Phenobarbitol and Human Acid-Base Chemistry

Prof. Sally Boudinot


1. History of Barbiturates

The history of the discovery of the class of drugs known as barbiturates is a classic tale, and typical of many classes of drugs. It is filled with romance, serendipity, taverns, chemistry, and a little luck. 

It is said that on the Day of St. Barbara, 1864, that artillery officers were celebrating their patron saint in a tavern (a common practice in Europe, even today, to celebrate one’s "saint day").

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Adolph von Baeyer

A German chemist, Adolph von Baeyer, founder of what was to become the Bayer Chemical Co., who in 1905 won the Nobel Prize in chemistry, happened in for some celebrating of his own. It was on that day that he had synthesized "malonylurea" from a reaction of urea with malonic acid, a chemical found in apples. No one knows exactly what he was trying to accomplish, but malonylurea became known as "Barbituric acid", making St. Barbara Day even more important!

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19th Century Russian
Icon of St. Barbara

Chemists in the late 19th and early 20th century had few tools to determine the properties of the chemical compounds they made.  And so they often decided they would use one tool they had - the reaction of their own body to the substances they produced.  Chemists tasted the stuff they made.  We don't know whether von Baeyer, himself, tasted barbituric acid, but someone did and found that it had no therapeutic significance. But its discovery led to a series of other derivatives of similar structure that opened avenues to drugs that were significant both therapeutically and socially. 

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Barbituric Acid

 In 1903, Fischer and von Mering were the first to synthesize a therapeutically active "barbiturate" by substituting two ethyl groups for two hydrogens attached to carbon.  When they  administered this new barbiturate to human subjects, the compound was found to induce sleep. The term for a drug that causes sleep induction is known as a somnolent or a hypnotic.

But here is where the story gets fuzzy! Two versions of how the compound got its name, so you pick which you want to believe. Version 1: von Mering was in Verona, Italy, when he heard of the compound’s synthesis by Fischer. Version 2 (for the romantics): Veronal, as it became known, caused a sensation of peace and solace that is associated with Verona. Diethyl barbituric Acid, as Veronal was known chemically, was a popular drug. It allowed sleep at night, and even caused drowsiness and relaxation when taken during the day.

Problem was, it was slow to take effect  and was very slow to wear off due to slow metabolism. So those who took it may wind up sleeping a day and a half! 

The chase was off. How could the onset of action be made faster, and the duration of action not quite as long? And of course, the hypnotic effect would remain unchanged. This was the goal.


These early   century chemists used the crudest of tools.  They measured the macroscopic result of their chemical synthesis by giving the chemicals to human subjects and observing the results.  Then they modified the molecular structure by changing the compounds they used in the reaction between malonic acid and urea.  The representations of the day were adequate in that the overall composition of the compounds was known - the ratio of carbon, hydrogen, oxygen and nitrogen atoms - the stochiometry.   The sequence of what atoms were bound to what was also known.

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Ball and stick model of phenobarbitol.
In this model, C is gray, H is white, O is red, N is blue.  Cylinders represent single and double bonds.  What are the advantages of this model structure over the depiction of barbituric acid (above)?  What are the deficiencies? 

In 1912, two independent teams of chemists synthesized what became known as Luminal, or phenobarbitol. In addition to the excellent hypnotic action, the compound was found to have anticonvulsant activity. The compound, given twice daily, kept seizures under control. And the hypnotic effects could be counteracted by administering amphetamines without affecting the anticonvulsant properties. 

Subsequent research on barbiturates began to understand that the lack of drug activity in barbituric acid and the slow acting effect of Veronal were caused by the same property - negligible or slow passage across the tissues that connect the gastrointestinal tract to the body's circulatory system.

The walls of the vessels through which the drugs must pass are composed of fatty molecules.  And we learn in our General Chemistry that if we want one substance to dissolve in another, they two materials must have some structural similarity - "like dissolves like".

But barbituric acid is insoluble in fat-like solvents and Veronal is only slightly more soluble.  The scientists needed to develop molecules that contained larger hydrocarbon groups that resembled the fatty components of the body's barriers.

This idea led to modification in the chemicals to yield very lipophilic compounds that crossed the blood-brain barrier quickly and those that could be administered intravenously for pre-surgical anesthesia. Manipulations of the side chain at position 5 have resulted in amobarbital (Amytal ), pentobarbital (Nembutal ), and secobarbital (Seconal ). These drugs have become widely known as drugs of abuse. Changes in position 2 have resulted in the short-acting barbiturates: hexobarbital (Evipal ), thiopental (Pentothal ) and methohexital (Brevital ). 

Many drugs in this class are still widely used today. The discovery of barbiturates and the research into the pharmacology and chemistry of these compounds led to the discovery of benzodiazepines. Drugs that are widely known in this class include Valium and Halcion . Benzodiazepines have largely replaced barbiturates in therapy except in anesthesia. Other anticonvulsant medications have largely replaced phenobarbitol. Many patients, however, still rely on its potent anticonvulsant properties with few side effects. And in today’s pharmaceutical marketplace, phenobarbitol has one characteristic that makes it unique: it is CHEAP!

Now let's take a look at this chemical marvel! 


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Case Study in Phenobarbitol
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2. Epilepsy: Etiology and Pathophysiology
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Prof. Sally Boudinot
College of Pharmacy
University of Georgia
Athens, GA