Barbiturate

From Wikipedia, the free encyclopedia

Barbituric acid, the parent structure of all barbiturates

A barbiturate is a drug that acts as a central nervous system depressant. Barbiturates are effective as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have largely been replaced by benzodiazepines and nonbenzodiazepines ("Z-drugs") in routine medical practice, particularly in the treatment of anxiety and insomnia, due to the significantly lower risk of addiction and 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.

The name barbiturate originates from the fact that they are all chemical derivatives of barbituric acid.

Uses

Medicine

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. 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 physician-assisted suicide, and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection. Barbiturates are frequently employed as euthanizing agents in small-animal veterinary medicine.

Interrogation

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 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. Lying is somewhat more complex than telling the truth, especially under the influence of a sedative-hypnotic drug.

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 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.

Chemistry

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

Sodium barbital and barbital have also been used as pH buffers for biological research, e.g., in immuno-electrophoresis or in fixative solutions.

Side effects

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

There are special risks to consider for older adults, and women who are pregnant. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of sixty-five are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose. 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. A rare adverse reaction to barbiturates is Stevens–Johnson syndrome, which primarily affects the mucous membranes.

Tolerance and dependence

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 (subsequently making it 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, 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

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

Mechanism of action

Barbiturates act as positive allosteric modulators and, at higher doses, as agonists of GABA_A receptors. 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, 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 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. 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.

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 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 GABA_A 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. 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. This is the mechanism responsible for the (mild to moderate) anesthetic effect of barbiturates in high doses when used in anesthetic concentration.

History

Barbituric acid was first synthesized November 27, 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. Another story was barbiturate was invented on the feast day of St. Barbara. Another story holds that Baeyer synthesized the substance from the collected urine of a Munich waitress named Barbara. No substance of medical value was discovered, however, until 1903 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.

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

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-drugs 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. In 1912, Bayer introduced another barbituric acid derivative, phenobarbital, under the trade name Luminal, as a sedative–hypnotic.

Society and culture

Legal status

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.

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 doctors 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 September 2020. 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" (all other barbiturates) were designated as being schedule III. Under the original CSA, no barbiturates were placed in schedule I, II, or V; however, amobarbital, pentobarbital, and secobarbital are schedule II controlled substances unless they are in a suppository dosage form.

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, 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". 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

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. 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. 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. Often poly drug abuse occurs: Barbiturates are consumed with or substituted by other available substances, most commonly alcohol.

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

Examples

Generic structure of a barbiturate, including numbering scheme

Barbiturates

Short Name	R1	R2	IUPAC Name
allobarbital	CH2CHCH2	CH2CHCH2	5,5-diallylbarbiturate
amobarbital	CH2CH3	(CH2)2CH(CH3)2	5-ethyl-5-isopentyl-barbiturate
aprobarbital	CH2CHCH2	CH(CH3)2	5-allyl-5-isopropyl-barbiturate
alphenal	CH2CHCH2	C6H5	5-allyl-5-phenyl-barbiturate
barbital	CH2CH3	CH2CH3	5,5-diethylbarbiturate
brallobarbital	CH2CHCH2	CH2CBrCH2	5-allyl-5-(2-bromo-allyl)-barbiturate
pentobarbital	CH2CH3	CHCH3(CH2)2CH3	5-ethyl-5-(1-methylbutyl)-barbiturate
phenobarbital	CH2CH3	C6H5	5-ethyl-5-phenylbarbiturate
Primidone
secobarbital	CH2CHCH2	CHCH3(CH2)2CH3	5-[(2R)-pentan-2-yl]-5-prop-2-enyl-barbiturate; 5-allyl-5-[(2R)-pentan-2-yl]-barbiturate

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 and R² being CH(CH₃)CH₂CH₂CH₃.

Celestial spheres

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Celestial_spheres 

Geocentric celestial spheres; Peter Apian's Cosmographia (Antwerp, 1539)

The celestial spheres, or celestial orbs, were the fundamental entities of the cosmological models developed by Plato, Eudoxus, Aristotle, Ptolemy, Copernicus, and others. In these celestial models, the apparent motions of the fixed stars and planets are accounted for by treating them as embedded in rotating spheres made of an aetherial, transparent fifth element (quintessence), like jewels set in orbs. Since it was believed that the fixed stars did not change their positions relative to one another, it was argued that they must be on the surface of a single starry sphere.

In modern thought, the orbits of the planets are viewed as the paths of those planets through mostly empty space. Ancient and medieval thinkers, however, considered the celestial orbs to be thick spheres of rarefied matter nested one within the other, each one in complete contact with the sphere above it and the sphere below. When scholars applied Ptolemy's epicycles, they presumed that each planetary sphere was exactly thick enough to accommodate them. By combining this nested sphere model with astronomical observations, scholars calculated what became generally accepted values at the time for the distances to the Sun: about 4 million miles (6.4 million kilometres), to the other planets, and to the edge of the universe: about 73 million miles (117 million kilometres). The nested sphere model's distances to the Sun and planets differ significantly from modern measurements of the distances, and the size of the universe is now known to be inconceivably large and continuously expanding.

Albert Van Helden has suggested that from about 1250 until the 17th century, virtually all educated Europeans were familiar with the Ptolemaic model of "nesting spheres and the cosmic dimensions derived from it". Even following the adoption of Copernicus's heliocentric model of the universe, new versions of the celestial sphere model were introduced, with the planetary spheres following this sequence from the central Sun: Mercury, Venus, Earth-Moon, Mars, Jupiter and Saturn.

Mainstream belief in the theory of celestial spheres did not survive the Scientific Revolution. In the early 1600s, Kepler continued to discuss celestial spheres, although he did not consider that the planets were carried by the spheres but held that they moved in elliptical paths described by Kepler's laws of planetary motion. In the late 1600s, Greek and medieval theories concerning the motion of terrestrial and celestial objects were replaced by Newton's law of universal gravitation and Newtonian mechanics, which explain how Kepler's laws arise from the gravitational attraction between bodies.

History

Early ideas of spheres and circles

In Greek antiquity the ideas of celestial spheres and rings first appeared in the cosmology of Anaximander in the early 6th century BC. In his cosmology both the Sun and Moon are circular open vents in tubular rings of fire enclosed in tubes of condensed air; these rings constitute the rims of rotating chariot-like wheels pivoting on the Earth at their centre. The fixed stars are also open vents in such wheel rims, but there are so many such wheels for the stars that their contiguous rims all together form a continuous spherical shell encompassing the Earth. All these wheel rims had originally been formed out of an original sphere of fire wholly encompassing the Earth, which had disintegrated into many individual rings. Hence, in Anaximanders's cosmogony, in the beginning was the sphere, out of which celestial rings were formed, from some of which the stellar sphere was in turn composed. As viewed from the Earth, the ring of the Sun was highest, that of the Moon was lower, and the sphere of the stars was lowest.

Following Anaximander, his pupil Anaximenes (c. 585–528/4) held that the stars, Sun, Moon, and planets are all made of fire. But whilst the stars are fastened on a revolving crystal sphere like nails or studs, the Sun, Moon, and planets, and also the Earth, all just ride on air like leaves because of their breadth. And whilst the fixed stars are carried around in a complete circle by the stellar sphere, the Sun, Moon and planets do not revolve under the Earth between setting and rising again like the stars do, but rather on setting they go laterally around the Earth like a cap turning halfway around the head until they rise again. And unlike Anaximander, he relegated the fixed stars to the region most distant from the Earth. The most enduring feature of Anaximenes' cosmos was its conception of the stars being fixed on a crystal sphere as in a rigid frame, which became a fundamental principle of cosmology down to Copernicus and Kepler.

After Anaximenes, Pythagoras, Xenophanes and Parmenides all held that the universe was spherical. And much later in the fourth century BC Plato's Timaeus proposed that the body of the cosmos was made in the most perfect and uniform shape, that of a sphere containing the fixed stars. But it posited that the planets were spherical bodies set in rotating bands or rings rather than wheel rims as in Anaximander's cosmology.

Emergence of the planetary spheres

Instead of bands, Plato's student Eudoxus developed a planetary model using concentric spheres for all the planets, with three spheres each for his models of the Moon and the Sun and four each for the models of the other five planets, thus making 26 spheres in all. Callippus modified this system, using five spheres for his models of the Sun, Moon, Mercury, Venus, and Mars and retaining four spheres for the models of Jupiter and Saturn, thus making 33 spheres in all. Each planet is attached to the innermost of its own particular set of spheres. Although the models of Eudoxus and Callippus qualitatively describe the major features of the motion of the planets, they fail to account exactly for these motions and therefore cannot provide quantitative predictions. Although historians of Greek science have traditionally considered these models to be merely geometrical representations, recent studies have proposed that they were also intended to be physically real or have withheld judgment, noting the limited evidence to resolve the question.

In his Metaphysics, Aristotle developed a physical cosmology of spheres, based on the mathematical models of Eudoxus. In Aristotle's fully developed celestial model, the spherical Earth is at the centre of the universe and the planets are moved by either 47 or 55 interconnected spheres that form a unified planetary system, whereas in the models of Eudoxus and Callippus each planet's individual set of spheres were not connected to those of the next planet. Aristotle says the exact number of spheres, and hence the number of movers, is to be determined by astronomical investigation, but he added additional spheres to those proposed by Eudoxus and Callippus, to counteract the motion of the outer spheres. Aristotle considers that these spheres are made of an unchanging fifth element, the aether. Each of these concentric spheres is moved by its own god—an unchanging divine unmoved mover, and who moves its sphere simply by virtue of being loved by it.

Ptolemaic model of the spheres for Venus, Mars, Jupiter, and Saturn with epicycle, eccentric deferent and equant point. Georg von Peuerbach, Theoricae novae planetarum, 1474.

In his Almagest, the astronomer Ptolemy (fl. ca. 150 AD) developed geometrical predictive models of the motions of the stars and planets and extended them to a unified physical model of the cosmos in his Planetary hypotheses. By using eccentrics and epicycles, his geometrical model achieved greater mathematical detail and predictive accuracy than had been exhibited by earlier concentric spherical models of the cosmos. In Ptolemy's physical model, each planet is contained in two or more spheres, but in Book 2 of his Planetary Hypotheses Ptolemy depicted thick circular slices rather than spheres as in its Book 1. One sphere/slice is the deferent, with a centre offset somewhat from the Earth; the other sphere/slice is an epicycle embedded in the deferent, with the planet embedded in the epicyclical sphere/slice. Ptolemy's model of nesting spheres provided the general dimensions of the cosmos, the greatest distance of Saturn being 19,865 times the radius of the Earth and the distance of the fixed stars being at least 20,000 Earth radii.

The planetary spheres were arranged outwards from the spherical, stationary Earth at the centre of the universe in this order: the spheres of the Moon, Mercury, Venus, Sun, Mars, Jupiter, and Saturn. In more detailed models the seven planetary spheres contained other secondary spheres within them. The planetary spheres were followed by the stellar sphere containing the fixed stars; other scholars added a ninth sphere to account for the precession of the equinoxes, a tenth to account for the supposed trepidation of the equinoxes, and even an eleventh to account for the changing obliquity of the ecliptic. In antiquity the order of the lower planets was not universally agreed. Plato and his followers ordered them Moon, Sun, Mercury, Venus, and then followed the standard model for the upper spheres. Others disagreed about the relative place of the spheres of Mercury and Venus: Ptolemy placed both of them beneath the Sun with Venus above Mercury, but noted others placed them both above the Sun; some medieval thinkers, such as al-Bitruji, placed the sphere of Venus above the Sun and that of Mercury below it.

Middle Ages

Astronomical discussions

The Earth within seven celestial spheres, from Bede, De natura rerum, late 11th century

A series of astronomers, beginning with the Muslim astronomer al-Farghānī, used the Ptolemaic model of nesting spheres to compute distances to the stars and planetary spheres. Al-Farghānī's distance to the stars was 20,110 Earth radii which, on the assumption that the radius of the Earth was 3,250 miles (5,230 kilometres), came to 65,357,500 miles (105,182,700 kilometres). An introduction to Ptolemy's Almagest, the Tashil al-Majisti, believed to be written by Thābit ibn Qurra, presented minor variations of Ptolemy's distances to the celestial spheres. In his Zij, Al-Battānī presented independent calculations of the distances to the planets on the model of nesting spheres, which he thought was due to scholars writing after Ptolemy. His calculations yielded a distance of 19,000 Earth radii to the stars.

Around the turn of the millennium, the Arabic astronomer and polymath Ibn al-Haytham (Alhacen) presented a development of Ptolemy's geocentric models in terms of nested spheres. Despite the similarity of this concept to that of Ptolemy's Planetary Hypotheses, al-Haytham's presentation differs in sufficient detail that it has been argued that it reflects an independent development of the concept. In chapters 15–16 of his Book of Optics, Ibn al-Haytham also said that the celestial spheres do not consist of solid matter.

Near the end of the twelfth century, the Spanish Muslim astronomer al-Bitrūjī (Alpetragius) sought to explain the complex motions of the planets without Ptolemy's epicycles and eccentrics, using an Aristotelian framework of purely concentric spheres that moved with differing speeds from east to west. This model was much less accurate as a predictive astronomical model, but it was discussed by later European astronomers and philosophers.

In the thirteenth century the astronomer al-'Urḍi proposed a radical change to Ptolemy's system of nesting spheres. In his Kitāb al-Hayáh, he recalculated the distance of the planets using parameters which he redetermined. Taking the distance of the Sun as 1,266 Earth radii, he was forced to place the sphere of Venus above the sphere of the Sun; as a further refinement, he added the planet's diameters to the thickness of their spheres. As a consequence, his version of the nesting spheres model had the sphere of the stars at a distance of 140,177 Earth radii.

About the same time, scholars in European universities began to address the implications of the rediscovered philosophy of Aristotle and astronomy of Ptolemy. Both astronomical scholars and popular writers considered the implications of the nested sphere model for the dimensions of the universe. Campanus of Novara's introductory astronomical text, the Theorica planetarum, used the model of nesting spheres to compute the distances of the various planets from the Earth, which he gave as 22,612 Earth radii or 73,387,747​¹⁰⁰⁄₆₆₀ miles. In his Opus Majus, Roger Bacon cited Al-Farghānī's distance to the stars of 20,110 Earth radii, or 65,357,700 miles, from which he computed the circumference of the universe to be 410,818,517​³⁄₇ miles. Clear evidence that this model was thought to represent physical reality is the accounts found in Bacon's Opus Majus of the time needed to walk to the Moon and in the popular Middle English South English Legendary, that it would take 8,000 years to reach the highest starry heaven. General understanding of the dimensions of the universe derived from the nested sphere model reached wider audiences through the presentations in Hebrew by Moses Maimonides, in French by Gossuin of Metz, and in Italian by Dante Alighieri.

Philosophical and theological discussions

Philosophers were less concerned with such mathematical calculations than with the nature of the celestial spheres, their relation to revealed accounts of created nature, and the causes of their motion.

Adi Setia describes the debate among Islamic scholars in the twelfth century, based on the commentary of Fakhr al-Din al-Razi about whether the celestial spheres are real, concrete physical bodies or "merely the abstract circles in the heavens traced out… by the various stars and planets." Setia points out that most of the learned, and the astronomers, said they were solid spheres "on which the stars turn… and this view is closer to the apparent sense of the Qur'anic verses regarding the celestial orbits." However, al-Razi mentions that some, such as the Islamic scholar Dahhak, considered them to be abstract. Al-Razi himself, was undecided, he said: "In truth, there is no way to ascertain the characteristics of the heavens except by authority [of divine revelation or prophetic traditions]." Setia concludes: "Thus it seems that for al-Razi (and for others before and after him), astronomical models, whatever their utility or lack thereof for ordering the heavens, are not founded on sound rational proofs, and so no intellectual commitment can be made to them insofar as description and explanation of celestial realities are concerned."

Christian and Muslim philosophers modified Ptolemy's system to include an unmoved outermost region, the empyrean heaven, which came to be identified as the dwelling place of God and all the elect. Medieval Christians identified the sphere of stars with the Biblical firmament and sometimes posited an invisible layer of water above the firmament, to accord with Genesis. An outer sphere, inhabited by angels, appeared in some accounts.

Edward Grant, a historian of science, has provided evidence that medieval scholastic philosophers generally considered the celestial spheres to be solid in the sense of three-dimensional or continuous, but most did not consider them solid in the sense of hard. The consensus was that the celestial spheres were made of some kind of continuous fluid.

Later in the century, the mutakallim Adud al-Din al-Iji (1281–1355) rejected the principle of uniform and circular motion, following the Ash'ari doctrine of atomism, which maintained that all physical effects were caused directly by God's will rather than by natural causes. He maintained that the celestial spheres were "imaginary things" and "more tenuous than a spider's web". His views were challenged by al-Jurjani (1339–1413), who maintained that even if the celestial spheres "do not have an external reality, yet they are things that are correctly imagined and correspond to what [exists] in actuality".

Medieval astronomers and philosophers developed diverse theories about the causes of the celestial spheres' motions. They attempted to explain the spheres' motions in terms of the materials of which they were thought to be made, external movers such as celestial intelligences, and internal movers such as motive souls or impressed forces. Most of these models were qualitative, although a few incorporated quantitative analyses that related speed, motive force and resistance. By the end of the Middle Ages, the common opinion in Europe was that celestial bodies were moved by external intelligences, identified with the angels of revelation. The outermost moving sphere, which moved with the daily motion affecting all subordinate spheres, was moved by an unmoved mover, the Prime Mover, who was identified with God. Each of the lower spheres was moved by a subordinate spiritual mover (a replacement for Aristotle's multiple divine movers), called an intelligence.

Renaissance

Thomas Digges' 1576 Copernican heliocentric model of the celestial orbs

Early in the sixteenth century Nicolaus Copernicus drastically reformed the model of astronomy by displacing the Earth from its central place in favour of the Sun, yet he called his great work De revolutionibus orbium coelestium (On the Revolutions of the Celestial Spheres). Although Copernicus does not treat the physical nature of the spheres in detail, his few allusions make it clear that, like many of his predecessors, he accepted non-solid celestial spheres. Copernicus rejected the ninth and tenth spheres, placed the orb of the Moon around the Earth, and moved the Sun from its orb to the center of the universe. The planetary orbs circled the center of the universe in the following order: Mercury, Venus, the great orb containing the Earth and the orb of the Moon, then the orbs of Mars, Jupiter, and Saturn. Finally he retained the eighth sphere of the stars, which he held to be stationary.

The English almanac maker, Thomas Digges, delineated the spheres of the new cosmological system in his Perfit Description of the Caelestiall Orbes … (1576). Here he arranged the "orbes" in the new Copernican order, expanding one sphere to carry "the globe of mortalitye", the Earth, the four classical elements, and the Moon, and expanding the sphere of stars infinitely to encompass all the stars and also to serve as "the court of the Great God, the habitacle of the elect, and of the coelestiall angelles."

Johannes Kepler's diagram of the celestial spheres, and of the spaces between them, following the opinion of Copernicus (Mysterium Cosmographicum, 2nd ed., 1621)

In the sixteenth century, a number of philosophers, theologians, and astronomers—among them Francesco Patrizi, Andrea Cisalpino, Peter Ramus, Robert Bellarmine, Giordano Bruno, Jerónimo Muñoz, Michael Neander, Jean Pena, and Christoph Rothmann—abandoned the concept of celestial spheres. Rothmann argued from observations of the comet of 1585 that the lack of observed parallax indicated that the comet was beyond Saturn, while the absence of observed refraction indicated the celestial region was of the same material as air, hence there were no planetary spheres.

Tycho Brahe's investigations of a series of comets from 1577 to 1585, aided by Rothmann's discussion of the comet of 1585 and Michael Maestlin's tabulated distances of the comet of 1577, which passed through the planetary orbs, led Tycho to conclude that "the structure of the heavens was very fluid and simple." Tycho opposed his view to that of "very many modern philosophers" who divided the heavens into "various orbs made of hard and impervious matter." Edward Grant found relatively few believers in hard celestial spheres before Copernicus and concluded that the idea first became common sometime between the publication of Copernicus's De revolutionibus in 1542 and Tycho Brahe's publication of his cometary research in 1588.

In his early Mysterium Cosmographicum, Johannes Kepler considered the distances of the planets and the consequent gaps required between the planetary spheres implied by the Copernican system, which had been noted by his former teacher, Michael Maestlin. Kepler's Platonic cosmology filled the large gaps with the five Platonic polyhedra, which accounted for the spheres' measured astronomical distance. In Kepler's mature celestial physics, the spheres were regarded as the purely geometric spatial regions containing each planetary orbit rather than as the rotating physical orbs of the earlier Aristotelian celestial physics. The eccentricity of each planet's orbit thereby defined the radii of the inner and outer limits of its celestial sphere and thus its thickness. In Kepler's celestial mechanics, the cause of planetary motion became the rotating Sun, itself rotated by its own motive soul. However, an immobile stellar sphere was a lasting remnant of physical celestial spheres in Kepler's cosmology.

Literary and visual expressions

"Because the medieval universe is finite, it has a shape, the perfect spherical shape, containing within itself an ordered variety....
"The spheres ... present us with an object in which the mind can rest, overwhelming in its greatness but satisfying in its harmony."

C. S. Lewis, The Discarded Image, p. 99

Dante and Beatrice gaze upon the highest Heaven; from Gustave Doré's illustrations to the Divine Comedy, Paradiso Canto 28, lines 16–39

In Cicero's Dream of Scipio, the elder Scipio Africanus describes an ascent through the celestial spheres, compared to which the Earth and the Roman Empire dwindle into insignificance. A commentary on the Dream of Scipio by the Roman writer Macrobius, which included a discussion of the various schools of thought on the order of the spheres, did much to spread the idea of the celestial spheres through the Early Middle Ages.

Nicole Oresme, Le livre du Ciel et du Monde, Paris, BnF, Manuscrits, Fr. 565, f. 69, (1377)

Some late medieval figures noted that the celestial spheres' physical order was inverse to their order on the spiritual plane, where God was at the center and the Earth at the periphery. Near the beginning of the fourteenth century Dante, in the Paradiso of his Divine Comedy, described God as a light at the center of the cosmos. Here the poet ascends beyond physical existence to the Empyrean Heaven, where he comes face to face with God himself and is granted understanding of both divine and human nature. Later in the century, the illuminator of Nicole Oresme's Le livre du Ciel et du Monde, a translation of and commentary on Aristotle's De caelo produced for Oresme's patron, King Charles V, employed the same motif. He drew the spheres in the conventional order, with the Moon closest to the Earth and the stars highest, but the spheres were concave upwards, centered on God, rather than concave downwards, centered on the Earth. Below this figure Oresme quotes the Psalms that "The heavens declare the Glory of God and the firmament showeth his handiwork."

The late-16th-century Portuguese epic The Lusiads vividly portrays the celestial spheres as a "great machine of the universe" constructed by God. The explorer Vasco da Gama is shown the celestial spheres in the form of a mechanical model. Contrary to Cicero's representation, da Gama's tour of the spheres begins with the Empyrean, then descends inward toward Earth, culminating in a survey of the domains and divisions of earthly kingdoms, thus magnifying the importance of human deeds in the divine plan.

Phenobarbital

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Phenobarbital 

Clinical data
Trade names	Luminal
AHFS/Drugs.com	Monograph
MedlinePlus	a682007
Pregnancy category	AU: D
Dependence liability	Low
Routes of administration	by mouth (PO), rectal (PR), parenteral (intramuscular and intravenous)
ATC code	N03AA02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: Schedule IV DE: Prescription only (Anlage III for higher doses) UK: Class B US: Schedule IV
Pharmacokinetic data
Bioavailability	>95%
Protein binding	20 to 45%
Metabolism	Liver (mostly CYP2C19)
Onset of action	within 5 min (IV) and 30 min (PO)
Elimination half-life	53 to 118 hours
Duration of action	4 hrs to 2 days
Excretion	Kidney and fecal
Identifiers

IUPAC name
CAS Number	50-06-6
PubChem CID	4763
IUPHAR/BPS	2804
DrugBank	DB01174
ChemSpider	4599
UNII	YQE403BP4D
KEGG	D00506
ChEBI	CHEBI:8069
ChEMBL	ChEMBL40
CompTox Dashboard (EPA)	DTXSID5021122
ECHA InfoCard	100.000.007
Chemical and physical data
Formula	C12H12N2O3
Molar mass	232.239 g·mol−1
3D model (JSmol)	Interactive image

Phenobarbital, also known as phenobarbitone or phenobarb, or by the trade name Luminal, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of epilepsy in developing countries. In the developed world, it is commonly used to treat seizures in young children, while other medications are generally used in older children and adults. It may be used intravenously, injected into a muscle, or taken by mouth. The injectable form may be used to treat status epilepticus. Phenobarbital is occasionally used to treat trouble sleeping, anxiety, and drug withdrawal and to help with surgery. It usually begins working within five minutes when used intravenously and half an hour when administered by mouth. Its effects last for between four hours and two days.

Side effects include a decreased level of consciousness along with a decreased effort to breathe. There is concern about both abuse and withdrawal following long-term use. It may also increase the risk of suicide. It is pregnancy category B or D (depending on how it is taken) in the United States and category D in Australia, meaning that it may cause harm when taken by pregnant women. If used during breastfeeding it may result in drowsiness in the baby. A lower dose is recommended in those with poor liver or kidney function, as well as elderly people. Phenobarbital, like other barbiturates works by increasing the activity of the inhibitory neurotransmitter GABA.

Phenobarbital was discovered in 1912 and is the oldest still commonly used anti-seizure medication. It is on the World Health Organization's List of Essential Medicines. It is the least expensive anti-seizure medication at around US$5 a year in the developing world. Access, however, may be difficult as some countries label it as a controlled drug.

Medical uses

Phenobarbital is used in the treatment of all types of seizures, except absence seizures. It is no less effective at seizure control than phenytoin, however phenobarbital is not as well tolerated. Phenobarbital may provide a clinical advantage over carbamazepine for treating partial onset seizures. Carbamazepine may provide a clinical advantage over phenobarbital for generalized onset tonic-clonic seizures. Its very long active half-life (53–118 hours) means for some people doses do not have to be taken every day, particularly once the dose has been stabilized over a period of several weeks or months, and seizures are effectively controlled.

The first-line drugs for treatment of status epilepticus are benzodiazepines, such as lorazepam or diazepam. If these fail, then phenytoin may be used, with phenobarbital being an alternative in the US, but used only third-line in the UK. Failing that, the only treatment is anaesthesia in intensive care. The World Health Organization (WHO) gives phenobarbital a first-line recommendation in the developing world and it is commonly used there.

Phenobarbital is the first-line choice for the treatment of neonatal seizures. Concerns that neonatal seizures in themselves could be harmful make most physicians treat them aggressively. No reliable evidence, though, supports this approach.

Phenobarbital is sometimes used for alcohol detoxification and benzodiazepine detoxification for its sedative and anti-convulsant properties. The benzodiazepines chlordiazepoxide (Librium) and oxazepam (Serax) have largely replaced phenobarbital for detoxification.

Phenobarbital is useful for insomnia and anxiety.

Other uses

Phenobarbital properties can effectively reduce tremors and seizures associated with abrupt withdrawal from benzodiazepines.

Phenobarbital is a cytochrome P450 inducer, and is used to reduce the toxicity of some drugs.

Phenobarbital is occasionally prescribed in low doses to aid in the conjugation of bilirubin in people with Crigler–Najjar syndrome, type II, or in patients with Gilbert's syndrome.

Phenobarbital can also be used to relieve cyclic vomiting syndrome symptoms.

Phenobarbital is a commonly used agent in high purity and dosage for lethal injection of "death row" criminals.

In infants suspected of neonatal biliary atresia, phenobarbital is used in preparation for a ^99mTc-IDA hepatobiliary (HIDA; hepatobiliary ^99mTc-iminodiacetic acid) study that differentiates atresia from hepatitis or cholestasis.

Phenobarbital is used as a secondary agent to treat newborns with neonatal abstinence syndrome, a condition of withdrawal symptoms from exposure to opioid drugs in utero.

In massive doses, phenobarbital is prescribed to terminally ill patients to allow them to end their life through physician-assisted suicide.

Like other barbiturates, phenobarbital can be used recreationally, but this is reported to be relatively infrequent.

Side effects

Sedation and hypnosis are the principal side effects (occasionally, they are also the intended effects) of phenobarbital. Central nervous system effects, such as dizziness, nystagmus and ataxia, are also common. In elderly patients, it may cause excitement and confusion, while in children, it may result in paradoxical hyperactivity.

Phenobarbital is a cytochrome P450 hepatic enzyme inducer. It binds transcription factor receptors that activate cytochrome P450 transcription, thereby increasing its amount and thus its activity. Due to this higher amount of CYP450, drugs that are metabolized by the CYP450 enzyme system will have decreased effectiveness. This is because the increased CYP450 activity increases the clearance of the drug, reducing the amount of time they have to work.

Caution is to be used with children. Among anti-convulsant drugs, behavioural disturbances occur most frequently with clonazepam and phenobarbital.

Contraindications

Acute intermittent porphyria, hypersensitivity to any barbiturate, prior dependence on barbiturates, severe respiratory insufficiency (as with chronic obstructive pulmonary disease), severe liver failure, pregnancy, and breastfeeding are contraindications for phenobarbital use.

Overdose

Phenobarbital causes a depression of the body's systems, mainly the central and peripheral nervous systems. Thus, the main characteristic of phenobarbital overdose is a "slowing" of bodily functions, including decreased consciousness (even coma), bradycardia, bradypnea, hypothermia, and hypotension (in massive overdoses). Overdose may also lead to pulmonary edema and acute renal failure as a result of shock, and can result in death.

The electroencephalogram (EEG) of a person with phenobarbital overdose may show a marked decrease in electrical activity, to the point of mimicking brain death. This is due to profound depression of the central nervous system, and is usually reversible.

Treatment of phenobarbital overdose is supportive, and mainly consists of the maintenance of airway patency (through endotracheal intubation and mechanical ventilation), correction of bradycardia and hypotension (with intravenous fluids and vasopressors, if necessary), and removal of as much drug as possible from the body. In very large overdoses, multi-dose activated charcoal is a mainstay of treatment as the drug undergoes enterohepatic recirculation. Urine alkalization (achieved with sodium bicarbonate) enhances renal excretion. Hemodialysis is effective in removing phenobarbital from the body, and may reduce its half-life by up to 90%. No specific antidote for barbiturate poisoning is available.

Mechanism of action

Phenobarbitol is as an allosteric modulator which extends the amount of time the chloride ion channel is open by interacting with GABA_A receptor subunits. Through this action, phenobarbital increases the flow of chloride ions into the neuron which decreases the excitability of the post-synaptic neuron. Hyperpolarizing this post-synaptic membrane leads to a decrease in the general excitatory aspects of the post-synaptic neuron. By making it harder to depolarize the neuron, the threshold for the action potential of the post-synaptic neuron will be increased. Phenobarbital stimulates GABA to accomplish this hyperpolarization. Direct blockade of excitatory glutamate signaling is also believed to contribute to the hypnotic/anticonvulsant effect that is observed with the barbiturates.

Pharmacokinetics

Phenobarbital has an oral bioavailability of about 90%. Peak plasma concentrations (C_max) are reached eight to 12 hours after oral administration. It is one of the longest-acting barbiturates available – it remains in the body for a very long time (half-life of two to seven days) and has very low protein binding (20 to 45%). Phenobarbital is metabolized by the liver, mainly through hydroxylation and glucuronidation, and induces many isozymes of the cytochrome P450 system. Cytochrome P450 2B6 (CYP2B6) is specifically induced by phenobarbital via the CAR/RXR nuclear receptor heterodimer. It is excreted primarily by the kidneys.

Veterinary uses

Phenobarbital is one of the initial drugs of choice to treat epilepsy in dogs, and is the initial drug of choice to treat epilepsy in cats.

It is also used to treat feline hyperesthesia syndrome in cats when anti-obsessional therapies prove ineffective.

It may also be used to treat seizures in horses when benzodiazepine treatment has failed or is contraindicated.

History

The first barbiturate drug, barbital, was synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering and was first marketed as Veronal by Friedr. Bayer et comp. By 1904, several related drugs, including phenobarbital, had been synthesized by Fischer. Phenobarbital was brought to market in 1912 by the drug company Bayer as the brand Luminal. It remained a commonly prescribed sedative and hypnotic until the introduction of benzodiazepines in the 1960s.

Phenobarbital's soporific, sedative and hypnotic properties were well known in 1912, but it was not yet known to be an effective anti-convulsant. The young doctor Alfred Hauptmann gave it to his epilepsy patients as a tranquilizer and discovered their seizures were susceptible to the drug. Hauptmann performed a careful study of his patients over an extended period. Most of these patients were using the only effective drug then available, bromide, which had terrible side effects and limited efficacy. On phenobarbital, their epilepsy was much improved: The worst patients suffered fewer and lighter seizures and some patients became seizure-free. In addition, they improved physically and mentally as bromides were removed from their regimen. Patients who had been institutionalised due to the severity of their epilepsy were able to leave and, in some cases, resume employment. Hauptmann dismissed concerns that its effectiveness in stalling seizures could lead to patients suffering a build-up that needed to be "discharged". As he expected, withdrawal of the drug led to an increase in seizure frequency – it was not a cure. The drug was quickly adopted as the first widely effective anti-convulsant, though World War I delayed its introduction in the U.S.

In 1939, a German family asked Adolf Hitler to have their disabled son killed; the five-month-old boy was given a lethal dose of Luminal after Hitler sent his own doctor to examine him. A few days later 15 psychiatrists were summoned to Hitler's Chancellery and directed to commence a clandestine euthanasia program.

In 1940, at a clinic in Ansbach, Germany, around 50 intellectually disabled children were injected with Luminal and killed that way. A plaque was erected in their memory in 1988 in the local hospital at Feuchtwanger Strasse 38, although a newer plaque does not mention that patients were killed using barbiturates on site. Luminal was used in the Nazi children's euthanasia program until at least 1943.

Phenobarbital was used to treat neonatal jaundice by increasing liver metabolism and thus lowering bilirubin levels. In the 1950s, phototherapy was discovered, and became the standard treatment.

Phenobarbital was used for over 25 years as prophylaxis in the treatment of febrile seizures. Although an effective treatment in preventing recurrent febrile seizures, it had no positive effect on patient outcome or risk of developing epilepsy. The treatment of simple febrile seizures with anticonvulsant prophylaxis is no longer recommended.

Society and culture

Names

Phenobarbital is the INN and phenobarbitone is the BAN.

Synthesis

Barbiturate drugs are obtained via condensation reactions between a derivative of diethyl malonate and urea in the presence of a strong base. The synthesis of phenobarbital uses this common approach as well but differs in the way in which this malonate derivative is obtained. The reason for this difference is due to the fact that aryl halides do not typically undergo nucleophilic substitution in Malonic ester synthesis in the same way as aliphatic organosulfates or halocarbons do. To overcome this lack of chemical reactivity two dominant synthetic approaches using benzyl cyanide as a starting material have been developed:

The first of these methods consists of a Pinner reaction of benzyl cyanide, giving phenylacetic acid ethyl ester. Subsequently, this ester undergoes cross Claisen condensation using diethyl oxalate, giving diethyl ester of phenyloxobutandioic acid. Upon heating this intermediate easily loses carbon monoxide, yielding diethyl phenylmalonate. Malonic ester synthesis using ethyl bromide leads to the formation of α-phenyl-α-ethylmalonic ester. Finally a condensation reaction with urea gives phenobarbital.

The second approach utilizes diethyl carbonate in the presence of a strong base to give α-phenylcyanoacetic ester. Alkylation of this ester using ethyl bromide proceeds via a nitrile anion intermediate to give the α-phenyl-α-ethylcyanoacetic ester. This product is then further converted into the 4-iminoderivative upon condensation with urea. Finally acidic hydrolysis of the resulting product gives phenobarbital.

Regulation

The level of regulation includes Schedule IV non-narcotic (depressant) (ACSCN 2285) in the United States under the Controlled Substances Act 1970—but along with a few other barbiturates and at least one benzodiazepine, and codeine, dionine, or dihydrocodeine at low concentrations, it also has exempt prescription and had at least one exempt OTC combination drug now more tightly regulated for its ephedrine content. The phenobarbitone/phenobarbital exists in subtherapeutic doses which add up to an effective dose to counter the overstimulation and possible seizures from a deliberate overdose in ephedrine tablets for asthma, which are now regulated at the federal and state level as: a restricted OTC medicine and/or watched precursor, uncontrolled but watched/restricted prescription drug & watched precursor, a Schedule II, III, IV, or V prescription-only controlled substance & watched precursor, or a Schedule V (which also has possible regulations at the county/parish, town, city, or district as well aside from the fact that the pharmacist can also choose not to sell it, and photo ID and signing a register is required) exempt Non-Narcotic restricted/watched OTC medicine.

Selected overdoses

The Japanese officers aboard the German submarine U-234 killed themselves with phenobarbital while the German crew members were on their way to the US to surrender (but before Japan had surrendered).

A mysterious woman, known as the Isdal Woman, was found dead in Bergen, Norway, on 29 November 1970. Her death was caused by some combination of burns, phenobarbital, and carbon monoxide poisoning; many theories about her death have been posited, and it is believed that she may have been a spy.

British veterinarian Donald Sinclair, better known as the character Siegfried Farnon in the "All Creatures Great and Small" book series by James Herriot, committed suicide at the age of 84 by injecting himself with an overdose of phenobarbital. Activist Abbie Hoffman also committed suicide by consuming phenobarbital, combined with alcohol, on April 12, 1989; the residue of around 150 pills was found in his body at autopsy. Also dying from an overdose was British actress Phyllis Barry in 1954 and actress/model Margaux Hemingway in 1996.

Thirty-nine members of the Heaven's Gate UFO religious group committed mass suicide in March 1997 by drinking a lethal dose of phenobarbital and vodka "and then lay down to die" hoping to enter an alien spacecraft.