Phenobarbital

Phenobarbital

Systematic (IUPAC) name
5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione
Clinical data
Trade names	Luminal
AHFS/Drugs.com	monograph
MedlinePlus	a682007
Pregnancy cat.	D(US)
Legal status	Schedule IV (US) Class B (UK)
Routes	Oral, rectal, parenteral (intramuscular and intravenous)
Pharmacokinetic data
Bioavailability	>95%
Protein binding	20 to 45%
Metabolism	Hepatic (mostly CYP2C19)
Half-life	53 to 118 hours
Excretion	Renal and fecal
Identifiers
CAS number	50-06-6 Y
ATC code	N05CA24 N03AA02
PubChem	CID 4763
DrugBank	APRD00184
ChemSpider	4599 Y
UNII	YQE403BP4D Y
KEGG	D00506 Y
ChEBI	CHEBI:8069 N
ChEMBL	CHEMBL40 Y
Chemical data
Formula	C12H12N2O3
Mol. mass	232.235 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C12H12N2O3/c1-2-12(8-6-4-3-5-7-8)9(15)13-11(17)14-10(12)16/h3-7H,2H2,1H3,(H2,13,14,15,16,17) Y Key:DDBREPKUVSBGFI-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Phenobarbital (INN) or phenobarbitone (former BAN) is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide,^[1] and the oldest still commonly used.^[2] It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the benzodiazepines for these indications. The World Health Organization recommends its use as first-line for partial and generalized tonic–clonic seizures (those formerly known as grand mal) in 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.^[3] In more affluent countries, it is no longer recommended as a first or second-line choice anticonvulsant for most seizure types,^[2][4] though it is still commonly used to treat neonatal seizures.

Phenobarbital (and phenobarbital sodium) is manufactured and supplied in various forms: in tablets of 15, 30, 60 and 100 mg (though not all are available in all countries: for example, in Australia only the 30 mg strength tablets are available); in an oral elixir (commonly 3 mg/mL in strength); and in a form for injection (as phenobarbital sodium - usually 200 mg/mL). The injectable form is used principally to control status epilepticus, while the oral forms are used for prophylactic and maintenance therapy. The dose range for epilepsy is 60–320 mg/day; its very long active half-life means that for some patients, doses do not have to be taken every day, particularly once the dose has been stabilised over a period of several weeks or months and seizures are effectively controlled. It is occasionally still used as a sedative/hypnotic in anxious or agitated patients who may be intolerant of or do not have access to benzodiazepines, neuroleptics and other, newer drugs. For this purpose phenobarbital has a lower dose range - around 30–120 mg/day; however this practice is uncommon in developed countries.^[5]

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 1960s.^[6]

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^[7] gave it to his epilepsy patients as a tranquilizer 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, 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 led 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.^[8]

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.^[9]

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 led to the introduction of Good Manufacturing Practice for drugs.^[9]

The drug predates the 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.^[10]

Phenobarbital was used for over 25 years as prophylaxis in the treatment of febrile seizures.^[11] 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.^[12][13]

Indications

Phenobarbital is indicated in the treatment of all types of seizures except absence seizures.^[4][14] Phenobarbital is no less effective at seizure control than more modern drugs such as phenytoin and carbamazepine. It is, however, significantly less well tolerated.^[15][16]

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.^[17] Failing that, the only treatment is anaesthesia in intensive care.^[14][18]

Phenobarbital is the first line choice for the treatment of neonatal seizures.^[5][19][20] 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.^[21]

Phenobarbital is sometimes indicated for alcohol and benzodiazepine detoxification for its sedative and anticonvulsant properties. The benzodiazepines chlordiazepoxide (Librium) and oxazepam (Serax) have largely replaced phenobarbital for detoxification.^[22]

Other uses

Phenobarbital is often used for the treatment of acute withdrawal from benzodiazepines.^{[citation needed]} Phenobarbital properties can effectively reduce tremors and seizures associated with abrupt withdrawal from benzodiazepines. Phenobarbital is a cytochrome P450 inducer. Its used to reduce the toxicity of some drugs.

Phenobarbital is occasionally prescribed in low doses to aid in the conjugation of bilirubin in patients suffering from Gilbert's Syndrome.

In infants suspected of neonatal biliary atresia, phenobarbital is used in preparation for a ^99mTc-IDA hepatobiliary study that differentiates atresia from hepatitis or chondrostasis.

Side effects

Sedation and hypnosis are the principal side effects (occasionally, they are also the intended 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. Another very rare side effect is amelogenesis imperfecta.^{[citation needed]}

Special precautions

Caution is to be used with children. Of anticonvulsant drugs behavioural disturbances occur most frequently with clonazepam and phenobarbital.^[23]

Contraindications

Acute intermittent porphyria, oversensitivity for barbiturates, prior dependence on barbiturates, severe respiratory insufficiency and hyperkinesia in children.

Mechanism of action

See barbiturates.

Overdose

Main article: Barbiturate overdose

Poisoning by barbiturates
Classification and external resources
ICD-10	T42.3
eMedicine	med/207

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 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.^[24]

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 fluids and vasopressors, 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%.^[24] There is no specific antidote for barbiturate poisoning.^[25]

British veterinarian Donald Sinclair, better known as "Siegfried 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.^[26]

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 – it remains in the body for a very long time (half-life of 2 to 7 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.^[27]

It may also be used to treat seizures in horses when benzodiazepine treatment has failed or is contraindicated.^[28]

Chemistry

Phenobarbital (5-ethyl-5-phenylbarbituric acid or 5-ethyl-5-phenylhexahydropyrimindin-2,4,6-trione) has been synthesized in several different ways.

• Bayer & Co., DE 247952  (1911).
• M.T. Inman, W.P. Bitler, U.S. Patent 2,358,072 (1944).
• Chamberlain, J. S.; Chap, J. J.; Doyle, J. E.; Spaulding, L. B. (1935). Journal of the American Chemical Society 57 (2): 352. doi:10.1021/ja01305a036.  edit
• Pinhey, J (1980). "The α-arylation of derivatives of malonic acid with aryllead triacetates. New syntheses of ibuprofen and phenobarbital". Tetrahedron Letters 21: 965. doi:10.1016/S0040-4039(00)77752-5.  edit

There is no major difference between them.

The first method consists of ethanolysis of benzyl cyanide in the presence of acid, giving phenylacetic acid ethyl ester, the methylene group of which undergoes acylation using diethyloxalate, giving diethyl ester of phenyloxobutandioic acid, which upon heating easily loses carbon oxide and turns into phenylmalonic ester. Alkylation of the obtained product using ethyl bromide in the presence of sodium ethoxide leads to the formation of α-phenyl-α- ethylmalonic ester, the condensation of which with urea gives phenobarbital.

Another method of phenobarbital synthesis starts with condensation of benzyl cyanide with diethylcarbonate in the presence of sodium ethoxide to give α-phenylcyanoacetic ester. Alkylation of the ester using ethyl bromide gives α-phenyl-α-ethylcyanoacetic ester, which is further converted into the 4-iminoderivative upon treatment with urea. Acidic hydrolysis of the resulting product gives phenobarbital.

External links

• U.S. National Library of Medicine: Drug Information Portal - Phenobarbital

References

1. ^ Kwan P, Brodie MJ (September 2004). "Phenobarbital for the treatment of epilepsy in the 21st century: a critical review". Epilepsia 45 (9): 1141–9. doi:10.1111/j.0013-9580.2004.12704.x. PMID 15329080. http://www3.interscience.wiley.com/cgi-bin/fulltext/118751051/HTMLSTART. 
2. ^ ^{a b} "Phenobarbital". Epilepsy Foundation. http://www.epilepsyfoundation.org/answerplace/Medical/treatment/medications/typesmedicine/phenobarbital.cfm. Retrieved 2006-09-07. 
3. ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. March 2005. http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf. Retrieved 2006-03-12. 
4. ^ ^{a b} NICE (2005-10-27). "CG20 Epilepsy in adults and children: NICE guideline". NHS. http://www.nice.org.uk/page.aspx?o=CG020NICEguideline. Retrieved 2006-09-06. 
5. ^ ^{a b} British Medical Association, Royal Pharmaceutical Society of Great Britain, Royal College of Paediatrics and Child Health and Neonatal and Paediatric Pharmacists Group (2006). "4.8.1 Control of epilepsy". British National Formulary for Children. London: BMJ Publishing. pp. 255–6. ISBN 0-85369-676-4. 
6. ^ Sneader, Walter (2005-06-23). Drug Discovery. John Wiley and Sons. p. 369. ISBN 0-471-89979-8. 
7. ^ Ole Daniel Enersen. "Alfred Hauptmann". http://www.whonamedit.com/doctor.cfm/2764.html. Retrieved 2006-09-06. 
8. ^ Scott,, Donald F (1993-02-15). The History of Epileptic Therapy. Taylor & Francis. pp. 59–65. ISBN 1-85070-391-4. 
9. ^ ^{a b} Rachel Sheremeta Pepling (June 2005). "Phenobarbital". Chemical and Engineering News 83 (25). http://pubs.acs.org/cen/coverstory/83/8325/8325phenobarbital.html. Retrieved 2006-09-06. 
10. ^ Michelle Meadows (January–February 2007). "The FDA Takes Action Against Unapproved Drugs". FDA Consumer magazine. http://permanent.access.gpo.gov/lps1609/www.fda.gov/fdac/features/2007/107_drug.html. Retrieved 2010-09-29. 
11. ^ John M. Pellock, W. Edwin Dodson, Blaise F. D. Bourgeois (2001-01-01). Pediatric Epilepsy. Demos Medical Publishing. p. 169. ISBN 1-888799-30-7. 
12. ^ Robert Baumann (2005-02-14). "Febrile Seizures". eMedicine. WebMD. http://www.emedicine.com/neuro/topic134.htm. Retrieved 2006-09-06. 
13. ^ various (March 2005). "Diagnosis and management of epilepsies in children and young people" (PDF). Scottish Intercollegiate Guidelines Network. pp. 15. http://www.sign.ac.uk/pdf/sign81.pdf. Retrieved 2006-09-07. 
14. ^ ^{a b} British National Formulary 51
15. ^ Taylor S, Tudur Smith C, Williamson PR, Marson AG (2003). Taylor, Stephen. ed. "Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures". Cochrane Database Systematic Reviews (2): CD002217. doi:10.1002/14651858.CD002217. PMID 11687150. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD002217/pdf_fs.html. Retrieved 2006-09-06. 
16. ^ Tudur Smith C, Marson AG, Williamson PR (2003). Tudur Smith, Catrin. ed. "Carbamazepine versus phenobarbitone monotherapy for epilepsy". Cochrane Database of Systematic Reviews (1): CD001904. doi:10.1002/14651858.CD001904. PMID 12535420. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD001904/pdf_fs.html. Retrieved 2006-09-06. 
17. ^ British Medical Association, Royal Pharmaceutical Society of Great Britain, Royal College of Paediatrics and Child Health and Neonatal and Paediatric Pharmacists Group (2006). "4.8.2 Drugs used in status epilepticus". British National Formulary for Children. London: BMJ Publishing. p. 269. ISBN 0-85369-676-4. 
18. ^ Kälviäinen R, Eriksson K, Parviainen I (2005). "Refractory generalised convulsive status epilepticus : a guide to treatment". CNS Drugs 19 (9): 759–68. doi:10.2165/00023210-200519090-00003. PMID 16142991. 
19. ^ John M. Pellock, W. Edwin Dodson, Blaise F. D. Bourgeois (2001-01-01). Pediatric Epilepsy. Demos Medical Publishing. p. 152. ISBN 1-888799-30-7. 
20. ^ Raj D Sheth (2005-03-30). "Neonatal Seizures". eMedicine. WebMD. http://www.emedicine.com/NEURO/topic240.htm. Retrieved 2006-09-06. 
21. ^ Booth D, Evans DJ (2004). Booth, David. ed. "Anticonvulsants for neonates with seizures". Cochrane Database of Systematic Reviews (3): CD004218. doi:10.1002/14651858.CD004218.pub2. PMID 15495087. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD004218/pdf_fs.html. Retrieved 2006-09-06. 
22. ^ http://www.aafp.org/afp/980700ap/miller.html
23. ^ Trimble MR; Cull C (1988). "Children of school age: the influence of antiepileptic drugs on behavior and intellect". Epilepsia 29 Suppl 3: S15–9. doi:10.1111/j.1528-1157.1988.tb05805.x. PMID 3066616. 
24. ^ ^{a b} Rania Habal (2006-01-27). "Barbiturate Toxicity". eMedicine. WebMD. http://www.emedicine.com/MED/topic207.htm. Retrieved 2006-09-14. 
25. ^ "Barbiturate intoxication and overdose". MedLine Plus. http://www.nlm.nih.gov/medlineplus/ency/article/000951.htm. Retrieved 15 July 2008. 
26. ^ King, Wayne (April 19, 1989). "Abbie Hoffman Committed Suicide Using Barbiturates, Autopsy Shows". The New York Times. http://query.nytimes.com/gst/fullpage.html?sec=health&res=950DE7D61F38F93AA25757C0A96F948260. Retrieved 2008-04-09. 
27. ^ Thomas, WB (2003). "Seizures and narcolepsy". In Dewey, Curtis W. (ed.). A Practical Guide to Canine and Feline Neurology. Ames, Iowa: Iowa State Press. ISBN 0-8138-1249-6. 
28. ^ Editor, Cynthia M. Kahn; associate editor Scott Line (February 8, 2005). Kahn, Cynthia M., Line, Scott, Aiello, Susan E. (ed.). ed. The Merck Veterinary Manual (9th ed.). John Wiley & Sons. ISBN 0-911910-50-6.