Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmacotherapy) is an imp ...
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
A developing country is a sovereign state with a lesser developed industrial base and a lower Human Development Index (HDI) relative to other countries. However, this definition is not universally agreed upon. There is also no clear agree ...
.
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.
Phenobarbital is occasionally used to treat
trouble sleeping
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
,
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
, 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
An altered level of consciousness is any measure of arousal other than normal. Level of consciousness (LOC) is a measurement of a person's arousability and responsiveness to stimuli from the environment.
A mildly depressed level of consciousne ...
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 following long-term use.
It may also increase the risk of
suicide.
It is
pregnancy category
The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does ''not'' include any risks conferred by pharmaceutical agents or their ...
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
Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that brea ...
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 GABA.
Phenobarbital was discovered in 1912 and is the oldest still commonly used
anti-seizure medication
Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of ...
. 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 b ...
s.
British National Formulary
The ''British National Formulary'' (BNF) is a United Kingdom (UK) pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about many medici ...
51 It is no less effective at seizure control than
phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The int ...
, but phenobarbital is not as well tolerated. Phenobarbital may provide a clinical advantage over
carbamazepine
Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...
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
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...
(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 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, i ...
s, such as
lorazepam
Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety disorders, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and chemot ...
or
diazepam. If these fail, then
phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The int ...
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
Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), a ...
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
Alcohol detoxification (also known as ''detox'') is the abrupt cessation of alcohol intake in individuals that have alcohol dependence. This process is often coupled with substitution of drugs that have effects similar to the effects of alcohol i ...
and
benzodiazepine detoxification for its sedative and anti-convulsant properties. The benzodiazepines
chlordiazepoxide
Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs.
Chlordiazepoxide has a medium to ...
(Librium) and
oxazepam
Oxazepam is a short-to-intermediate-acting benzodiazepine. Oxazepam is used for the treatment of anxiety and insomnia and in the control of symptoms of alcohol withdrawal syndrome.
It is a metabolite of diazepam, prazepam, and temazepam, and has ...
(Serax) have largely replaced phenobarbital for detoxification.
Phenobarbital is useful for
insomnia and
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
.
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 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 comp ...
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 t ...
in people with
Crigler–Najjar syndrome, type II, or in people with
Gilbert's syndrome
Gilbert syndrome (GS) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority. Many people never have symptoms. Occasionally jaundice (a slight yellowish color of the skin or whites of the eyes) ...
.
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 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
Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malignan ...
.
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 Utero'' is the third and final studio album by American rock band Nirvana. It was released on September 21, 1993, by DGC Records. After breaking into the mainstream with their second album, ''Nevermind'' (1991), Nirvana hired Steve Albini ...
''.
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
Photopharmacology, an emerging approach in medicine, involves activating and deactivating photoswitchable molecules with light for target drug delivery. Clinicians use the energy of light to change the shape and chemical properties of a drug, res ...
.
Side effects
Sedation and hypnosis are the principal side effects (occasionally, they are also the intended effects) of phenobarbital.
Central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
effects, such as dizziness,
nystagmus
Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...
and
ataxia
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
, 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 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 comp ...
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
Clonazepam, sold under the brand names Klonopin and Rivotril, is a medication used to prevent and treat seizures, panic disorder, anxiety disorders, and the movement disorder known as akathisia. It is a tranquilizer of the benzodiazepine clas ...
and phenobarbital.
Contraindications
Acute intermittent porphyria
Acute intermittent porphyria (AIP) is a rare metabolic disorder affecting the production of heme resulting from a deficiency of the enzyme porphobilinogen deaminase. It is the most common of the acute porphyrias.
Signs and symptoms
The clinica ...
, hypersensitivity to any barbiturate, prior dependence on barbiturates, severe
respiratory insufficiency (as with
chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce m ...
), 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 a ...
and
peripheral nervous systems. Thus, the main characteristic of phenobarbital overdose is a "slowing" of bodily functions, including decreased
consciousness
Consciousness, at its simplest, is sentience and awareness of internal and external existence. However, the lack of definitions has led to millennia of analyses, explanations and debates by philosophers, theologians, linguisticians, and scien ...
(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
Pulmonary edema, also known as pulmonary congestion, is excessive liquid accumulation in the tissue and air spaces (usually alveoli) of the lungs. It leads to impaired gas exchange and may cause hypoxemia and respiratory failure. It is due to ...
and
acute renal failure
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.
Causes of AKI are cla ...
as a result of
shock
Shock may refer to:
Common uses Collective noun
*Shock, a historic commercial term for a group of 60, see English numerals#Special names
* Stook, or shock of grain, stacked sheaves
Healthcare
* Shock (circulatory), circulatory medical emerge ...
, 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 au ...
. 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
The respiratory tract is the subdivision of the respiratory system involved with the process of respiration in mammals. The respiratory tract is lined with respiratory epithelium as respiratory mucosa.
Air is breathed in through the nose t ...
patency (through
endotracheal intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic tube into the trachea (windpipe) to maintain an open airway or to serve as a conduit through which to administer certain drugs. It is frequentl ...
and
mechanical ventilation
Mechanical ventilation, assisted ventilation or intermittent mandatory ventilation (IMV), is the medical term for using a machine called a ventilator to fully or partially provide artificial ventilation. Mechanical ventilation helps move ai ...
), 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 i ...
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
Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
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 to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...
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
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
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 signaling is also believed to contribute to the hypnotic/anticonvulsant effect that is observed with the barbiturates.
Pharmacokinetics
Phenobarbital has an oral
bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
of about 90%.
Peak plasma concentration
Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose. It is a standard measurement in pha ...
s (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 t ...
(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
Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.
Func ...
) 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 heterodimer. It is excreted primarily by the
kidneys.
Veterinary uses
Phenobarbital is one of the first line drugs of choice to treat
epilepsy in
dog
The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the wolf. Also called the domestic dog, it is derived from the extinct Pleistocene wolf, and the modern wolf is the dog's nearest living relative. ...
s, as well as
cat
The cat (''Felis catus'') is a domestic species of small carnivorous mammal. It is the only domesticated species in the family Felidae and is commonly referred to as the domestic cat or house cat to distinguish it from the wild members of ...
s.
[
It is also used to treat ]feline hyperesthesia syndrome
First reported in 1980 by J. Tuttle in a scientific article, feline hyperesthesia syndrome, also known as rolling skin disease, is a complex and poorly understood syndrome that can affect domestic cats of any age, breed, and sex. The syndrome m ...
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, i ...
treatment has failed or is contraindicated.
History
The first barbiturate drug, barbital
Barbital (or barbitone), marketed under the brand names Veronal for the pure acid and Medinal for the sodium salt, was the first commercially available barbiturate. It was used as a sleeping aid (hypnotic) from 1903 until the mid-1950s. The chemic ...
, was synthesized in 1902 by German chemists Emil Fischer
Hermann Emil Louis Fischer (; 9 October 1852 – 15 July 1919) was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fischer projection, a symbolic way of dra ...
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 Minkow ...
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 pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of business include pharmaceutica ...
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, i ...
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 gave it to his epilepsy patients as a tranquilizer
A tranquilizer is a drug that is designed for the treatment of anxiety, fear, tension, agitation, and disturbances of the mind, specifically to reduce states of anxiety and tension.
Etymology
Tranquilizer, as a term, was first used by F.F. Yon ...
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
A bromide ion is the negatively charged form (Br−) of the element bromine, a member of the halogens group on the periodic table. Most bromides are colorless. Bromides have many practical roles, being found in anticonvulsants, flame-retardant ...
, 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
Adolf Hitler (; 20 April 188930 April 1945) was an Austrian-born German politician who was dictator of Germany from 1933 until his death in 1945. He rose to power as the leader of the Nazi Party, becoming the chancellor in 1933 and then ...
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
Involuntary euthanasia occurs when euthanasia is performed on a person who would be able to provide informed consent, but does not, either because they do not want to die, or because they were not asked.
Involuntary euthanasia is contrasted with ...
.
In 1940, at a clinic in Ansbach
Ansbach (; ; East Franconian: ''Anschba'') is a city in the German state of Bavaria. It is the capital of the administrative region of Middle Franconia. Ansbach is southwest of Nuremberg and north of Munich, on the river Fränkische Rezat, ...
, 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
Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral pal ...
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 t ...
levels. In the 1950s, phototherapy was discovered, and became the standard treatment.
Phenobarbital was used for over 25 years as prophylaxis
Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
in the treatment of febrile seizure
A febrile seizure, also known as a fever fit or febrile convulsion, is a seizure associated with an increased body temperature but without any intracranial infection. Febrile seizures affect 2–7% of children and are more common in boys than gi ...
s. 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
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
and phenobarbitone is the BAN.
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 reaction
In organic chemistry, a condensation reaction is a type of chemical reaction in which two molecules are combined to form a single molecule, usually with the loss of a small molecule such as water. If water is lost, the reaction is also known as a ...
s between a derivative of diethyl malonate and urea
Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid.
Urea serves an important ...
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
The conjugate acids are in :Carboxylic acids.
{{Commons category, Carboxylate ions, Carboxylate anions
Carbon compounds
Oxyanions ...
derivative is obtained. The reason for this difference is due to the fact that aryl halide In organic chemistry, an aryl halide (also known as haloarene) is an aromatic compound in which one or more hydrogen atoms, directly bonded to an aromatic ring are replaced by a halide. The haloarene are different from haloalkanes because they exhi ...
s do not typically undergo nucleophilic substitution
In chemistry, a nucleophilic substitution is a class of chemical reactions in which an electron-rich chemical species (known as a nucleophile) replaces a functional group within another electron-deficient molecule (known as the electrophile). Th ...
in Malonic ester synthesis
The malonic ester synthesis is a chemical reaction where diethyl malonate or another ester of malonic acid is alkylated at the carbon alpha (directly adjacent) to both carbonyl groups, and then converted to a substituted acetic acid. The major d ...
in the same way as aliphatic
In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane ...
organosulfate
Organosulfates are a class of organic compounds sharing a common functional group with the structure R-O-SO3−. The SO4 core is a sulfate group and the R group is any organic residue. All organosulfates are formally esters derived from alcohols ...
s 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
In chemistry, reactivity is the impulse for which a chemical substance undergoes a chemical reaction, either by itself or with other materials, with an overall release of energy.
''Reactivity'' refers to:
* the chemical reactions of a single ...
two dominant synthetic approaches using benzyl cyanide
Benzyl cyanide (abbreviated BnCN) is an organic compound with the chemical formula C6H5CH2CN. This colorless oily aromatic liquid is an important precursor to numerous compounds in organic chemistry.
Preparation
Benzyl cyanide can be produced via ...
as a starting material have been developed:
The first of these methods consists of a Pinner reaction
The Pinner reaction refers to the acid catalysed reaction of a nitrile with an alcohol to form an imino ester salt (alkyl imidate salt); this is sometimes referred to as a Pinner salt.
The reaction is named after Adolf Pinner, who first described ...
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
The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone. It is named after Rain ...
using diethyl oxalate
In organic chemistry, an ethyl group (abbr. Et) is an alkyl substituent with the formula , derived from ethane (). ''Ethyl'' is used in the International Union of Pure and Applied Chemistry's nomenclature of organic chemistry for a saturated ...
, giving diethyl ester of phenyloxobutandioic acid. Upon heating this intermediate easily loses carbon monoxide
Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simpl ...
, yielding diethyl phenylmalonate. Malonic ester synthesis
The malonic ester synthesis is a chemical reaction where diethyl malonate or another ester of malonic acid is alkylated at the carbon alpha (directly adjacent) to both carbonyl groups, and then converted to a substituted acetic acid. The major d ...
using ethyl bromide leads to the formation of α-phenyl-α-ethylmalonic ester. Finally a condensation reaction
In organic chemistry, a condensation reaction is a type of chemical reaction in which two molecules are combined to form a single molecule, usually with the loss of a small molecule such as water. If water is lost, the reaction is also known as a ...
with urea
Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid.
Urea serves an important ...
gives phenobarbital.
The second approach utilizes diethyl carbonate
Diethyl carbonate (sometimes abbreviated DEC) is an ester of carbonic acid and ethanol with the formula OC(OCH2CH3)2. At room temperature (25 °C) diethyl carbonate is a colorless liquid with a low flash point.
Diethyl carbonate is used ...
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 Administrative Controlled Substances Code Number (ACSCN) is a number assigned to drugs listed on the schedules created by the US Controlled Substances Act (CSA). The ACSCN is defined in 21 CFR § 1308.03(a).
Each chemical/drug on one of the schedu ...
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
The Isdal Woman ( no, Isdalskvinnen, 1930–1945 – November 1970) is a placeholder name given to an unidentified woman who was found dead at Isdalen ("The Ice Valley") in Bergen, Norway, on 29 November 1970.
Although police at the time ruled a ...
, was found dead in Bergen
Bergen (), historically Bjørgvin, is a city and municipality in Vestland county on the west coast of Norway. , its population is roughly 285,900. Bergen is the second-largest city in Norway. The municipality covers and is on the peninsula ...
, Norway, on 29 November 1970. Her death was caused by some combination of burns, phenobarbital, and carbon monoxide
Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simpl ...
poisoning; many theories about her death have been posited, and it is believed that she may have been a spy
Espionage, spying, or intelligence gathering is the act of obtaining secret or confidential information (intelligence) from non-disclosed sources or divulging of the same without the permission of the holder of the information for a tangibl ...
. 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
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Barbiturates
Anxiolytics
CYP3A4 inducers
Hypnotics
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IARC Group 2B carcinogens
GABAA receptor positive allosteric modulators
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