabarbital or amobarbital. The barbiturates can cause allergic reactions and skin rashes, which may be accompanied by mild liver injury. Paradoxically, phenobarbital has been linked to many instances of hypersensitivity reactions with accompanying liver disease that can be severe, including drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN], while the other barbiturates have not. The barbiturates are also potent inducers of many hepatic enzymes. In animal models, phenobarbital causes enlargement of hepatocytes with marked increases in protein and lipid content of the endoplasmic reticulum, causing an increased granularity to the hepatocyte cytoplasm. Hepatic enzymes that are induced with chronic barbiturate use include multiple microsomal enzymes such as CYP 1A2, 2C9, 2C19 and 3A4 as well as glucuronyl transferase, delta-aminolevulinic acid, and aldehyde dehydrogenase. Thus, chronic use of barbiturates may increase the metabolism of many drugs and endogenous substances including steroid hormones, cholesterol, bile salts and vitamins.

Likelihood score for amobarbital, pentobarbital and secobarbital: E (unlikely causes of clinically apparent liver injury).

Mechanism of Injury

The reason why phenobarbital, but not amobarbital, butabarbital or secobarbital has been linked to hepatotoxicity is not known, but may merely be that the conventional barbiturates are infrequently used and used in relatively low doses for short periods only. The mechanism of phenobarbital hepatotoxicity is thought to be hypersensitivity and it commonly presents with DRESS syndrome. Hypersensitivity reactions can occur with other barbiturates, but hepatic involvement has not been described in the literature.

Drug Class: Sedatives and Hypnotics

Drugs in the Subclass, Barbiturates: Amobarbital, Butabarbital, Phenobarbital, Secobarbital

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Amobarbital – Generic, Amytal®

Phenobarbital – Generic

Secobarbital – Generic, Seconal®

DRUG CLASS

Sedatives and Hypnotics

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Amobarbital 57-43-2 C11-H18-N2-O3 image 134970867 in the ncbi pubchem database
Phenobarbital 50-06-6 C12-H12-N2-O3 image 134970852 in the ncbi pubchem database
Secobarbital 76-73-3 C12-H18-N2-O3 image 134971831 in the ncbi pubchem database

ANNOTATED BIBLIOGRAPHY

References updated: 03 October 2021

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    (12 year old boy developed fever and rash 7 days after switching from phenytoin to phenobarbital [bilirubin 3.1 mg/dL, ALT 187 U/L, Alk P 400 U/L], resolving rapidly upon stopping).
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    (Two children, one boy and one girl, ages 6 and 7 developed rash [SJS/TEN] 26 and 28 days after starting phenobarbital after cranial radiotherapy for brain tumors; liver test results not provided).
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    (Among 40 cases of drug induced severe cutaneous reactions [DRESS or SJS/TEN] seen over 20 years at a single referral hospital in Thailand, 20 were due to phenobarbital, 17 to phenytoin and 3 to carbamazepine; among cases due to phenobarbital, ALT levels average 71 U/L [range 26-4243], weak association found with a CYP2C19*2 variant).
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    (Retrospective review of 2164 infants undergoing 2419 magnetic resonance imaging sessions requiring sedation and given either oral or iv pentobarbital, found that time to onset was faster with iv drug [7 vs 18 min], but quality of sedation and time to recovery were similar as were adverse events [1.3% vs 0.8%; none were liver related], the general findings favoring oral administration).
  • López-Muñoz F, Ucha-Udabe R, Alamo C. The history of barbiturates a century after their clinical introduction. Neuropsychiatr Dis Treat. 2005;1:329–43. [PMC free article: PMC2424120] [PubMed: 18568113]
    (History of the discovery of the barbiturates and development of synthetic formulations, about 50 of which came to market starting with phenobarbital [Luminol] in 1912, pentobarbital [Neonal] in 1922, most being used as sleeping aids and as therapy of schizophrenia, and later found to have anticonvulsant activity and to be useful in sedation and preanesthesia, but more recently replaced with safer and less addictive therapies).
  • McCleary K, Barrash J, Granner M, Manzel K, Greider A, Jones R. The safety and efficacy of propofol as a replacement for amobarbital in intracarotid Wada testing of presurgical patients with epilepsy. Epilepsy Behav. 2018;78:25–29. [PubMed: 29169082]
    (The difficulty in obtaining amobarbital led to its replacement with propofol in mild sedation, and comparison of efficacy and safety using historical controls suggested similar rates of successful anesthesia and similar rates of adverse events; no mention of liver-related symptoms).
  • Schlatter J, Kabiche S, Sellier N, Fontan JE. Oral pentobarbital suspension for children sedation during MR imaging. Ann Pharm Fr. 2018;76:286–290. [PubMed: 29655484]
    (Among 81 children undergoing magnetic resonance imaging given oral pentobarbital for sedation, the success of obtaining imaging varied by age, being 100% below age 1 but only 42% in 4 to 8 year olds; adverse events were rare but [from a literature review] could include oxygen desaturation, prolonged sedation, paradoxical excitement, and vomiting; no mention of liver injury).

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