Fluadinazolam is a benzodiazepine derivative developed in 1973, with sedative and anxiolytic effects.
It is a derivative of the never commercially marketed benzodiazepine adinazolam and has similarly been sold as a designer drug.
Delorazepam, also known as chlordesmethyldiazepam and nordiclazepam, is a drug which is a benzodiazepine and a derivative of desmethyldiazepam.
It is marketed in Italy, where it is available under the trade name EN and Dadumir. Delorazepam (chlordesmethyldiazepam) is also an active metabolite of the benzodiazepine drugs diclazepam and cloxazolam. Adverse effects may include hangover type effects, drowsiness, behavioural impairments and short-term memory impairments. Similar to other benzodiazepines delorazepam has anxiolytic, skeletal muscle relaxant, hypnotic and anticonvulsant properties.
Delorazepam is mainly used as an anxiolytic because of its long elimination half-life; showing superiority over the short-acting drug lorazepam. In comparison with the antidepressant drugs, paroxetine and imipramine, delorazepam was found to be more effective in the short-term but after 4 weeks the antidepressants showed superior anti-anxiety effects.
Delorazepam is also used as a premedication for dental phobia for its anxiolytic properties. High doses of Delorazepam may be administered the night before a dental (or other medical) procedure in order to provide relief from anxiety-associated insomnia that night with the effects persisting long enough to sufficiently treat anxiety the next day.
Delorazepam has also demonstrated effectiveness in treating alcohol withdrawal.
Delorazepam is available in tablet and liquid drop formulations. The liquid drop formulation is absorbed more quickly and has improved bioavailibility.
Delorazepam is well absorbed after administration, reaching peak plasma levels within 1-2 hours. It has a very long elimination half-life and can still be detected 72 hours after dosing. Bioavailability is about 77%. Peak plasma levels occur at just over one hour after administration. Significant accumulation occurs of delorazepam due to its slow metabolism; the elderly metabolise delorazepam and its active metabolite slower than younger individuals, resulting in a dose of delorazepam accumulating faster and peaking at a higher plasma concentration than an equal dose administered to a younger individual. The elderly also have a poorer response to the therapeutic effects and a higher rate of adverse effects. The elimination half-life of delorazepam is 80-115 hours. The active metabolite of delorazepam is lorazepam and represents about 15-24% of the parent drug (delorazepam). The pharmacokinetics of delorazepam are not altered if it is taken with food, except for some slowing of absorption. Delorazepams potency is approximately equal to that of lorazepam, being ten times more potent by weight than diazepam (1 mg delorazepam = 1 mg lorazepam = 5 mg diazepam), typical doses range from 0.5 mg-2 mg. Treatment is generally initiated at 1 mg for healthy adults and 0.5 mg in paediatric and geriatric patients and patients with mild renal impairment, treatment is contraindicated in patients with moderate or severe renal impairment.
Delorazepam hosts all the classic side-effects of GABAA full agonists (such as most benzodiazepines). These include sedation/somnolence, dizziness/ataxia, amnesia, reduced inhibition, increased talkativeness/sociability, euphoria, impaired judgement, hallucinations, and respiratory depression. Paradoxical reactions including increased anxiety, excitation, and aggression may occur and are more common in elderly, paediatric, and schizophrenic patients. In rare instances, delorazepam may cause suicidal ideation and actions.
Long term use of delorazepam (as well as all other benzodiazepines) has been found to increase long term cognitive deficits (persisting longer than sixth months) which some researchers claim to be permanent. Short term use may occasionally cause depression and the risk of depressive symptoms occurring increases considerably with longer terms of use, delorazepam is not intended to be used for more than 2-4 weeks unless it used only occasionally on an as-needed basis. When being used on an as-needed basis the need for delorazepam therapy should be re-evaluated each time a new prescription for delorazepam is issued, and alternative medications should be considered if patients begin to take delorazepam habitually (many days in a row).
The most serious effect of long term delorazepam use is dependence, with withdrawal symptoms which mimic delirium tremens presenting when delorazepam use is discontinued. Although the withdrawal effects from delorazepam are generally less severe than its shorter-acting counterparts, they can be life-threatening. Slow de-titration of delorazepam over a period of weeks or months is generally suggested to minimise the severity of withdrawal. Psychological effects of withdrawal such as rebound anxiety and insomnia have been known to persist for months after physical dependence has been successfully treated.
Delorazepam is contraindicated in those with severe schizophrenia or schizo-affective disorders, those with a known allergy or hypersensitivity to delorazepam or related benzodiazepines, and those with moderate to severe renal impairment (delorazepam is sometimes administered at a reduced dose to patients with mild renal impairment). Delorazepam is generally considered to be contraindicated in patients with severe acute or chronic illnesses but is occasionally used in the palliative care of terminal patients during their last days/weeks of life.
Patients with a history of substance and/or alcohol use are believed to have an increased risk of abusing delorazepam (as well as all other benzodiazepines), this must be considered when a physician prescribes delorazepam to such patients. Although all patients being treated with delorazepam should be routinely monitored for signs of use and diversion of medication, increased monitoring of patients with a history of substance and/or alcohol use is always warranted. Non-medical benzodiazepine use in patients who have them prescribed on an as-needed basis for chronic/refractory anxiety, insomnia, and intermittent muscle spasms has occurred and generally occurs very slowly, becoming evident only after months or years since the initiation of therapy. Monitoring of patients actively using delorazepam should never be discontinued even if the patients has been stable on the medication for many months or years.
Caution must be used when delorazepam is administered alongside other sedative medications (ex. opiates, barbiturates, z-drugs, and phenothiazines) due to an increased risk of sedation, ataxia, and (potentially fatal) respiratory depression. Although overdoses of benzodiazepines alone rarely result in death, the combination of benzodiazepines and other sedatives (particularly other gabaminergic drugs such as barbiturates and alcohol) is far more likely to result in death.
People with renal failure on haemodialysis have a slow elimination rate and a reduced volume of distribution of the drug. Liver disease has a profound effect on the elimination rate of delorazepam, resulting in the half-life almost doubling to 395 hours, whereas healthy patients showed an elimination half-life of 204 hours on average. Caution is recommended when using delorazepam in patients with liver disease.
Phenazolam, (Clobromazolam, DM-II-90, BRN 4550445) is a benzodiazepine derivative which acts as a potent sedative and hypnotic drug.
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.
Clobromazolam was made illegal in Serbia in May 2019, and in Italy in March 2020.
Cloxazolam is a benzodiazepine derivative that has anxiolytic, sedative, and anticonvulsant properties.
It is not widely used; as of August 2018 it was marketed in Belgium, Luxembourg, Portugal, Brazil, and Japan. In 2019, it has been retired from the Belgian market.
Introdction
Gidazepam, also known as hydazepam or hidazepam, is a drug which is an atypical benzodiazepine derivative, developed in the Soviet Union.
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.
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.
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.
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 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.
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.
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.
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.
As of October 2015, phenazepam is a controlled substance in China.
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.
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.
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]
Russia:
Cinazepam (BD-798, sold under brand name Levana) is an atypical benzodiazepine derivative.
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.
3-Hydroxyphenazepam is a benzodiazepine with hypnotic, sedative, anxiolytic, and anticonvulsant properties.
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.
Flutemazepam was developed at a team at Stabilimenti Chimici Farmaceutici Riuniti SpA in the mid 1970s.
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.
Fluadinazolam is a benzodiazepine derivative developed in 1973, with sedative and anxiolytic effects.
It is a derivative of the never commercially marketed benzodiazepine adinazolam and has similarly been sold as a designer drug.
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