Phenobarbital

Phenobarbital

Overview
Phenobarbital or phenobarbitone (former BAN
British Approved Name
A British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia...

) is a barbiturate
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...

, first marketed as Luminal by Friedr. Bayer et comp
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...

. It is the most widely used anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...

 worldwide, and the oldest still commonly used. It also has sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....

 and hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...

 properties but, as with other barbiturates, has been superseded by the benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...

s for these indications. The World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 recommends its use as first-line for partial and generalized tonic–clonic seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

s (those formerly known as grand mal) in developing countries
Developing country
A developing country, also known as a less-developed country, is a nation with a low level of material well-being. Since no single definition of the term developing country is recognized internationally, the levels of development may vary widely within so-called developing countries...

.
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Encyclopedia
Phenobarbital or phenobarbitone (former BAN
British Approved Name
A British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia...

) is a barbiturate
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...

, first marketed as Luminal by Friedr. Bayer et comp
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...

. It is the most widely used anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...

 worldwide, and the oldest still commonly used. It also has sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....

 and hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...

 properties but, as with other barbiturates, has been superseded by the benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...

s for these indications. The World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 recommends its use as first-line for partial and generalized tonic–clonic seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

s (those formerly known as grand mal) in developing countries
Developing country
A developing country, also known as a less-developed country, is a nation with a low level of material well-being. Since no single definition of the term developing country is recognized internationally, the levels of development may vary widely within so-called 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. In more affluent countries, it is no longer recommended as a first or second-line choice anticonvulsant for most seizure types,
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
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...

, 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
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

 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
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....

/hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...

 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.

History


The first barbiturate drug, barbital
Barbital
Barbital , also called barbitone, was the first commercially marketed barbiturate. It was used as a sleeping aid from 1903 until the mid-1950s. The chemical names for barbital are diethylmalonyl urea or diethylbarbituric acid...

, was synthesized in 1902 by German chemists Emil Fischer
Emil Fischer
Emil Fischer may refer to:* Emil Fischer , German dramatic basso* Franz Joseph Emil Fischer , German chemist, worked with oil and coal* Hermann Emil Fischer , German Nobel laureate in chemistry...

 and Joseph von Mering
Joseph von Mering
Josef, Baron von Mering was a German physician.Working at the University of Strasbourg, Mering was the first person to discover that one of the pancreatic functions is the production of insulin, a hormone which controls blood sugar levels.Mering was curious about the...

 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 benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...

s in the 1960s.

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 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
Potassium bromide
Potassium bromide is a salt, widely used as an anticonvulsant and a sedative in the late 19th and early 20th centuries, with over-the-counter use extending to 1975 in the United States. Its action is due to the bromide ion...

, 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
World War I
World War I , which was predominantly called the World War or the Great War from its occurrence until 1939, and the First World War or World War I thereafter, was a major war centred in Europe that began on 28 July 1914 and lasted until 11 November 1918...

 delayed its introduction in the U.S.

Phenobarbital was used to treat neonatal jaundice
Neonatal jaundice
Neonatal jaundice or Neonatal hyperbilirubinemia is a yellowing of the skin and other tissues of a newborn infant. A bilirubin level of more than 85 umol/l manifests clinical jaundice in neonates whereas in adults a level of 34 umol/l would look icteric...

 by increasing liver metabolism and thus lowering bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...

 levels. In the 1950s, phototherapy was discovered, and became the standard treatment.

In 1940, Winthrop Chemical produced sulfathiazole
Sulfathiazole
Sulfathiazole is an organosulfur compound that has been used as a short-acting sulfa drug. It once was a common oral and topical antimicrobial until less toxic alternatives were discovered. It is still occasionally used, sometimes in combination with sulfabenzamide and sulfacetamide, and in...

 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 investigation was highly critical of Winthrop and the scandal led to the introduction of Good Manufacturing Practice
Good Manufacturing Practice
"Good manufacturing practice" or "GMP" are practices and the systems required to be adapted in pharmaceutical manufacturing, quality control, quality system covering the manufacture and testing of pharmaceuticals or drugs including active pharmaceutical ingredients, diagnostics, foods,...

 for drugs.

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.

Phenobarbital was used for over 25 years as prophylaxis in the treatment of febrile seizure
Febrile seizure
A febrile seizure, also known as a fever fit or febrile convulsion, is a convulsion associated with a significant rise in body temperature...

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.

Indications


Phenobarbital is indicated in the treatment of all types of seizures except absence seizure
Absence seizure
Absence seizures are one of several kinds of seizures. These seizures are sometimes referred to as petit mal seizures ....

s. Phenobarbital is no less effective at seizure control than more modern drugs such as phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...

 and carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...

. It is, however, significantly less well tolerated.

The first line drugs for treatment of status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...

 are fast acting benzodiazepines such as diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...

 or lorazepam
Lorazepam
Lorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...

. If these fail then phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...

 may be used, with phenobarbital being an alternative in the U.S. but used only third line in the UK.
Failing that, the only treatment is anaesthesia in intensive care.

Phenobarbital is the first line choice for the treatment of neonatal seizures. 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.

Phenobarbital is sometimes indicated for alcohol and benzodiazepine detoxification for its sedative and anticonvulsant properties. The benzodiazepines chlordiazepoxide
Chlordiazepoxide
Chlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...

 (Librium) and oxazepam
Oxazepam
Oxazepam , is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative...

 (Serax) have largely replaced phenobarbital for detoxification.

Other uses


Phenobarbital is often used for the treatment of acute withdrawal from benzodiazepines. 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
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...

 in patients suffering from Gilbert's Syndrome
Gilbert's syndrome
Gilbert's syndrome , often shortened to GS, also called Gilbert-Meulengracht syndrome, is the most common hereditary cause of increased bilirubin and is found in up to 5% of the population...

.

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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 effects like dizziness, nystagmus and ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...

 are also common. In elderly patients, it may cause excitement and confusion while in children, it may result in paradoxical hyperactivity
Paradoxical reaction
A paradoxical reaction or paradoxical effect is when medical treatment, usually a drug, has the opposite effect to that which would normally be expected.An example of a paradoxical reaction is when a pain relief medication causes an increase in pain...

. Another very rare side effect is amelogenesis imperfecta
Amelogenesis imperfecta
Amelogenesis imperfecta presents with abnormal formation of the enamel or external layer of teeth. Enamel is composed mostly of mineral, that is formed and regulated by the proteins in it...

.

Special precautions


Caution is to be used with children. Of anticonvulsant drugs behavioural disturbances occur most frequently with clonazepam
Clonazepam
Clonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...

 and phenobarbital.

Contraindications


Acute intermittent porphyria
Acute intermittent porphyria
Acute intermittent porphyria is a rare autosomal dominant metabolic disorder affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin. It is characterized by a deficiency of the enzyme porphobilinogen deaminase. Acute intermittent porphyria is the second most common...

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

Overdose


Phenobarbital causes a "depression" of the body's systems, mainly the central
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 and peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...

s; thus, the main characteristic of phenobarbital overdose is a "slowing" of bodily functions, including decreased consciousness
Consciousness
Consciousness is a term that refers to the relationship between the mind and the world with which it interacts. It has been defined as: subjectivity, awareness, the ability to experience or to feel, wakefulness, having a sense of selfhood, and the executive control system of the mind...

 (even coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...

), bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

, bradypnea
Bradypnea
Bradypnea refers to an abnormally slow breathing rate...

, hypothermia
Hypothermia
Hypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...

, and hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

 (in massive overdoses). Overdose may also lead to pulmonary edema
Pulmonary edema
Pulmonary edema , or oedema , is fluid accumulation in the air spaces and parenchyma of the lungs. It leads to impaired gas exchange and may cause respiratory failure...

 and acute renal failure
Acute renal failure
Acute kidney injury , previously called acute renal failure , is a rapid loss of kidney function. Its causes are numerous and include low blood volume from any cause, exposure to substances harmful to the kidney, and obstruction of the urinary tract...

 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
Brain death
Brain death is the irreversible end of all brain activity due to total necrosis of the cerebral neurons following loss of brain oxygenation. It should not be confused with a persistent vegetative state...

. This is due to profound depression of the central nervous system, and is usually reversible.

Treatment of phenobarbital overdose is supportive, and consists mainly in the maintenance of airway
Airway
The pulmonary airway comprises those parts of the respiratory system through which air flows, conceptually beginning at the nose and mouth, and terminating in the alveoli...

 patency (through endotracheal intubation and mechanical ventilation
Mechanical ventilation
In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...

), correction of bradycardia and hypotension (with intravenous fluid
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...

s 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
Gastric lavage
Gastric lavage, also commonly called stomach pumping or Gastric irrigation, is the process of cleaning out the contents of the stomach. It has been used for over 200 years as a means of eliminating poisons from the stomach. Such devices are normally used on a person who has ingested a poison or...

 (stomach pumping) or use of activated charcoal. Hemodialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...

 is effective in removing phenobarbital from the body, and may reduce its half-life by up to 90%. There is no specific antidote for barbiturate poisoning.

British veterinarian Donald Sinclair, better known as "Siegfried Farnon" in the "All Creatures Great and Small" books of James Herriot
James Herriot
James Herriot was the pen name of James Alfred Wight, OBE, FRCVS also known as Alf Wight , an English veterinary surgeon and writer, who used his many years of experiences as a veterinarian to write a series of books of stories about animals and their owners...

 committed suicide at the age of 84 by injecting himself with an overdose of phenobarbital. Activist Abbie Hoffman
Abbie Hoffman
Abbot Howard "Abbie" Hoffman was a political and social activist who co-founded the Youth International Party ....

 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.

Pharmacokinetics


Phenobarbital has an oral bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

 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
Plasma protein binding
A drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, β‚ and γ...

 (20 to 45%). Phenobarbital is metabolized by the liver, mainly through hydroxylation
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...

 and glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...

, and induces many isozyme
Isozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...

s of the cytochrome P450 system
Cytochrome P450 oxidase
The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...

. Cytochrome P450 2B6 (CYP2B6
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.- Function :...

) is specifically induced by Phenobarbital via the CAR
Čar
Čar is a village in the municipality of Bujanovac, Serbia. According to the 2002 census, the town has a population of 296 people.-References:...

/RXR
RXR
RXR may stand for*The Retinoid X receptor found in cells.*A Railway Crossing also called a Level crossing*Revco, American company, NYSE code RXR...

 nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...

 heterodimer. It is excreted primarily by the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

s.

Veterinary uses


Phenobarbital is one of the initial drugs of choice to treat epilepsy
Epilepsy in animals
Epilepsy can occur in animals other than humans . It is characterized by recurrent, unprovoked seizures. Canine epilepsy is often genetic. Epilepsy in cats and other pets is rarer, likely because there is no hereditary component to epilepsy in these animals.-Canine epilepsy:In dogs, epilepsy is...

 in dog
Dog
The domestic dog is a domesticated form of the gray wolf, a member of the Canidae family of the order Carnivora. The term is used for both feral and pet varieties. The dog may have been the first animal to be domesticated, and has been the most widely kept working, hunting, and companion animal in...

s, and is the initial drug of choice to treat epilepsy in 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 horse
Horse
The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...

s when benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...

 treatment has failed or is contraindicated.

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., (1911).
  • M.T. Inman, W.P. Bitler, (1944).

There is no major difference between them.

The first method consists of ethanolysis of benzyl cyanide
Benzyl cyanide
Benzyl cyanide is an organic compound with the chemical formula C6H5CH2CN. This colorless oily aromatic liquid is a precursor to several derivatives.-Synthesis, reactions, and applications:...

 in the presence of acid, giving phenylacetic acid
Phenylacetic acid
Phenylacetic acid is an organic compound containing a phenyl functional group and a carboxylic acid functional group. It is a white solid with a disagreeable odor...

 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
Sodium ethoxide
Sodium ethoxide is an alkoxide salt with the chemical formula C2H5ONa.-Preparation:It is commercially available as a white solid, or as a solution in ethanol. It is easily prepared in the laboratory by reacting sodium metal with ethanol:...

 leads to the formation of α-phenyl-α-
ethylmalonic ester, the condensation of which with urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....

 gives phenobarbital.

Another method of phenobarbital synthesis starts with condensation of benzyl cyanide with
diethylcarbonate in the presence of sodium ethoxide
Sodium ethoxide
Sodium ethoxide is an alkoxide salt with the chemical formula C2H5ONa.-Preparation:It is commercially available as a white solid, or as a solution in ethanol. It is easily prepared in the laboratory by reacting sodium metal with ethanol:...

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.

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