barbiturate

barbiturate, any one of a group of drugs that act as depressants on the central nervous system. High doses depress both nerve and muscle activity and inhibit oxygen consumption in the tissues. In low doses barbiturates act as sedatives, i.e., they have a tranquilizing effect; increased doses have a hypnotic or sleep-inducing effect; still larger doses have anticonvulsant and anesthetic activity. The mechanism of action on the central nervous system is not known. The barbiturates are all derivatives of barbituric acid, which was first prepared in 1864 by the German organic chemist Adolf von Baeyer.

The drugs differ widely in the duration of their action, which depends on the rapidity with which they are distributed in body tissues, degraded, and excreted. Ultrashort-acting barbiturates such as thiopental sodium (Pentothal) are often used as general anesthetics. Secobarbital (Seconal) and pentobarbital sodium (Nembutal) are short-acting barbiturates, amobarbital (Amytal) is intermediate in duration of action, and phenobarbital (Luminal) is a long-acting derivative.

Barbiturates are used to relax patients before surgery, as anticonvulsants, and as sleeping pills. They also are commonly abused. Taken regularly, barbiturates can be psychologically and physically addictive (see drug addiction and drug abuse). Barbiturate addicts must be withdrawn from the drug gradually to avoid severe withdrawal symptoms such as convulsions. Overdose can cause coma or death. In the United States the manufacture and distribution of barbiturates were brought under federal control by the 1965 Drug Abuse and Control Act, and they are legally available only by prescription.

Any of a class of heterocyclic compounds based on the parent structure, uric acid, and used in medicine. They depress the central nervous system, acting particularly on certain parts of the brain, though they tend to depress the functioning of all the body's tissues. Long-acting barbiturates (e.g., barbital and phenobarbital) are used to treat epilepsy. Intermediate ones (e.g., amobarbital) are used to treat insomnia, short-acting ones (e.g., pentobarbital) to overcome difficulty in falling asleep (one aspect of insomnia), and ultra-short-acting ones (e.g., thiopental sodium) to induce unconsciousness in surgical patients before administration of other anesthetics. Prolonged use of barbiturates may lead to addiction. Sudden withdrawal can be fatal; addicts must be weaned from the drug under medical supervision. Overdoses can result in coma and even death; barbiturates are particularly dangerous, even at normal doses, when combined with alcoholic beverages.

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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. 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 the benzodiazepines mainly due to benzodiazepines being significantly less dangerous in overdose. Barbiturates are derivatives of barbituric acid.

History

Barbituric acid, was first synthesized on December 4, 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 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.

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, due to the addiction liability associated with 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 due to their extremely long half-life, patients would awake with a residual "hang-over" effect and feel groggy. 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.

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.

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.

Barbiturates are classified as ultrashort-, short-, intermediate-, and long-acting, depending on how quickly they act and how long their effects last. Barbiturates are still widely used in surgical anesthesia, especially to induce anesthesia. 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.

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

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. Long-acting barbiturates take effect within one to two hours and last 12 hours or longer.

Other non-therapeutic uses

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. Thiopental is 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.

Mechanism of action

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 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 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. Barbiturates produce their pharmacological effects by increasing the length of time the chloride ion channel remains open at the GABA_A receptor whereas benzodiazepines increase the opening frequency of the chloride ion channel at the GABA_A receptor. The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose.

Tolerance, dependence and overdose

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. Barbiturate use can lead to both psychological and physical dependence and the drugs have a high abuse liability. Psychological addiction to barbiturates can develop quickly. The GABA_A 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. 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.

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. 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.

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. 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.

Recreational misuse and abuse

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.

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 psychic dependence may also develop with repeated use. Other effects of barbiturate intoxication include drowsiness, lateral and vertical nystagmus, slurred speech and ataxia, decreased anxiety, a loss of inhibitions. Barbiturates are also misused to alleviate the adverse or withdrawal effects of illicit drug misuse.

Drug abusers tend to prefer short-acting and intermediate-acting barbiturates. 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.

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

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.

Examples

Barbiturates

Short Name	R5	R5	Full 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

See also

• Benzodiazepines

References

External links

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