Phenobarbital

Legend has it that in 1864, Johann Friedrich Wilhelm Adolf von Baeyer, of Bayer Pharmaceuticals fame, popped into a local pub after concocting a new compound, malonylurea. Apparently, he walked in on a lively celebration of St. Barbara, patron saint of artillerymen. Inspired by the revelry, Bayer renamed his new compound barbituric acid, a combination of the words Barbara and urea.

Though several compounds would be derived from barbituric acid over time, creating a whole class of compounds known as the barbiturates, Baeyer did not see much therapeutic use for his acid and set it aside.

Emil Fischer and Joseph von Mering uncovered the medical value of the barbiturates in 1903. Their compound, diethylbarbituric acid, or Veronal, helped dogs fall asleep. Barbiturates became the patron saint of insomniacs.

Barbiturates also provided a safer and more effective relief option for people suffering from epileptic seizures. Before the barbiturates, potassium bromide was the first chemical treatment for controlling seizures. Sir Charles Locock first used the compound to control seizures in patients in 1857. Though potassium bromide caused serious side effects, such as psychosis and dermatitis, it remained the only form of treatment for seizures until the beginning of the 20th century.

In 1912, Bayer Pharmaceuticals introduced phenobarbital to the market under the name Luminal. Not only was the compound an effective sleeping aid, but it also exhibited properties as an anticonvulsant without the toxicity of potassium bromide. Phenobarbital blocks certain receptors in the brain, preventing the abnormal electrical discharges that trigger epileptic seizures.

Though no longer relied upon as a first-line treatment, phenobarbital still remains an active component in the treatment of seizures, making it the oldest epilepsy medicine still in use. Even pets suffering from seizures now benefit from phenobarbital.

The barbiturate also found a calling treating jaundice in newborns. A high level of bilirubin, an insoluble breakdown product of hemoglobin, creates the yellow hue of jaundiced babies. Severe jaundice can create neurological problems. Phenobarbital lowers bilirubin levels by increasing liver metabolism.

Phototherapy (exposure to light) replaced phenobarbital after it was accidentally discovered in the 1950s to effectively and safely lower bilirubin levels; it remains the most common treatment option today.

Part of the long-lasting appeal of phenobarbital, especially in developing countries, is its low price--a 30-day supply generally costs $10 or less.

St. Barbara's compound is not a complete "wonder drug," however, and has some serious side effects. Some of the drawbacks of phenobarbital include drowsiness and behavioral changes. And barbiturates in general are notorious for their tolerance issues. Over time, increasing doses are necessary to maintain the same level of effectiveness. The therapeutic dose limit for barbiturates, however, is dangerously close to its toxic level. Accidental overdose or mixture with alcohol can prove fatal, as was probably the case with Marilyn Monroe's death in 1962.

Phenobarbital played a role in an earlier scandal and indirectly influenced the development of current Good Manufacturing Practices. In December 1940, Winthrop Chemical accidentally produced sulfathiazole tablets contaminated with phenobarbital. Each tablet contained about 350 mg of phenobarbital, while the average adult sleep-inducing dose was only 100-150 mg. Used to treat bacterial infections, sulfathiazole had relatively low toxicity and was often prescribed in large doses. Hundreds of deaths and injuries resulted from the accidental intake of such large amounts of phenobarbital.

A Food & Drug Administration investigation revealed that the contamination most likely occurred during the tablet-making process. Winthrop produced sulfathiazole and phenobarbital tablets in the same room on adjacent machines, which were often used interchangeably. Even though Winthrop knew of the contamination in December, cases of the contaminated pills were still surfacing three months later.

Winthrop's poor quality-control system, failure to report the contamination to FDA, and failure to quickly and effectively recall the tainted pills prompted FDA to require detailed controls of sulfathiazole production at Winthrop. The incident strongly influenced the 1962 drug amendments to the 1938 Food, Drug & Cosmetic Act, which tightened controls over pharmaceuticals and mandated Good Manufacturing Practices.

Few pharmaceuticals share phenobarbital's claim to fame: A saint's namesake that is capable of taming seizures and is responsible for both the death of movie stars and the birth of Good Manufacturing Practices.

Phenobarbital 

Name: 5-Ethyl-5-phenyl-2,4,6 (1H,3H,5H)-pyrimidinetrione

CAS Registry: 50-06-6

Other names: Luminal, Eskabarb, Solfoton, Talpheno, phenobarbitone

First marketed: 1912, Bayer

Did you know that phenobarbital may reduce the effectiveness of birth control pills?