Phenobarbital

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Phenobarbital

Phenobarbital (INN

International Nonproprietary Name

An International Nonproprietary Name is the official non-proprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization ....
) 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 medication that act as central nervous system depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia....
, first marketed as Luminal
Luminal

Luminal may mean:* A trade name for the anti-epileptic drug phenobarbital* Luminal , a film by Italian director Andrea Vecchiato starring Denis Lavant....
by Friedr. Bayer et comp

Bayer

Bayer Aktiengesellschaft is a Germany chemical industry and pharmaceutical company founded in Barmen, Germany in 1863. Today it is headquartered in Leverkusen, North Rhine-Westphalia, Germany....
. It is the most widely used anticonvulsant

Anticonvulsant

The anticonvulsants are a diverse group of pharmacology used in the treatment of epilepsy seizures. Anticonvulsants are also increasingly being used the treatment of bipolar disorder, since many seem to act as mood stabilizers....
worldwide and the oldest still commonly used. It also has sedative

Sedative

A sedative is a substance that induces sedation by reducing irritability or excitement.At higher doses it may result in slurred speech, staggering gait , poor judgment, and slow, uncertain reflexes....
and hypnotic

Hypnotic

Hypnotic drugs induce sleep, used in the treatment of insomnia and in surgical anesthesia. Because drugs in this class generally produce dose-dependent effects, ranging from anxiolysis to production of unconsciousness, they are often referred to collectively as sedative-hypnotic drugs....
properties but, as with other barbiturates, has been superseded by the benzodiazepine

Benzodiazepine

The benzodiazepines are a class of psychoactive drugs with varying hypnotic, sedative, anxiolytic , anticonvulsant, muscle relaxant and anterograde amnesia properties, which are mediated by slowing down the central nervous system....
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....
recommends its use as first-line for partial and generalized tonic-clonic

Tonic-clonic seizure

Tonic-clonic seizures are a type of generalized seizure affecting the entire brain. Formerly known as grand mal seizures or gran mal seizures, these terms are now discouraged and rarely used in a clinical setting....
seizure

Seizure

An epileptic seizure is a transient symptom of abnormal, excessive or synchronous neuronal activity in the brain. It can manifest as an alteration in mental state, tonic or clonic movements, convulsions, and various other psychic symptoms ....
s (those formerly known as Grand Mal) in developing countries

Developing country

A developing country is a country that has often low standards of democracy, industrialisation, Social work, and Human rights for its citizens....
.

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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....
, was synthesized in 1902 by German chemists Emil Fischer

Emil Fischer

Emil Fischer may refer to:* Emil Fischer , famous German dramatic basso* Franz Joseph Emil Fischer , German chemist* Hermann Emil Fischer , German chemist...
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....
at Bayer. By 1904 several related drugs, including phenobarbital, had been synthesized by Fischer. Phenobarbital was brought to market in 1912 by the drug company Bayer using the brand Luminal. It remained a commonly prescribed sedative and hypnotic until the introduction of benzodiazepines in the 1950s.

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 tranquiliser 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. 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, or the First World War , was a global military conflict which involved the Great powers, organized into two opposing military alliances: the Allies of World War I and the Central Powers....
delayed its introduction in the U.S.

Between 1934-1945 Phenobarbital

Phenobarbital

Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Bayer. It is the most widely used anticonvulsant worldwide and the oldest still commonly used....
, under the brand name Luminal

Luminal

Luminal may mean:* A trade name for the anti-epileptic drug phenobarbital* Luminal , a film by Italian director Andrea Vecchiato starring Denis Lavant....
, was used by German

Germany

Germany , officially the Federal Republic of Germany , is a country in Central Europe. It is bordered to the north by the North Sea, Denmark, and the Baltic Sea; to the east by Poland and the Czech Republic; to the south by Austria and Switzerland; and to the west by France, Luxembourg, Belgium, and the Netherlands....
doctors under the Nazi party endorsed policy of eugenics

Eugenics

Eugenics is a scientific field involving the controlled breeding of humans in order to achieve desirable traits in future generations. Eugenics was at its height in first half of the 20th century and was largely abandoned with the end of World War II....
to kill children born with disease or deformities. Code-named Operation T-4, this policy of murdering German

Germany

Germany , officially the Federal Republic of Germany , is a country in Central Europe. It is bordered to the north by the North Sea, Denmark, and the Baltic Sea; to the east by Poland and the Czech Republic; to the south by Austria and Switzerland; and to the west by France, Luxembourg, Belgium, and the Netherlands....
-born children and adults deemed not to meet the standards of the Aryan

Aryan

Aryan is an English language loanword. As the American Heritage Dictionary of the English Language states at the beginning of its definition, "[it] is one of the ironies of history that Aryan, a word nowadays referring to the blond-haired, blue-eyed physical ideal of Nazi Germany, originally referred to a people who looked vastly di...
race was a pre-cursor to the Holocaust and many of the medical staff involved were later to transfer to Nazi Concentration Camps where their expertise in killing was put to further use.

Phenobarbital was used to treat neonatal jaundice

Neonatal jaundice

Neonatal jaundice is a yellowing of the skin and other tissues of a newborn infant. A bilirubin level of more than 5 mg/dL manifests clinical jaundice in neonates whereas in the adults 2 mg/dL would look icteric....
by increasing liver metabolism and thus lowering bilirubin

Bilirubin

Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is formed from hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile, and its levels are elevated in certain diseases....
levels. In the 1950s, phototherapy was discovered, and became the standard treatment.

In 1940, Winthrop Chemical produced sulfathiazole

Sulfathiazole

Sulfathiazole is a short-acting Sulfonamide . It used to be a common oral and topical antimicrobial until less toxic alternatives were discovered....
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 U.S. Food and Drug Administration is an Government agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods, dietary supplements, Medications, vaccines, Biopharmaceutical, blood transfusion, medical devices, Electromagnetic radiation-emitting devices, veteri...
investigation was highly critical of Winthrop and the scandal lead to the introduction of Good Manufacturing Practice

Good Manufacturing Practice

Good Manufacturing Practice or GMP is a term that is recognized worldwide for the control and management of manufacturing and quality control testing of foods, pharmaceutical products, and medical devices....
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

Prophylaxis

Prophylaxis is any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease. Roughly, prophylactic measures are divided between primary prophylaxis and secondary prophylaxis ....
in the treatment of febrile seizure

Febrile seizure

A febrile seizure, also known as a fever fit or febrile convulsion is a convulsion triggered by a rise in body temperature. They most commonly occur in children between the ages of 6 months and 3 years and are twice as common in boys than girls....
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 .In absence seizures, the person may appear to be staring into space with or without jerking or Muscle contraction movements of the eye muscles....
s. Phenobarbital is no less effective at seizure control than more modern drugs such as phenytoin

Phenytoin

Carbamazepine

Carbamazepine is an anticonvulsant and mood stabilizer drug used primarily in the treatment of epilepsy and bipolar disorder. It is also used to treat Attention-deficit hyperactivity disorder, ADHD, schizophrenia, phantom limb syndrome, paroxysmal extreme pain disorder, and trigeminal neuralgia....
. It is, however, significantly less well tolerated.

The first line drugs for treatment of status epilepticus

Status epilepticus

Status epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between seizures for greater than 30 minutes....
are fast acting benzodiazepines such as diazepam

Diazepam

Diazepam , first marketed as Valium by Hoffmann-La Roche, is a benzodiazepine derivative drug. It possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant and amnestic properties....
or lorazepam

Lorazepam

Lorazepam, initially marketed under the brand names Ativan and Temesta, is a benzodiazepine drug with short to medium duration of action....
. If these fail then phenytoin

Phenytoin

Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to dampen the unwanted, runaway 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.

Side effects

Sedation and hypnosis are the principal side effects of phenobarbital. Central nervous system

Central nervous system

The central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of multicellular organisms....
effects like dizziness, nystagmus

Nystagmus

Pathologic nystagmus is a form of involuntary eye movement. It is characterized by alternating smooth pursuit in one direction and saccadic movement in the other direction....
and ataxia

Ataxia

Ataxia is a neurology sign and symptom consisting of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of 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.

Special precautions

Caution in children. Of anticonvulsant drugs behavioural disturbances occur most frequently with clonazepam

Clonazepam

Clonazepam is a benzodiazepine derivative with highly potent anticonvulsant, muscle relaxant and anxiolytic properties. It is marketed by Hoffmann-La Roche under the trade-names Klonopin in the United States and Rivotril in various other English speaking countries....
and phenobarbital.

Contraindications

Acute intermittent porphyria

Acute intermittent porphyria is a rare autosomal Dominance Metabolism affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin....
, 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 functions to coordinate the activity of all parts of the bodies of multicellular organisms....
and peripheral nervous system

Peripheral nervous system

The peripheral nervous system resides or extends outside the central nervous system , which consists of the brain and spinal cord. The main function of the PNS is to connect the CNS to the limbs and organs....
s; thus, the main characteristic of phenobarbital overdose is a "slowing" of bodily functions, including decreased consciousness

Consciousness

Consciousness is a difficult term to define, because the word is used and understood in a wide variety of ways, so that it frequently happens that what one person sees as a definition of consciousness is seen by others as about something else altogether....
(even coma

Coma

In medicine, a coma is a profound state of unconsciousness. A comatose person cannot be awakened, fails to respond normally to pain or light, does not have sleep-wake cycles, and does not take voluntary actions....
), bradycardia

Bradycardia

Bradycardia , as applied to adult medicine, is defined as a resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min....
, bradypnea

Bradypnea

Bradypnea , British English spelling bradypnoea refers to an abnormally slow breathing rate. The rate at which bradypnea is diagnosed depends upon the age of the patient....
, hypothermia

Hypothermia

Hypothermia is a condition in which an organism's temperature drops below that required for normal metabolism and bodily functions. In warm-blooded animals, core body temperature is maintained near a constant level through biologic homeostasis....
, and hypotension

Hypotension

In physiology and medicine, hypotension refers to an abnormally low blood pressure. This is best understood as a physiologic state, rather than a disease....
(in massive overdoses). Overdose may also lead to pulmonary edema

Pulmonary edema

Pulmonary edema , or oedema , is swelling and/or fluid accumulation in the lungs. It leads to impaired gas exchange and may cause respiratory failure....
and acute renal failure

Acute renal failure

Acute renal failure , also known as acute kidney failure or acute kidney injury, is a rapid loss of renal function due to damage to the kidneys, resulting in retention of nitrogenous and non-nitrogenous waste products that are normally excreted by the kidney....
as a result of shock.

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 isa legal definition of death that emerged in the 1960s as a response to the ability to resuscitate individuals and mechanically keep the heart and lungs working....
. 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 airways are those parts of the respiratory system through which air flows, to get from the external environment to the alveoli.The airway begins at the mouth or nose, and accesses the vertebrate trachea via the pharynx....
patency (through endotracheal intubation and mechanical ventilation

Mechanical ventilation

In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous respiration .Mechanical ventilation is typically used after an invasive intubation, a procedure wherein an endotracheal tube or tracheostomy tube is inserted into the airway....
), correction of bradycardia and hypotension (with intravenous fluid

Intravenous therapy

File:Infuuszakjes.jpgIntravenous therapy or IV therapy is the giving of liquid substances directly into a vein. It can be intermittent or continuous; continuous administration is called an intravenous drip....
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....
(stomach pumping) or use of activated charcoal. Hemodialysis

Hemodialysis

File:Plugged into dialysis.jpgIn medicine, hemodialysis is a method for removing waste products such as potassium and urea, as well as free water from the blood when the kidneys are in renal failure....
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

All Creatures Great and Small

All Creatures Great and Small may refer to:*All Creatures Great and Small , a 1975 film adaptation of James Herriot's first novel*All Creatures Great and Small , a BBC television adaptation of James Herriot's novels...
" books of James Herriot

James Herriot

James Herriot is the pen name of James Alfred Wight, Order of the British Empire, also known as Alf Wight , a Great Britain veterinarian and writer....
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 social and political activism in the United States who co-founded the Youth International Party . Later he became a fugitive from the law, living under an alias and working as an enviromentalist following a conviction for dealing cocaine....
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 used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetics properties of medication....
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....
(20 to 45%). Phenobarbital is metabolized by the liver, mainly through hydroxylation

Hydroxylation

Hydroxylation is any chemistry process that introduces one or more hydroxyl groups into a compound thereby oxidation it. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases....
and glucuronidation, 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 , or different regulatory properties....
s of the cytochrome P450 system

Cytochrome P450 oxidase

Cytochrome P450 is a very large and diverse superfamily of hemoproteins found in all domains of life. Cytochromes P450 use a plethora of both exogenous and endogenous compounds as substrates in enzymatic reactions....
. Cytochrome P450 2B6 (CYP2B6

CYP2B6

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....
) is specifically induced by Phenobarbital via the CAR/RXR nuclear receptor

Nuclear receptor

In the field of molecular biology, nuclear receptors are a class of proteins found within the interior of cells that are responsible for sensing the presence of hormone and certain other molecules....
heterodimer. It is excreted primarily by the kidney

Kidney

The kidneys are Organ that have numerous biological roles. Their primary role is to maintain the homeostasis balance of bodily fluids by filtering and secreting Metabolomics#Metabolitess and minerals from the blood and excreting them, along with water , as urine....
s.

Veterinary uses

Phenobarbital is one of the initial drugs of choice to treat epilepsy

Epilepsy

Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizure s. These seizures are transient signs and/or symptoms of abnormal, excessive or synchronous neuronal activity in the brain....
in dog

Dog

The dog is a domesticated subspecies of the Gray Wolf, a member of the Canidae family of the order Carnivora. The term is used for both feral and pet varieties....
s, and is the initial drug of choice to treat epilepsy in cats.

It may also be used to treat seizures in horse

Horse

The horse is a hoofed mammal, a subspecies of one of seven extant species of the family Equidae. The horse has evolution of the horse over the past 45 to 55 million years from a small multi-toed creature into the large, odd-toed ungulate animal of today....
s when benzodiazepine

Benzodiazepine

Illicit Use

The High Incident Bandits

North Hollywood shootout

The North Hollywood shootout was an armed confrontation between two heavily-armed and armored bank robbery, Larry Eugene Phillips, Jr. and Emil Matasareanu, and patrol and SWAT officers of the Los Angeles Police Department in North Hollywood, California, Los Angeles, California on February 28, 1997....
used phenobarbital prior to committing the North Hollywood Bank of America robbery

North Hollywood shootout