Barbiturates drug

Barbiturates

Prescription barbiturates

Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, hypnotics, and anticonvulsants. Barbiturates also have analgesic effects^{[citation needed]}; however, these effects are somewhat weak, preventing barbiturates from being used in surgery in the presence of other analgesics (opioids or volatile anesthetics such as halothane).

Barbiturates have addiction potential, both physical and psychological. They have largely been replaced by benzodiazepines in routine medical practice - particularly in the treatment of anxiety and insomnia, due to the significant decrease in risk of overdose and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, euthanasia, capital punishment, and assisted suicide.^[1]Barbiturates are derivatives of barbituric acid.^[2]

Medical uses[edit]

Barbiturates such as phenobarbital were long used as anxiolytics and hypnotics, but today have been largely replaced by benzodiazepines for these purposes because of less potential for lethal overdoses.^[3][4][5]However, barbiturates are still used as anticonvulsants, as para-operative sedatives (ex. sodium thiopental), and analgesics for cluster headaches/ migraines (ex. Fioricet).

Other uses related to their physiological properties[edit]

Barbiturates in high doses are used for physician-assisted suicide (PAS), and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection.^[6][7] Barbiturates are frequently employed as euthanizing agents in small animal veterinary medicine.

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 be much more likely to provide the truth whilst under the influence of this drug. 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.^[8] The memory impairing effects and cognitive impairments induced by the drug are thought to reduce a subject's ability to invent and remember lies. This practice is no longer considered legally admissible in court due 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.^[9]

Side effects[edit]

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Barbituates were ranked 5th in dependence, 3rd in physical harm, and 4th in social harm.^[10]

There are special risks to consider for older adults, women who are pregnant, and babies. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of sixty-five are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose.^[11] When barbiturates are taken during pregnancy, the drug passes through the mother's bloodstream to her fetus. After the baby is born, it may experience withdrawal symptoms and have trouble breathing. In addition, nursing mothers who take barbiturates may transmit the drug to their babies through breast milk.^[12] A rare adverse reaction to barbiturates is Stevens-Johnson syndrome, which primarily affects the mucous membranes.

Tolerance and dependence[edit]

Main article: Barbiturate dependence

With regular use, tolerance to the effects of barbiturates develops. As with all GABAergic drugs barbiturate withdrawal produces potentially fatal effects such as seizures in a manner reminiscent of delerium tremens and benzodiazepine withdrawal although its more direct mechanism of GABA agonism makes barbiturate withdrawal more severe than that of alcohol or benzodiazepines (subsequently making it one of the most dangerous withdrawals of any known addictive substance). Similar 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 affected worse 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 due to the high lethality and relatively sudden onset of the withdrawal, attempting to quit "cold turkey" may result in serious neurological damage, severe physical injuries received during convulsions, and even death via glutamatergic excitotoxicity.

Overdose[edit]

Main article: Barbiturate overdose

Some symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgement, drowsiness, shallow breathing, staggering, and, in severe cases, coma or death. The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. The lethal dose is highly variable among different members of the class with superpotent barbiturates such as pentobarbital being potentially fatal in considerably lower doses than the low-potency barbiturates such as butalbital. Even in inpatient settings, however, the development of tolerance is still a problem, as dangerous and unpleasant withdrawal symptoms can result when the drug is stopped after dependence has developed. 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 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 due to additive CNS and respiratory depressant effects. In the case of benzodiazepines, not only do they have additive effects, barbiturates also increase the binding affinity of the benzodiazepine binding site, 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 increase 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/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 drugs effects have worn 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),^[13] 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 inhibition 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 with a barbiturate overdose include Charles Boyer, Dalida, Phyllis Hyman, Carole Landis, Jean Seberg, Abbie Hoffman, Felix Hausdorff and C. P. Ramanujam. Others who have died as a result of barbiturate overdose include Judy Garland, Marilyn Monroe, Ellen Wilkinson, Dorothy Kilgallen, Brian Epstein, Alan Wilson, Jimi Hendrix, Edie Sedgwick, Inger Stevens and Kenneth Williams; in some cases these have been speculated to be suicides as well. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal.

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.^[14] Other effects of barbiturateintoxication include drowsiness, lateral and vertical nystagmus, slurred speech and ataxia, decreased anxiety, a loss of inhibitions. Barbiturates are also used to alleviate the adverse or withdrawal effects of illicit drug use, in a manner similar to long-acting benzodiazepines such as diazepam and clonazepam.^[15][16]

Drug users tend to prefer short-acting and intermediate-acting barbiturates.^[17] 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, bluebirds, dolls, wallbangers, yellows, downers, goofballs, sleepers, 'reds & blues' and tooties.^[18]

Mechanism of action[edit]

Barbiturates act as positive allosteric modulators, and at higher doses, as agonists of GABA_A receptors.^[19] GABA is the principal inhibitory neurotransmitter in the mammalian central nervous system (CNS). Barbiturates bind to the GABA_A receptor at multiple homologous transmembrane pockets located at subunit interfaces,^[20] which are binding sites distinct from GABA itself and also distinct from the benzodiazepinebinding 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 GABA_A 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.^[21] Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABA_A receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABA_A 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.^[22][23]

Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABA_A receptor channel is only one of several representatives. This superfamily of ion channels includes the neuronal nACh receptor channel, the 5-HT₃ receptor channel, and the glycine receptor channel. However, while GABA_A receptor currents are increased by barbiturates (and other general anaesthetics), 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 anaesthetic concentrations of both thiopental and pentobarbital.^[24] 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.^[25] This is the mechanism responsible for the (mild to moderate) anesthetic effect of barbiturates in high doses when used in anesthetic concentration

Legal status[edit]

• During World War II, military personnel in the Pacific region were given "goofballs" to allow them to tolerate the heat and humidity of daily working conditions. Goofballs were distributed to reduce the demand on the respiratory system, as well as maintaining blood pressure, to combat the extreme conditions. Many soldiers returned with addictions that required several months of rehabilitation before discharge. This led to growing dependency problems, often exacerbated by indifferent doctors prescribing high doses to unknowing patients through the 1950s and 1960s.^{[citation needed]}
• In the late 1950s and 1960s, increasing published reports of barbiturate overdoses and dependence problems led physicians to cut back their prescription, particularly for spurious requests. This eventually led to the scheduling of barbiturates as controlled drugs.

• In the United States, the Controlled Substances Act of 1970 classified most barbiturates as controlled substances—and they remain so as of September 2015. Barbital, methylphenobarbital (also known asmephobarbital), 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"^[26] (all other barbiturates) were designated as schedule III. Under the original CSA, no barbiturates were placed in schedule I, II, or V,^[27] however amobarbital, pentobarbital, and secobarbital are schedule II controlled substances unless they are in a suppository dosage form.^[28]
• 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, regulatessecobarbital 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".^[29] The combination medication Fioricet, consisting of butalbital, caffeine, and paracetamol (acetaminophen), however, is specifically exempted from controlled substance status, while its siblingFiorinal, which contains aspirin instead of paracetamol and may contain codeine phosphate, remains a schedule III drug.