Phenobarbital 1588678 223698293 2008-07-05T09:23:57Z DOI bot 6652755 Citation maintenance. Formatted: title, doi. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{Drugbox| | IUPAC_name = 5-ethyl-5-phenylpyrimidine-2,4,6(1''H'',3''H'',5''H'')-trione | Other_name = 5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione | image = Phenobarbital.png | width = 120 | image2 = Phenobarbital3d_updated.png | width2 = 180 | CAS_number = 50-06-6 | ATC_prefix = N05 | ATC_suffix = CA24 | ATC_supplemental = {{ATC|N03|AA02}} | PubChem = 4763 | DrugBank = APRD00184 | C=12 | H=12 | N=2 | O=3 | molecular_weight = 232.235 g/mol | bioavailability = >95% | metabolism = [[Liver|Hepatic]] (mostly [[CYP2C19]]) | protein_bound = 20 to 45% | elimination_half-life = 53 to 118 hours | excretion = [[Kidney|Renal]] and fecal | pregnancy_US = D | legal_AU = | legal_UK = Class B | legal_US = Schedule IV | legal_status = | routes_of_administration = Oral, rectal, parenteral ([[intramuscular injection|intramuscular]] and [[intravenous therapy|intravenous]]) }} '''Phenobarbital''' ([[International Nonproprietary Name|INN]]) or '''phenobarbitone''' (former [[British Approved Name|BAN]]) is a [[barbiturate]], first marketed as '''[[Luminal]]''' by [[Bayer|Friedr. Bayer et comp]]. It is the most widely used [[anticonvulsant]] worldwide and the oldest still in use. It also has [[sedative]] and [[hypnotic]] properties but, as with other barbiturates, has been superseded by the [[benzodiazepine]]s for these indications. The [[World Health Organization]] recommends its use as first-line for partial and generalized [[Tonic-clonic seizure|tonic-clonic]] [[seizure]]s (those formerly known as Grand Mal) in [[developing country|developing countries]]. It is a ''core'' medicine in the [[WHO Model List of Essential Medicines]], which is a list of minimum medical needs for a basic health care system.<ref name="essentialWHO">{{cite web | year = March 2005 | url = http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf | title = WHO Model List of Essential Medicines | format = PDF | publisher = World Health Organization | accessdate = 2006-03-12 }}</ref> In more affluent countries it is no longer recommended as a first-line medication, however it is relied on as an alternate when a patient fails to respond to treatment with more modern AED's (Anti-Epileptic-Drugs).<ref name="NICEguidelines2004">{{cite web | url = http://www.nice.org.uk/page.aspx?o=CG020NICEguideline | title = CG20 Epilepsy in adults and children: NICE guideline | accessdate = 2006-09-06 | author = NICE | authorlink = National Institute for Health and Clinical Excellence | date = [[2005-10-27]] | publisher = [[National Health Service|NHS]] }}</ref><ref name="epilepsyfoundation">{{cite web | url = http://www.epilepsyfoundation.org/answerplace/Medical/treatment/medications/typesmedicine/phenobarbital.cfm | title = Phenobarbital | accessdate = 2006-09-07 | publisher = Epilepsy Foundation }}</ref> It is still commonly used around the world to treat [[neonatal]] seizures.<ref name="BNFc4.8.1">{{cite book | title =[[British National Formulary for Children]] | chapter = 4.8.1 Control of epilepsy | pages = 255-6 | author = [[British Medical Association]], [[Royal Pharmaceutical Society of Great Britain]], [[Royal College of Paediatrics and Child Health]] and Neonatal and Paediatric Pharmacists Group | date= 2006 | id = ISBN 0-85369-676-4 }}</ref> ==History== The first barbiturate drug, [[barbital]], was synthesized in 1902 by German chemists [[Emil Fischer]] and [[Joseph von Mering]] at Bayer. By 1904 several related drugs, including phenobarbital, had been synthesized by Fischer. Phenobarbital was brought to market in 1912 by the drug company Bayer using the brand Luminal. It remained a commonly prescribed sedative and hypnotic until the introduction of benzodiazepines in the 1950s.<ref name="Sneader2005">{{cite book | last = Sneader | first = Walter | title = Drug Discovery | accessdate = 2006-09-06 | date= 2005-06-23 | publisher = John Wiley and Sons | id = ISBN 0-471-89979-8 | pages = 369 }}</ref> Phenobarbital's soporific, sedative and hypnotic properties were well known in 1912, but nobody knew it was also an effective anticonvulsant. The young doctor [[Alfred Hauptmann]]<ref>{{cite web | url = http://www.whonamedit.com/doctor.cfm/2764.html | title = Alfred Hauptmann | accessdate [[2006-09-06]] | author = Ole Daniel Enersen }}</ref> gave it to his epilepsy patients as a tranquiliser and discovered that their epileptic attacks 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, [[potassium bromide|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 regime. Patients who had been institutionalised due to the severity of their epilepsy were able to leave and, in some cases, resume employment. Hauptman dismissed concerns that its effectiveness in stalling epileptic attacks could lead to patients suffering a build-up that needed to be "discharged". As he expected, withdrawal of the drug lead to an increase in seizure frequency – it was not a cure. The drug was quickly adopted as the first widely effective anticonvulsant, though [[World War I]] delayed its introduction in the U.S.<ref name="Scott1993">{{cite book | last = Scott, | first = Donald F | title = The History of Epileptic Therapy | accessdate = 2006-09-06 | date = [[1993-02-15]] | publisher = Taylor & Francis | id = ISBN 1-85070-391-4 | pages = 59-65 }}</ref> Between 1934-1945 [[Phenobarbital]], under the brand name [[Luminal]], was used by [[Germany|German]] doctors under the [[Nazi]] party endorsed policy of [[eugenics]] to kill children born with disease or deformities. Code-named [[Operation T-4]], this policy of murdering [[Germany|German]]-born children and adults deemed not to meet the standards of the [[Aryan]] race was a pre-cursor to the [[Holocaust]] and many of the medical staff involved were later to transfer to Nazi [[Concentration Camps]] where their expertise in killing was put to further use.<ref name="Pitz2006">{{cite web | url = http://www.post-gazette.com/pg/06354/747359-42.stm | title = A Warhol show explores Germany's Master Race philosophy | accessdate = 2007-03-20 | author = Marylynne Pitz | date = [[2006-12-20]] | work = Post-Gazette | publisher = PG Publishing Co., Inc. }}</ref> <ref name="Schaefer2004">{{cite web | url=http://www.thenewatlantis.com/archive/5/schaefer.htm | title=The Legacy of Nazi Medicine | accessdate = 2007-03-20 | author=Naomi Schaefer | year=2004 | month=March | publisher=The New Atlantis, Number 5 | pages=54-60 }}</ref> 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.<ref name="Pepling2005">{{cite journal | author = Rachel Sheremeta Pepling | year = 2005 | month = 06 | title = Phenobarbital | journal = Chemical and Engineering News | volume = 83 | issue = 25 | url = http://pubs.acs.org/cen/coverstory/83/8325/8325phenobarbital.html | accessdate = 2006-09-06 }}</ref> In 1940, Winthrop Chemical produced [[sulfathiazole]] tablets that were contaminated with phenobarbital. This occurred because both tablets were produced side-by-side and equipment could be interchanged. Each antibacterial tablet contained more than twice the required dose of phenobarbital necessary to induce sleep. Hundreds of patients died or were injured as a result. A U.S. [[Food and Drug Administration]] investigation was highly critical of Winthrop and the scandal lead to the introduction of [[Good Manufacturing Practice]] for drugs.<ref name="Pepling2005"/> The drug itself through predated FDA approval processes and has failed to be formally cleared for use in subsequent years. Guidance was issued in June 2006 of plans to enforce US approval for unapproved drugs.<ref>{{cite web| author=Michelle Meadows |title=The FDA Takes Action Against Unapproved Drugs |url=http://www.fda.gov/fdac/features/2007/107_drug.html |date=January-February 2007 |publisher=FDA Consumer magazine |accessdate=2007-09-27}}</ref> Phenobarbital was used for over 25 years as [[prophylaxis]] in the treatment of [[febrile seizure]]s.<ref name="Scott1993Febrile">{{cite book | author = John M. Pellock, W. Edwin Dodson, Blaise F. D. Bourgeois | title = Pediatric Epilepsy | accessdate = 2006-09-06 | date = [[2001-01-01]] | publisher = Demos Medical Publishing | id = ISBN 1-888799-30-7 | pages = 169 }}</ref> 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.<ref name="Baumann2005">{{cite web | url = http://www.emedicine.com/neuro/topic134.htm | title = Febrile Seizures | accessdate = 2006-09-06 | author = Robert Baumann | date = [[2005-02-14]] | work = eMedicine | publisher = WebMD }}</ref><ref name="SIGN81">{{cite web | url=http://www.sign.ac.uk/pdf/sign81.pdf | title=Diagnosis and management of epilepsies in children and young people | accessdate = 2006-09-07 | author=various | year=2005 | month=March | publisher=Scottish Intercollegiate Guidelines Network | pages=15 }}</ref> ==Indications== Phenobarbital is indicated in the treatment of all types of seizures except [[absence seizure]]s.<ref name="NICEguidelines2004"/><ref name="BNF51">[[British National Formulary]] 51</ref> Phenobarbital is no less effective at seizure control than more modern drugs such as [[phenytoin]] and [[carbamazepine]]. It is, however, significantly less well tolerated.<ref name="Taylor">{{cite journal | author = Taylor S, Tudur Smith C, Williamson PR, Marson AG | title = Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures | journal = Cochrane Database Systematic Reviews | issue = 2 | year = 2003 | doi = 10.1002/14651858.CD002217 | pmid = 11687150 | url = http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD002217/pdf_fs.html | accessdate = 2006-09-06 }}</ref><ref name="TudurSmith2003">{{cite journal | author = Tudur Smith C, Marson AG, Williamson PR | title = Carbamazepine versus phenobarbitone monotherapy for epilepsy | journal = Cochrane Database of Systematic Reviews | issue = 1 | year = 2003 | doi = 10.1002/14651858.CD001904 | pmid = 12535420 | url = http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD001904/pdf_fs.html | accessdate = 2006-09-06 }}</ref> The first line drugs for treatment of [[status epilepticus]] are fast acting benzodiazepines such as [[diazepam]] or [[lorazepam]]. If these fail then [[phenytoin]] may be used, with phenobarbital being an alternative in the U.S. but used only third line in the UK.<ref name="BNFc4.8.2">{{cite book | title =[[British National Formulary for Children]] | chapter = 4.8.2 Drugs used in status epilepticus | pages = 269 | author = [[British Medical Association]], [[Royal Pharmaceutical Society of Great Britain]], [[Royal College of Paediatrics and Child Health]] and Neonatal and Paediatric Pharmacists Group | date= 2006 | id = ISBN 0-85369-676-4 }}</ref> Failing that, the only treatment is [[anaesthesia]] in [[intensive care]].<ref name="BNF51"/><ref name="Kalvaiainen2005">{{cite journal | author = Kälviäinen R, Eriksson K, Parviainen I | title = Refractory generalised convulsive status epilepticus : a guide to treatment | journal = CNS Drugs | volume = 19 | issue = 9 | pages = 759–68 | year = 2005 | pmid = 16142991 | doi = 10.2165/00023210-200519090-00003 }}</ref> Phenobarbital is the first line choice for the treatment of [[neonatal]] seizures.<ref name="BNFc4.8.1"/><ref name="Scott1993Neonatal">{{cite book | author = John M. Pellock, W. Edwin Dodson, Blaise F. D. Bourgeois | title = Pediatric Epilepsy | accessdate = 2006-09-06 | date = [[2001-01-01]] | publisher = Demos Medical Publishing | id = ISBN 1-888799-30-7 | pages = 152 }}</ref><ref name="Sheth2005">{{cite web | url = http://www.emedicine.com/NEURO/topic240.htm | title = Neonatal Seizures | accessdate = 2006-09-06 | author = Raj D Sheth | date = [[2005-03-30]] | work = eMedicine | publisher = WebMD }}</ref> Concerns that neonatal seizures in themselves could be harmful make most physicians treat them aggressively. There is, however, no reliable evidence to support this approach.<ref name="Booth2004">{{cite journal | author = Booth D, Evans DJ | title = Anticonvulsants for neonates with seizures | journal = Cochrane Database of Systematic Reviews | issue = 3 | year = 2004 | doi = 10.1002/14651858.CD004218.pub2 | pmid = 15495087 | url = http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD004218/pdf_fs.html | accessdate = 2006-09-06 }}</ref> ==Side effects== Sedation and hypnosis are the principal side effects of phenobarbital. [[Central nervous system]] effects like 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. ==Special precautions== Caution in children. Of anticonvulsant drugs behavioural disturbances occur most frequently with [[clonazepam]] and phenobarbital.<ref>{{cite journal | journal = Epilepsia | year = 1988| volume = 29 Suppl 3| pages = S15–9| title = Children of school age: the influence of antiepileptic drugs on behavior and intellect| author = Trimble MR| coauthors = Cull C| pmid = 3066616| doi = 10.1111/j.1528-1157.1988.tb05805.x}}</ref> ==Contraindications== [[Acute intermittent porphyria]], oversensitivity for barbiturates, prior dependence on barbiturates, severe respiratory insufficiency and hyperkinesia in children. ==Overdose== {{Infobox_Disease | Name = Poisoning by barbiturates | ICD10 = {{ICD10|T|42|3|t|36}} | eMedicineSubj = med | eMedicineTopic = 207 | }} Phenobarbital causes a "depression" of the body's systems, mainly the [[central nervous system|central]] and [[peripheral nervous system]]s; 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 (medical)|shock]]. The [[electroencephalogram]] 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.<ref name="Habal">{{cite web | url = http://www.emedicine.com/MED/topic207.htm | title = Barbiturate Toxicity | accessdate = 2006-09-14 | author = Rania Habal | date = [[2006-01-27]] | work = eMedicine | publisher = WebMD }}</ref> Treatment of phenobarbital overdose is supportive, and consists mainly in the maintenance of [[airway]] patency (through [[endotracheal intubation]] and [[mechanical ventilation]]), correction of bradycardia and hypotension (with [[intravenous therapy|intravenous fluid]]s and [[vasopressor]]s, if necessary) and removal of as much drug as possible from the body. Depending on how much time has elapsed since ingestion of the drug, this may be accomplished through [[gastric lavage]] (stomach pumping) or use of [[activated charcoal]]. [[Hemodialysis]] is effective in removing phenobarbital from the body, and may reduce its half-life by up to 90%.<ref name="Habal"/> There is no specific antidote for barbiturate poisoning. British veterinarian [[Donald Sinclair (veterinarian)|Donald Sinclair]], better known as "Sigfried Farnon" in the "[[All Creatures Great and Small]]" books of [[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.<ref>{{cite news | title = Abbie Hoffman Committed Suicide Using Barbiturates, Autopsy Shows |last = King | first = Wayne | date = [[April 19]] [[1989]] | work = [[The New York Times]] | url = http://query.nytimes.com/gst/fullpage.html?sec=health&res=950DE7D61F38F93AA25757C0A96F948260 | accessdate = 2008-04-09}}</ref> ==Pharmacokinetics== Phenobarbital has an oral [[bioavailability]] of approximately 90%. Peak plasma concentrations are reached 8 to 12 hours after oral administration. It is one of the longest-acting barbiturates available &ndash; it remains in the body for a very long time (half-life of 2 to 7 days) and has very low [[Plasma protein binding|protein binding]] (20 to 45%). Phenobarbital is metabolized by the liver, mainly through [[hydroxylation]] and [[glucuronidation]], and induces most [[isozyme]]s of the [[cytochrome P450 oxidase|cytochrome P450 system]]. Cytochrome P450 2B6 System is more specifically induced by Phenobarbital. It is excreted primarily by the [[kidney]]s. ==Veterinary uses== Phenobarbital is one of the initial drugs of choice to treat [[epilepsy]] in [[dog]]s, and is the initial drug of choice to treat epilepsy in cats.<ref name = Dewey> {{cite book | author = Thomas, WB | title = Seizures and narcolepsy. ''In: Dewey, Curtis W. (ed.)'' A Practical Guide to Canine and Feline Neurology | publisher = Iowa State Press | location = Ames, Iowa | year = 2003 | id = ISBN 0-8138-1249-6}}</ref> It may also be used to treat seizures in [[horse]]s when [[benzodiazepine]] treatment has failed or is contraindicated.<ref name = MVM> {{cite book |editor= Kahn, Cynthia M., Line, Scott, Aiello, Susan E. (ed.) |title= [[Merck Veterinary Manual|The Merck Veterinary Manual]] |date= February 8, 2005 |publisher= [[John Wiley & Sons]] |edition= 9th ed. |id= ISBN 0-911910-50-6}}</ref> == Illicit Use == The [[High Incident Bandits]] used phenobarbital prior to committing the [[North Hollywood shootout|North Hollywood Bank of America robbery]].<ref><i>Shootout!: North Hollywood Shootout</i>, History Channel Documentary (last viewed May 11, 2008).</ref> Phenobarbital was mixed with [[vodka]] and consumed by the [[Heaven's Gate (religious group)|Heaven's Gate Cult]] members to commit suicide on March 26, 1997.{{Fact|date=December 2007}} ==References== {{reflist|2}} {{Barbiturates}} {{Anticonvulsants}} {{Hypnotics and sedatives}} [[Category:Barbiturates]] [[Category:Hypnotics]] [[Category:Anticonvulsants]] [[de:Phenobarbital]] [[es:Fenobarbital]] [[fr:Phénobarbital]] [[gl:Fenobarbital]] [[it:Fenobarbital]] [[hu:Fenobarbitál]] [[nl:Fenobarbital]] [[ja:フェノバルビタール]] [[no:Fenobarbital]] [[pl:Fenobarbital]] [[pt:Fenobarbital]] [[ro:Fenobarbital]] [[ru:Фенобарбитал]] [[fi:Fenobarbitaali]] [[sv:Fenobarbital]] [[tr:Fenobarbital]]