Phenobarbital, also known asphenobarbitone orphenobarb, sold under the brand nameLuminal among others, is amedication of thebarbiturate type.[6] It is recommended by theWorld Health Organization (WHO) for the treatment of certain types ofepilepsy indeveloping countries.[8] In the developed world, it is commonly used to treatseizures inyoung children,[9] while other medications are generally used in older children and adults.[10] It is also used for veterinary purposes.[11]
It may be administered by slowintravenous infusion (IV infusion),intramuscularly (IM), ororally (swallowed by mouth).Subcutaneous administration is not recommended.[6] The IV or IM (injectable forms) may be used to treatstatus epilepticus if other drugs fail to achieve satisfactory results.[6] Phenobarbital is occasionally used to treatinsomnia,anxiety, andbenzodiazepine withdrawal (as well as withdrawal from certain other drugs in specific circumstances), and prior to surgery as ananxiolytic and to inducesedation.[6] It usually begins working within five minutes when used intravenously and half an hour when administered orally.[6] Its effects last for between four hours and two days.[6][7]
Potentially serious side effects include adecreased level of consciousness andrespiratory depressant.[6] There is potential for bothabuse andwithdrawal following long-term use.[6] It may also increase the risk ofsuicide.[6]
It ispregnancy category D in Australia, meaning that it may cause harm when taken during pregnancy.[6][12] If used duringbreastfeeding it may result in drowsiness in the baby.[13] Phenobarbital works by increasing the activity of the inhibitoryneurotransmitterGABA.[6]
Phenobarbital was discovered in 1912 and is the oldest still commonly usedanti-seizure medication.[14][15] It is on theWorld Health Organization's List of Essential Medicines.[16]
Phenobarbital is used in the treatment of all types ofseizures, exceptabsence seizures.[17][18] It is no less effective at seizure control thanphenytoin, but phenobarbital is not as well tolerated.[19] Phenobarbital may provide a clinical advantage overcarbamazepine for treatingpartial onset seizures. Carbamazepine may provide a clinical advantage over phenobarbital forgeneralized onset tonic-clonic seizures.[20]
The first-line drugs for treatment ofstatus epilepticus arebenzodiazepines, such aslorazepam,clonazepam,midazolam, ordiazepam. If these fail, thenphenytoin may be used, with phenobarbital being an alternative in the US (favored in infants), but used only third-line in the UK.[21] Failing that, the only treatment isanaesthesia inintensive care.[18][22] TheWorld Health Organization (WHO) gives phenobarbital a first-line recommendation in the developing world and it is commonly used there.[8][23]
Phenobarbital is the first-line choice for the treatment ofneonatal seizures.[24][25][26][27] Concerns that neonatal seizures in themselves could be harmful make most physicians treat them aggressively. No reliable evidence, though, supports this approach.[28]
Phenobarbital is sometimes used foralcohol detoxification andbenzodiazepine detoxification for itssedative and anti-convulsant properties. The benzodiazepineschlordiazepoxide (Librium) andoxazepam (Serax) have largely replaced phenobarbital for detoxification.[29]
Phenobarbital is useful forinsomnia andanxiety.[30]
Phenobarbital properties can effectively reduce tremors and seizures associated with abrupt withdrawal from benzodiazepines.
Phenobarbital is occasionally prescribed in low doses to aid in the conjugation ofbilirubin in people withCrigler–Najjar syndrome, type II,[31] or in people withGilbert's syndrome.[32] In infants suspected of neonatalbiliary atresia, phenobarbital is used in preparation for a99mTc-IDA hepatobiliary (HIDA;hepatobiliary99mTc-iminodiaceticacid) study that differentiates atresia fromhepatitis orcholestasis.
In massive doses, phenobarbital is prescribed to terminally ill people to allow them to end their life throughphysician-assisted suicide.[33]
Like other barbiturates, phenobarbitalcan be used recreationally,[34] but this is reported to be relatively infrequent.[35]
The synthesis of a photoswitchable analog (DASA-barbital) and phenobarbital has been described for use as a research compound inphotopharmacology.[36]
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 andataxia, are also common. In elderly patients, it may cause excitement and confusion, while in children, it may result inparadoxical hyperactivity.[37]
Phenobarbital is acytochrome P450 hepatic enzyme inducer. It binds transcription factor receptors that activate cytochrome P450 transcription, thereby increasing its amount and thus its activity.[38] Caution is to be used with children. Among anti-convulsant drugs, behavioural disturbances occur most frequently withclonazepam and phenobarbital.[39]
Acute intermittent porphyria, hypersensitivity to any barbiturate, prior dependence on barbiturates, severerespiratory insufficiency (as withchronic obstructive pulmonary disease), severeliver failure, pregnancy, and breastfeeding are contraindications for phenobarbital use.[37]
Phenobarbital causes a depression of the body's systems, mainly thecentral andperipheral nervous systems. Thus, the main characteristic of phenobarbital overdose is a "slowing" of bodily functions, including decreasedconsciousness (evencoma),bradycardia,bradypnea,hypothermia, andhypotension (in massive overdoses). Overdose may also lead topulmonary edema andacute renal failure as a result ofshock and can result in death.
Theelectroencephalogram (EEG) of a person with phenobarbital overdose may show a marked decrease in electrical activity, to the point of mimickingbrain death. This is due to profound depression of the central nervous system and is usually reversible.[40]
Treatment of phenobarbital overdose issupportive, and mainly consists of the maintenance ofairway patency (throughendotracheal intubation andmechanical ventilation), correction of bradycardia and hypotension (withintravenous fluids andvasopressors, 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%.[40] No specific antidote for barbiturate poisoning is available.[41]
Phenobarbital acts as anallosteric modulator which extends the amount of time the chloride ion channel is open by interacting withGABAA receptor subunits. Through this action, phenobarbital increases the flow ofchloride ions into the neuron which decreases the excitability of thepost-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 todepolarize the neuron, thethreshold for the action potential of the post-synaptic neuron will be increased.[42]
Direct blockade of glutamatergicAMPA andkainate receptors are also believed to contribute to the hypnotic/anticonvulsant effect that is observed with phenobarbital.[43][44]
Phenobarbital has an oralbioavailability of about 90%.Peak plasma concentrations (Cmax) 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 lowprotein binding (20 to 45%). Phenobarbital is metabolized by the liver, mainly throughhydroxylation andglucuronidation and induces manyisozymes of thecytochrome P450 system. Cytochrome P450 2B6 (CYP2B6) is specifically induced by phenobarbital via theCAR/RXRnuclear receptorheterodimer. It is excreted primarily by thekidneys.[45]
The first barbiturate drug,barbital, was synthesized in 1902 by German chemistsEmil Fischer andJoseph von Mering and was first marketed as Veronal byFriedr. 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 companyBayer as the brand Luminal. It remained a commonly prescribed sedative and hypnotic until the introduction ofbenzodiazepines in the 1960s.[46]
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 doctorAlfred Hauptmann[47] gave it to his epilepsy patients as atranquilizer 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[clarification needed] patients had 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 developing 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, thoughWorld War I delayed its introduction in the U.S.[48]
In 1939, a German family askedAdolf 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 program ofinvoluntary euthanasia.[49][50]
In 1940, at a clinic inAnsbach, 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.[51][52] Luminal was used in the Nazichildren's euthanasia program until at least 1943.[53][54]
Phenobarbital was used to treatneonatal jaundice by increasing liver metabolism and thus loweringbilirubin levels. In the 1950s,phototherapy was discovered, and became the standard treatment.[55]
Phenobarbital was used for over 25 years asprophylaxis in the treatment offebrile seizures.[56] 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.[57][58]
Phenobarbital is theINN and phenobarbitone is theBAN.
Barbiturate drugs are obtained viacondensation reactions between aderivative ofdiethyl malonate andurea in the presence of a strongbase.[59] The synthesis of phenobarbital uses this common approach as well but differs in the way in which thismalonate derivative is obtained. The reason for this difference is becausearyl halides do not typically undergonucleophilic substitution inMalonic ester synthesis in the same way asaliphaticorganosulfates orhalocarbons do.[60] To overcome this lack ofchemical reactivity two dominant synthetic approaches usingbenzyl cyanide as a starting material have been developed:
The first of these methods consists of aPinner reaction of benzyl cyanide, givingphenylacetic acid ethyl ester.[61] Subsequently, this ester undergoes crossClaisen condensation usingdiethyl oxalate, giving diethyl ester of phenyloxobutandioic acid. Upon heating this intermediate easily losescarbon monoxide, yieldingdiethyl phenylmalonate.[62]Malonic ester synthesis usingethyl bromide leads to the formation of α-phenyl-α-ethylmalonic ester. Finally, acondensation reaction withurea gives phenobarbital.[59]
The second approach utilizesdiethyl carbonate in the presence of a strong base to give α-phenylcyanoacetic ester.[63][64] Alkylation of this ester using ethyl bromide proceeds via anitrile anion intermediate to give the α-phenyl-α-ethylcyanoacetic ester.[65] This product is then further converted into the 4-iminoderivative upon condensation with urea. Finally acidichydrolysis of the resulting product gives phenobarbital.[66]
A new synthetic route based on diethyl 2-ethyl-2-phenylmalonate and urea has been described.[36]
The level of regulation includesSchedule 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 onebenzodiazepine, andcodeine,dionine, ordihydrocodeine at low concentrations, it also has exempt prescription and had at least one exempt OTC combination drug now more tightly regulated for itsephedrine content.[67] 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 forasthma, 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 aSchedule 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.[68]
A mysterious woman, known as theIsdal Woman, was found dead inBergen, Norway, on 29 November 1970. Her death was caused by some combination of burns, phenobarbital, andcarbon monoxide poisoning; many theories about her death have been posited, and it is believed that she may have been aspy.[69]
British veterinarianDonald Sinclair, better known as the character Siegfried Farnon in the "All Creatures Great and Small" book series byJames Herriot, committed suicide at the age of 84 by injecting himself with an overdose of phenobarbital. ActivistAbbie Hoffman also committed suicide by consuming phenobarbital, combined withalcohol, on 12 April 1989; the residue of around 150 pills was found in his body at autopsy.[70]
Thirty-nine members of theHeaven's Gate UFO cult 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.[71]
Phenobarbital is one of the first-line drugs of choice to treatepilepsy indogs, as well ascats.[11]
It is also used to treatfeline hyperesthesia syndrome in cats when anti-obsessional therapies prove ineffective.[72]
It may also be used to treat seizures inhorses whenbenzodiazepine treatment has failed or is contraindicated.[73]
Bilirubin concentrations during phenobarbital administration do not return to normal but are typically in the range of 51-86 µmol/L (3-5 mg/dL). Although the incidence of kernicterus in CN-II is low, instances have occurred, not only in infants but also in adolescents and adults, often in the setting of an intercurrent illness, fasting, or another factor that temporarily raises the serum bilirubin concentration above baseline and reduces serum albumin levels. For this reason, phenobarbital therapy is highly recommended, a single bedtime dose often suffices to maintain clinically safe serum bilirubin concentrations.
Despite their widespread use during the first half of the 20th century, no barbiturate succeeded in eliminating the main drawbacks of these drugs, which were the phenomena of dependence and death by overdose
The case was to provide the rationale for a secret Nazi decree that led to 'mercy killings' of almost 300,000 mentally and physically handicapped people. The Kretschmars wanted their son dead but most of the other children were forcibly taken from their parents to be killed.
Hitler later signed a secret decree permitting the euthanasia of disabled infants. Sympathetic physicians and nurses from around the country--many not even Nazi party members--cooperated in the horror that followed. Formal 'protective guidelines' were created, including the creation of a panel of 'expert referees,' which judged which infants were eligible for the program.
In the late 1980s, important developments occurred at the clinic that led to the first publication on the subject and the display of two plaques. Dr. Reiner Weisenseel wrote his dissertation under Dr. Athen, then the director of the Ansbacher Bezirkskrankenhaus, on the involvement of the clinic in Euthanasia crimes, including the operation of the Kinderfachabteilung. In 1988 two members of the Green Party as well as the regional diet (Bezirkstag) were horrified to find portraits of physicians involved in Nazi euthanasia crimes among the honorary display of medical personnel in the administrative building, and they successfully petitioned to have these portraits removed. Since 1992 a plaque hangs in the entry hallway of the administrative building. It reads: 'In the Third Reich the Ansbach facility delivered to their death more than 2000 of the patients entrusted to it as life unworthy of living: They were transferred to killing facilities or starved to death. In their own way, many people incurred responsibility.' It continues: 'Half a century later full of shame we commemorate the victims and call to remember the Fifth Commandment.' The killing of childrenspecifically transferred to the clinic to be murdered is not noted. The plaque does not address that that euthanasia victims were not only starved or transported to gassing facilities but killed using barbiturates on site.
Two Polish physicians reported at the time that 235 children from ages up to 14 were listed in the booklet, of whom 221 had died. An investigation revealed that the medical records of the children had been falsified, as those records showed a far lower dosage of Luminal given to them than was entered into the Luminal booklet. For example, the medical records for Marianna N. showed for 16 January 1943 (she died on that day) a dosage of 0.1 g of Luminal, whereas the Luminal booklet showed the actual dosage as 0.4 g, or four times the dosage recommended for her body weight.
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