Barbituric acid, the basic structure of all barbiturates

Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants. Barbiturates also have analgesic effects, however these effects are somewhat weak, preventing barbiturates from being used in surgery in the absence of other analgesics. They have addiction potential, both physical and psychological. Barbiturates have now largely been replaced by benzodiazepines in routine medical practice - for example, in the treatment of anxiety and insomnia – mainly because benzodiazepines are significantly less dangerous in overdose. However, barbiturates are still used in general anesthesia, for epilepsy, and assisted suicide.^[1] Barbiturates are derivatives of barbituric acid.^[2]

History[link]

Barbituric acid was first synthesized December 6, 1864, by German researcher Adolf von Baeyer. This was done by condensing urea (an animal waste product) with diethyl malonate (an ester 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 feast of Saint Barbara—the patron saint of artillerists. An artillery officer is said to have christened the new substance by amalgamating Barbara with urea.^[3] Another story holds that Von Baeyer synthesized the substance from the collected urine of a Munich waitress named Barbara.^[4] No substance of medical value was discovered, however, until 1903 when two German scientists 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.^[3]

It was not until the 1950s that the behavioural disturbances and physical dependence potential of barbiturates became recognized.^[5]

While barbituric acid itself does not have any direct effect on the central nervous system, chemists have derived over 2,500 compounds from it that possess pharmacologically active qualities. The broad class of barbiturates is further broken down and classified according to speed of onset and duration of action. Ultrashort-acting barbiturates are commonly used for anesthesia because their extremely short duration of action allows for greater control. These properties allow doctors to rapidly put a patient "under" in emergency surgery situations. Doctors can also bring a patient out of anesthesia just as quickly, should complications arise during surgery. The middle two classes of barbiturates are often combined under the title "short/intermediate-acting." These barbiturates are also employed for anesthetic purposes, and are also sometimes prescribed for anxiety or insomnia. This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by the benzodiazepines for these purposes. The final class of barbiturates are known as long-acting barbiturates (the most notable one being phenobarbital, which has a half-life of roughly 92 hours). This class of barbiturates is used almost exclusively as anticonvulsants, although on rare occasions they are prescribed for daytime sedation. Barbiturates in this class are not used for insomnia, because, owing to their extremely long half-life, patients would awake with a residual "hang-over" effect and feel groggy.

Barbiturates can in most cases be used either as the free acid or as salts of sodium, calcium, potassium, magnesium, lithium, etc. Codeine- and Dionine-based salts of barbituric acid have been developed. In 1912, Bayer introduced another barbituric acid derivative, phenobarbital, under the trade name Luminal, as a sedative-hypnotic.^[6]

Therapeutic uses[link]

Barbiturates such as phenobarbital were long used as anxiolytics and hypnotics. Today, benzodiazepines have largely supplanted them for these purposes, because benzodiazepines have less potential for lethal overdoses.^[7][8][9]

Other uses related to their physiological properties[link]

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.^[10][11] Thiopental is an ultra-short acting barbiturate that is marketed under the name sodium pentothal. It is often mistaken for "truth serum" or sodium amytal, an intermediate-acting barbiturate that is used for sedation and to treat insomnia, but was also used in so-called sodium amytal "interviews" where the person being questioned would be much more likely to provide the truth whilst under the influence of this drug. When dissolved in water, sodium amytal can be swallowed, or it can be administered by intravenous injection. The drug does not itself force people to tell the truth, but is thought to decrease inhibitions, making subjects more likely to be caught off guard when questioned.^[12]

Mechanism of action[link]

The principal mechanism of action of barbiturates is believed to be their affinity for the GABA_A receptor (Acts on GABA : BDZ receptor Cl^- channel complex). GABA is the principal inhibitory neurotransmitter in the mammalian central nervous system (CNS). Barbiturates bind to the GABA_A receptor at the beta subunit, which are binding sites 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. At higher concentration, they inhibit the Ca²⁺-dependent release of neurotransmitters.^[13] Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABA_A receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABA_A receptor (pharmacodynamics: This increases the potency of GABA). The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose.^[14][15]

Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABA_A receptor channel is only one of several representatives. This superfamily of ion channels includes the neuronal nAChR channel, the 5HT3R channel, the GlyR channel and others. However, while GABA_A receptor currents are increased by barbiturates (and other general anaesthetics), ligand-gated ion channels that are predominantly permeable for cationic ions are blocked by these compounds. For example, neuronal nAChR channels are blocked by clinically relevant anaesthetic concentrations of both thiopental and pentobarbital.^[16] Such findings implicate (non-GABA-ergic) ligand-gated ion channels, e.g. the neuronal nAChR channel, in mediating some of the (side) effects of barbiturates.^[17]

Tolerance, dependence, overdose, and adverse reaction[link]

Older adults and pregnant women and babies should consider the risks associated with barbiturate use. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of sixty-five are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose.^[18] When barbiturates are taken during pregnancy, the drug passes through the mother's bloodstream to her fetus. After the baby is born, it may experience withdrawal symptoms and have trouble breathing. In addition, nursing mothers who take barbiturates may transmit the drug to their babies through breast milk.^[19]

Tolerance and dependence[link]

With regular use, tolerance to the effects of barbiturates develops.

Overdose[link]

Symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgment, drowsiness, shallow breathing, staggering, and in severe cases coma and death. The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. The amount of 1 g in dose orally can be highly poisonous with dosages from 2g to 10 g being generally fatal depending on the person tolerance level. Even in inpatient settings, however, the development of tolerance is still a problem, as dangerous and unpleasant withdrawal symptoms can result when the drug is stopped after dependence has developed. Barbiturates in overdose with other CNS (central nervous system) depressants for example, alcohol, opiates or benzodiazepines is even more dangerous due to additive CNS and respiratory depressant effects. In the case of benzodiazepines not only do they have additive effects, barbiturates also increase the binding affinity of the benzodiazepine binding site thus leading to an exaggerated effect of benzodiazepines.

Marilyn Monroe and Judy Garland both died of barbiturate overdose.

Adverse reaction[link]

A rare adverse reaction to barbiturates is Stevens–Johnson syndrome, which primarily affects the mucous membranes.

Recreational use[link]

Barbiturates produce effects similar to ethanol during intoxication. The symptoms of barbiturate intoxication include respiratory depression, lowered blood pressure, fatigue, fever, unusual excitement, irritability, dizziness, poor concentration, sedation, confusion, impaired coordination, impaired judgment, addiction, and respiratory arrest, which may lead to death.^[20]

Recreational users^[who?] report that a barbiturate high gives them feelings of relaxed contentment and euphoria. The main risk of acute barbiturate abuse is respiratory depression. Physical and psychological dependence may also develop with repeated use.^[21] Other effects of barbiturate intoxication include drowsiness, lateral and vertical nystagmus, slurred speech and ataxia, decreased anxiety, a loss of inhibitions. Barbiturates are also used to alleviate the adverse or withdrawal effects of illicit drug misuse.^[22][23]

Drug users tend to prefer short-acting and intermediate-acting barbiturates.^[24] The most commonly abused are amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). A combination of amobarbital and secobarbital (called Tuinal) is also highly abused. Short-acting and intermediate-acting barbiturates are usually prescribed as sedatives and sleeping pills. These pills begin acting fifteen to forty minutes after they are swallowed, and their effects last from five to six hours. Veterinarians use pentobarbital to anesthetise animals before surgery; in large doses, it can be used to euthanise animals.^[25]

Slang terms for barbiturates include barbs, bluebirds, dolls, downers, goofballs, sleepers and tooties.^[26]

Legal status[link]

In the 1940s, military personnel were given "Goofballs" during WWII in the South Pacific region to allow soldiers to tolerate the heat and humidity of daily working conditions. Goofballs were distributed to lower the respiratory system and blood pressure to combat the extreme conditions. Many soldiers returned with addictions that required several months of rehabilitation before discharge. This led to addiction problems through the 1950s and 1960s.

In the 1950s and 1960s, increasing reports began to be published about barbiturate overdoses and dependence problems, which eventually led to the scheduling of barbiturates as controlled drugs.

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 secobarbital, amobarbital, butalbital, cyclobarbital, and pentobarbital as schedule III, and allobarbital, methylphenobarbital, phenobarbital, and vinylbital as schedule IV scheduled substances.

Other uses in chemistry[link]

In 1988, the synthesis and binding studies of an artificial receptor binding barbiturates by 6 complementary hydrogen bonds was published.^[27] Since this first article, different kind of receptors were designed, as well as different barbiturates and cyanurates, not for their efficiencies as drugs but for applications in supramolecular chemistry, in the conception of materials and molecular devices.

Examples[link]

generic structure of a barbiturate, including numbering scheme

See also[link]

Pharmacy and Pharmacology portal

• Benzodiazepines
• The Dille–Koppanyi reagent, used as a spot test for barbiturates.
• The Zwikker reagent, also used as a spot test for barbiturates.

References[link]

External links[link]

Look up barbiturate in Wiktionary, the free dictionary.

• U.S. Drug Enforcement Administration Source for some public domain text used on this page.
• History of Barbiturates