Barbiturate

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Barbiturates are drugs that act as central nervous system depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. Some are also used as anticonvulsants.

Barbiturates are derivatives of barbituric acid.

1 History
2 Mechanism of Action
3 Therapeutic use
4 Potential for addiction
5 Toxicity and overdose
6 Recreational use
7 Other non-therapeutical use
8 Famous users
9 External links

[edit] History

Barbituric acid was first synthesized on December 4, 1864, by German researcher Adolf von Baeyer. This was done by combining urea (an animal waste product) with malonic acid (derived from the acid of apples). There are several stories about how the substance got its name. The most likely story is that von Baeyer and his colleagues went to celebrate their discovery in a tavern where the town's artillery garrison were also celebrating the day of Saint Barbara — the patron saint of artillerists. An artillery officer is said to have christened the new substance by amalgamating Barbara with urea. [1]

Barbituric acid itself is not pharmacologically active, but chemists immediately began making a great variety of derivatives for potential use as drugs. No substance of medical value was discovered, however, until 1903 when two German chemists working at Bayer, Emil Fischer and Joseph von Mering, discovered that barbital was very effective in putting dogs to sleep. Barbital was then marketed by Bayer under the trade name Veronal. It is said that Von Mering proposed this name because the most peaceful place he knew was the Italian city of Verona. [2]

In 1912, Bayer introduced another barbituric acid derivative, Phenobarbital, under the trade name Luminal, as a sedative-hypnotic.

In the 1950s and 1960s, reports began to be published about side effects and dependence related to barbiturates.

In 1970 several barbiturates were designated in the United States as controlled substances with the passage of the American Controlled Substances Act of 1970. Pentobarbital, secobarbital and amobarbital were designated schedule II drugs, butabarbital schedule III, and barbital and phenobarbital schedule IV.

In 1971 the Convention on Psychotropic Substances was signed in Vienna. Designed to regulate amphetamines, barbiturates, and other synthetics, the treaty today regulates amobarbital (schedule III), butalbital (III), cyclobarbital (III), pentobarbital (III), allobarbital (IV), methylphenobarbital (IV), phenobarbital (IV), secobarbital (IV), and vinylbital (IV) as scheduled substances.

[edit] Mechanism of Action

The principal mechanism of action of barbiturates is believed to be their affinity for the GABA_A receptor. GABA is the principal inhibitory neurotransmitter in the mammalian Central Nervous System (CNS). Barbiturates bind to the GABA_A receptor at a binding site distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABA-ergic effect, barbiturates also block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABA_A receptors and inhibit excitatory AMPA receptors can explain the CNS-depressant effects of these agents.^[1]

[edit] Therapeutic use

Barbiturates were long used as anxiolytics and hypnotics. Today benzodiazepines have largely supplanted them for these purposes, because benzodiazepines have less potential for abuse and less danger of lethal overdose. Today, fewer than 10 percent of all sedative/hypnotic prescriptions in the United States are for barbiturates.^{[citation needed]}

Barbiturates are still widely used in surgical anesthesia, especially to induce anesthesia.

Phenobarbital is used for as an anticonvulsant for people suffering from seizure disorders such as febrile seizures, tonic-clonic seizures, status epilepticus, and eclampsia.^[2]

[edit] Potential for addiction

Barbiturates are habit forming and lead to physical withdrawal symptoms. These can include tremors, anxiety, weakness, restlessness, nausea and vomiting, delirium, tonic-clonic or grand mal seizures, and cardiac arrest. Death can result from seizures or cardiac arrest.

[edit] Toxicity and overdose

Mild to moderate barbiturate toxicity mimics alcohol intoxication. Severe acute barbiturate toxicity results in central nervous system problems, including lethargy and coma. Constricted pupils, confusion, hypotension, poor coordination, respiratory depression, and coma may be found on physical exams. Although a barbiturate serum level may be obtained, the clinical presentation predicts the seriousness of the overdose. Attention must be given to the ABC's - airway, breathing and circulation. Gastric lavage and multiple doses of activated charcoal may be used to decontaminate the gastrointestinal system. Intravenous fluids and forced diuresis and alkalinization should be used for long acting barbiturate intoxication. In severe cases, hemodialysis may be necessary. Early deaths are usually a result of shock or cardiopulmonary arrest. Later deaths are usually the result of pulmonary complications such as aspiration pneumonia or pulmonary edema.

[edit] Recreational use

Barbiturates were very popular in the first half of the twentieth century. In moderate amounts, these drugs produce a state of intoxication that is remarkably similar to alcohol intoxication. Symptoms include slurred speech, loss of motor coordination, and impaired judgment. Depending on the dose, frequency, and duration of use, one can rapidly develop tolerance, physical dependence, and psychological dependence on barbiturates. With the development of tolerance, the margin of safety between the effective dose and the lethal dose becomes very narrow. That is, in order to obtain the same level of intoxication, the tolerant abuser may raise his or her dose to a level that may result in coma or death. Although many individuals have taken barbiturates therapeutically without harm, concern about the addiction potential of barbiturates and the ever-increasing number of fatalities associated with them led to the development of alternative medications, namely benzodiazepines.

[edit] Other non-therapeutical use

Barbiturates in high doses are used for physician-assisted suicide (PAS), and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection.

[edit] Famous users

Abbie Hoffman - anarchist in the 1960s, committed suicide
Ryunosuke Akutagawa - the renowned Japanese writer who wrote Rashomon, committed suicide by overdosing on barbiturates on July 24, 1927.
Adolf Hitler - Speculated addiction to methamphetamine and Cocaine, used barbiturates to sleep.
Judy Garland died from an accidental barbiturate overdose
Gertrude Hullett, a patient of the suspected British serial killer John Bodkin Adams, died from an overdose in 1956. He was charged with her murder but controversially acquitted.
Allison Malon died from an accidental barbiturates overdose
Marilyn Monroe also died from an overdose of barbiturates, as did George Sanders, Kenneth Williams (although an open verdict was recorded) and Jean Seberg.
Michael Rabin, one of the most prodigious violinists America has ever had, became dependent on barbiturates and his death was partially linked to abuse of these drugs.
Jimi Hendrix's death was a combination of barbiturate overdose and vomit inhalation (pulmonary aspiration).
Edie Sedgwick died in 1971 of barbiturate overdose. Death was said to be accidental/suicidal.
Tim Buckley, singer-songwriter and father of Jeff Buckley, died from an accidental overdose of heroin, alcohol, and barbiturates.
Ruan Lingyu committed suicide by overdosing on barbiturates on March 8, 1935.
Johnny Cash abused barbiturates during the height of his career.
Elvis Presley used barbiturates in the last years of his life, but whether this contributed to his death is disputed.
Margaux Hemingway died from an overdose of phenobarbital.
Dorothy Kilgallen died in 1965 of an alcohol and Seconal overdose. It is unclear whether the overdose was accidental or murder.
Diane Arbus committed suicide in 1971 by taking barbiturates and slitting open her wrists.
Pier Angeli died in 1971 of an overdose of barbiturates.
Inger Stevens committed suicide in 1970 of an overdose of barbiturates at the age of 36.
Donald Sinclair Better known as "Siegfred Farnon" in James Herriot's collective books "All Things Great and Small". He committed suicide in 1995.
Jean Seberg Actress died from a barbiturate overdose in Paris, 1979.