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Barbituric acid, the basic structure of all barbiturates

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 total anesthesia. They are also effective as anxiolytics, hypnotics and as anticonvulsants. 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 Barbiturates have now largely been replaced by benzodiazepines in routine medical practice – for example, in the treatment of anxiety and insomnia – mainly because benzodiazepines are significantly less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, as well as for epilepsy. Barbiturates are derivatives of barbituric acid.



[edit] History

Barbituric acid was first synthesized on 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.[1] 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.[1]

It wasn’t until the 1950s that the behavioural disturbances and physical dependence potential of barbiturates became recognised.[2]

While barbituric acid itself does not have any effect on the central nervous system, to date, chemists have derived over 2,500 compounds that do possess pharmacologically active qualities. The broad class of barbiturates is broken down further 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 (most notably 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 as either 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.[3]

[edit] Therapeutic uses

Barbiturates like pentobarbital and 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.[4][5][6]

Barbiturates are classified as ultrashort-, short-, intermediate-, and long-acting, depending on how quickly they act and how long their effects last.[7] Barbiturates are still widely used in surgical anesthesia, especially to induce anesthesia, though their use during induction of anesthesia has largely been supplanted by Propofol. Ultrashort barbiturates such as thiopental (Pentothal) produce unconsciousness within about a minute of intravenous (IV) injection. These drugs are used to prepare patients for surgery; other general anesthetics like nitrous oxide are then used to keep the patient from waking up before the surgery is complete. Because Pentothal and other ultrashort-acting barbiturates are typically used in hospital settings, they are not very likely to be abused, noted the DEA.[8]

Phenobarbital is used as an anticonvulsant for people suffering from seizure disorders such as febrile seizures, tonic-clonic seizures, status epilepticus, and eclampsia.[9]

Long-acting barbiturates such as phenobarbital (Luminal) and mephobarbital (Mebaral) are prescribed for two main reasons. When taken at bedtime, they help treat insomnia. When taken during the day, they have sedative effects that can aid in the treatment of tension and anxiety. These same effects have been found helpful in the treatment of convulsive conditions like epilepsy. Phenobarbital has also been used in the treatment of delirium tremens during alcohol detoxification, although benzodiazepines have a more favorable safety profile and are more often used.[10] Long-acting barbiturates take effect within one to two hours and last 12 hours or longer.[8]

[edit] Other uses related to their physiological properties

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.[11][12] Thiopental, an ultra-short acting barbiturate that is marketed under the name Sodium Pentothal, is sometimes used as a “truth serum”. When dissolved in water, it can be swallowed or 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.[13]

[edit] Mechanism of action

The principal mechanism of action of barbiturates is believed to be their affinity for the GABAA 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 GABAA receptor at the alpha 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 GABAA 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.[9] Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABAA receptor (pharmacokinetics: this increases the efficacy of GABA) whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABAA receptor (pharmacokinetics: 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]

[edit] Tolerance, dependence and overdose

Older adults and pregnant women 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.[16] 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.[17]

[edit] Tolerance and dependence

With regular use tolerance to the effects of barbiturates develops. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect.[18] Barbiturate use can lead to both psychological and physical dependence and the drugs have a high abuse liability.[19] Psychological addiction to barbiturates can develop quickly. The GABAA receptor, one of barbiturates’ main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric “high” that results from their abuse.[19] The mechanism by which barbiturate tolerance develops is believed to be different than that of ethanol or benzodiazepines, even though these drugs have been shown to exhibit cross-tolerance with each other.[20] The management of a physical dependence on barbiturates is stabalisation on the long-acting barbiturate phenobarbitol followed by a gradual titration down of dose. The slowly eliminated phenobarbitol lessens the severity of the withdrawal syndrome and reduces the chances of serious barbiturate withdrawal effects such as seizures.[21] Antipsychotics are not recommended for barbiturate withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines eg chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required.[22]

[edit] Overdose

An overdose results when a person takes a larger-than-prescribed dose of a drug. Symptoms of an overdose typically include; sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgment, drowsiness or coma, shallow breathing, staggering and in severe cases coma and death.[23] The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. 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.[18] Barbiturates in overdose with other CNS 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.[24]

[edit] Recreational use

Like ethanol, barbiturates are intoxicating and produce similar effects 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.[25]

Recreational users 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.[26] 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.[27][28]

Drug users tend to prefer short-acting and intermediate-acting barbiturates.[29] 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.[8]

Slang terms for barbiturates include; barbs, bluebirds, blues, downers, goofballs, tooties and yellow jackets.[30]

[edit] Legal status

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.

[edit] Other uses in chemistry

In 1988, the synthesis and binding studies of an artificial receptor binding barbiturates by 6 complementary hydrogen bonds was published.[31] 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.

[edit] Examples

Short Name R5 R5 IUPAC Name
Allobarbital CH2CHCH2 CH2CHCH2 5,5-diallylbarbiturate
Amobarbital CH2CH3 CH2CH2CH(CH3)2 5-ethyl-5-isopentyl-barbiturate
Aprobarbital CH2CHCH2 CH(CH3)2 5-allyl-5-isopropyl-barbiturate
Alphenal CH2CHCH2 C6H5 5-allyl-5-phenyl-barbiturate
Barbital CH2CH3 CH2CH3 5,5-diethylbarbiturate
Brallobarbital CH2CHCH2 CH2CBrCH2 5-allyl-5-(2-bromo-allyl)-barbiturate
Phenobarbital CH2CH3 C6H5 5-phenyl-5-ethylbarbiturate

[edit] See also

  • Benzodiazepines

[edit] References

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[edit] External links

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