Barbiturates and epilepsy: phenobarbitone in cases of epilepsy

Of the inorganic compounds, bromide of potassium was the only one which proved successful in treating epilepsy. During the nineteenth century, chemists were also focused on creating naturally occurring substances out of pure chemicals.

With Wohler’s synthesis of urea in the early 1800’s, organic chemistry was born. By the end of the century, the German chemist, Kekule discovered the structure of the benzene ring.

He reported his discovery to the German Chemical Society in 1890 in a now famous account of a vision he received in a semi-dream state.

He said that he had been working on the problem for many hours with no success and then dozed off before the fire. While dozing, he saw atoms dancing before his eyes.

They then formed long rows twining and twisting like snakes, and then, suddenly, one of the snakes had seized hold of its own tail, and the form whirled mockingly before my eyes.

As if by a flash of lightening, I awoke; and this time also I spent the rest of the night working out the consequences of my hypothesis.

The significance of Kekule’s dream was its revelation that the bonding action of atoms into stable molecular structures is a dynamic process. This new notion allowed chemistry to progress. Thousands of new compounds could be created and then screened for therapeutic value.

The synthesis of barbituric acid occurred on St Barbara’s Day in 1864, hence the name. A whole line of sedative and hypnotic drugs later evolved from barbituric acid. One such drug was phenobarbitone.

Phenobarbitone was initially used as a sedative in cases of insomnia, hysteria and other agitated states.

A few years after its development, an article was published in a German medical journal in 1912 reporting success in the clinical use of phenobarbitone in cases of epilepsy. (Phenobarbitone was produced and marketed under the name Luminal by Farbwerke Fr. Bayer and Co.)

In the article, Dr. Alfred Hauptmann reports that he first prescribed Luminal as a sedative for states of epileptic agitation.

From there, he began to prescribe it over long periods of time in cases of severe epilepsy and observed that, for the first time, seizures were controlled.

The patients he treated with Luminal were ones who experienced severe attacks several times a day, and who had been treated with high doses of bromides for many years.

He reported that even in the most severe cases he never had to prescribe more than 300 mgs per day.

Luminal had a twofold effect on epilepsy. First, the frequency of attacks diminished considerably and, in mild cases, ceased altogether. Second, the nature of the attacks changed from severe to mild with patients awakening lucidly.

Hauptmann also stated that Luminal allowed many patients to be released from the hospital and some to return to their former occupations. He also reported no harmful side effects from long term usage.

He made it clear that Luminal did not cure epilepsy because when treatment stopped, there was an immediate increase in frequency of attacks or a return of attacks in mild cases where the drug had stopped them.

The use of phenobarbitone in the treatment of epilepsy became widespread throughout Europe soon after the publication of Hauptmann’s article. The same was not true in the United State until the end of World War I in 1918.

In a study carried out for the US National Institutes of Health in the 1970’s, Coatsworth noted that phenobarbitone was the most widely prescribed medication for epilepsy worldwide.

He also noted that toxic hepatic and haematological manifestations do occur in rare instances and that it has a sedative effect with chronic administration.

Coatsworth warned that it should be regarded as hazardous because of dependency, use as an illicit drug, and the danger of suicidal overdose.

Another warning was that the drug must be withdrawn extremely slowly or else convulsions are almost inevitable.

In treating children with the drug to prevent repeated febrile seizures, hyperactivity may be a side-effect. With the middle aged and elderly, depression is a possible side-effect.