Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era

Sedatives in the second part of the 19^th century

(Educational Series 2. Bulletin 5. Vignette 2)

Preamble:

“Sedatives in the second part of the 19^th century” is based on the section on “Sedatives” in Thomas A. Ban’s “Psychopharmacology” (Baltimore: Williams and Wilkins; 1969) and on Thomas A. Ban’s article on “Serendipity in drug discovery,” published in Dialogues in Clinical Neuroscience (2006; 8: 335-44).  

Sedatives in the second part of the 19^th century

            Sedatives are substances which produce a generalized (global) inhibition of behavioral and/or central nervous system activity. They reduce “psychic arousal” without autonomic effects. All sedatives induce sleep when given in sufficiently high doses. Those “sedatives” which are particularly useful for facilitating sleep are referred to as “hypnotics.”

            There were three widely used classes of sedatives introduced into medicine and psychiatry during the second part of the 19^th century: inorganic salts, chloral derivatives and cyclic ethers. Potassium bromide, chloral hydrate and paraldehyde, respectively, were extensively used drugs. 

            Potassium Bromide is the oldest widely used sedative in medicine. It is the potassium salt of bromine, a chemical element, first isolated in 1826 from the ashes of seaweed by A.J. Balard, an apothecary in Montpelier, France. In its natural form bromine is too corrosive to be ingested. As a potassium salt, it is well tolerated (Balard 1826; Löwig 1829).

French clinicians believed that bromine was a substitute for iodine and began using potassium bromide in a variety of disorders without tangible therapeutic effect. In 1857, 31 years after bromine was isolated, Charles Lockock, a London internist, discovered the anticonvulsant and sedative action of the drug. His discovery was one of the many quaint examples in which an utterly false theory led to correct empirical results.   Lockock, like most physicians of his time, believed that there was a cause-effect relationship between masturbation, convulsions and epilepsy. Bromides were known to curb sex drive. Lockock’s rationale was to control epilepsy, i.e., convulsions, by reducing the frequency of masturbation (Garrison 1960). The treatment was a success insofar as control of convulsions was concerned. It also brought to attention the sedating properties of the drug (Balme 1975).

During the second half of the 19^th century potassium bromide and other inorganic bromide salts were widely used as sedatives and anticonvulsants (Shorter 1997). They were undoubtedly effective, but their relatively low therapeutic efficacy coupled with high toxicity had by the mid-20^th century virtually eliminated them from clinical use (Lehmann and Ban 1970).

It was just a few years after the first clinical application of bromides, in the 1850s, that the first chloral derivative, chloral hydrate, was introduced. Similar to potassium bromide, the discovery of the sedative and hypnotic properties of chloral hydrate was also the result of an erroneous idea, but in this case of a chemical theory.

Chloral, or trichloroacetaldehyde, was first prepared in 1832 by Justus von Liebig, a professor of chemistry in Giessen (Germany).  It was about 37 years later, in 1869, that its hydrate, chloral hydrate, was introduced into clinical therapeutics by Otto Liebreich, a professor of pharmacology in Berlin.  Liebreich assumed that one of the components into which chloral hydrate splits in the body is chloroform and since chloroform induces sleep, so would chloral hydrate. Although no chloroform results from the degradation of chloral hydrate, chloral hydrate became the first synthetically produced reliable hypnotic. Today, after almost 150 years after its introduction, it is still used in clinical practice (Ban 2004).

Paraldehyde, a cyclic ether, is a polymer of acetaldehyde without a free aldehyde group. It was first observed in 1835 by Julius von Liebig and synthesized in 1848 by H. Weidenbusch. Subsequently, however, 35 years passed before it was introduced, in 1883 by Vincenzo Cervello (1883, 1884), into clinical use. Introduction of paraldehyde was a success. The substance was used extensively for many years, particularly in mental hospitals. However, by the mid-1950, its use became almost entirely restricted to the control and treatment of the withdrawal symptoms of alcoholics (Lehmann and Ban 1970).

It was in 1863, between the introduction of potassium bromide and chloral hydrate into clinical use that malonylurea, the condensation product of urea and malonic acid was first synthesized by Adolph von Baeyer. Apparently, Baeyer celebrated the synthesis of the substance with his friends on St. Barbara’s Day, the patron saint of artillery officers (Fiesler 1944). Whether the name “barbituric acid” for malonylurea was the result   of adding urea to the name of this saint or the name of a popular Munich waitress will never be known. Although “barbituric acid” itself is an inactive preparation, it is carrier for synthetic preparations from which at least 50 were introduced during the first 50 years of the 20^th century. During those years, sedative and hypnotic barbiturates were the most extensively prescribed drugs in medicine, not only in psychiatry.

References:

Baeyer A. Untersuchungen ueber die Hamsauregruppe. Annalen der Chemie, 1863; 127: 1–27; 199–236.

Balard A. Memoir on a peculiar substance contained in sea water. Annals of Philosophy 1826; 28: 381–7.

Balme RH. Early medicinal use of bromides. Journal of the Royal College of Physicians 1976; 10: 205-208.

Ban TA. Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A review of developments in the 20^th century. In: Ban TA, Healy D, Shorter E, eds. Reflections on Twentieth-Century Psychopharmacology.   Budapest, Hungary; Animula; 2004; 697-72.

Cervello V. Sull'azione fisiologica della paraldeide e contributo allo studio del cloralio idrato.

Archivio per le Scienze Mediche 1883; 6: 177–14.

Cervello V.  Recherches cliniques et physiologiques sur la paraldehyde Archives italiennes de biologie, 1884; 6: 113–34.

Fiesler LF. Organic Chemistry. Boston: Heath and Company; 1944.

Garrison FH. An Introduction to the History of Medicine. Fourth Edition. Philadelphia and London; W.B. Saunders Company; 1960.

Lehmann HE,  Ban TA. Pharmacotherapy of Tension and Anxiety. Springfield; Charles C. Thomas Publisher; 1970; 12-13.

Liebig J. Ueber die Verbindungen welche durch die Einwirkung des Chlors auf Alcohol, Aether, Olbildendes Gas und Effiggeist Entstehen. Liebigs Annalen der Pharmazie 1832; 1: 182-230.

Liebig J   Ueber die Producte der Oxydation des Alkohols.  Annalen der Chemie 1835; 14: 133–67.

Liebreich MEP. Das Chloral hydrate, ein neues Hypnoticum und Anaestheticum, und dessen Anwendung in die Medizin. Eine Arzneimeittel –Untersuchung. Nerlin: Muller; 1869.

Löwig CJ. Das Brom und seine chemischen Verhältnisse" (Bromine and its chemical relationships). Heidelberg; Carl Winter: 1829.

Shorter E. A History of Psychiatry. New York/Chichester/ Brisbane/Toronto/ /Weinheim; John Wiley & Sons, Inc.; 1997; 190-238.

Weidenbusch, H.  Ueber einige Producte der Einwirkung von Alkalien und Säuren auf den Aldehyd. Annalen der Chemie, 1848:  66: 152-165.

February 15, 2018

Preamble:

“Sedatives in the second part of the 19^th century” is based on the section on “Sedatives” in Thomas A. Ban’s “Psychopharmacology” (Baltimore: Williams and Wilkins; 1969) and on Thomas A. Ban’s article on “Serendipity in drug discovery,” published in Dialogues in Clinical Neuroscience (2006; 8: 335-44).   

Sedatives in the second part of the 19^th century

            Sedatives are substances which produce a generalized (global) inhibition of behavioral and/or central nervous system activity. They reduce “psychic arousal” without autonomic effects. All sedatives induce sleep when given in sufficiently high doses. Those “sedatives” which are particularly useful for facilitating sleep are referred to as “hypnotics.”

            There were three widely used classes of sedatives introduced into medicine and psychiatry during the second part of the 19^th century: inorganic salts, chloral derivatives and cyclic ethers. Potassium bromide, chloral hydrate and paraldehyde, respectively, were extensively used drugs. 

            Potassium Bromide is the oldest widely used sedative in medicine. It is the potassium salt of bromine, a chemical element, first isolated in 1826 from the ashes of seaweed by A.J. Balard, an apothecary in Montpelier, France. In its natural form bromine is too corrosive to be ingested. As a potassium salt, it is well tolerated (Balard 1826; Lowig 1829).

French clinicians believed that bromine was a substitute for iodine and began using potassium bromide in a variety of disorders without tangible therapeutic effect. In 1857, 31 years after bromine was isolated, Charles Lockock, a London internist, discovered the anticonvulsant and sedative action of the drug. His discovery was one of the many quaint examples in which an utterly false theory led to correct empirical results.   Lockock, like most physicians of his time, believed that there was a cause-effect relationship between masturbation, convulsions and epilepsy. Bromides were known to curb sex drive. Lockock’s rationale was to control epilepsy, i.e., convulsions, by reducing the frequency of masturbation (Garrison 1960). The treatment was a success insofar as control of convulsions was concerned. It also brought to attention the sedating properties of the drug (Balme 1975).

During the second half of the 19^th century potassium bromide and other inorganic bromide salts were widely used as sedatives and anticonvulsants (Shorter 1997). They were undoubtedly effective, but their relatively low therapeutic efficacy coupled with high toxicity had by the mid-20^th century virtually eliminated them from clinical use (Lehmann and Ban 1970).

It was just a few years after the first clinical application of bromides, in the 1850s, that the first chloral derivative, chloral hydrate, was introduced. Similar to potassium bromide, the discovery of the sedative and hypnotic properties of chloral hydrate was also the result of an erroneous idea, but in this case of a chemical theory.

Chloral, or trichloroacetaldehyde, was first prepared in 1832 by Justus von Liebig, a professor of chemistry in Giessen (Germany).  It was about 37 years later, in 1869, that its hydrate, chloral hydrate, was introduced into clinical therapeutics by Otto Liebreich, a professor of pharmacology in Berlin.  Liebreich assumed that one of the components into which chloral hydrate splits in the body is chloroform and since chloroform induces sleep, so would chloral hydrate. Although no chloroform results from the degradation of chloral hydrate, chloral hydrate became the first synthetically produced reliable hypnotic. Today, after almost 150 years after its introduction, it is still used in clinical practice (Ban 2004).

Paraldehyde, a cyclic ether, is a polymer of acetaldehyde without a free aldehyde group. It was first observed in 1835 by Julius von Liebig and synthesized in 1848 by H. Weidenbusch. Subsequently, however, 35 years passed before it was introduced, in 1883 by Vincenzo Cervello (1883, 1884), into clinical use. Introduction of paraldehyde was a success. The substance was used extensively for many years, particularly in mental hospitals. However, by the mid-1950, its use became almost entirely restricted to the control and treatment of the withdrawal symptoms of alcoholics (Lehmann and Ban 1970).

It was in 1863, between the introduction of potassium bromide and chloral hydrate into clinical use that malonylurea, the condensation product of urea and malonic acid was first synthesized by Adolph von Baeyer. Apparently, Baeyer celebrated the synthesis of the substance with his friends on St. Barbara’s Day, the patron saint of artillery officers (Fiesler 1944). Whether the name “barbituric acid” for malonylurea was the result   of adding urea to the name of this saint or the name of a popular Munich waitress will never be known. Although “barbituric acid” itself is an inactive preparation, it is carrier for synthetic preparations from which at least 50 were introduced during the first 50 years of the 20^th century. During those years, sedative and hypnotic barbiturates were the most extensively prescribed drugs in medicine, not only in psychiatry.

References

Baeyer A. Untersuchungen ueber die Hamsauregruppe. Annalen der Chemie, 1863; 127: 1–27; 199–236.

Balard A. Memoir on a peculiar substance contained in sea water. Annals of Philosophy 1826; 28: 381–7.

Balme RH. Early medicinal use of bromides. Journal of the Royal College of Physicians 1976; 10: 205-208.

Ban TA. Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A review of developments in the 20^th century. In: Ban TA, Healy D, Shorter E, eds. Reflections on Twentieth-Century Psychopharmacology.   Budapest, Hungary; Animula; 2004; 697-72.

Cervello V. Sull'azione fisiologica della paraldeide e contributo allo studio del cloralio idrato.

Archivio per le Scienze Mediche 1883; 6: 177–14.

Cervello V.  Recherches cliniques et physiologiques sur la paraldehyde Archives italiennes de biologie, 1884; 6: 113–34.

Fiesler LF. Organic Chemistry. Boston: Heath and Company; 1944.

Garrison FH. An Introduction to the History of Medicine. Fourth Edition. Philadelphia and London; W.B. Saunders Company; 1960.

Lehmann HE, Ban TA. Pharmacotherapy of Tension and Anxiety. Springfield; Charles C. Thomas Publisher; 1970; 12-13.

Liebig J. Ueber die Verbindungen welche durch die Einwirkung des Chlors auf Alcohol, Aether, Olbildendes Gas und Effiggeist Entstehen. Liebigs Annalen der Pharmazie 1832; 1: 182-230.

Liebig J   Ueber die Producte der Oxydation des Alkohols.  Annalen der Chemie 1835; 14: 133–67.

Liebreich MEP. Das Chloral hydrate, ein neues Hypnoticum und Anaestheticum, und dessen Anwendung in die Medizin. Eine Arzneimeittel –Untersuchung. Nerlin: Muller; 1869.

Löwig CJ. Das Brom und seine chemischen Verhältnisse" (Bromine and its chemical relationships.) Heidelberg; Carl Winter: 1829.

Shorter E. A History of Psychiatry. New York/Chichester/ Brisbane/Toronto. Weinheim; John Wiley & Sons, Inc.; 1997; 190-238.

Weidenbusch, H.  Ueber einige Producte der Einwirkung von Alkalien und Säuren auf den Aldehyd. Annalen der Chemie, 1848:  66: 152-165.

February 15, 2018