Phenobarbital

Phenobarbital arrives with the measured patience of a substance that has been in clinical use for over a century. The onset is slow, typically taking forty-five minutes to an hour, and it begins as a gradual heaviness that settles into the body like sediment drifting to the bottom of a still pool. The muscles relax first -- a deep, spreading looseness that starts in the large muscle groups and works outward. There is a warmth in the body, diffuse and comforting, and the first hints of cognitive slowing, as though the clock speed of thought has been reduced by a fraction.

The come-up builds with the same unhurried pace. Over the course of an hour or more, the sedation deepens from a gentle heaviness to a more insistent pull toward stillness. The mind slows noticeably: thoughts form at a reduced rate and carry less complexity, and the usual mental multitasking that characterizes waking consciousness simplifies into a single, slow stream. There is an anxiolytic component -- worry diminishes, and the emotional tone becomes more neutral -- but it is secondary to the sedation, which is the dominant effect. The body feels dense and warm, each limb weighted with a comfortable gravity that makes the very concept of standing seem unnecessarily ambitious.

At the peak, phenobarbital reveals its character as a substance of blunt, undiscriminating depression of the central nervous system. The sedation is thorough and encompassing, extending from the muscles to the mind in a single, unified heaviness. There is a mild intoxication -- a slightly drunken quality to perception and movement -- but it lacks the euphoria that more recreational barbiturates provide. Coordination is significantly impaired, speech is slowed and slightly slurred, and the eyes feel heavy with a persistent drowsiness. The emotional landscape is flat and quiet, neither unpleasant nor particularly rewarding, just calm in the most fundamental and unadorned sense of the word.

The offset is extended, reflecting the substance's long half-life. The sedation diminishes over many hours, and a residual drowsiness can persist for a full day or longer. Sleep during the active period is deep and prolonged, and waking brings a slow, gradual return of normal cognition and coordination. The overall impression is one of venerable pharmacological bluntness -- a substance from a simpler era of psychopharmacology, effective and unpretentious, doing its single job with the steady reliability of an old machine.

Barbiturates behave similarly to benzodiazepines. Phenobarbital binds to an allosteric site on the GABAA receptor and potentiates the effects of the endogenous ligand, gamma-aminobutyric acid. When barbiturates bind to the GABAA receptor, it causes the ion pore to open for extended periods of time, causing an increase of intracellular chlorine ion concentrations. As this site is the most prolific inhibitory receptor set within the brain, its modulation results in the sedating (or calming effects) of barbiturates on the nervous system. Phenobarbital's biological half life is 53-118 hours. It is metabolized by the liver and excreted by the kidneys and intestines.

Phenobarbital has an oral bioavailability of about 90%. Peak plasma concentrations (Cmax) 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 (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) is specifically induced by phenobarbital via the CAR/RXR nuclear receptor heterodimer. It is excreted primarily by the kidneys.

moderate toxicity relative to dose. However, phenobarbital is lethal when mixed with depressants like alcohol or opioids]]. Phenobarbital has a higher risk of death or serious adverse effects associated with concurrent depressant use than other drugs such as benzodiazepines. There have been studies linking the use of barbiturates, particularly phenobarbital, with the development of cancer .

It is strongly recommended that one use harm reduction practices when using this drug. -extremely physically and psychologically addictive. Barbiturate withdrawal is medically serious and can potentially cause a life-threatening withdrawal syndrome that can cause seizures, psychosis, and death. Drugs which lower the seizure threshold such as tramadol and amphetamine should be avoided during withdrawal.

Tolerance will develop to the sedative-hypnotic effects of phenobarbital after prolonged use. It is unknown exactly how long it takes for tolerance to reach baseline. Phenobarbital presents cross-tolerance with all barbiturates, meaning that after its consumption all barbiturates will have a reduced effect.

Although many drugs are safe on their own, they can become dangerous and even life-threatening when combined with other substances. The list below contains some common potentially dangerous combinations, but may not include all of them. Certain combinations may be harmless in low doses of each but still increase the potential risk of death. Independent research should always be done to ensure that a combination of two or more substances is safe before consumption.

• Depressants** (1,4-Butanediol, 2-methyl-2-butanol, alcohol, barbiturates, GHB/GBL, methaqualone, opioids) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation, sedation and amnesia caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should try to fall asleep in the recovery position or have a friend move them into it.
• Dissociatives** - This combination can lead to an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
• Stimulants** - It is unsafe to combine barbiturates with stimulants due to the risk of excessive intoxication. Stimulants decrease the sedative effect of barbiturates, which is the main factor most people consider when determining their level of intoxication. Once the stimulant wears off, the effects of barbiturates will be considerably increased, leading to intensified disinhibition as well as other effects. If combined, one should strictly limit themselves to only dosing a certain amount of barbiturates per hour. This combination can also potentially result in severe dehydration if hydration is not monitored.
• Overdose

Barbiturate overdose may occur when a barbiturate is taken in extremely heavy quantities or concurrently with other depressants. This is particularly dangerous with other GABAergic depressants such as benzodiazepines and alcohol since they work in a similar fashion, but bind to distinct allosteric sites on the GABAA receptor, thus their effects potentiate one another. Benzodiazepines increase the frequency in which the chlorine ion pore opens on the GABAA receptor while barbiturates increase the duration in which they are open, meaning when both are consumed, the ion pore will open more frequently and stay open longer. Barbiturate overdose is a medical emergency that may lead to a coma, permanent brain injury or death if not treated promptly and properly. Barbiturate overdose has an increased frequency of serious adverse effects when compared to other depressants.

Symptoms of a barbiturate overdose may include severe thought deceleration, slurred speech, confusion, delusions, respiratory depression, coma or death.

Internationally, phenobarbital is listed in Schedule IV of the UN Convention on Psychotropic Substances.

• Australia: Phenobarbitone is listed in Schedule 4, making it a prescription only medicine.

• Canada: Phenobarbital is a Schedule IV controlled substance.

• Germany: Phenobarbital is controlled under Anlage III BtMG (Narcotics Act, Schedule III). It can only be prescribed on a narcotic prescription form, except preparations which contain up to 10% or up to 300 mg phenobarbital in each dosage form.

• Russia: Phenobarbital is a Schedule III controlled substance since 2013. but phenobarbital is also found in the medicines Corvalol or Valocordin, which is dispensed without a doctor’s prescription.

• Switzerland: Phenobarbital is a controlled substance specifically named under Verzeichnis B. Medicinal use is permitted.

• United Kingdom: Phenobarbitone is a Class B controlled substance.

• United States: Phenobarbital is a Schedule IV controlled substance.

• Depressants

• Benzodiazepines

• GABA

• Phenobarbital (Wikipedia)

• Phenobarbital (Isomer Design)

• Phenobarbital (DrugBank)

The first barbiturate drug, barbital, was synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering and was first marketed as Veronal by Friedr. Bayer et comp. By 1904, several related drugs, including phenobarbital, had been synthesized by Fischer. Phenobarbital was brought to market in 1912 by the drug company Bayer as the brand Luminal. It remained a commonly prescribed sedative and hypnotic until the introduction of benzodiazepines in the 1960s.

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 and discovered their seizures were susceptible to the drug. Hauptmann performed a careful study of his patients over an extended period. Most of these patients were using the only effective drug then available, bromide, which had terrible side effects and limited efficacy. On phenobarbital, their epilepsy was much improved: those with the most severe disease had fewer and lighter seizures while some patients became seizure-free. In addition, they improved physically and mentally as bromides were removed from their regimen. Patients who had been institutionalised due to the severity of their epilepsy were able to leave and, in some cases, resume employment. Hauptmann dismissed concerns that its effectiveness in stalling seizures could lead to patients developing a build-up that needed to be "discharged". As he expected, withdrawal of the drug led to an increase in seizure frequency – it was not a cure. The drug was quickly adopted as the first widely effective anti-convulsant, though World War I delayed its introduction in the U.S.

In 1939, a German family asked Adolf Hitler to have their disabled son killed; the five-month-old boy was given a lethal dose of Luminal after Hitler sent his own doctor to examine him. A few days later 15 psychiatrists were summoned to Hitler's Chancellery and directed to commence a clandestine program of involuntary euthanasia.

In 1940, at a clinic in Ansbach, Germany, around 50 intellectually disabled children were injected with Luminal and killed that way. A plaque was erected in their memory in 1988 in the local hospital at FeuchtwangerStrasse 38, although a newer plaque does not mention that patients were killed using barbiturates on site. Luminal was used in the Nazi children's euthanasia program until at least 1943.

Phenobarbital was used to treat neonatal jaundice by increasing liver metabolism and thus lowering bilirubin levels. In the 1950s, phototherapy was discovered, and became the standard treatment.

Phenobarbital was used for over 25 years as prophylaxis in the treatment of febrile seizures. Although an effective treatment in preventing recurrent febrile seizures, it had no positive effect on patient outcome or risk of developing epilepsy. The treatment of simple febrile seizures with anticonvulsant prophylaxis is no longer recommended.