Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a
medication of the
barbiturate
Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as we ...
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. In developed countries it is used for veterinary purposes.
It may be used
intravenously, injected into a muscle, or taken by mouth.
The injectable form may be used to treat
status epilepticus
Status epilepticus (SE), or status seizure, is a single seizure lasting more than 5 minutes or 2 or more seizures within a 5-minute period without the person returning to normal between them. Previous definitions used a 30-minute time limit. The s ...
.
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
Abuse is the improper usage or treatment of a thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, crimes, or other t ...
and
withdrawal
Withdrawal means "an act of taking out" and may refer to:
* Anchoresis (withdrawal from the world for religious or ethical reasons)
* ''Coitus interruptus'' (the withdrawal method)
* Drug withdrawal
* Social withdrawal
* Taking of money from a ban ...
following long-term use.
It may also increase the risk of
suicide
Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and s ...
.
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
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
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.
Medical uses
Phenobarbital is used in the treatment of all types of seizures, except
absence seizure
Absence seizures are one of several kinds of generalized seizures. These seizures are sometimes referred to as petit mal seizures (from the French for "little illness", a term dated in the late 18th century). Absence seizures are characterized by ...
s.
[ British National Formulary 51] It is no less effective at seizure control than
phenytoin, but 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
Status epilepticus (SE), or status seizure, is a single seizure lasting more than 5 minutes or 2 or more seizures within a 5-minute period without the person returning to normal between them. Previous definitions used a 30-minute time limit. The s ...
are
benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s, 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 seizure
A neonatal seizure is a seizure in a baby younger than age 4-weeks that is identifiable by an electrical recording of the brain. It is an occurrence of abnormal, paroxysmal, and persistent ictal rhythm with an amplitude of 2 microvolts in the elec ...
s.
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
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
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
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
in people with
Crigler–Najjar syndrome, type II, or in people with
Gilbert's syndrome.
Phenobarbital can also be used to relieve
cyclic vomiting syndrome
Cyclic vomiting syndrome (CVS) is a chronic functional condition of unknown pathogenesis. CVS is characterized as recurring episodes lasting a single day to multiple weeks. Each episode is divided into four phases: inter-episodic, prodrome, vom ...
symptoms.
Phenobarbital is a commonly used agent in high purity and dosage for
lethal injection
Lethal injection is the practice of injecting one or more drugs into a person (typically a barbiturate, paralytic, and potassium solution) for the express purpose of causing rapid death. The main application for this procedure is capital puni ...
of "death row" criminals.
In infants suspected of neonatal
biliary atresia
Biliary atresia, also known as extrahepatic ductopenia and progressive obliterative cholangiopathy, is a childhood disease of the liver in which one or more bile ducts are abnormally narrow, blocked, or absent. It can be congenital or acquired. I ...
, 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 people 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.
The synthesis of a photoswitchable analog (DASA-barbital) and phenobarbital has been described for use as research compound in
photopharmacology.
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
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
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
Central is an adjective usually referring to being in the center of some place or (mathematical) object.
Central may also refer to:
Directions and generalised locations
* Central Africa, a region in the centre of Africa continent, also known as ...
and
peripheral nervous systems. Thus, the main characteristic of phenobarbital overdose is a "slowing" of bodily functions, including decreased
consciousness (even
coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...
),
bradycardia
Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...
,
bradypnea
Bradypnea is abnormally slow breathing. The respiratory rate at which bradypnea is diagnosed depends on the age of the person, with the limit higher during childhood.
Age ranges
* Age 0–1 year < 30 breaths per minute
* Age 1–3 years < 25 br ...
,
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
Brain death is the permanent, irreversible, and complete loss of brain function which may include cessation of involuntary activity necessary to sustain life. It differs from persistent vegetative state, in which the person is alive and some aut ...
. 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
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
and
vasopressor
An antihypotensive agent, also known as a vasopressor agent or simply vasopressor, or pressor, is any substance, whether endogenous or a medication, that tends to raise low blood pressure. Some antihypotensive drugs act as vasoconstrictors to inc ...
s, 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
Phenobarbital is as an
allosteric modulator
In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a Receptor (biochemistry), receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allos ...
which extends the amount of time the chloride ion channel is open by interacting with
GABAA 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
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
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
Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...
(20 to 45%). Phenobarbital is metabolized by the liver, mainly through
hydroxylation
In chemistry, hydroxylation can refer to:
*(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound.
*(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...
and
glucuronidation, and induces many
isozymes of the
cytochrome P450 system
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various com ...
. Cytochrome P450 2B6 (
CYP2B6) is specifically induced by phenobarbital via the
CAR
A car or automobile is a motor vehicle with wheels. Most definitions of ''cars'' say that they run primarily on roads, seat one to eight people, have four wheels, and mainly transport people instead of goods.
The year 1886 is regarded as ...
/
RXR nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...
heterodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
. It is excreted primarily by the
kidneys.
Veterinary uses
Phenobarbital is one of the first line drugs of choice to treat
epilepsy in
dogs, as well as
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
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
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
Josef, Baron von Mering (28 February 1849, in Cologne – 5 January 1908, at Halle an der Saale, Germany) was a German physician.
Working at the University of Strasbourg, Mering was the first person to discover (in conjunction with Oskar Minkowsk ...
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
Bayer AG (, commonly pronounced ; ) is a German multinational corporation, multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of busi ...
as the brand Luminal. It remained a commonly prescribed sedative and hypnotic until the introduction of benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s 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
Alfred Hauptmann (born August 29, 1881 in Gleiwitz, Upper Silesia, died April 5, 1948 in Boston, Massachusetts) was a German-Jewish psychiatrist and neurologist.
His most important contribution remained the article written in 1912 on the effectiv ...
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 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.
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.
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
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
levels. In the 1950s, phototherapy
Light therapy, also called phototherapy or bright light therapy is intentional daily exposure to direct sunlight or similar-intensity artificial light in order to treat medical disorders, especially seasonal affective disorder (SAD) and circadi ...
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
Ban, or BAN, may refer to:
Law
* Ban (law), a decree that prohibits something, sometimes a form of censorship, being denied from entering or using the place/item
** Imperial ban (''Reichsacht''), a form of outlawry in the medieval Holy Roman ...
.
Synthesis
Barbiturate
Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as we ...
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 halocarbon
Halocarbon compounds are chemicals in which one or more carbon atoms are linked by covalent bonds with one or more halogen atoms (fluorine, chlorine, bromine or iodine – ) resulting in the formation of organofluorine compounds, organochlori ...
s 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
Phenylacetic acid (PAA; conjugate base phenylacetate), also known by various synonyms, is an organic compound containing a phenyl functional group and a carboxylic acid functional group. It is a white solid with a strong honey-like odor. Endogen ...
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
Diethyl phenylmalonate is an aromatic Diethyl malonate, malonic ester used in the synthesis of Biological half-life, moderate to long lasting barbiturates such as phenobarbital.
Chemical synthesis
Unlike other malonic esters that are derived via ...
. 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 Nitrile anions is jargon from the organic product resulting from the deprotonation of alkylnitriles. The proton(s) α to the nitrile group are sufficiently acidic that they undergo deprotonation by strong bases, usually lithium-derived. The produc ...
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.
A new synthetic route based on diethyl 2-ethyl-2-phenylmalonate and urea has been described.
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
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. The story has been the subject of a BBC Podcast, "Death in Ice Valley".
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
Abbot Howard "Abbie" Hoffman (November 30, 1936 – April 12, 1989) was an American political and social activist who co-founded the Youth International Party ("Yippies") and was a member of the Chicago Seven. He was also a leading proponen ...
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.
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.
References
External links
*
{{Authority control
Barbiturates
Anxiolytics
CYP3A4 inducers
Hypnotics
World Health Organization essential medicines
IARC Group 2B carcinogens
GABAA receptor positive allosteric modulators
Bayer brands
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