Phenobarbital

Source: Wikipedia, the free encyclopedia.
Not to be confused with Pentobarbital.
Not to be confused with Luminol.
Phenobarbital
2D chemical structure of phenobarbital
3D ball-and-stick model of phenobarbital
Clinical data
Trade namesLuminal, Sezaby
AHFS/Drugs.comMonograph
MedlinePlusa682007
Pregnancy
category
  • AU: D
parenteral
Drug classBarbiturate
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability>95%
Protein binding20 to 45%
MetabolismLiver (mostly CYP2C19)
Onset of actionwithin 5 min (IV) and 30 min (PO)[4]
Elimination half-life53 to 118 hours
Duration of action4 hrs[4] to 2 days[5]
ExcretionKidney and fecal
Identifiers
  • 5-Ethyl-5-phenyl-1,3-diazinane-2,4,6-trione
JSmol)
  • O=C1NC(=O)NC(=O)C1(c2ccccc2)CC
  • 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) checkY
  • Key:DDBREPKUVSBGFI-UHFFFAOYSA-N checkY
  (verify)

Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a

intravenously, injected into a muscle, or taken by mouth.[4] The injectable form may be used to treat status epilepticus.[4] Phenobarbital is occasionally used to treat trouble sleeping, anxiety, and drug withdrawal and to help with surgery.[4] It usually begins working within five minutes when used intravenously and half an hour when administered by mouth.[4] Its effects last for between four hours and two days.[4][5]

Side effects include a

GABA.[4]

Phenobarbital was discovered in 1912 and is the oldest still commonly used

anti-seizure medication.[12][13] It is on the World Health Organization's List of Essential Medicines.[14]

Medical uses

Phenobarbital is used in the treatment of all types of seizures, except

partial onset seizures. Carbamazepine may provide a clinical advantage over phenobarbital for generalized onset tonic-clonic seizures.[18] 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.[citation needed
]

The first-line drugs for treatment of

intensive care.[16][20] The World Health Organization (WHO) gives phenobarbital a first-line recommendation in the developing world and it is commonly used there.[6][21]

Phenobarbital is the first-line choice for the treatment of neonatal seizures.[22][23][24][25] Concerns that neonatal seizures in themselves could be harmful make most physicians treat them aggressively. No reliable evidence, though, supports this approach.[26]

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.[27]

Phenobarbital is useful for insomnia and anxiety.[28]

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.[citation needed]

Phenobarbital is occasionally prescribed in low doses to aid in the conjugation of

Crigler–Najjar syndrome, type II,[29] or in people with Gilbert's syndrome.[30]
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.[citation needed]

In infants suspected of neonatal

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 people to allow them to end their life through

physician-assisted suicide.[31]

Like other barbiturates, phenobarbital

can be used recreationally,[32] but this is reported to be relatively infrequent.[33]

The synthesis of a photoswitchable analog (DASA-barbital) and phenobarbital has been described for use as research compound in photopharmacology.[34]

Side effects

Sedation and hypnosis are the principal side effects (occasionally, they are also the intended effects) of phenobarbital.

nystagmus and ataxia, are also common. In elderly patients, it may cause excitement and confusion, while in children, it may result in paradoxical hyperactivity.[35]

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.[36] Caution is to be used with children. Among anti-convulsant drugs, behavioural disturbances occur most frequently with clonazepam and phenobarbital.[37]

Contraindications

respiratory insufficiency (as with chronic obstructive pulmonary disease), severe liver failure, pregnancy, and breastfeeding are contraindications for phenobarbital use.[35]

Overdose

Main article: Barbiturate overdose

Phenobarbital causes a depression of the body's systems, mainly the

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.[38]

Treatment of phenobarbital overdose is

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%.[38] No specific antidote for barbiturate poisoning is available.[39]

Mechanism of action

Phenobarbital is as an

glutamate signaling is also believed to contribute to the hypnotic/anticonvulsant effect that is observed with the barbiturates.[41]

Pharmacokinetics

Phenobarbital has an oral

heterodimer. It is excreted primarily by the kidneys.[42]

Veterinary uses

Phenobarbital is one of the first line drugs of choice to treat epilepsy in dogs, as well as cats.[9]

It is also used to treat feline hyperesthesia syndrome in cats when anti-obsessional therapies prove ineffective.[43]

It may also be used to treat seizures in horses when benzodiazepine treatment has failed or is contraindicated.[44]

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.[45]

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

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[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, though World War I delayed its introduction in the U.S.[47]

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 program of involuntary euthanasia.[48][49]

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.[50][51] Luminal was used in the Nazi children's euthanasia program until at least 1943.[52][53]

Phenobarbital was used to treat

phototherapy was discovered, and became the standard treatment.[54]

Phenobarbital was used for over 25 years as

prophylaxis in the treatment of febrile seizures.[55] 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.[56][57]

Society and culture

Names

Phenobarbital is the

INN and phenobarbitone is the BAN
.

Synthesis

Phenobarbital sodium salt

aliphatic organosulfates or halocarbons do.[59] 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

ethyl bromide leads to the formation of α-phenyl-α-ethylmalonic ester. Finally, a condensation reaction with urea gives phenobarbital.[58]

The second approach utilizes diethyl carbonate in the presence of a strong base to give α-phenylcyanoacetic ester.[62][63] Alkylation of this ester using ethyl bromide proceeds via a nitrile anion intermediate to give the α-phenyl-α-ethylcyanoacetic ester.[64] This product is then further converted into the 4-iminoderivative upon condensation with urea. Finally acidic hydrolysis of the resulting product gives phenobarbital.[65]

A new synthetic route based on diethyl 2-ethyl-2-phenylmalonate and urea has been described.[34]

Regulation

The level of regulation includes

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.[67]

Selected overdoses

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.[68]

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.[69]

Thirty-nine members of the Heaven'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.[70]

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External links

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