Barbiturate

Source: Wikipedia, the free encyclopedia.

Barbituric acid, the parent structure of all barbiturates

Barbiturates

controlled
in most countries due to the risks associated with such use.

Barbiturates have largely been replaced by

tension headaches, euthanasia, capital punishment, and assisted suicide.[3]

Uses

Medicine

Barbiturates, such as

overdose.[4][5][6] However, barbiturates are still used as anticonvulsants (e.g., phenobarbital and primidone) and general anesthetics (e.g., sodium thiopental
).

Barbiturates in high doses are used for medical aid in dying, and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection.[7][8] Barbiturates are frequently employed as euthanizing agents in small-animal veterinary medicine.

Interrogation

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 incorrectly be thought to be more likely to provide the truth whilst under the influence of the drug.[9] 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 and slow creative thinking, making subjects more likely to be caught off guard when questioned, and increasing the possibility of the subject revealing information through emotional outbursts. Lying is somewhat more complex than telling the truth, especially under the influence of a sedative-hypnotic drug.[10]

The memory-impairing effects and cognitive impairments induced by sodium thiopental are thought to reduce a subject's ability to invent and remember lies. This practice is no longer considered legally admissible in court, owing to findings that subjects undergoing such interrogations may form false memories, putting the reliability of all information obtained through such methods into question. Nonetheless, it is still employed in certain circumstances by defense and law enforcement agencies as a "humane" alternative to torture interrogation when the subject is believed to have information critical to the security of the state or agency employing the tactic.[11]

Chemistry

In 1988, the synthesis and binding studies of an artificial receptor binding barbiturates by six complementary hydrogen bonds was published.[12] 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.

The preferred IUPAC name of the base compound, barbituric acid, is 1,3-diazinane-2,4,6-trione. Different barbiturates have different substituents in the basic structure, mainly in position 5 on the ring.[13] In modern chemistry the barbiturates are often presented by its Hirshfeld surface representations showing its intermolecular interactions [1] calculated with CrystalExplorer Program. Sodium barbital and

pH buffers for biological research, e.g., in immuno-electrophoresis or in fixative solutions.[14][15]

Classification

Barbiturates are classified based on the duration of action. Examples of each class include:[16]

  • Ultra short acting (30 minutes):
    methohexitone
  • Short acting (2 hours):
    secobarbitone
  • Intermediate acting (3–6 hours):
    amobarbitone
    , butabarbitone
  • Long acting (6 hours):
    phenobarbitone

Indications

Indications for the use of barbiturates include:[17]

Side effects

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Barbiturates were ranked third in physical harm, fourth in social harm, and fifth in dependence.[18]

There are special risks to consider for older adults, and women who are pregnant. 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.[19] When barbiturates are taken during pregnancy, the drug passes through the placenta to the 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.[20] A rare adverse reaction to barbiturates is Stevens–Johnson syndrome, which primarily affects the mucous membranes.

Common side effects

  • Nausea
  • Hypotension
  • Headache
  • Drowsiness
  • Skin rash

Serious side effects

  • Confusion
  • Coma
  • Hallucination
  • Fainting
  • Slow breathing[21]

Rare side effects

Tolerance and dependence

Main article: Barbiturate dependence

With regular use,

benzodiazepine withdrawal although its more direct mechanism of GABA agonism makes barbiturate withdrawal even more severe than that of alcohol
or benzodiazepines. It is considered one of the most dangerous withdrawals of any known addictive substance. Similarly to benzodiazepines, the longer acting barbiturates produce a less severe withdrawal syndrome than short acting and ultra-short acting barbiturates. Withdrawal symptoms are dose-dependent with heavier users being more affected than lower-dose addicts.

The pharmacological treatment of barbiturate withdrawal is an extended process often consisting of converting the patient to a long-acting benzodiazepine (i.e. Valium), followed by slowly tapering off the benzodiazepine. Mental cravings for barbiturates can last for months or years in some cases and counselling/support groups are highly encouraged by addiction specialists. Patients should never try to tackle the task of discontinuing barbiturates without consulting a doctor, owing to the high lethality and relatively sudden onset of the withdrawal. Attempting to quit "cold turkey" may result in neurological damage due to excitotoxicity, severe physical injuries received during convulsions, and even death resulting from arrhythmias during grande Mal seizures, paralleling death caused by delirium tremens.[citation needed]

Overdose

Main article: Barbiturate overdose

Some symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgement, drowsiness, shallow breathing, staggering, and, in severe cases, coma or death. The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. The

lethal dose
is highly variable among different members of the class, with superpotent barbiturates such as pentobarbital being potentially fatal in considerably lower doses than the low-potency barbiturates such as butalbital. Even in inpatient settings, 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. Tolerance to the anxiolytic and sedative effects of barbiturates tends to develop faster than tolerance to their effects on smooth muscle, respiration, and heart rate, making them generally unsuitable for a long time psychiatric use. Tolerance to the anticonvulsant effects tends to correlate more with tolerance to physiological effects, however, meaning that they are still a viable option for long-term epilepsy treatment.

Barbiturates in overdose with other CNS (central nervous system) depressants (e.g. alcohol, opiates, benzodiazepines) are even more dangerous owing 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, leading to exaggerated benzodiazepine effects. (ex. If a benzodiazepine increases the frequency of channel opening by 300%, and a barbiturate increases the duration of their opening by 300%, then the combined effects of the drugs increases the channels' overall function by 900%, not 600%).

The longest-acting barbiturates have half-lives of a day or more, and subsequently result in bioaccumulation of the drug in the system. The therapeutic and recreational effects of long-acting barbiturates wear off significantly faster than the drug can be eliminated, allowing the drug to reach toxic concentrations in the blood following repeated administration (even when taken at the therapeutic or prescribed dose) despite the user feeling little or no effects from the plasma-bound concentrations of the drug. Users who consume alcohol or other sedatives after the drug's effects have worn off, but before it has cleared the system, may experience a greatly exaggerated effect from the other sedatives which can be incapacitating or even fatal.

Barbiturates induce a number of hepatic CYP enzymes (most notably CYP2C9, CYP2C19, and CYP3A4),[22] leading to exaggerated effects from many prodrugs and decreased effects from drugs which are metabolized by these enzymes to inactive metabolites. This can result in fatal overdoses from drugs such as codeine, tramadol, and carisoprodol, which become considerably more potent after being metabolized by CYP enzymes. Although all known members of the class possess relevant enzyme induction capabilities, the degree of induction overall as well as the impact on each specific enzyme span a broad range, with phenobarbital and secobarbital being the most potent enzyme inducers and butalbital and talbutal being among the weakest enzyme inducers in the class.

People who are known to have killed themselves by barbiturate overdose include Stefan Zweig, Charles Boyer, Ruan Lingyu, Dalida, Jeannine Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, C. P. Ramanujam, George Sanders, Jean Seberg, Lupe Vélez and the members of Heaven's Gate cult. Others who have died as a result of barbiturate overdose include Pier Angeli, Brian Epstein, Judy Garland, Jimi Hendrix, Marilyn Monroe, Inger Stevens, Dinah Washington, Ellen Wilkinson, and Alan Wilson; in some cases these have been speculated to be suicides as well. Those who died of a combination of barbiturates and other drugs include Rainer Werner Fassbinder, Dorothy Kilgallen, Malcolm Lowry, Edie Sedgwick and Kenneth Williams. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal (she was hospitalized with burns, the doctors treating her not being aware of her barbiturate addiction).

Contraindications

The use of Barbiturates is contraindicated in the following conditions:

  • variegate porphyria (because of induction of enzymes needed for porphyria synthesis by barbiturates)
  • Status asthmaticus (because of respiratory depression caused by the barbiturates)[23]

Mechanism of action

Barbiturates act as positive

voltage-dependent calcium channels.[26]
Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the
GABAA 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.[27][28]

Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABAA receptor channel is only one of several representatives. This

nACh receptor channel, the 5-HT3 receptor channel, and the glycine receptor channel. However, while GABAA receptor currents are increased by barbiturates (and other general anesthetics), 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 anesthetic concentrations of both thiopental and pentobarbital.[29] 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.[30]
This is the mechanism responsible for the (mild to moderate) anesthetic effect of barbiturates in high doses when used in anesthetic concentration.

Interactions

Drug interactions with barbiturates are:[21]

  • alcohol
  • opioids
  • benzodiazepines
  • anticoagulants
  • antihistamines
  • atazanavir
  • birth-control pills
  • boceprevir

Caution

Caution is needed in people using:[21]

  • Medications such as opioids or benzodiazepines
  • Alcohol

Caution is also required in patients with:

  • Asthma
  • Kidney- or liver-problems
  • Heart-disease
  • Substance use disorder
  • Depression
  • History of suicidal thoughts

History

Veronal. It is said that Mering proposed this name because the most peaceful place he knew was the Italian city of Verona.[31] In 1912, Bayer introduced another barbituric acid derivative, phenobarbital, under the trade name Luminal, as a sedative–hypnotic.[33]

It was not until the 1950s that the behavioral disturbances and physical dependence potential of barbiturates became recognized.[34]

Barbituric acid itself does not have any direct effect on the

Z-drug such as zolpidem, zaleplon and eszopiclone for sleep. 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.

Society and culture

Legal status

During World War II, military personnel in the Pacific region were given "goofballs" to improve their tolerance of the heat and humidity of daily working conditions. Goofballs reduced the demand on the respiratory system, as well as maintaining blood pressure. Many soldiers returned with addictions that required several months of rehabilitation before discharge. This led to growing dependency problems, often exacerbated by indifferent physicians prescribing high doses to unknowing patients through the 1950s and 1960s. [citation needed]

In the late 1950s and 1960s, an increasing number of published reports of barbiturate

overdoses
and dependence problems led physicians to reduce their prescription, particularly for spurious requests. This eventually led to the scheduling of barbiturates as controlled drugs.

In the Netherlands, the Opium Law classifies all barbiturates as List II drugs, with the exception of secobarbital, which is on List I.

There is a small group of List II drugs for which physicians have to write the prescriptions according to the same, tougher guidelines as those for List I drugs (writing the prescription in full in letters, listing the patients name, and have to contain the name and initials, address, city and telephone number of the licensed prescriber issuing the prescriptions, as well as the name and initials, address and city of the person the prescription is issued to). Among that group of drugs are the barbiturates amobarbital, butalbital, cyclobarbital, and pentobarbital.

In the United States, the

mephobarbital), and phenobarbital are designated schedule IV drugs, and "Any substance which contains any quantity of a derivative of barbituric acid, or any salt of a derivative of barbituric acid"[35] (all other barbiturates) were designated as being schedule III. Under the original CSA, no barbiturates were placed in schedule I, II, or V;[36] however, amobarbital, pentobarbital, and secobarbital are schedule II controlled substances unless they are in a suppository dosage form.[37]

In 1971, the

Fiorinal, which contains aspirin instead of paracetamol and may contain codeine
phosphate, remains a schedule III drug.

Recreational use

Recreational users report that a barbiturate high gives them feelings of relaxed contentment and

benzodiazepines such as diazepam and clonazepam.[41][42]
Often polysubstance use occurs and barbiturates are consumed with or substituted by other available substances, most commonly alcohol.

People who use substances tend to prefer short-acting and intermediate-acting barbiturates.[43] The most commonly used are amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). A combination of amobarbital and secobarbital (called Tuinal) is also highly used. 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.

Slang terms for barbiturates include barbs, barbies, bluebirds, dolls, wallbangers, yellows, downers, goofballs, sleepers, 'reds & blues', and tooties.[44]

Examples

Generic structure of a barbiturate, including numbering scheme
Barbiturates
Short name R1 R2 IUPAC name Duration of action
allobarbital
CH2CHCH2
CH2CHCH2
 5,5-diallylbarbiturate Short-acting
amobarbital[45] CH2CH3
(CH2)2CH(CH3)2
 5-ethyl-5-isopentyl-barbiturate Intermediate-acting
aprobarbital
CH2CHCH2
CH(CH3)2
 5-allyl-5-isopropyl-barbiturate Intermediate-acting
alphenal
CH2CHCH2
C6H5
 5-allyl-5-phenyl-barbiturate Intermediate-acting
barbital CH2CH3 CH2CH3 5,5-diethylbarbiturate Long-acting
brallobarbital
CH2CHCH2
CH2CBrCH2
 5-allyl-5-(2-bromo-allyl)-barbiturate Short-acting
pentobarbital[45] CH2CH3 CH CH3(CH2)2CH3 5-ethyl-5-(1-methylbutyl)-barbiturate Short-acting
phenobarbital[45] CH2CH3
C6H5
 5-ethyl-5-phenylbarbiturate Long-acting
primidone CH2CH3 C6H5 5-ethyl-5-phenyl-1,3-diazinane-4,6-dione

(it lacks oxygen at #2 position of generic barbiturate structure)

Long-acting
secobarbital[45]
CH2CHCH2
CHCH3(CH2)2CH3
 5-[(2R)-pentan-2-yl]-5-prop-2-enyl-barbiturate; 5-allyl-5-[(2R)-pentan-2-yl]-barbiturate Short-acting
thiopental
 CH2CH3 CHCH3(CH2)2CH3 5-ethyl-5-(1-methylbutyl)-2-thiobarbiturate

(the oxygen at #2 position is replaced by a sulfur)

Ultrashort-acting

Thiopental is a barbiturate with one of the C=O double bonds (with the carbon being labelled 2 in the adjacent diagram) replaced with a C=S double bond, R1 being CH2CH3 (ethyl) and R3) being CH(CH3)CH2CH2CH3 (sec-pentyl). Thiopental is no longer available in the United States.[46]

See also

Explanatory notes

  1. ^ The most often cited standard pronunciation is /bɑːrˈbɪtjʊrɪt/ bar-BIT-yuu-rit; however, at least in the United States, the more commonly used colloquial pronunciation is /bɑːrˈbɪtjuɪt/ bar-BIT-ew-it.[1]

References

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  35. ^ Pub. L. 91-513, 27 October 1970, Sec. 202(c) Sched. III(b)(1)
  36. ^ 21 U.S.C. § 812
  37. ^ 21 U.S.C. § §1308.12
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External links and further reading

Look up barbiturate in Wiktionary, the free dictionary.