Barbital (or barbitone), sold under the brand names Veronal for the pure acid and Medinal for the sodium salt, was the first commercially available barbiturate. It was used as a sleeping aid (hypnotic) from 1903 until the mid-1950s. The chemical names for barbital are diethylmalonyl urea or diethylbarbituric acid; hence, the sodium salt is known also as sodium diethylbarbiturate.
Synthesis
Barbital, then called "Veronal", was first synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering, who published their discovery in 1903.[2] Barbital was prepared by condensing diethylmalonic ester with urea in the presence of sodium ethoxide, or by adding at least two molar equivalents of ethyl iodide to the silver salt of malonylurea (barbituric acid) or possibly to a basic solution of the acid. The result was an odorless, slightly bitter, white crystalline powder.[3]
Its introduction followed the investigations of Fischer and von Mering on the pharmacological properties of certain open and closed acylureas (then called ureides). Led by the impression that hypnotic action appears to be largely dependent on the presence of ethyl groups, they prepared diethylacetyl urea, diethylmalonyl urea (i.e., Barbital itself), and dipropylmalonyl urea. All three were found to be hypnotics: the first was about equal in power to the already-known sulphonal (now sulfonmethane), whilst the third was four times as powerful, but its use was attended by prolonged after-effects. Veronal was found to be midway.[3]
Bottle for "Veronal" crystals, named after the Italian city of Verona, was the first commercially available barbiturate, manufactured by Bayer.
Barbital was marketed in 1904 by Bayer as "Veronal," while the soluble salt of barbital was marketed by Schering as "Medinal." It was dispensed for "insomnia induced by nervous excitability."[4][unreliable source?] It was provided in either crystal form or in capsules. The therapeutic dose was ten to fifteen grains (0.6–1 grams).[citation needed] 3.5 to 4.4 grams (55 to 68 grains) is considered the lethal dose.[citation needed]
Pharmacology
Barbital was considered to be a great improvement over the existing hypnotics. Its taste was slightly bitter, but better than the strong, unpleasant taste of the commonly used bromides. It had few side effects, and its therapeutic dose was far below the toxic dose. However, prolonged usage resulted in tolerance to the drug, requiring higher doses to reach the desired effect. "I'm literally saturated with it", the Russian tsarina Alexandra Feodorovna confessed to a friend.[5] Fatal overdoses of this slow-acting hypnotic were common. Pioneering aviator Arthur Whitten Brown (of "transatlantic flight of Alcock and Brown" fame) died of an accidental overdose.
A photoswitchable derivative of barbital based on a donor-acceptor Stenhouse adduct (DASA) has been developed for research purposes (photopharmacology). DASA-barbital shows neuronal activity via GABAA receptors and reversible photoisomerization in water using cyclodextrin.[6]
pH buffer
Solutions of sodium barbital have also been used as pH buffers for biological research, e.g., in immunoelectrophoresis or in fixative solutions.[7][8] As barbital is a controlled substance, barbital-based buffers have largely been replaced by other substances.[9]
Poisoning
Veronal from Bayer in glass tubes with cork caps - 10 tablets probably produced around 1940
Eric Mareo, son of playwright Raimund Pechotsch, murdered his wife Thelma with Veronal. Thelma's lesbian lover Freda Stark was a key witness at the trial.[14]
In fiction
In the D. H. Lawrence story, The Lovely Lady, the titular character dies from a self-administered overdose.[15]
Barbital, under the name of Veronal, has been used as a plot device in the author Agatha Christie's murder mysteries.[16]
Barbital was also used as a plot device in the CBS television legal drama, Perry Mason, in the episode, The Case of the Missing Element (1963).[17]
^Fischer E, von Mering J (1903). "Ueber eine neue Klasse von Schlafmitteln" [About a new class of sleeping pills]. Therapie der Gegenwart (in German). 44: 97–101.
^Finley E (1919). "Veronal". The American Materia Medica, Therapeutics and Pharmacognosy. p. 115. Retrieved 25 July 2015.
^Dehn L (1922). The Real Tsaritsa. Boston: Little Brown. p. 138.
^Castagna R, Maleeva G, Pirovano D, Matera C, Gorostiza P (August 2022). "Donor-Acceptor Stenhouse Adduct Displaying Reversible Photoswitching in Water and Neuronal Activity". Journal of the American Chemical Society. 144 (34): 15595–15602. doi:10.1021/jacs.2c04920. hdl:2445/188733. PMID35976640. S2CID251623598.
^Kuhlmann WD (10 September 2006). "Buffer Solutions"(PDF). Archived from the original(PDF) on 9 November 2016. Retrieved 28 July 2014.
Dombrowski SM, Krishnan R, Witte M, Maitra S, Diesing C, Waters LC, Ganguly R (October 1998). "Constitutive and barbital-induced expression of the Cyp6a2 allele of a high producer strain of CYP6A2 in the genetic background of a low producer strain". Gene. 221 (1): 69–77. doi:10.1016/s0378-1119(98)00436-3. PMID9852951.
