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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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Last Update: March 1, 2016.



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.


Barbiturates are a family of compounds that have sedative and hypnotic activities and act as nonselective central nervous system (CNS) depressants. Phenobarbital has also been used as an anticonvulsant, acting by suppression of spread of seizure activity by enhancing the effect of gamma aminobutyric acid (GABA). Phenobarbital (fee" noe bar' bi tal) 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, butabarbital, pentobarbital and secobarbital are used as sedatives and hypnotics and not as anticonvulsants. These and several other barbiturates were introduced into medical use in the United States in the 1950s as sedatives, hypnotics (short term treatment of insomnia) and preanesthetic agents. They are now rarely used, having been largely 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 butabarbital (bue' ta 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. Pentobarbital is no longer available in the United States. Current indications for the barbiturates include short term treatment of insomnia and as a preanesthetic agent. 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, mephobarbital, methohexital and pentobarbital. Secobarbital is classified as a Schedule II substance, indicating that it has definite potential for physical and psychological dependence and abuse. Frequent side effects include drowsiness, sedation, hypotension, nausea, headache and skin rash.


Despite wide scale previous use, there is little evidence that the conventional barbiturates 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 secobarbita, butabarbitall or amobarbital. The barbiturates can cause allergic reactions and skin rashes, which may be accompanied by mild liver injury. While phenobarbital has been linked to hypersensitivity reactions (including Stevens Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) with clinically apparent liver injury, 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: 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 can present as the DRESS syndrome (drug reaction, rash, eosinophilia and systemic symptoms). 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



Amobarbital – Generic, Amytal®

Secobarbital – Generic, Seconal®


Sedatives and Hypnotics


Product labeling at DailyMed, National Library of Medicine, NIH


Amobarbital Chemical Structure
Secobarbital Chemical Structure


References updated: 01 March 2016

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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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    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to a barbiturate).


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