How dangerous is barbiturates over doses

History of a sleeping pill

Veronalby Ruth H. Anders, Witten

It came onto the market 100 years ago: Veronal - a new type of hypnotic that promoted sleep in small doses and had a narcotic effect in larger doses. Doctors and patients alike raved about its good tolerability with no side effects. The drug manufactured by Bayer and Merck became a bestseller and heralded the era of barbiturates.

The veronal inventors were Emil Fischer and Joseph von Mering, 1902 Nobel Prize winners in chemistry, and recognized clinicians, the other. Because von Mering, who took the drug on a train journey from Berlin to Basel, allegedly only woke up in Verona and liked the city so much, the drug was given the illustrious name Veronal.

By the turn of the century there were a good two dozen substances for the manufacture of sleeping pills. The physiological chemist Sigmund Fränkel compared their structures, looked for “hypnophoric” similarities, tried to eliminate “toxicophoric” structural elements and finally sketched a hypothetical blueprint for an “ideal sleeping pill”: one loaded with two ethyl groups on a carbon atom, otherwise completely physiologically indifferent core.

Systematized research

Fränkel had no idea of ​​the nature of a suitable carrier core. Nobody has ever asked why von Mering envisaged barbituric acid as the basic molecule. As a clinician, he did not have extensive knowledge of chemistry, and barbituric acid did not claim the particular interest of chemists.

In 1864, Adolf von Baeyer, Liebig's successor on the Munich “chemistry throne”, laboriously and laboriously converted alloxan into a substance that was more acidic than acetic acid, but did not contain any carboxyl groups or any of the other acidic functions known at the time. By breaking it down, he identified it as malonylurea and named it barbituric acid after the deceptive alchemist Barbara von Cilly, wife of Emperor Sigismund.

Barbituric acid did not show any physiological effects. Von Mering decided to try it as a carrier core and to test diethylbarbituric acid pharmacologically.

However, he did not succeed in producing the substance, and the chemists he initially consulted also failed in the task. He therefore turned to Emil Fischer, who at the time was revered by his specialist colleagues as the “shining star in the firmament of chemistry”.

The accomplished synthesist effortlessly managed to provide a dozen and a half barbituric acid derivatives for the pharmacological investigations. Due to fewer animal experiments with dogs, von Mering selected three substances for clinical testing. Tests were carried out on patients in psychiatric institutions, in accordance with the customs of the time.

E.Desired hang-over

After completion of the “clinical trial”, preference was given to veronal. The drug put the patient into what appeared to be a deep, dreamless sleep. The next day a sedative effect was noticeable - at that time not undesirable for mentally ill people, later an unacceptable side effect as a so-called "hang-over". After taking it in the evening, 80 to 90 percent of the active ingredients were still in the organism in the morning. Fatigue and daytime tiredness were the result. Diethylbarbituric acid showed an almost alarming stability with a half-life of almost 100 hours.

Fischer and von Mering certainly did not find the ideal sleep aid, but they did discover an unusually versatile lead structure.

In five decades, almost one and a half thousand structural analogs of veronal have been synthesized and pharmacologically characterized, more intensively and carefully than in von Mering's animal experiments. It was observed that the mechanism of action is basically the same for all barbiturates, the different duration of action is pharmacokinetically determined and that it depends on the current concentration at the site of action whether the effect is anxiolytic, sedative, hypnotic or narcotic. The relative importance of absorption, distribution, biotransformation and excretion, which are now common pharmaceutical tools, became evident not least through studies in the barbiturate group.

However, von Mering made the grossest misjudgment when he failed to recognize the hypnotic potential of thiobarbituric acids. Fischer had also synthesized the thiourea derivative analogous to veronal. On the basis of a single dog experiment, it was rejected by von Mering. It was not until three decades later that the suitability of thiobarbituric acids for intravenous anesthesia was recognized.

Has fallen into disrepute

In addition to their sedative-hypnotic effect, barbiturates influence breathing, blood pressure and heart rate to a not insignificant extent. Long-term chronic abuse leads to physical and psychological dependence. There is also a great danger of acute poisoning in the event of an overdose.

Veronal fell into disrepute soon after its launch. The over-the-counter drug was increasingly seen as a "suicide weapon" and from 1908 onwards it was only allowed to be sold in pharmacies with a prescription. However, nothing changed in its popularity. It even found its way into literature. The most famous example: In Arthur Schnitzler's novella “Fräulein Else” from 1924, the main protagonist of the same name takes her own life with Veronal.

The small difference between the effective and lethal or harmful dose of the barbituric acid derivatives was one reason why they were displaced from the market by benzodiazepines and other substances from the 1960s onwards. The production of the "scandalous" Veronal was finally stopped completely.

© 2003 GOVI-Verlag
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