What is Phenobarbital?

Introduction

Phenobarbital, also known as phenobarbitone or phenobarb, or by the trade name Luminal, is a medication of the barbiturate type.

It is recommended by the World Health Organisation (WHO) for the treatment of certain types of epilepsy in developing countries. In the developed world, it is commonly used to treat seizures in young children, while other medications are generally used in older children and adults. 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, anxiety, and drug withdrawal and to help with surgery. It usually begins working within five minutes when used intravenously and half an hour when administered by mouth. Its effects last for between four hours and two days.

Side effects include a decreased level of consciousness along with a decreased effort to breathe. There is concern about both abuse and withdrawal following long-term use. It may also increase the risk of suicide. It is pregnancy category B or D (depending on how it is taken) in the United States and category D in Australia, meaning that it may cause harm when taken by pregnant women. If used during breastfeeding it may result in drowsiness in the baby. A lower dose is recommended in those with poor liver or kidney function, as well as elderly people. Phenobarbital, like other barbiturates works by increasing the activity of the inhibitory neurotransmitter GABA.

Phenobarbital was discovered in 1912 and is the oldest still commonly used anti-seizure medication. It is on the WHO’s List of Essential Medicines.

Brief History

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 tranquiliser and discovered their seizures were susceptible to the drug. Hauptmann performed a careful study of his patients over an extended period. Most of these patients were using the only effective drug then available, bromide, which had terrible side effects and limited efficacy. On phenobarbital, their epilepsy was much improved: The worst patients suffered 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 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 anti-convulsant, though World War I delayed its introduction in the US.

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 programme of involuntary euthanasia.

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

Medical Uses

Phenobarbital is used in the treatment of all types of seizures, except absence seizures. It is no less effective at seizure control than phenytoin, however phenobarbital is not as well tolerated. Phenobarbital may provide a clinical advantage over carbamazepine for treating partial onset seizures. Carbamazepine may provide a clinical advantage over phenobarbital for generalised onset tonic-clonic seizures. Its very long active half-life (53-118 hours) means for some people doses do not have to be taken every day, particularly once the dose has been stabilised over a period of several weeks or months, and seizures are effectively controlled.

The first-line drugs for treatment of status epilepticus are benzodiazepines, such as lorazepam or diazepam. If these fail, then phenytoin may be used, with phenobarbital being an alternative in the US, but used only third-line in the UK. Failing that, the only treatment is anaesthesia in intensive care. The 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 seizures. Concerns that neonatal seizures in themselves could be harmful make most physicians treat them aggressively. No reliable evidence, though, supports this approach.

Phenobarbital is sometimes used for alcohol detoxification and benzodiazepine detoxification for its sedative and anti-convulsant properties. The benzodiazepines chlordiazepoxide (Librium) and oxazepam (Serax) have largely replaced phenobarbital for detoxification.

Phenobarbital is useful for insomnia and anxiety.

Other Uses

Phenobarbital properties can effectively reduce tremors and seizures associated with abrupt withdrawal from benzodiazepines.

Phenobarbital is a cytochrome P450 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 in people with Crigler-Najjar syndrome, type II,[26] or in people with Gilbert’s syndrome. Phenobarbital can also be used to relieve cyclic vomiting syndrome 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, phenobarbital is used in preparation for a 99mTc-IDA hepatobiliary (HIDA; hepatobiliary 99mTc-iminodiacetic acid) study that differentiates atresia from hepatitis or cholestasis.

Phenobarbital is used as a secondary agent to treat newborns with neonatal abstinence syndrome, a condition of withdrawal symptoms from exposure to opioid drugs in utero.

In massive doses, phenobarbital is prescribed to terminally ill people to allow them to end their life through physician-assisted suicide.

Like other barbiturates, phenobarbital can be used recreationally, but this is reported to be relatively infrequent.

Side Effects

Sedation and hypnosis are the principal side effects (occasionally, they are also the intended effects) of phenobarbital. Central nervous system effects, such as dizziness, nystagmus and ataxia, are also common. In elderly patients, it may cause excitement and confusion, while in children, it may result in paradoxical hyperactivity.

Phenobarbital is a cytochrome P450 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 metabolised by the CYP450 enzyme system will have decreased effectiveness. This is because the increased CYP450 activity increases the clearance of the drug, reducing the amount of time they have to work.

Caution is to be used with children. Among anti-convulsant drugs, behavioural disturbances occur most frequently with clonazepam and phenobarbital.

Contraindications

Acute intermittent porphyria, hypersensitivity to any barbiturate, prior dependence on barbiturates, severe respiratory insufficiency (as with chronic obstructive pulmonary disease), severe liver failure, pregnancy, and breastfeeding are contraindications for phenobarbital use.

Overdose

Refer to Barbiturate Overdose.

Phenobarbital causes a depression of the body’s systems, mainly the central and peripheral nervous systems. Thus, the main characteristic of phenobarbital overdose is a “slowing” of bodily functions, including decreased consciousness (even coma), bradycardia, bradypnea, hypothermia, and hypotension (in massive overdoses). Overdose may also lead to pulmonary oedema and acute renal failure as a result of shock, and can result in death.

The electroencephalogram (EEG) of a person with phenobarbital overdose may show a marked decrease in electrical activity, to the point of mimicking brain death. This is due to profound depression of the central nervous system, and is usually reversible.

Treatment of phenobarbital overdose is supportive, and mainly consists of the maintenance of airway patency (through endotracheal intubation and mechanical ventilation), correction of bradycardia and hypotension (with intravenous fluids and vasopressors, 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 alkalisation (achieved with sodium bicarbonate) enhances renal excretion. Haemodialysis 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

Phenobarbitol is as an allosteric modulator which extends the amount of time the chloride ion channel is open by interacting with GABAA receptor subunits. Through this action, phenobarbital increases the flow of chloride ions into the neuron which decreases the excitability of the post-synaptic neuron. Hyperpolarising this post-synaptic membrane leads to a decrease in the general excitatory aspects of the post-synaptic neuron. By making it harder to depolarise the neuron, the threshold for the action potential of the post-synaptic neuron will be increased. Phenobarbital stimulates GABA to accomplish this hyperpolarisation. Direct blockade of excitatory glutamate signalling is also believed to contribute to the hypnotic/anticonvulsant effect that is observed with the barbiturates.

Pharmacokinetics

Phenobarbital has an oral bioavailability of about 90%. Peak plasma concentrations (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.

Veterinary Uses

Phenobarbital is one of the initial drugs of choice to treat epilepsy in dogs, as well as cats. It is also used to treat feline hyperesthesia syndrome in cats when anti-obsessional therapies prove ineffective.

It may also be used to treat seizures in horses when benzodiazepine treatment has failed or is contraindicated.

Society and Culture

Names

Phenobarbital is the INN and phenobarbitone is the BAN.

Synthesis

Barbiturate drugs are obtained via condensation reactions between a derivative of diethyl malonate and urea in the presence of a strong base. The synthesis of phenobarbital uses this common approach as well but differs in the way in which this malonate derivative is obtained. The reason for this difference is due to the fact that aryl halides do not typically undergo nucleophilic substitution in Malonic ester synthesis in the same way as aliphatic organosulfates or halocarbons do. To overcome this lack of chemical reactivity two dominant synthetic approaches using benzyl cyanide as a starting material have been developed:

  • The first of these methods consists of a Pinner reaction of benzyl cyanide, giving phenylacetic acid ethyl ester. Subsequently, this ester undergoes cross Claisen condensation using diethyl oxalate, giving diethyl ester of phenyloxobutandioic acid. Upon heating this intermediate easily loses carbon monoxide, yielding diethyl phenylmalonate. Malonic ester synthesis using ethyl bromide leads to the formation of α-phenyl-α-ethylmalonic ester. Finally a condensation reaction with urea gives phenobarbital.
  • The second approach utilises diethyl carbonate in the presence of a strong base to give α-phenylcyanoacetic ester. Alkylation of this ester using ethyl bromide proceeds via a nitrile anion 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.

Regulation
The level of regulation includes Schedule IV non-narcotic (depressant) (ACSCN 2285) in the United States under the Controlled Substances Act 1970—but along with a few other barbiturates and at least one benzodiazepine, and codeine, dionine, or dihydrocodeine at low concentrations, it also has exempt prescription and had at least one exempt OTC combination drug now more tightly regulated for its ephedrine content.[63] 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.[64]

Selected Overdoses

The Japanese officers aboard the German submarine U-234 killed themselves with phenobarbital while the German crew members were on their way to the US to surrender (but before Japan had surrendered).

A mysterious woman, known as the Isdal Woman, was found dead in Bergen, Norway, on 29 November 1970. Her death was caused by some combination of burns, phenobarbital, and carbon monoxide poisoning; many theories about her death have been posited, and it is believed that she may have been a spy.

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 also committed suicide by consuming phenobarbital, combined with alcohol, on 12 April 1989; the residue of around 150 pills was found in his body at autopsy. Also dying from an overdose was British actress Phyllis Barry in 1954 and actress/model Margaux Hemingway in 1996.

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.

What is Phenazolam?

Introduction

Phenazolam, (Clobromazolam, DM-II-90, BRN 4550445) is a benzodiazepine derivative which acts as a potent sedative and hypnotic drug.

Background

It was first invented in the early 1980s, but was never developed for medical use. It has been sold over the internet as a designer drug, first being identified in seized samples by a laboratory in Sweden in March 2016.

Legality

Clobromazolam was made illegal in Serbia in May 2019, and in Italy in March 2020.

What is Nefazodone?

Introduction

Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued.

BMS withdrew it from the market by 2004 due to decreasing sales due to the rare incidence of severe liver damage and the onset of generic competition. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient-years. Generic versions were introduced in 2003.

Nefazodone is a phenylpiperazine compound and is related to trazodone. It has been described as a serotonin antagonist and reuptake inhibitor (SARI) due to its combined actions as a potent serotonin 5-HT2A receptor and 5-HT2C receptor antagonist and weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).

Brief History

Nefazodone was discovered by scientists at Bristol-Myers Squibb (BMS) who were seeking to improve on trazodone by reducing its sedating qualities.

BMS obtained marketing approvals worldwide for nefazodone in 1994. It was marketed in the US under the brand name Serzone and in Europe under the brand name Dutonin.

In 2002, the US Food and Drug Administration (FDA) obligated BMS to add a black box warning about potential fatal liver toxicity to the drug label. Worldwide sales in 2002 were $409 million.

In 2003 Public Citizen filed a citizen petition asking the FDA to withdraw the marketing authorisation in the US, and in early 2004 the organisation sued the FDA to attempt to force withdrawal of the drug. The FDA issued a response to the petition in June 2004 and filed a motion to dismiss, and Public Citizen withdrew the suit.

Generic versions were introduced in the US in 2003 and Health Canada withdrew the marketing authorization that year.

Sales of nefazodone were about $100 million in 2003. By that time it was also being marketed under the additional brand names Serzonil, Nefadar, and Rulivan.

In April 2004, BMS announced that it was going discontinue the sale of Serzone in the US in June 2004 and said that this was due to declining sales. By that time BMS had already withdrawn the drug from the market in Europe, Australia, New Zealand and Canada.

As of 2012 generic nefazodone was available in the US.

Medical Uses

Nefazodone is used to treat major depressive disorder, aggressive behaviour, and panic disorder.

Available Forms

Nefazodone is available as 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg tablets for oral ingestion.

Side Effects

Nefazodone can cause severe liver damage, leading to a need for liver transplant, and death. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient-years. By the time that it started to be withdrawn in 2003, nefazodone had been associated with at least 53 cases of liver injury, with 11 deaths, in the United States, and 51 cases of liver toxicity, with 2 cases of liver transplantation, in Canada. In a Canadian study which found 32 cases in 2002, it was noted that databases like that used in the study tended to include only a small proportion of suspected drug reactions.

Common and mild side effects of nefazodone reported in clinical trials more often than placebo include dry mouth (25%), sleepiness (25%), nausea (22%), dizziness (17%), blurred vision (16%), weakness (11%), lightheadedness (10%), confusion (7%), and orthostatic hypotension (5%). Rare and serious adverse reactions may include allergic reactions, fainting, painful/prolonged erection, and jaundice.

Nefazodone is not especially associated with increased appetite and weight gain.

Interactions

Nefazodone is a potent inhibitor of CYP3A4, and may interact adversely with many commonly used medications that are metabolized by CYP3A4.

Pharmacology

Pharmacodynamics

Nefazodone acts primarily as a potent antagonist of the serotonin 5-HT2A receptor and to a lesser extent of the serotonin 5-HT2C receptor. It also has high affinity for the α1-adrenergic receptor and serotonin 5-HT1A receptor, and relatively lower affinity for the α2-adrenergic receptor and dopamine D2 receptor. Nefazodone has low but significant affinity for the serotonin, norepinephrine, and dopamine transporters as well, and therefore acts as a weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It has low but potentially significant affinity for the histamine H1 receptor, where it is an antagonist, and hence may have some antihistamine activity. Nefazodone has negligible activity at muscarinic acetylcholine receptors, and accordingly, has no anticholinergic effects.

Pharmacokinetics

The bioavailability of nefazodone is low and variable, about 20%. Its plasma protein binding is approximately 99%, but it is bound loosely.

Nefazodone is metabolized in the liver, with the main enzyme involved thought to be CYP3A4. The drug has at least four active metabolites, which include hydroxynefazodone, para-hydroxynefazodone, triazoledione, and meta-chlorophenylpiperazine. Nefazodone has a short elimination half-life of about 2 to 4 hours. Its metabolite hydroxynefazodone similarly has an elimination half-life of about 1.5 to 4 hours, whereas the elimination half-lives of triazoledione and mCPP are longer at around 18 hours and 4 to 8 hours, respectively. Due to its long elimination half-life, triazole is the major metabolite and predominates in the circulation during nefazodone treatment, with plasma levels that are 4 to 10 times higher than those of nefazodone itself. Conversely, hydroxynefazodone levels are about 40% of those of nefazodone at steady state. Plasma levels of mCPP are very low at about 7% of those of nefazodone; hence, mCPP is only a minor metabolite. mCPP is thought to be formed from nefazodone specifically by CYP2D6.

The ratios of brain-to-plasma concentrations of mCPP to nefazodone are 47:1 in mice and 10:1 in rats, suggesting that brain exposure to mCPP may be much higher than plasma exposure. Conversely, hydroxynefazodone levels in the brain are 10% of those in plasma in rats. As such, in spite of its relatively low plasma concentrations, brain exposure to mCPP may be substantial, whereas that of hydroxynefazodone may be minimal.

Chemistry

Nefazodone is a phenylpiperazine; it is an alpha-phenoxyl derivative of etoperidone which in turn was a derivative of trazodone.

Society and Culture

Generic Names

Nefazodone is the generic name of the drug and its INN and BAN, while néfazodone is its DCF and nefazodone hydrochloride is its USAN and USP.

Brand Names

Nefazodone has been marketed under a number of brand names including Dutonin (AT, ES, IE, UK), Menfazona (ES), Nefadar (CH, DE, NO, SE), Nefazodone BMS (AT), Nefazodone Hydrochloride Teva (US), Reseril (IT), Rulivan (ES), and Serzone (AU, CA, US). As of 2017, it remains available only on a limited basis as Nefazodone Hydrochloride Teva in the United States.

Research

The use of nefazodone to prevent migraine has been studied, due to its antagonistic effects on the 5-HT2A and 5-HT2C receptors.

What is Gidazepam?

Introdction

Gidazepam, also known as hydazepam or hidazepam, is a drug which is an atypical benzodiazepine derivative, developed in the Soviet Union.

Background

It is a selectively anxiolytic benzodiazepine. It also has therapeutic value in the management of certain cardiovascular disorders. It can also be used for a treatment to giddiness.

Gidazepam is a prodrug for its active metabolite 7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-one (desalkylgidazepam or bromo-nordazepam). It is used as an antianxiety drug. Its anxiolytic effects can take several hours to manifest after dosing however, as it is the active metabolite which primarily gives the anxiolytic effects, and Gidazepam’s half-life is among the longest of all GABA-ergic agonists.

What is Phenazepam?

Introduction

Phenazepam (also known in Russia as bromdihydrochlorphenylbenzodiazepine) is a benzodiazepine drug, which was developed in the Soviet Union in 1975, and now produced in Russia and some CIS countries.

Phenazepam is used in the treatment of various mental disorders such as psychiatric schizophrenia and anxiety. It can be used as a premedication before surgery as it augments the effects of anaesthetics. Recently, phenazepam has gained popularity as a recreational drug; misuse has been reported in the United Kingdom, Finland, Sweden, and the United States.

Refer to 3-Hydroxyphenazepam and Cinazepam.

Indications

  • Neurosis, neurosis-like, psychopathic (personality disorder), psychopathic-like and other conditions accompanied by fear, anxiety, increased irritability, and emotional lability.
  • Brief reactive psychosis and hypochondriasis-senestopathic syndrome.
  • Vegetative dysfunction and vegetative lability.
  • Insomnia.
  • Alcohol withdrawal syndrome.
  • Temporal lobe epilepsy and myoclonic epilepsy (used only occasionally as better options exist).
  • Hyperkinesia and tics.
  • Muscle spasticity.

Usually, a course of treatment with phenazepam should not normally exceed 2 weeks (in some cases therapy may be prolonged for up to 2 months) due to the risk of drug abuse and dependence. To prevent withdrawal syndrome, it is necessary to reduce the dose gradually.

Chemistry

Phenazepam is a drug of the benzodiazepine class. Benzodiazepine drugs contain a benzene ring fused to a diazepine ring, which is a seven membered ring with the two nitrogen constituents located at R1 and R4. The benzyl ring of phenazepam is substituted at R7 with a bromine group. Like most benzodiazepines, phenazepam has a phenyl ring in R5 which is substituted by chlorine in the R2′ group. Phenazepam also contains an oxygen group double bonded to R2 of its diazepine ring to form a ketone. This oxygen substitution at R2 is shared with other benzodiazepine drugs with the suffix -azepam.

Like other benzodiazepines, phenazepam (7-bromo-5-(2-chlorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one) is composed of a benzene ring fused to a seven-membered 1,4-diazepine ring. A 2-chlorophenyl ring is attached at the 5-position and a bromine is attached at the 7-position. Phenazepam has a molecular formula of C15H10BrClN2O and a molecular weight of 349.6 g/mol.

Side Effects

Side effects include hiccups, dizziness, loss of coordination and drowsiness, along with anterograde amnesia which can be quite pronounced at high doses. As with other benzodiazepines, in case of abrupt discontinuation following prolonged use, severe withdrawal symptoms may occur including restlessness, anxiety, insomnia, seizures, convulsions and death, though because of its intermediate half-life as well as that of its active metabolites, these withdrawal symptoms may take two or more days to manifest.

Contraindications and Special Caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.

Phenazepam should not be taken with alcohol or any other CNS depressants. Phenazepam should not be used therapeutically for periods of longer than one month including tapering on and off the drug as recommended for any benzodiazepine in the British national formulary. Some patients may require longer term treatment.

Phenazepam was found to be a component in some herbal incense mixtures in Australia and New Zealand in 2011, namely “Kronic”. The particular product variety was withdrawn shortly from the market after and replaced with a new formulation.

Synthesis

First, 2-(o-chlorobenzoylamino)-5-bromo-2-chlorobenzophenone is prepared by acylation of p-bromoaniline with o-chlorobenzoic acid acyl chloride in the presence of a zinc chloride catalyst. This is hydrolysed with aqueous sulfuric acid to yield 2-amino-5-bromo-2′-chlorobenzophenone, which is then acylated with hydrochloride of aminoacetic acid acyl chloride in chloroform to form 2-(aminomethylkarbonylamino)-5-bromo-2-chlorobenzophenone hydrochloride, which is converted to a base with aqueous ammonia and then thermally cyclized to bromodihydrochlorophenylbenzodiazepine (phenazepam).

Hydrochloride of aminoacetic acid acyl chloride is prepared by chemical treating glycine with phosphorus pentachloride (PCl5) in chloroform.

This method of Phenazepam synthesis was developed in the 1970s at the Physico-Chemical Institute of the Academy of Sciences of the Ukrainian SSR.

Detection in Biological Fluids

Phenazepam may be measured in blood or plasma by chromatographic methods. Blood phenazepam concentrations are typically less than 30 μg/L during therapeutic usage, but have frequently been in the 100–600 μg/L range in automotive vehicle operators arrested for impaired driving ability.

China

As of October 2015, phenazepam is a controlled substance in China.

United States

Under federal United States law, phenazepam is not currently classified as a controlled substance, as the Federal Analog Act only provides for automatic assumed classification of chemicals “substantially similar” to existing Schedule I or Schedule II drugs, whereas all controlled benzodiazepines under the Controlled Substances Act are classified as Schedule IV. Although phenazepam is currently not controlled, sale for human use remains illegal in the United States. Suppliers attempt to circumvent this regulation by placing a “Not for human use” disclaimer on the product’s label.

Individual states in the United States often ban these analogue drugs by name as they appear. Since 2012, Louisiana has classified phenazepam as a controlled dangerous substance. This ban affects several products, some of which were sold at retail stores under the guise of air freshener or similar, containing phenazepam yet claiming not to be for human use. This legislation was introduced after one such product, branded as “Zannie” and marketed as an air freshener rapidly gained publicity as the subject of numerous media reports, attracting the attention of officials. The ensuing investigation effort, led by Senator Fred Mills and Louisiana Poison Centre Director Mark Ryan, positively identified the active ingredient of “Zannie” as phenazepam. According to Ryan, chemical analysis identified the active ingredient as “100 percent phenazepam”.

Paul Halverson, director and state health officer for the Arkansas Department of Health, approved an emergency rule to ban the sale and distribution of phenazepam shortly after the Louisiana ban.

United Kingdom

Phenazepam is a class C drug in the UK.

The UK home office banned importation of phenazepam on Friday 22 July 2011 while it drafted legislation, released in January 2012 to become law at the end of March 2012. The bill was quashed following advice from the ACMD as it included two non-abusable steroids. There was a new discussion about its fate on 23 April 2012, where it was decided that the bill would be rewritten and phenazepam would still be banned.

It was eventually banned on 13 June 2012 as a class C, schedule II drug.

Elsewhere

Phenazepam was classified as a narcotic in Finland in July 2014.

Phenazepam is considered a narcotic in Norway, as per a 23 March 2010 Health Department addition to the Regular Narcotic List.

In Russia, while the drug is considered a prescription medication (but not a controlled one, as all other benzodiazepines except tofisopam), some pharmacies sell it without prescriptions required. Since 22 March 2021 phenazepam must be a controlled substance in Russia.

In Estonia, phenazepam is a Schedule IV substance under the Narcotic Drugs and Psychotropic Substances Act. Schedule IV is the lowest classification of psychoactive substances in Estonia. It includes prescribed drugs, including other benzodiazepines.

UN Single Convention on Narcotic Drugs
On 8 March 2016 at its 59th Session, the Commission on Narcotic Drugs (CND) added Phenazepam to relevant schedules of the Single Convention on Narcotic Drugs of 1961.[33]

Trade Names

Russia:

  • «Феназепам» (Phenazepam) tablets 0.25, 0.5 and 1 mg, solution for intramuscular and intravenous injection 1 mg/mL (0.1%).
  • «Элзепам» (Elzepam) tablets 0.5 and 1 mg, solution for intramuscular and intravenous injection 1 mg/mL (0.1%).
  • «Фензитат» (Phenzitat) tablets 0.5 and 1 mg.
  • «Фенорелаксан» (Phenorelaxan) tablets 0.5 and 1 mg, solution for intramuscular and intravenous injection 1 mg/mL (0.1%).
  • «Транквезипам» (Trankvezipam) tablets 0.5 and 1 mg, solution for intramuscular and intravenous injection 1 mg/mL (0.1%).
  • «Фезипам» (Phezipam) tablets 0.5 and 1 mg (not to be confused with «Фезам» (Phezam) which contains cinnarizine/piracetam).
  • «Фезанеф» (Phezanef) tablets 1 mg.

What is Cinazepam?

Introduction

Cinazepam (BD-798, sold under brand name Levana) is an atypical benzodiazepine derivative.

Background

It produces pronounced hypnotic, sedative, and anxiolytic effects with minimal myorelaxant side effects. In addition, unlike many other benzodiazepine and nonbenzodiazepine hypnotics such as diazepam, flunitrazepam, and zopiclone, cinazepam does not violate sleep architecture, and the continuity of slow-wave sleep and REM sleep are proportionally increased. As such, cinazepam produces a sleep state close to physiological, and for that reason, may be advantageous compared to other, related drugs in the treatment of insomnia and other sleep disorders.

Cinazepam has an order of magnitude lower affinity for the benzodiazepine receptor of the GABAA complex relative to other well-known hypnotic benzodiazepines such as nitrazepam and phenazepam. Moreover, in mice, it is rapidly metabolised, with only 5% of the base compound remaining within 30 minutes of administration. As such, cinazepam is considered to be a benzodiazepine prodrug; specifically, to 3-hydroxyphenazepam, as the main active metabolite.

What is 3-Hydroxyphenazepam?

Introduction

3-Hydroxyphenazepam is a benzodiazepine with hypnotic, sedative, anxiolytic, and anticonvulsant properties.

Background

It is an active metabolite of phenazepam, as well as the active metabolite of the benzodiazepine prodrug cinazepam. Relative to phenazepam, 3-hydroxyphenazepam has diminished myorelaxant properties, but is about equivalent in most other regards.

Like other benzodiazepines, 3-hydroxyphenazepam behaves as a positive allosteric modulator of the benzodiazepine site of the GABAA receptor with an EC50 value of 10.3 nM.

It has been sold online as a designer drug.

What is Flutemazepam?

Introduction

Flutemazepam was developed at a team at Stabilimenti Chimici Farmaceutici Riuniti SpA in the mid 1970s.

Background

It is a drug which is a 3-hydroxy benzodiazepine derivative and an analogue of temazepam that has hypnotic, sedative, amnesiac, anxiolytic, anticonvulsant and skeletal muscle relaxant properties. It is most closely related in structure to temazepam and is indicated for the treatment of severe insomnia. Flutemazepam has properties similar to temazepam, and it has been found to be very effective for the treatment of severe states of anxiety, panic attacks, and severe insomnia.