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Barbiturates[a] are a class of depressant drugs that are chemically derived from barbituric acid.[2] They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have been used recreationally for their anti-anxiety and sedative effects, and are thus controlled in most countries due to the risks associated with such use.
Barbiturates have largely been replaced by benzodiazepines and nonbenzodiazepines ("Z-drugs") in routine medical practice, particularly in the treatment of anxiety disorders and insomnia, because of the significantly lower risk of overdose, and the lack of an antidote for barbiturate overdose. Despite this, barbiturates are still in use for various purposes: in general anesthesia, epilepsy, treatment of acute migraines or cluster headaches, acute tension headaches, euthanasia, capital punishment, and assisted suicide.[3]
Uses
[edit]Medicine
[edit]Barbiturates, such as phenobarbital, were long used as anxiolytics and hypnotics. Intermediate-acting barbiturates reduce time to fall asleep, increase total sleep time, and reduce REM sleep time. Today they have been largely replaced by benzodiazepines for these purposes because the latter are less toxic in drug 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
[edit]Sodium 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 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
[edit]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]. Sodium barbital and barbital have also been used as pH buffers for biological research, e.g., in immuno-electrophoresis or in fixative solutions.[14][15]
Classification
[edit]Barbiturates are classified based on the duration of action. Examples of each class include:[16]
- Ultra short acting (30 minutes): thiopentone, methohexitone
- Short acting (2 hours): hexobarbitone, cyclobarbitone, pentobarbitone, secobarbitone
- Intermediate acting (3–6 hours): amobarbitone, butabarbitone
- Long acting (6 hours): phenobarbitone
Indications
[edit]Indications for the use of barbiturates include:[17]
- Seizure
- Neonatal withdrawal syndrome
- Insomnia
- Anxiety
- Inducing anesthesia
Side effects
[edit]
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 65 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.
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Common side effects
[edit]- Nausea
- Hypotension
- Headache
- Drowsiness
- Skin rash
Serious side effects
[edit]- Confusion
- Coma
- Hallucination
- Fainting
- Slow breathing[21]
Rare side effects
[edit]Tolerance and dependence
[edit]With regular use, tolerance to the effects of barbiturates develops. Research shows tolerance can develop with even one administration of a barbiturate. As with all GABAergic drugs, barbiturate withdrawal produces potentially fatal effects such as seizures, in a manner reminiscent of delirium tremens and 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
[edit]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, Carole Landis, 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, , 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, Marilyn Monroe 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
[edit]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
[edit]Barbiturates act as positive allosteric modulators and, at higher doses, as agonists of GABAA receptors.[24] GABA is the principal inhibitory neurotransmitter in the mammalian central nervous system (CNS). Barbiturates bind to the GABAA receptor at multiple homologous transmembrane pockets located at subunit interfaces,[25] 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 GABAergic effect, barbiturates also block AMPA and kainate receptors, subtypes of ionotropic 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 superior CNS-depressant effects of these agents to alternative GABA potentiating agents such as benzodiazepines and quinazolinones. At higher concentration, they inhibit the Ca2+-dependent release of neurotransmitters such as glutamate via an effect on P/Q-type 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 Cys-loop receptor superfamily of ion channels includes the neuronal 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
[edit]Drug interactions with barbiturates are:[21]
- alcohol
- opioids
- benzodiazepines
- anticoagulants
- antihistamines
- atazanavir
- birth-control pills
- boceprevir
Caution
[edit]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
[edit]Barbituric acid was first synthesized 27 November 1864, by German chemist Adolf von Baeyer. This was done by condensing urea with diethyl malonate. There are several stories about how the substance got its name. The most likely story is that 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 artillerymen. An artillery officer is said to have christened the new substance by amalgamating Barbara with urea.[31] Another story holds that Baeyer synthesized the substance from the collected urine of a Munich waitress named Barbara.[32] No substance of medical value was discovered, however, until 1902 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 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]
Since the 1970s, most barbiturates were replaced by benzodiazepines.[35]
Barbituric acid itself does not have any direct effect on the central nervous system and 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 and 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
[edit]Legal status
[edit]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 Controlled Substances Act of 1970 classified most barbiturates as controlled substances—and they remain so as of August 2023[update]. Barbital, methylphenobarbital (also known as 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"[36] (all other barbiturates) were designated as being schedule III. Under the original CSA, no barbiturates were placed in schedule I, II, or V;[37] however, amobarbital, pentobarbital, and secobarbital are now schedule II controlled substances unless they are in a suppository dosage form.[38]
In 1971, the Convention on Psychotropic Substances was signed in Vienna. Designed to regulate amphetamines, barbiturates, and other synthetics, the 34th version of the treaty, as of 25 January 2014[update], regulates secobarbital as schedule II, amobarbital, butalbital, cyclobarbital, and pentobarbital as schedule III, and allobarbital, barbital, butobarbital, mephobarbital, phenobarbital, butabarbital, and vinylbital as schedule IV on its "Green List".[39] The combination medication Fioricet, consisting of butalbital, caffeine, and paracetamol (acetaminophen), however, is specifically exempted from controlled substance status, while its sibling Fiorinal, which contains aspirin instead of paracetamol and may contain codeine phosphate, remains a schedule III drug.
Recreational use
[edit]Recreational users report that a barbiturate high gives them feelings of relaxed contentment and euphoria. Physical and psychological dependence may also develop with repeated use.[40] Chronic misuse of barbiturates is associated with significant morbidity. One study found that 11% of males and 23% of females with a sedative-hypnotic misuse die by suicide.[41] Other effects of barbiturate intoxication include drowsiness, lateral and vertical nystagmus, slurred speech and ataxia, decreased anxiety, and loss of inhibitions. Barbiturates are also used to alleviate the adverse or withdrawal effects of illicit drug use, in a manner similar to long-acting benzodiazepines such as diazepam and clonazepam.[42][43] 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.[44] 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.[45]
Examples
[edit]
| Short name | R1 | R2 | IUPAC name | Duration of action |
|---|---|---|---|---|
| allobarbital | CH2CHCH2 | CH2CHCH2 | 5,5-diallylbarbiturate | Short-acting |
| amobarbital[46] | 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[46] | CH2CH3 | CH CH3(CH2)2CH3 | 5-ethyl-5-(1-methylbutyl)-barbiturate | Short-acting |
| phenobarbital[46] | 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[46] | 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.[47]
See also
[edit]- Benzodiazepine
- Psycholeptic
- Dille–Koppanyi reagent, Zwikker reagent, and others spot tests for barbiturates
Explanatory notes
[edit]- ^ 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 /bɑːrˈbɪtʃuɪt/ bar-BIH-chew-it.[1]
References
[edit]- ^ Vaux, Bert and Scott Golder. 2003. The Harvard Dialect Survey Archived 30 April 2016 at the Wayback Machine. Cambridge, MA: Harvard University Linguistics Department.
- ^ Edward R. Garrett; Jacek T. Bojarski†; Gerald J. Yakatan (21 September 2006). "Kinetics of hydrolysis of barbituric acid derivatives". Journal of Pharmaceutical Sciences. 60 (8): 1145–54. doi:10.1002/jps.2600600807. PMID 5127086.
- ^ "DIGNITAS". Archived from the original on 9 October 2018. Retrieved 14 June 2011.
- ^ Whitlock FA (14 June 1975). "Suicide in Brisbane, 1956 to 1973: the drug-death epidemic". Med J Aust. 1 (24): 737–43. doi:10.5694/j.1326-5377.1975.tb111781.x. PMID 239307.
- ^ Johns MW (1975). "Sleep and hypnotic drugs". Drugs. 9 (6): 448–78. doi:10.2165/00003495-197509060-00004. PMID 238826. S2CID 38775294.
- ^ Jufe, GS (2007). "Nuevos hipnóticos: perspectivas desde la fisiología del sueño [New hypnotics: perspectives from sleep physiology]" (PDF). Vertex (Buenos Aires, Argentina) (in Spanish). 18 (74): 294–9. PMID 18265473. Archived from the original (PDF) on 26 February 2021. Retrieved 12 February 2017.
- ^ "Administration and Compounding Of Euthanasic Agents". Archived from the original on 7 June 2008. Retrieved 15 July 2008.
- ^ Daniel Engber (3 May 2006). "Why do lethal injections have three drugs?". Slate Magazine. Archived from the original on 6 November 2018. Retrieved 15 July 2008.
- ^ Brown, David (20 November 2006). "Some Believe 'Truth Serums' Will Come Back". The Washington Post. Retrieved 26 July 2023.
- ^ "Neuroscience for Kids – Barbiturates". Archived from the original on 16 June 2008. Retrieved 2 June 2008.
- ^ Stocks, JT (1998). "Recovered memory therapy: a dubious practice technique". Social Work. 43 (5): 423–36. doi:10.1093/sw/43.5.423. PMID 9739631.
- ^ Chang, Suk Kyu.; Hamilton, Andrew D. (1988). "Molecular recognition of biologically interesting substrates: Synthesis of an artificial receptor for barbiturates employing six hydrogen bonds". Journal of the American Chemical Society. 110 (4): 1318–1319. Bibcode:1988JAChS.110.1318C. doi:10.1021/ja00212a065.
- ^ "Barbiturates drug profile | www.emcdda.europa.eu". www.emcdda.europa.eu. Retrieved 22 December 2021.
- ^ "Wolf D. Kuhlmann, "Buffer Solutions"" (PDF). 10 September 2006. Archived from the original (PDF) on 9 November 2016. Retrieved 28 July 2014.
- ^ Steven E. Ruzin (1999). Plant Microtechnique and Microscopy. Oxford University Press. Archived from the original on 3 June 2019. Retrieved 28 July 2014.
- ^ "JaypeeDigital | Drugs Acting on Central Nervous System Sedative-Hypnotics, Alcohols, Antiepileptics and Antiparkinsonian Drugs". www.jaypeedigital.com. Retrieved 22 December 2021.
- ^ Skibiski, Jeanie; Abdijadid, Sara (2021), "Barbiturates", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30969553, retrieved 21 December 2021
- ^ Nutt, D; King, LA; Saulsbury, W; Blakemore, C (24 March 2007). "Development of a rational scale to assess the harm of drugs of potential misuse". Lancet. 369 (9566): 1047–53. doi:10.1016/s0140-6736(07)60464-4. PMID 17382831. S2CID 5903121.
- ^ WebMD. "Toxicity, Barbiturate". eMedicine. Archived from the original on 20 July 2008. Retrieved 15 July 2008.
- ^ Nau H; Kuhnz W; Egger HJ; Rating D; Helge H (November 1982). "Anticonvulsants during pregnancy and lactation. Transplacental, maternal and neonatal pharmacokinetics". Clin Pharmacokinet. 7 (6): 508–43. doi:10.2165/00003088-198207060-00003. PMID 6819105. S2CID 20617888.
- ^ a b c d "Barbiturates: Side Effects, Dosages, Treatment, Interactions, Warnings". RxList. Retrieved 22 December 2021.
- ^ "Livertox". Archived from the original on 2 July 2019. Retrieved 21 June 2019.
- ^ Skibiski, Jeanie; Abdijadid, Sara (2021), "Barbiturates", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30969553, retrieved 21 December 2021
- ^ Löscher, W.; Rogawski, M. A. (2012). "How theories evolved concerning the mechanism of action of barbiturates". Epilepsia. 53: 12–25. doi:10.1111/epi.12025. PMID 23205959. S2CID 4675696.
- ^ Chiara, D. C.; Jayakar, S. S.; Zhou, X.; Zhang, X.; Savechenkov, P. Y.; Bruzik, K. S.; Miller, K. W.; Cohen, J. B. (15 May 2013). "Specificity of Intersubunit General Anesthetic-binding Sites in the Transmembrane Domain of the Human α1β3γ2 γ-Aminobutyric Acid Type A (GABAA) Receptor". Journal of Biological Chemistry. 288 (27): 19343–19357. doi:10.1074/jbc.M113.479725. PMC 3707639. PMID 23677991.
- ^ Brunton, Laurence L.; Lazo, John S.; Parker, Keith L.; Goodman, Louis Sanford; Gilman, Alfred Goodman (2005). Goodman & Gilman's Pharmacological Basis of Therapeutics. McGraw-Hill. ISBN 978-0-07-142280-2.
- ^ Neil Harrison; Wallace B Mendelson; Harriet de Wit (2000). "Barbiturates". Neuropsychopharmacology. Retrieved 15 July 2008.
...Barbiturates therefore promote entry of GABA-activated channels into a long-lived open state, whereas [benzodiazepines] increase only the frequency of channel opening into the initial open state. These mechanistic studies reveal interesting details of the changes in channel gating caused by barbiturates but as yet have yielded no insights into the molecular sites of action. An additional interesting effect of barbiturates is direct gating of the channels, i.e., the barbiturates may open the channel even in the absence of GABA. This usually occurs at significantly higher concentrations than those that potentiate the actions of GABA; these concentrations also are generally higher than those required for clinically effective anesthesia.
- ^ Siegel, George J.; Bernard W. Agranoff; Stephen K. Fisher; R. Wayne Albers; Michael D. Uhler (1999) [1998]. "Part 2 Chapter 16". Basic Neurochemistry – Molecular, Cellular and Medical Aspects (Sixth ed.). Lippincott Williams and Wilkins. ISBN 978-0-397-51820-3. Retrieved 1 July 2008.
- ^ Weber, M; Motin, L; Gaul, S; Beker, F; Fink, RH; Adams, DJ (January 2005). "Intravenous anaesthetics inhibit nicotinic acetylcholine receptor-mediated currents and Ca2+ transients in rat intracardiac ganglion neurons". British Journal of Pharmacology. 144 (1): 98–107. doi:10.1038/sj.bjp.0705942. PMC 1575970. PMID 15644873.
- ^ Franks, NP; Lieb, WR (23 November 1998). "Which molecular targets are most relevant to general anaesthesia?". Toxicology Letters. 100–101: 1–8. doi:10.1016/S0378-4274(98)00158-1. PMID 10049127.
- ^ a b "Barbiturates". Archived from the original on 7 November 2007. Retrieved 31 October 2007.
- ^ Medical Curiosities. Youngson, Robert M. London: Robinson Publishing, 1997. Page 276.
- ^ Sneader, Walter (23 June 2005). Drug Discovery. John Wiley and Sons. p. 369. ISBN 978-0-471-89979-2.
- ^ Galanter, Marc; Kleber, Herbert D. (1 July 2008). The American Psychiatric Publishing Textbook of Substance Abuse Treatment (4th ed.). United States of America: American Psychiatric Publishing Inc. p. 217. ISBN 978-1-58562-276-4.
- ^ Hans Bangen: Geschichte der medikamentösen Therapie der Schizophrenie. Berlin 1992, ISBN 3-927408-82-4, Page 24.
- ^ Pub. L. 91-513, 27 October 1970, Sec. 202(c) Sched. III(b)(1)
- ^ 21 U.S.C. § 812
- ^ 21 U.S.C. § §1308.12
- ^ "List of Psychotropic Substances under International Control ("Green List")" (PDF). International Narcotics Control Board. 25 January 2014. Archived from the original (PDF) on 24 September 2015. Retrieved 19 December 2013.
- ^ Schlatter J; Sitbon N; Saulnier JL (17 February 2001). "[Drugs and drug abusers]". Presse Med. 30 (6): 282–7. PMID 11252979.
- ^ Allgulander C, Ljungberg L, Fisher LD (May 1987). "Long-term prognosis in addiction on sedative and hypnotic drugs analyzed with the Cox regression model". Acta Psychiatr Scand. 75 (5): 521–31. doi:10.1111/j.1600-0447.1987.tb02828.x. PMID 3604738. S2CID 168126.
- ^ Emedicine Health. "Barbiturate Abuse". p. 1. Archived from the original on 2 August 2008. Retrieved 15 July 2008.
- ^ Faulkner TP; Hayden JH; Mehta CM; Olson DA; Comstock EG (1979). "Dose-response studies on tolerance to multiple doses of secobarbital and methaqualone in a polydrug abuse population". Clin Toxicol. 15 (1): 23–37. doi:10.3109/15563657908992476. PMID 498734.
- ^ Coupey SM (August 1997). "Barbiturates". Pediatr Rev. 18 (8): 260–4. doi:10.1542/pir.18-8-260. PMID 9255991.
- ^ Hamid H.; El-Mallakh RS; Vandeveir K (March 2005). "Substance Abuse: Medical and Slang Terminology". South Med J. 98 (3): 350–362. doi:10.1097/01.SMJ.0000153639.23135.6A. PMID 15813163. S2CID 29194849.
- ^ a b c d Smith, Roger; Bogusz, Maciej J (22 September 2011). "phenobarbital"+"secobarbital"+"amobarbital"+"r1"+"r2" Forensic Science (2 ed.). Elsevier. p. 245. ISBN 9780080554259. Retrieved 21 December 2013.
- ^ Skibiski, Jeanie; Abdijadid, Sara (2021), "Barbiturates", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30969553, retrieved 8 July 2021
External links and further reading
[edit]
- López-Muñoz, F.; Ucha-Udabe, R.; Alamo, C. (2005). "The history of barbiturates a century after their clinical introduction". Neuropsychiatric Disease and Treatment. 1 (4): 329–343. PMC 2424120. PMID 18568113.
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Barbiturate
View on GrokipediaChemical Structure and Classification
Derivatives of Barbituric Acid
Barbiturates constitute a class of sedative-hypnotic drugs obtained by modifying barbituric acid, the parent compound chemically known as pyrimidine-2,4,6(1H,3H,5H)-trione, which itself exhibits no central nervous system depressant effects.[6][7] The key structural alteration involves disubstitution at the 5-position of the barbituric acid ring with alkyl, aryl, or other lipophilic groups, such as ethyl and phenyl in phenobarbital (5-ethyl-5-phenylbarbituric acid) or ethyl and 1-methylbutyl in pentobarbital.[8][9] This modification enhances lipid solubility and enables binding to GABA_A receptors, conferring pharmacological activity.[1] Synthesis of these derivatives typically proceeds via condensation of diethyl malonate derivatives—alkylated at the alpha position—with urea or thiourea under basic conditions, followed by cyclization and hydrolysis.[10] More than 2,500 such compounds have been synthesized since the early 20th century, with variations in substituents influencing potency, duration of action, and solubility; for instance, dialkyl substitutions like in barbital (5,5-diethylbarbituric acid) yield longer-acting agents, while aryl-alkyl combinations produce intermediate effects.[11][8] Further derivatization includes replacement of the 2-position oxygen with sulfur, forming thiobarbiturates such as thiopental (5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid), which exhibit greater lipophilicity, rapid onset, and ultrashort duration due to redistribution from the brain.[12] Approximately 50 barbiturate derivatives have entered clinical use, including phenobarbital (introduced 1912), pentobarbital, and secobarbital, though many were later restricted due to safety profiles.[7][1] These structural insights underpin classifications by duration, with short-acting agents favoring branched alkyl chains at C-5 for quicker metabolism.[11]Duration-Based Classification
Barbiturates are classified based on the duration of their sedative-hypnotic effects, which correlates with their lipid solubility and rate of redistribution from the brain to peripheral tissues, influencing onset, peak action, and termination of effect independent of hepatic metabolism in many cases.[13] This system divides them into ultra-short-acting, short-acting, intermediate-acting, and long-acting categories, guiding clinical applications from rapid anesthesia induction to chronic seizure control.[1] Ultra-short-acting barbiturates exhibit effects lasting approximately 5 to 30 minutes following intravenous administration, primarily due to rapid redistribution into less vascularized tissues.[14] Examples include thiopental (also known as thiopentone), which has an onset of 10 to 30 seconds and a hypnotic duration of 5 to 10 minutes, and methohexital, with similar pharmacokinetics suited for brief procedures.[1] These agents are almost exclusively reserved for anesthesia induction owing to their fleeting action.[15] Short-acting barbiturates produce hypnosis for 2 to 6 hours, with oral onset in 15 to 30 minutes and peak effects within 1 to 2 hours.[14] Representative compounds are pentobarbital (Nembutal), featuring a half-life of 15 to 50 hours but shorter hypnotic duration due to redistribution, and secobarbital (Seconal), often used historically for preoperative sedation or short-term insomnia treatment.[1][16] Intermediate-acting barbiturates have durations of 3 to 8 hours, balancing sedation needs for procedures or sleep without excessive hangover effects.[17] Amobarbital (Amytal) exemplifies this group, with hypnotic effects lasting 4 to 6 hours after oral dosing, while butalbital, typically combined in formulations for tension headaches, shares comparable kinetics.[14] Long-acting barbiturates sustain effects for 6 to 12 hours or longer, often extending to 24 hours or more for hypnotic purposes, owing to slower redistribution and reliance on metabolic elimination.[15] Phenobarbital (Luminal), with a half-life of 37 to 140 hours, is the prototypical agent, employed for epilepsy management due to its prolonged anticonvulsant activity despite accumulation risks.[16][1]| Category | Approximate Hypnotic Duration | Key Examples |
|---|---|---|
| Ultra-short-acting | 5–30 minutes | Thiopental, methohexital |
| Short-acting | 2–6 hours | Pentobarbital, secobarbital |
| Intermediate-acting | 3–8 hours | Amobarbital, butalbital |
| Long-acting | 6–12+ hours | Phenobarbital |
History
Discovery and Synthesis
Barbituric acid, the parent compound of barbiturates, was first synthesized on November 27, 1864, by German chemist Adolf von Baeyer through the condensation of urea and malonic acid.[18] The name derives from the fact that Baeyer prepared it on the feast day of Saint Barbara.[19] Although barbituric acid itself exhibited no significant pharmacological activity, its structure provided a foundation for subsequent derivatization efforts aimed at exploring potential therapeutic applications.[2] The synthesis process involved reacting urea with diethyl malonate under basic conditions, yielding the cyclic barbituric acid core characterized by two carbonyl groups adjacent to a nitrogen atom in a pyrimidine ring.[7] This method was later refined by French chemist Édouard Grimaux in 1879, improving yields and purity for further chemical investigations into uric acid derivatives.[20] Early work focused on structural elucidation rather than biological effects, as barbituric acid and initial analogs showed no hypnotic or sedative properties in preliminary tests.[21] Breakthrough in pharmacological utility occurred in 1903 when Emil Fischer, a Nobel laureate in chemistry and former collaborator of Baeyer, synthesized 5,5-diethylbarbituric acid (barbital).[7] Fischer patented the compound in January 1903, and pharmacologist Joseph von Mering demonstrated its potent hypnotic effects in animal models, particularly dogs, leading to its introduction as Veronal, the first clinically viable barbiturate sedative.[2] This discovery marked the transition from purely synthetic curiosity to therapeutic agent, with barbital's diethyl substitution at the 5-position of the barbituric acid ring conferring central nervous system depression.[22] Subsequent alkylations and variations on this scaffold enabled the rapid proliferation of barbiturate derivatives.[10]Medical Adoption and Expansion
The first barbiturate adopted for clinical use was barbital (also known as Veronal), whose sedative and hypnotic properties were identified in 1903 by researchers Josef von Mering and Emil Fischer; it was introduced commercially by Bayer in 1904 as a treatment for insomnia and nervousness, offering a safer alternative to existing agents like bromides.[2] This marked the initial medical adoption, with barbital rapidly gaining acceptance for its reliability in inducing sleep without the toxicity issues of prior sedatives.[2] The success of barbital spurred extensive research and synthesis efforts, leading to the development of phenobarbital (Luminal) in 1911 by Heinrich Hörlein at Bayer, which was marketed in 1912 primarily for sedation but quickly established as an effective anticonvulsant for epilepsy after Alfred Hauptmann demonstrated its ability to suppress seizures without excessive drowsiness.[2][23] By the 1920s, pharmaceutical companies such as Eli Lilly and Abbott Laboratories accelerated expansion through new derivatives, including amobarbital (Amytal) in 1923 for sedation, secobarbital (Seconal) in 1929, and pentobarbital (Nembutal) in 1930 for both sedation and epilepsy management.[2] Further innovation in the 1930s extended barbiturate applications to anesthesia, exemplified by thiopental (Pentothal) introduced by Abbott in 1935, which enabled rapid intravenous induction and revolutionized surgical procedures by allowing shorter-acting, controllable sedation compared to inhalational agents.[2] Over the early to mid-20th century, more than 2,500 barbiturates were synthesized, with approximately 50 achieving clinical use, dominating therapeutic categories such as anxiolytics, hypnotics, and pre-anesthetic medications from the 1920s until the mid-1950s, when they comprised nearly all available options for these indications.[2] This proliferation reflected their perceived efficacy and versatility in addressing central nervous system disorders, though later scrutiny revealed limitations in safety margins.[2]Decline Due to Safety Concerns
The widespread use of barbiturates began to decline in the mid-20th century primarily due to their narrow therapeutic index, which made accidental and intentional overdoses highly lethal; doses producing sedation could readily escalate to respiratory depression, coma, and death without a clear safety margin.[5] Unlike safer alternatives, barbiturates lacked a ceiling effect on CNS depression, leading to frequent fatalities—by the 1950s and 1960s, they were implicated in a significant proportion of drug-related suicides and accidental poisonings, with postmortem data showing barbiturates in up to 20-30% of such cases in some Western countries.[2] Dependence developed rapidly with chronic use, characterized by tolerance requiring escalating doses and severe withdrawal symptoms including seizures and delirium, further eroding their favorability for long-term therapy.[24] The introduction of benzodiazepines marked a pivotal shift, as these agents offered anxiolytic and hypnotic effects with markedly lower risks of fatal overdose and dependence; chlordiazepoxide (Librium) was approved by the FDA in 1960, followed by diazepam (Valium) in 1963, rapidly supplanting barbiturates for treating anxiety, insomnia, and seizures due to their wider safety profile and reduced respiratory suppression even at high doses.[25] By the late 1960s, clinical guidelines increasingly recommended benzodiazepines over barbiturates, contributing to a steep drop in barbiturate prescriptions—U.S. data indicate a decline from peak usage in the 1950s to less than 10% of sedative prescriptions by the 1980s.[2] Regulatory responses amplified this decline amid rising abuse concerns; the U.S. Controlled Substances Act of 1970 classified most barbiturates as Schedule II (high abuse potential) or III drugs, imposing strict prescribing limits and monitoring, while similar controls emerged in Europe following reports of widespread misuse in the 1960s counterculture era.[24] These measures, coupled with accumulating evidence of barbiturate-related hospital admissions for toxicity—often involving synergistic effects with alcohol—solidified their relegation to niche roles like refractory epilepsy and anesthesia induction, where their potency remains unmatched but risks are managed in controlled settings.[5][2]Pharmacology
Mechanism of Action
Barbiturates exert their central nervous system depressant effects primarily through positive allosteric modulation of γ-aminobutyric acid type A (GABA_A) receptors, the predominant inhibitory receptors in the brain.[1] These receptors are ligand-gated chloride channels composed of multiple subunits, including α, β, and γ isoforms. Barbiturates bind to a site distinct from the orthosteric GABA-binding pocket, typically involving interactions with the α and β subunits in the transmembrane domain, which enhances GABA's affinity and efficacy.[1] [26] This modulation prolongs the duration of chloride channel opening triggered by GABA, increasing chloride influx into postsynaptic neurons, which hyperpolarizes the membrane and suppresses neuronal excitability and firing.[27] Unlike benzodiazepines, which primarily increase the frequency of channel opening, barbiturates' prolongation of open time contributes to their greater potency in inducing sedation, hypnosis, and anesthesia.[27] At higher concentrations, corresponding to anesthetic or anticonvulsant doses, barbiturates can directly activate GABA_A receptors independently of GABA, further augmenting chloride conductance and inhibitory tone.[1] [27] This direct gating is evident in studies using recombinant receptors and neuronal cultures, where compounds like pentobarbital elicit chloride currents without agonist presence, distinguishing barbiturates from weaker modulators.[28] The β subunit's second and third transmembrane domains, including specific methionine residues, are critical for this barbiturate sensitivity, as demonstrated in mutagenesis experiments.[27] Secondary mechanisms include antagonism of excitatory glutamate receptors, such as AMPA/kainate subtypes, and inhibition of glutamate release via presynaptic P/Q-type voltage-gated calcium channels, which reduce excitatory neurotransmission and reinforce overall CNS depression.[27] [26] However, GABA_A modulation remains the dominant pathway, with potency varying by barbiturate structure and receptor subunit composition; for instance, phenobarbital shows less direct activation than pentobarbital, correlating with differential sedative profiles.[27]Pharmacokinetics and Metabolism
Barbiturates exhibit variable pharmacokinetics depending on their chemical structure and lipophilicity, influencing their absorption, distribution, metabolism, and excretion. Most are well-absorbed orally, with phenobarbital achieving peak plasma concentrations in 2 to 4 hours and approximately 90% bioavailability in adults, though neonates show reduced bioavailability.[1] Intravenous administration provides rapid onset for applications like status epilepticus or anesthesia, while rectal or intramuscular routes offer alternatives with varying absorption rates.[1] Distribution is characterized by high lipid solubility, enabling rapid crossing of the blood-brain barrier and extensive tissue penetration, including into the central nervous system.[1] Highly lipophilic agents like thiopental and methohexital undergo quick redistribution from brain to peripheral tissues such as muscle and fat, which primarily terminates their ultra-short hypnotic effects after moderate doses (e.g., 5 mg/kg for thiopental), rather than relying on metabolism.[1][29] Larger doses prolong action by saturating redistribution sites, shifting dependence toward slower elimination processes.[29] Plasma protein binding varies, affecting free drug levels available for pharmacological action. Metabolism occurs predominantly in the liver through oxidation via cytochrome P450 enzymes, converting lipophilic barbiturates into inactive, water-soluble metabolites.[1] Phenobarbital, a long-acting barbiturate, undergoes extensive hepatic biotransformation and potently induces CYP1A2, CYP2B6, CYP2C9, and CYP3A4/5 enzymes, accelerating its own clearance (autoinduction) and that of co-administered drugs, which contributes to tolerance development as half-life shortens by approximately 4.6 hours per day with chronic use.[1] Shorter-acting barbiturates like secobarbital follow similar pathways but with faster rates, while ultra-short agents like thiopental exhibit first-order kinetics at low doses but non-linear elimination at higher doses due to saturation.[1] Primidone, a barbiturate precursor, is metabolized to phenobarbital and phenylethylmalonamide.[1] Excretion is primarily renal, with most barbiturates eliminated as metabolites in urine; phenobarbital is unique in that about 25% is excreted unchanged, a process enhanced by urinary alkalinization or osmotic diuresis to ionize the weakly acidic drug and prevent tubular reabsorption.[1] Elimination rates are faster in younger individuals and slower in the elderly, infants, or those with hepatic impairment, influencing dosing adjustments.[1] For thiopental and methohexital, metabolism and excretion play secondary roles to redistribution in determining clinical duration, with methohexital cleared about three times faster than thiopental, reducing accumulation risks.[29] These pharmacokinetic properties underpin the classification of barbiturates by duration of action—ultra-short (e.g., thiopental, 3-8 minutes hypnotic effect), short-to-intermediate (e.g., secobarbital, 15-40 hours half-life), and long (e.g., phenobarbital, 53-118 hours initially)—and explain their potential for drug interactions via enzyme induction.[1][29]Therapeutic Applications
Human Medical Uses
Barbiturates are primarily employed in human medicine for their sedative-hypnotic and anticonvulsant properties, though their use has significantly diminished since the mid-20th century due to narrower therapeutic indices and the availability of safer alternatives like benzodiazepines.[1] Specific indications include seizure management, where long-acting agents such as phenobarbital remain a first-line option for controlling generalized tonic-clonic seizures and status epilepticus, particularly in neonates and resource-limited settings.[30] [31] In 2022, the U.S. Food and Drug Administration approved phenobarbital sodium (Sezaby) specifically for treating neonatal seizures in term and preterm infants, highlighting its role in pediatric neurology when other therapies fail.[32] For anesthesia, ultra-short-acting barbiturates like thiopental (pentothal) are used intravenously to induce rapid unconsciousness, typically within 30-45 seconds, in surgical procedures requiring quick onset, though propofol has largely supplanted them in routine practice.[14] [12] Preoperative sedation and anxiety relief also utilize intermediate-acting barbiturates such as butabarbital, administered orally or rectally to calm patients prior to surgery, but only short-term to minimize dependence risks.[1] [33] In neonatal care, barbiturates address withdrawal syndromes from intrauterine opioid exposure, with phenobarbital titrated to suppress symptoms like irritability and tremors, often at doses of 3-5 mg/kg/day divided every 12 hours.[1] Limited applications persist for refractory insomnia unresponsive to non-pharmacologic interventions or safer hypnotics, where short-acting forms like secobarbital may be prescribed cautiously for 1-2 weeks.[34] Phenobarbital occasionally serves as an adjunct for benzodiazepine withdrawal, leveraging its long half-life (approximately 53-118 hours in adults) to taper dependence gradually.[35] Overall, contemporary guidelines from bodies like the American Academy of Neurology recommend barbiturates primarily for epilepsy in developing regions or when cost and enzyme-inducing effects (e.g., for metabolizing other anticonvulsants) are advantageous.[36]Veterinary and Procedural Uses
In veterinary medicine, phenobarbital serves as a primary anticonvulsant for managing idiopathic epilepsy and other seizure disorders in dogs and cats, with typical oral dosages of 2-4 mg/kg twice daily achieving therapeutic serum levels of 15-45 μg/mL to suppress seizure activity.[37][38] The U.S. Food and Drug Administration conditionally approved phenobarbital tablets (Fidoquel-CA1) on September 6, 2023, specifically for controlling seizures associated with idiopathic epilepsy in dogs, reflecting its established efficacy despite potential side effects like sedation, ataxia, and hepatotoxicity requiring periodic monitoring.[39] In cats, once-daily dosing has demonstrated 88% seizure remission rates without notable compliance issues or adverse effects in controlled studies.[40] Sodium pentobarbital, often combined with phenytoin sodium (e.g., in products like Euthasol), remains the standard agent for humane euthanasia in small animals such as dogs and cats, administered intravenously at doses of 1 mL per 4.5 kg to induce rapid unconsciousness and cardiac arrest within seconds.[41][42] This method is endorsed by the American Veterinary Medical Association for its reliability and minimal pain, though it poses environmental risks, including secondary poisoning of scavengers like bald eagles via residue in euthanized carcasses, prompting FDA warnings since 2003 and guidelines for proper disposal to prevent tissue rendering.[43][44] Shortages, as occurred in 2021-2022, have necessitated alternatives like intracardiac or intraperitoneal injection in moribund animals, but intravenous pentobarbital is preferred for its speed and humane profile across species including horses, where brain activity flattens within 10 seconds.[45][46] For procedural sedation and anesthesia induction, ultra-short-acting barbiturates like thiopental are employed in veterinary practice to facilitate rapid onset for short, non-painful interventions or general anesthesia setup, with intravenous doses of 4-8 mg/kg in dogs and cats producing unconsciousness in under 30 seconds but requiring caution in lean breeds due to fat redistribution prolonging recovery.[47][48] However, their use has declined in favor of agents like propofol owing to cardiovascular depression, histamine release, and smoother recoveries, limiting current applications primarily to scenarios where alternatives are unavailable or contraindicated, such as in hypovolemic patients where effects are studied but not routinely recommended.[49][50] In large animals, thiobarbiturates are occasionally combined with other agents for induction, though antithyroid effects in hyperthyroid patients warrant avoidance.[51]Risks and Adverse Effects
Acute Side Effects and Toxicity
Acute side effects of barbiturates at therapeutic doses primarily involve central nervous system depression, manifesting as drowsiness, dizziness, ataxia, nystagmus, and slurred speech.[1] These effects arise from the drugs' enhancement of GABA_A receptor activity, leading to neuronal hyperpolarization and reduced excitability across various brain regions.[24] Paradoxical excitation, such as agitation or hyperactivity, can occur particularly in elderly patients or children, though this is less common than sedative effects.[5] Toxicity emerges with doses exceeding therapeutic levels, due to barbiturates' narrow therapeutic index, where the margin between effective and lethal concentrations is small—exemplified by phenobarbital's range of 10-30 mg/L for efficacy versus higher levels causing severe impairment.[1] [24] Initial toxic symptoms include profound sedation, impaired coordination, clouded mentation, and hypotension from vasodilation.[5] As plasma concentrations rise, progression to coma, respiratory depression progressing to apnea, and cardiovascular instability ensues, with hypoventilation causing hypoxia and acidosis.[52] [5] Severe overdose, often intentional but also accidental given the drugs' pharmacokinetics allowing accumulation in adipose tissue, leads to multi-organ failure risks including renal impairment from hypotension and rhabdomyolysis.[24] Approximately 10% of barbiturate overdoses result in fatality, primarily from respiratory arrest or secondary complications like aspiration pneumonia.[53] Lethality is exacerbated by co-ingestion with alcohol or opioids, which synergistically depress respiration via shared GABAergic and mu-opioid pathways.[14] Barbiturates' zero-order elimination kinetics further heightens toxicity risk, as clearance becomes saturated, prolonging effects unpredictably.[5]Dependence, Tolerance, and Withdrawal
Barbiturates induce tolerance through adaptive changes in the central nervous system, primarily involving downregulation of GABAA receptor sensitivity and alterations in chloride channel function, necessitating higher doses to achieve equivalent sedative or hypnotic effects.[54] This tolerance develops rapidly with regular use, often within days to weeks, particularly to the mood-altering and respiratory depressant effects, though anticonvulsant efficacy may persist longer.[1][9] Physical dependence arises from prolonged exposure, even at therapeutic doses, as the body adapts to the drug's suppression of neuronal excitability, leading to a state where cessation disrupts homeostasis.[1] Psychological dependence accompanies this, driven by reinforcement of anxiolytic effects, with risks escalating with duration and dosage; for instance, phenobarbital use beyond short-term indications frequently results in dependence requiring tapered discontinuation.[1][55] Withdrawal manifests 2 to 4 days after abrupt cessation in dependent individuals, progressing from mild autonomic hyperactivity to severe neurological symptoms including anxiety, tremor, nausea, insomnia, and potentially life-threatening seizures or delirium tremens-like states due to unchecked excitatory neurotransmission.[56][57] The syndrome's severity correlates with prior dosage and chronicity, often exceeding that of benzodiazepines because of barbiturates' steeper dose-response curve and lack of ceiling effect on GABA enhancement, with mortality risks from status epilepticus or cardiovascular collapse if unmanaged.[58] Management typically involves gradual tapering with long-acting barbiturates or substitution with benzodiazepines under medical supervision to mitigate rebound hyperexcitability.[1][58]Overdose Management and Lethality
Barbiturates exhibit a narrow therapeutic index, with the margin between effective doses and those causing severe toxicity or death being particularly small, predisposing users to life-threatening overdose even at modestly supratherapeutic levels.[5] Overdose primarily manifests through profound central nervous system depression, leading to coma, respiratory failure via hypoventilation and apnea, hypotension from myocardial depression and vasodilation, and potential cardiac arrhythmias; these effects are exacerbated by co-ingestion with alcohol, opioids, or benzodiazepines due to additive respiratory suppression.[24] The minimum lethal oral dose varies by compound and tolerance, typically ranging from 2-3 grams for short-acting agents like pentobarbital to 6-10 grams for long-acting phenobarbital in non-tolerant individuals, though chronic users may survive higher amounts due to developed tolerance.[59] Case fatality rates in suicidal overdoses involving barbiturates have been reported as 5.8-12.2%, higher than for many other drug classes, reflecting their potent depressant effects.[60] With modern supportive care, in-hospital mortality remains low at 0.5-2%, but untreated or delayed cases carry high lethality, particularly in the elderly or those with comorbidities like cardiovascular disease.[5] [24] Management of barbiturate overdose centers on supportive measures, as no specific antidote exists, unlike benzodiazepines which respond to flumazenil.[5] Initial stabilization follows advanced trauma life support protocols, prioritizing airway protection via endotracheal intubation if Glasgow Coma Scale scores indicate risk of aspiration, mechanical ventilation for respiratory depression, and circulatory support with intravenous fluids or vasopressors for hypotension.[61] Gastrointestinal decontamination with activated charcoal is recommended within 1-2 hours of ingestion to reduce absorption, particularly effective for long-acting barbiturates; multiple-dose regimens may further enhance elimination via enterohepatic recirculation.[52] Patients require continuous monitoring of vital signs, electrocardiography for arrhythmias, and laboratory assessment of electrolytes, renal function, and drug levels, with alkaline diuresis historically used but now largely supplanted by extracorporeal methods.[61] For severe intoxications, especially with phenobarbital where half-life prolongation in overdose can extend coma to days, enhanced elimination techniques such as hemodialysis or hemoperfusion are indicated to accelerate clearance, reducing coma duration and complications like pneumonia or rhabdomyolysis. These interventions are prioritized in cases with levels exceeding 100 mcg/mL for phenobarbital or refractory hypotension, with evidence showing reduced mortality when applied early.[62] Naloxone may be trialed if opioids are suspected as co-ingestants but lacks efficacy against pure barbiturate effects.[63] Recovery typically involves intensive care observation until spontaneous ventilation resumes, with full neurological assessment to detect sequelae like persistent cognitive impairment.[61]Comparative Efficacy and Safety
Barbiturates Versus Benzodiazepines
Barbiturates and benzodiazepines both potentiate the inhibitory effects of gamma-aminobutyric acid (GABA) at GABA_A receptors in the central nervous system, but differ in their binding sites and downstream effects. Barbiturates bind to a distinct site on the GABA_A receptor, prolonging the duration of chloride channel opening, which leads to deeper and more prolonged neuronal hyperpolarization.[64] In contrast, benzodiazepines bind to a specific high-affinity site on the GABA_A receptor, increasing the frequency of channel opening without prolonging individual openings, resulting in less intense suppression of neuronal activity.[64] This mechanistic distinction contributes to barbiturates' greater potency and broader suppression of central nervous system functions, including at non-GABAergic synapses.[1] A primary clinical difference lies in their therapeutic indices and overdose risks. Barbiturates exhibit a narrow therapeutic index, where the dose required for therapeutic effect is close to the toxic dose, heightening the risk of respiratory depression, hypotension, and coma even at standard doses.[65] Overdose with barbiturates frequently proves fatal due to profound respiratory arrest and cardiovascular collapse, with no effective reversal agent available beyond supportive care.[5] Benzodiazepines, however, possess a wider therapeutic index, with lethal doses typically 100- to 500-fold higher than therapeutic ones, and rarely cause death when taken alone, though they can exacerbate risks when combined with other depressants like alcohol or opioids.[66] Flumazenil serves as a specific antagonist for benzodiazepine overdose, enabling reversal in many cases.[1]| Aspect | Barbiturates | Benzodiazepines |
|---|---|---|
| Therapeutic Index | Narrow; high overdose lethality | Wide; lower fatal overdose risk alone |
| Respiratory Depression | Dose-dependent and profound, even at therapeutic levels | Milder; ceiling effect limits severity |
| Dependence Potential | High; rapid tolerance development | High but slower onset; cross-tolerance possible |
| Clinical Preference | Limited to refractory seizures, anesthesia induction | First-line for anxiety, acute seizures, sedation |
Reasons for Therapeutic Replacement
Barbiturates have been progressively replaced in therapeutic applications by benzodiazepines and other sedative-hypnotics primarily due to their narrow therapeutic index, which is the ratio between the dose producing the desired effect and the dose causing toxicity. This narrow margin results in a small difference between effective sedative or anticonvulsant doses and those leading to severe respiratory depression or coma, elevating the risk of accidental or intentional overdose.[70][65][71] In contrast, benzodiazepines exhibit a wider therapeutic index, allowing for safer administration with reduced likelihood of fatal outcomes even at higher doses, as they cause less profound suppression of respiratory drive. Barbiturates' mechanism of prolonging GABA_A receptor channel opening leads to maximal channel activation at high doses, lacking a ceiling effect that benzodiazepines possess, which contributes to their higher lethality in overdose scenarios.[72][73][66] The propensity for rapid tolerance, physical dependence, and severe withdrawal symptoms further diminished barbiturates' favorability, as chronic use necessitates escalating doses to maintain efficacy, heightening abuse potential and complicating discontinuation. Benzodiazepines, while not devoid of dependence risks, offer more manageable withdrawal profiles and antagonists like flumazenil for reversal, facilitating their preference in treating anxiety, insomnia, and procedural sedation.[1][68][74] This shift accelerated in the mid-20th century following the introduction of benzodiazepines in the 1960s, with barbiturate prescriptions declining sharply over subsequent decades as clinical evidence highlighted their inferior safety relative to alternatives like non-benzodiazepine hypnotics for sleep disorders. Despite retained niche uses in refractory epilepsy or certain anesthetics, the overall therapeutic displacement reflects empirical prioritization of agents minimizing iatrogenic harm.[75][1][24]Controversies and Societal Debates
Truth Serum Applications and Limitations
Barbiturates such as sodium amytal (amobarbital) and sodium thiopental have been employed in so-called "truth serum" applications since the early 20th century, primarily to facilitate interrogations by reducing psychological inhibitions and inducing a hypnotic, confessional state.[76] These drugs were administered intravenously to suspects or witnesses in psychiatric narcoanalysis sessions, with the aim of eliciting suppressed memories or admissions during states of sedation where critical faculties are impaired.[77] Historical use peaked during World War II and the Cold War, including by U.S. military intelligence and the CIA's MKUltra program (1953–1973), which tested sodium thiopental among other agents for extracting information from prisoners or spies through chemical interrogation techniques.[78] Pioneering work by University of Wisconsin psychiatrist William Bleckwenn in the 1930s demonstrated sodium amytal's potential to break catatonic states in schizophrenia patients, leading to its extension into forensic contexts despite lacking empirical validation for veracity enhancement.[79] Proponents claimed these barbiturates worked by depressing the central nervous system, lowering resistance to suggestion and promoting free association akin to hypnosis, as observed in clinical trials where subjects became unusually loquacious under dosages of 200–600 mg.[80] In practice, applications extended to police investigations in the U.S. and Europe until the mid-20th century, with isolated cases like the 1922 use of scopolamine (a related alkaloid, later supplemented by barbiturates) in Texas criminal probes yielding purported confessions.[81] However, declassified CIA assessments from the 1950s–1960s, including those under MKUltra Subproject 68, revealed inconsistent results, with drugs often producing rambling narratives rather than reliable disclosures.[78] Despite these applications, barbiturates do not function as genuine truth serums, as no pharmacological agent can compel veridical statements or override willful deception, according to evaluations by intelligence agencies and pharmacologists.[78] Subjects under influence exhibit heightened suggestibility, confabulation, and fantasy production, leading to fabricated details indistinguishable from facts; for instance, a 2013 experimental interrogation with sodium thiopental resulted in voluble but inaccurate responses from the subject.[80] Scientific reviews confirm that while barbiturates disrupt executive function and inhibitory controls—via GABA receptor potentiation—they fail to differentiate truth from falsehood, with error rates exceeding 50% in controlled tests due to residual cognitive biases and motivational lying.[77] Courts worldwide, including U.S. federal rulings from the 1960s onward, deem such evidence inadmissible owing to unreliability and violation of due process, as affirmed in cases like Townsend v. Sain (1963).[82] Additional limitations include ethical prohibitions against non-consensual use, as outlined in psychiatric guidelines since the 1950s, and physiological risks such as respiratory depression or paradoxical excitation, which can terminate sessions prematurely or induce amnesia, further obscuring any potential insights.[83] Post-MKUltra disclosures in 1977 Senate hearings highlighted abuses, including unwitting dosing leading to psychological harm, underscoring the causal disconnect between sedation and truth extraction.[84] Modern consensus, informed by neuropharmacology, attributes any confessional effects to disinhibition rather than enhanced honesty, rendering barbiturates obsolete for interrogative purposes in favor of psychological and technological alternatives.[76]Role in Euthanasia, Assisted Suicide, and Capital Punishment
Barbiturates, particularly pentobarbital and secobarbital, have been employed in jurisdictions permitting euthanasia and assisted suicide due to their capacity to induce rapid unconsciousness followed by respiratory arrest at high doses. In physician-assisted suicide under Oregon's Death with Dignity Act, eligible terminally ill patients receive prescriptions for secobarbital (typically 9-10 grams, equivalent to 90-100 capsules crushed and dissolved in liquid) or pentobarbital for self-administration, resulting in death within minutes to hours in the majority of cases reported annually since the law's enactment in 1997.[85] [86] In Switzerland, organizations such as Dignitas facilitate assisted suicide by providing oral pentobarbital solutions (around 15 grams), which patients ingest to achieve coma and subsequent cardiorespiratory failure, with protocols established since the early 2000s.[87] For active euthanasia in the Netherlands and Belgium, where physician administration is legal, barbiturates like pentobarbital (2-10 grams intravenously) are standard to first render the patient unconscious before additional agents ensure death, aligning with national guidelines emphasizing reliability and minimal distress.[88] These applications leverage barbiturates' pharmacological mechanism of enhancing GABA-mediated inhibition, leading to profound sedation and suppression of vital functions, though survival has occurred rarely from sublethal ingestions due to vomiting or incomplete absorption.[89] In capital punishment, barbiturates serve as the primary anesthetic in lethal injection protocols across U.S. states and federal executions, intended to ensure unconsciousness prior to cardiac arrest from subsequent drugs. Pentobarbital emerged as a single-drug alternative around 2010 amid shortages of sodium thiopental, with states like Texas administering 5 grams intravenously to condemned individuals, causing death via central nervous system and respiratory depression within 10-20 minutes when properly dosed.[90] The U.S. federal government adopted a one-drug pentobarbital protocol in 2019 for executions resumed after a 17-year hiatus, sourcing the compound domestically to bypass European export bans imposed since 2011 on drugs intended for lethal use.[91] [92] Compounding pharmacies have become key suppliers for states including Missouri and Texas, producing pentobarbital in unmarked facilities under secrecy laws to evade manufacturer refusals and legal challenges, with Texas procuring batches from local pharmacies like Rite-Away from 2019 through at least 2023.[93] [94] Concerns over sourcing reliability have prompted some states to stockpile or experiment with alternatives, yet pentobarbital remains prevalent for its proven lethality in controlled intravenous administration.[95]Legal and Regulatory Framework
Controlled Substance Status
In the United States, barbiturates are classified as controlled substances under the Controlled Substances Act of 1970, administered by the Drug Enforcement Administration (DEA), with scheduling determined by abuse potential, medical utility, and dependence liability. Short-acting barbiturates such as secobarbital and pentobarbital are placed in Schedule II, reflecting their high potential for abuse alongside accepted uses in anesthesia and acute sedation.[96] [97] Intermediate-acting compounds like amobarbital also fall under Schedule II.[1] Longer-acting barbiturates, including phenobarbital used for epilepsy management, are scheduled in Schedule IV due to comparatively lower abuse risk.[96] Certain formulations, such as those containing butalbital, are classified in Schedule III.[98] Schedule II and III status mandates strict prescription requirements, including no refills without new authorization and inventory tracking for manufacturers and pharmacies, while Schedule IV allows limited refills under medical supervision.[99] Internationally, barbiturates are regulated under the 1971 United Nations Convention on Psychotropic Substances, which lists twelve specific compounds across its Schedules II, III, and IV based on therapeutic value versus risk of misuse. Schedule II includes high-potency sedatives like secobarbital and amobarbital, requiring stringent import/export controls and medical justifications; Schedule III covers intermediates like pentobarbital; and Schedule IV encompasses milder agents such as phenobarbital, permitting broader medical access with safeguards against diversion.[9] [100] Parties to the convention, numbering over 180 nations as of 2021, must limit production to medical and scientific needs, enforce licensing, and report statistics to the International Narcotics Control Board.[101] In the United Kingdom, barbiturates are designated Class B drugs under the Misuse of Drugs Act 1971, carrying penalties of up to 5 years imprisonment and unlimited fines for unlawful possession or supply, with most placed in Schedule 3 of the Misuse of Drugs Regulations 2001 to restrict non-medical handling.[102] [103] Prescriptions require safe custody storage and detailed record-keeping, prohibiting private imports without Home Office approval. In Canada, they are controlled under the Controlled Drugs and Substances Act as narcotics or designated substances, necessitating prescriptions and compliance with federal monitoring for cross-border transport.[104] European Union member states align with UN schedules, implementing national variations such as Schedule IV classifications for phenobarbital in several countries, emphasizing veterinary and limited human therapeutic exemptions.[9] These frameworks stem from documented risks of overdose and dependence established in mid-20th-century epidemiological data, prioritizing harm reduction through regulated access over prohibition.[105]Patterns of Non-Medical Use
Non-medical use of barbiturates primarily involves seeking sedative, euphoric, or disinhibiting effects, often to counteract stimulation from other substances or to induce relaxation akin to alcohol intoxication. Such misuse became evident in the 1930s, with users reporting "drunk-like" states from oral ingestion, escalating through the mid-20th century as prescriptions proliferated for anxiety and insomnia.[106][2] By the 1960s and 1970s, recreational patterns intensified, including polydrug combinations with alcohol, opioids, or stimulants like amphetamines to balance highs or enhance sedation, though this amplified overdose lethality due to synergistic respiratory depression.[107][97] Abuse methods typically entail oral consumption of diverted prescriptions, with higher-risk patterns featuring intravenous injection in dependent users to achieve rapid onset, though this is less common today owing to availability constraints.[108] Users, frequently those already addicted to other depressants or stimulants, escalate doses to tolerate tolerance, leading to cycles of bingeing followed by withdrawal-driven compulsion.[109] Historical data from U.S. congressional inquiries in the early 1970s highlighted barbiturates' role in widespread sedative abuse, often among urban populations and polysubstance users, prompting tighter controls.[110] Current patterns reflect sharp decline since the 1970s, driven by prescription reductions, benzodiazepine substitution, and Schedule II/III classifications under the Controlled Substances Act, rendering non-medical access sporadic via illicit diversion or stockpiles. In 2018, an estimated 405,000 Americans aged 12 and older reported past-year misuse, representing under 0.2% of that population, with adolescent involvement minimal at about 2% of 12th graders.[63][111] Lifetime exposure to abuse affects roughly 9% of Americans, but active patterns cluster among older adults with legacy prescriptions or those in opioid recovery substituting for withdrawal symptoms.[112] Drug testing data confirm rarity, with barbiturate positives comprising only 1.1% of abuse panels over extended periods.[113] Despite low prevalence, residual risks persist in polysubstance contexts, underscoring barbiturates' niche but hazardous non-medical niche.[114]Specific Compounds and Examples
Barbiturates are classified by duration of action, influencing their clinical applications: ultra-short-acting for induction of anesthesia, short- to intermediate-acting for hypnosis and sedation, and long-acting for seizure control.[14][1] Phenobarbital, a long-acting barbiturate with a half-life of 37 to 140 hours, is primarily used as an anticonvulsant for epilepsy and febrile seizures in children, and occasionally for preoperative sedation or alcohol withdrawal management.[16][1] Secobarbital, a short-acting compound with effects lasting 15 to 50 hours in terms of elimination half-life, was historically prescribed as a hypnotic for short-term insomnia treatment but is now rarely used due to risks of dependence.[16][14] Pentobarbital, another short- to intermediate-acting barbiturate, serves as a sedative-hypnotic for preoperative anxiety, seizure control in emergencies, and has been employed in euthanasia protocols and capital punishment in some jurisdictions.[1][97] Thiopental, an ultra-short-acting intravenous agent, is utilized for rapid induction of general anesthesia, providing unconsciousness within seconds, though its use has declined with safer alternatives.[1][14] Butalbital, an intermediate-acting barbiturate, is combined with caffeine and analgesics in formulations like Fioricet for tension headaches, despite limited evidence of superior efficacy over non-barbiturate options and potential for misuse.[1][97] Primidone, a barbiturate derivative, functions as an anticonvulsant for essential tremors and epilepsy, metabolized partly to phenobarbital, with a shorter half-life of 5 to 15 hours.[16][1]| Compound | Duration of Action | Primary Uses |
|---|---|---|
| Phenobarbital | Long-acting | Anticonvulsant for epilepsy[16] |
| Secobarbital | Short-acting | Hypnotic for insomnia (historical)[14] |
| Pentobarbital | Short- to intermediate-acting | Sedation, seizures, euthanasia[97] |
| Thiopental | Ultra-short-acting | Anesthesia induction[1] |
| Butalbital | Intermediate-acting | Headache relief in combinations[1] |