Barbiturates, such asphenobarbital, were long used asanxiolytics andhypnotics. Intermediate-acting barbiturates reduce time to fall asleep, increase total sleep time, and reduce REM sleep time. Today they have been largely replaced bybenzodiazepines for these purposes because the latter are less toxic in drugoverdose.[4][5][6] However, barbiturates are still used as anticonvulsants (e.g.,phenobarbital andprimidone) and general anesthetics (e.g.,sodium thiopental).
Sodium thiopental is an ultra-short-acting barbiturate that is marketed under the name Sodium Pentothal. It is often mistaken for "truth serum", orsodium 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]
In 1988, the synthesis and binding studies of an artificial receptor binding barbiturates by six complementaryhydrogen bonds was published.[12] Since this first article, different kind of receptors were designed, as well as different barbiturates andcyanurates, not for their efficiencies as drugs but for applications insupramolecular 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 andbarbital have also been used aspH buffers for biological research, e.g., in immuno-electrophoresis or in fixative solutions.[14][15]
Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged indelphic 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 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 isStevens–Johnson syndrome, which primarily affects the mucous membranes.
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 ofdelirium tremens andbenzodiazepine withdrawal although its more direct mechanism of GABA agonism makes barbiturate withdrawal even more severe than that ofalcohol 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]
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. Thelethal 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 inbioaccumulation 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 hepaticCYP enzymes (most notablyCYP2C9,CYP2C19, andCYP3A4),[22] leading to exaggerated effects from manyprodrugs and decreased effects from drugs which are metabolized by these enzymes to inactive metabolites. This can result in fatal overdoses from drugs such ascodeine,tramadol, andcarisoprodol, 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.
Barbiturates act aspositive allosteric modulators and, at higher doses, asagonists ofGABAA receptors.[23]GABA is the principal inhibitoryneurotransmitter in themammaliancentral nervous system (CNS). Barbiturates bind to the GABAA receptor at multiple homologous transmembrane pockets located at subunit interfaces,[24] which are binding sites distinct fromGABA itself and also distinct from thebenzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABAergic effect, barbiturates also blockAMPA andkainate receptors, subtypes ofionotropic 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 andquinazolinones. At higher concentration, they inhibit theCa2+-dependent release of neurotransmitters such as glutamate via an effect onP/Q-typevoltage-dependent calcium channels.[25]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 theGABAA 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 tobenzodiazepines in overdose.[26][27]
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. ThisCys-loop receptor superfamily of ion channels includes the neuronalnACh receptor channel, the5-HT3 receptor channel, and theglycine 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.[28] 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.[29] This is the mechanism responsible for the (mild to moderate) anesthetic effect of barbiturates in high doses when used in anesthetic concentration.
Barbituric acid was first synthesized 27 November 1864, byGerman chemistAdolf von Baeyer. This was done bycondensingurea withdiethyl 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 atavern where the town'sartillerygarrison were also celebrating the feast ofSaint Barbara – the patron saint of artillerymen. An artillery officer is said to have christened the new substance by amalgamatingBarbara withurea.[30] Another story holds that Baeyer synthesized the substance from the collected urine of a Munich waitress named Barbara.[31] No substance of medical value was discovered, however, until 1902 when two German scientists working atBayer,Emil Fischer andJoseph von Mering, discovered thatbarbital was very effective in putting dogs to sleep. Barbital was then marketed by Bayer under thetrade nameVeronal. It is said that Mering proposed this name because the most peaceful place he knew was theItalian city ofVerona.[30] In 1912, Bayer introduced another barbituric acid derivative,phenobarbital, under the trade name Luminal, as asedative–hypnotic.[32]
It was not until the 1950s that the behavioral disturbances and physical dependence potential of barbiturates became recognized.[33]
Barbituric acid itself does not have any direct effect on thecentral 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 foranesthesia 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 foranxiety orinsomnia. This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by thebenzodiazepines andZ-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 asanticonvulsants, 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- anddionine-based salts of barbituric acid have been developed.
DuringWorld 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 barbiturateoverdoses and dependence problems led physicians to reduce their prescription, particularly for spurious requests. This eventually led to the scheduling of barbiturates as controlled drugs.
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 barbituratesamobarbital,butalbital,cyclobarbital, andpentobarbital.
In the United States, theControlled Substances Act of 1970 classified most barbiturates as controlled substances—and they remain so as of August 2023[update].Barbital,methylphenobarbital (also known asmephobarbital), andphenobarbital are designatedschedule 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 beingschedule III. Under the original CSA, no barbiturates were placed in schedule I, II, or V;[36] however, amobarbital, pentobarbital, and secobarbital are now schedule II controlled substances unless they are in a suppository dosage form.[37]
In 1971, theConvention on Psychotropic Substances was signed inVienna. Designed to regulateamphetamines, barbiturates, and other synthetics, the 34th version of thetreaty, as of 25 January 2014[update], regulates secobarbital as schedule II, amobarbital, butalbital, cyclobarbital, and pentobarbital as schedule III, andallobarbital,barbital,butobarbital,mephobarbital,phenobarbital,butabarbital, andvinylbital as schedule IV on its "Green List".[38] The combination medicationFioricet, consisting of butalbital, caffeine, andparacetamol (acetaminophen), however, is specifically exempted from controlled substance status, while its siblingFiorinal, which contains aspirin instead of paracetamol and may containcodeine phosphate, remains a schedule III drug.
Recreational users report that a barbiturate high gives them feelings of relaxed contentment andeuphoria. Physical and psychological dependence may also develop with repeated use.[39] Chronic misuse of barbiturates is associated with significant morbidity. One study found that 11% of males and 23% of females with asedative-hypnotic misuse die by suicide.[40] Other effects of barbiturateintoxication includedrowsiness,lateral andverticalnystagmus,slurred speech andataxia, 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-actingbenzodiazepines such asdiazepam andclonazepam.[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 areamobarbital (Amytal),pentobarbital (Nembutal), andsecobarbital (Seconal). A combination of amobarbital and secobarbital (calledTuinal) 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]
(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 beingCH2CH3 (ethyl) and R3) beingCH(CH3)CH2CH2CH3 (sec-pentyl). Thiopental is no longer available in the United States.[46]
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^Neil Harrison; Wallace B Mendelson; Harriet de Wit (2000)."Barbiturates". Neuropsychopharmacology. Retrieved15 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.
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