Zapizolam is a pyridodiazepine drug, which is a benzodiazepine analogue of pyridotriazolodiazepine group.
It has sedative and anxiolytic effects similar to those produced by benzodiazepine derivatives, and has been sold illicitly as a designer drug.
A pyridotriazolodiazepine is a heterocyclic compound containing pyridine and triazole rings fused to a diazepine ring.
Pyridotriazolodiazepines forms the central structure of zapizolam. Zapizolam is poorly researched, but probably it is a sedative and/or anxiolytic, like other benzodiazepine derivatives, especially triazolobenzodiazepines (such as alprazolam).
The World Health Organisation (WHO) Mental Health Gap Action Programme (mhGAP) aims at scaling up services for mental, neurological and substance use disorders for countries especially with low- and middle-income.
Mental, neurological, and substance use disorders are common in all regions of the world, affecting every community and age group across all income countries. While 14% of the global burden of disease is attributed to these disorders, most of the people affected – 75% in many low-income countries – do not have access to the treatment they need.
As such, the programme asserts that with proper care, psychosocial assistance and medication, tens of millions could be treated for depression, schizophrenia, and epilepsy, prevented from suicide and begin to lead normal lives – even where resources are scarce.
The following overview is from the WHO ‘mhGAP Mental Health Gap Programme: Scaling Up Care for Mental, Neurological, and Substance Use Disorders’ published on 01 January 2008:
Mental, neurological and substance use disorders are highly prevalent and burdensome globally. The gap between what is urgently needed and what is available to reduce the burden is still very wide.
WHO recognizes the need for action to reduce the burden, and to enhance the capacity of Member States to respond to this growing challenge. mhGAP is WHO’s action plan to scale up services for mental, neurological and substance use disorders for countries especially with low and lower middle incomes. The priority conditions addressed by mhGAP are: depression, schizophrenia and other psychotic disorders, suicide, epilepsy, dementia, disorders due to use of alcohol, disorders due to use of illicit drugs, and mental disorders in children. The mhGAP package consists of interventions for prevention and management for each of these priority conditions.
Successful scaling up is the joint responsibility of governments, health professionals, civil society, communities, and families, with support from the international community. The essence of mhGAP is building partnerships for collective action. A commitment is needed from all partners to respond to this urgent public health need and the time to act is now!
WHO mhGAP Mental Health Gap Action Programme: Scaling Up Care for Mental, Neurological, and Substance Use Disorders (WHO site; published 01 January 2008).
Outline of the Mental Health Gap Action Programme (mhGAP) (WHO site).
Clinical Review: WHO Mental Health Gap Action Programme (mhGAP) Intervention Guide: A Systematic Review of Evidence from Low and Middle-Income Countries (BMJ Journals: Evidence-Based Mental Health).
Flualprazolam is a tranquiliser of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring.
It was first synthesised in 1976, but was never marketed. It has subsequently been sold as a designer drug, first being definitively identified as such in Sweden in 2018. It can be described as the 2′-fluoro derivative of alprazolam, or the fluoro instead of chloro analogue of triazolam, and has similar sedative and anxiolytic effects.
Flualprazolam is banned in Sweden, also is illegal in the UK. In December 2019, the World Health Organisation recommended flualprazolam for international scheduling as a Schedule IV medication under the Convention on Psychotropic Substances.
Clonazolam (also known as clonitrazolam) is a drug of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring.
It has had very little research done about its effects and metabolism, and has been sold online as a designer drug. The synthesis of clonazolam was first reported in 1971 and the drug was described as the most active compound in the series tested.
Clonazolam is reported to be highly potent and concerns have been raised that it and flubromazolam in particular may pose comparatively higher risk than other designer benzodiazepines due to their ability to produce strong sedation and amnesia at as little as 0.5 mg.
In the UK, clonazolam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.
It is an unscheduled medicine and not FDA approved. Virginia State Law has declared all of the following medications are now schedule I: clonazolam, etizolam, flualprazolam, flubromazolam, and flubromazepam. Minnesota declared clonazolam a Schedule I drug in August 2020.
In Australia, clonazolam is classified as a controlled substance in some states.
Sweden’s public health agency suggested classifying clonazolam as a hazardous substance on 01 June 2015.
Clonazolam’s effects are similar to other benzodiazepines, such as anxiolysis, disinhibition, lethargy, muscle relaxation, and euphoria. While no dose of clonazolam is considered “safe” due to its lack of research and extreme potency, doses higher than 0.5 mg can cause benzodiazepine overdose in some individuals. The effects of a benzodiazepine overdose include sedation, confusion, insufficient breathing, loss of consciousness, and death. Because dependence can occur in a short period of time, or even with a large initial dose, withdrawal symptoms (including seizures and death) may occur acutely following the period of intoxication.
Flubromazolam (JYI-73) is a triazolobenzodiazepine (TBZD), which are benzodiazepine (BZD) derivatives.
Flubromazolam is reputed to be highly potent, and concerns have been raised that clonazolam and flubromazolam in particular may pose comparatively higher risks than other designer benzodiazepines, due to their ability to produce strong sedation and amnesia at oral doses of as little as 0.5 mg. Life-threatening adverse reactions have been observed at doses of only 3 mg of flubromazolam.
Flubromazolam has been classified as an illegal substance in Sweden after seizures by customs and police, as well as indications from the EMCDDA of wider use as a recreational drug.
Flubromazolam is illegal in Switzerland as of December 2015.
In the UK, flubromazolam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.
Eszopiclone, sold under the brand-name Lunesta among others, is a medication used in the treatment of insomnia.
Evidence supports slight to moderate benefit up to six months. It is taken orally. Common side effects include headache, dry mouth, nausea, and dizziness. Severe side effects may include suicidal thoughts, unhealthy non-medical use, hallucinations, and angioedema. Greater care is recommended in those with liver problems and older people. Rapid decreasing of the dose may result in withdrawal. Eszopiclone is classified as a nonbenzodiazepine sedative hypnotic and as a cyclopyrrolone. It is the S-stereoisomer of zopiclone. It works by interacting with the GABA receptors.
Approved for medical use in the United States in 2004, eszopiclone is available as generic medication. In 2017, it was the 214th most commonly prescribed medication in the United States, with more than two million prescriptions. Eszopiclone is not sold in the European Union, as in 2009 the EMA ruled that it was too similar to zopiclone to be considered a new patentable product.
In a controversial 2009 article in the New England Journal of Medicine, “Lost in Transmission — FDA Drug Information That Never Reaches Clinicians”, it was reported that the largest of three Lunesta trials found that compared to placebo Lunesta “was superior to placebo” while it only shortened initial time falling asleep by 15 minutes on average. “Clinicians who are interested in the drug’s efficacy cannot find efficacy information in the label: it states only that Lunesta is superior to placebo. The FDA’s medical review provides efficacy data, albeit not until page 306 of the 403-page document. In the longest, largest phase 3 trial, patients in the Lunesta group reported falling asleep an average of 15 minutes faster and sleeping an average of 37 minutes longer than those in the placebo group. However, on average, Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvement in next-day alertness or functioning.”
On 11 September 2007, Sepracor signed a marketing deal with British pharmaceutical company GlaxoSmithKline for the rights to sell eszopiclone (under the name Lunivia rather than Lunesta) in Europe. Sepracor was expected to receive approximately $155 million if the deal went through. In 2008 Sepracor submitted an application to the EMA (the European Union’s equivalent to the US FDA) for authorisation to market the drug in the EU, and initially received a favourable response. However, Sepracor withdrew its authorization application in 2009 after the EMA stated it would not be granting eszopiclone ‘new active substance’ status, as it was essentially pharmacologically and therapeutically too similar to zopiclone to be considered a new patentable product. Since the patent on zopiclone has expired, this ruling would have allowed rival companies to also legally produce cheaper generic versions of eszopiclone for the European market. As of November 2012, Sepracor has not resubmitted its authorisation application and eszopiclone is not available in Europe. The deal with GSK fell through, and GSK instead launched a $3.3 billion deal to market Actelion’s almorexant sleeping tablet, which entered phase 3 medical trials before development was abandoned due to side effects.
A 2018 Cochrane review found that it produced moderate improvement in sleep onset and maintenance. The authors suggest that where preferred non-pharmacological treatment strategies have been exhausted, eszopiclone provides an efficient treatment for insomnia. In 2014, the USFDA asked that the starting dose be lowered from 2 milligrams to 1 milligram after it was observed in a study that even 8 hours after taking the drug at night, some people were not able to cope with their next-day activities like driving and other activities that require full alertness.
Eszopiclone is slightly effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. Kirsch et al. found the benefit over placebo to be of questionable clinical significance. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produce a reasonably large clinical response. It is not recommended for chronic use in the elderly.
Sedative hypnotic drugs including eszopiclone are more commonly prescribed to the elderly than to younger patients despite benefits of medication being generally unimpressive. Care should be taken in choosing an appropriate hypnotic drug and if drug therapy is initiated it should be initiated at the lowest possible dose to minimise side effects.
In 2015, the American Geriatrics Society reviewed the safety information about eszopiclone and similar drugs and concluded that the “nonbenzodiazepine, benzodiazepine receptor agonist hypnotics (eszopiclone, zaleplon, zolpidem) are to be avoided without consideration of duration of use because of their association with harms balanced with their minimal efficacy in treating insomnia.”
The review made this determination both because of the relatively large dangers to elderly individuals from zolpidem and other “z-drugs” together with the fact the drugs have “minimal efficacy in treating insomnia.” This was a change from the 2012 AGS recommendation, which suggested limiting use to 90 days or less. The review stated: “the 90‐day‐use caveat [was] removed from nonbenzodiazepine, benzodiazepine receptor agonist hypnotics, resulting in an unambiguous ‘avoid’ statement (without caveats) because of the increase in the evidence of harm in this area since the 2012 update.”
An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, including eszopiclone appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin receptor agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.
A 2009 meta-analysis found a higher rate of infections.
Sleeping pills, including eszopiclone, have been associated with an increased risk of death.
Hypersensitivity to eszopiclone is a contra-indication to its use. Some side effects are more common than others. Recommendations around use of eszopiclone may be altered by other health conditions. These conditions or circumstances may occur in people that have lowered metabolism and other conditions. The presence of liver impairment, lactation and activities requiring mental alertness (e.g. driving) may be considered when determining frequency and dosage.
A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking eszopiclone or other hypnotic drugs compared to those taking a placebo.
In the United States eszopiclone is a schedule IV controlled substance under the Controlled Substances Act. Use of eszopiclone may lead to physical and psychological dependence. The risk of non-medical use and dependence increases with the dose and duration of usage and concomitant use of other psychoactive substances. The risk is also greater in patients with a history of alcohol use disorder or other substance use disorder or history of psychiatric disorders. Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks.
A study funded and carried out by Sepracor, the manufacturer of eszopiclone, found no signs of tolerance or dependence in a group of patients followed for up to six months.
A study of non-medical use potential of eszopiclone found that in persons with a known history of non-medical benzodiazepine use, eszopiclone at doses of 6 and 12 mg produced effects similar to those of diazepam 20 mg. The study found that at these doses which are two or more times greater than the maximum recommended doses, a dose-related increase in reports of amnesia, sedation, sleepiness, and hallucinations was observed for both eszopiclone (Lunesta) as well as for diazepam (Valium).
According to the US Prescribing Information, overdoses of eszopiclone up to 90 times the recommended dose have been reported in which the patient fully recovered. According to the May 2014 edition of the official US Prescribing Information, fatalities have been reported only in cases in which eszopiclone was combined with other drugs or alcohol.
Poison control centres reported that between 2005 and 2006 there were 525 total eszopiclone overdoses recorded in the state of Texas, the majority of which were intentional suicide attempts.
If consumed within the last hour, eszopiclone overdose can be treated with the administration of activated charcoal or via gastric lavage.
There is an increased risk of central nervous system depression when eszopiclone is taken together with other CNS depressant agents, including antipsychotics, sedative hypnotics (like barbiturates or benzodiazepines), antihistamines, opioids, phenothiazines, and some antidepressants. There is also increased risk of central nervous system depression with other medications that inhibit the metabolic activities of the CYP3A4 enzyme system of the liver. Medications that inhibit this enzyme system include nelfinavir, ritonavir, ketoconazole, itraconazole and clarithromycin. Alcohol also has an additive effect when used concurrently with eszopiclone. Eszopiclone is most effective if it is not taken after a heavy meal with high fat content.
Eszopiclone acts on benzodiazepine binding site situated on GABAA neurons as a positive allosteric modulator. Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between .45 and 1.3 hours. The elimination half-life of eszopiclone is approximately 6 hours and it is extensively metabolized by oxidation and demethylation. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; thus, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Less than 10% of the orally administered dose is excreted in the urine as racemic zopiclone. In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam.
Lormetazepam, sold under the brand name Noctamid among others, is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative and temazepam analogue. It possesses hypnotic, anxiolytic, anticonvulsant, sedative, and skeletal muscle relaxant properties.
It was patented in 1961 and came into medical use in 1980. Lormetazepam is not approved for sale in the United States or Canada. It is licensed in the UK as 0.5 and 1 mg tablets for short-term treatment (2-4 weeks) of moderately severe insomnia. It is licensed in the Netherlands as 1 and 2 mg tablets, under the brand names Loramet and Noctamid and as generic, available from several manufacturers. It is sold in Poland as Noctofer. A Dutch analysis stated that lormetazepam could be suitable to be included in drug prescribing formularies, although zolpidem, zopiclone, and temazepam appear better.
Lormetazepam is considered a hypnotic benzodiazepine and is officially indicated for moderate to severe insomnia. Lormetazepam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or falling asleep. Hypnotics should only be used on a short-term basis or, in those with chronic insomnia, on an occasional basis.
Side effects of lormetazepam are similar to those of other hypnotic benzodiazepines and can for the most part be regarded as a class effect. In a sleep study, 1 mg lormetazepam increased total sleep time, reduced wakefulness, but did not alter REM sleep. However, at 2 mg doses, there were significant increases in stage 3 sleep and reductions in REM sleep. Rebound effects have been reported after chronic use including rebound REM. In one clinical trial with patients who had prior experience with older hypnotics temazepam and nitrazepam, most preferred lormetazepam due to less heavy sedation, amnesia, and residual effects. Some side effects, including drowsiness, amnesia, and respiratory depression, are increased when lormetazepam is combined with other drugs with similar effects, e.g. alcohol and nonbenzodiazepine drugs.
Although lormetazepam has been associated with adversely affecting immediate and delayed recall memory functions, studies have shown that lormetazepam’s amnesic properties may be lesser compared to other hypnotic benzodiazepines. For example, in a 1984 study comparing the amnesic effects of lormetazepam to temazepam and flurazepam showed that amnesia was smallest after lormetazepam and greatest after temazepam, which had produced greater amnesia than both lormetazepam and flurazepam by a significant margin.
Side effects of lormetazepam include:
Residual “hangover” effects after nighttime administration of lormetazepam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.
Benzodiazepines require special precaution if used during pregnancy, in children, in alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders. Lormetazepam may be unsuitable for the elderly due to residual effects on memory and body sway which may result in falls. Lormetazepam causes impaired driving skills, thus caution is required in individuals who drive or operate machinery.
The risks of tolerance, dependence, and withdrawal are very low when the drug is used for 2-4 weeks only, and lormetazepam is generally a safe and effective drug when used for no longer than 2-4 weeks. Some sleep disturbance in the form of rebound insomnia can, however, occur even after short-term usage of 7 days. Those with a history of addiction may be at increased risk of problems of tolerance and dependence especially those with a past history of dependency on sedative hypnotic drugs.
Lormetazepam as with other benzodiazepines is generally only recommended for short-term use (2-4 weeks) due to tolerance and loss of efficacy. Tolerance to and loss of the sedative effects of benzodiazepine hypnotics can occur within 14 days of regular use. Some studies however suggest such treatments retain their effectiveness in the long term – such a lack of consistency in the findings of many studies could be due to the variation of responses to benzodiazepine treatment.
Dependence is the medical term for addiction. Dependence can either be psychological and/or physical. Psychological dependence can manifest itself as a reliance on a drug to cope with everyday life or in the form of craving. Physical dependence occurs due to physiological adaptations occurring as the body attempts to overcome the drugs effects which is known as tolerance and the continuing need to take the drug to avoid or suppress withdrawal symptoms which can sometimes resemble the original condition being treated. When the dose or the drug is discontinued withdrawal symptoms typically occur. Lormetazepam as with all other benzodiazepines produces both physical and psychological dependence but the main problem of concern is physical dependence which appears in the form of the benzodiazepine withdrawal syndrome after the dosage is reduced or the drug is stopped completely. The dependence induced by lormetazepam is related to changes in the sensitivity of the GABA-BZD receptor complex.
Withdrawal symptoms which can occur from stopping benzodiazepines such as lormetazepam can include:
Abrupt or over rapid withdrawal from high doses can provoke:
Withdrawal symptoms typically subside after 4-8 weeks but in approximately 10-15% of individuals symptoms can persist for many months and in rare cases years. Some “Withdrawal Symptoms” can emerge despite a constant dosage with the body needing extra dosage in order to feel normal. This is sometimes associated with dosage escalation.
Lormetazepam has a short to intermediate half-life of approximately 10-12 hours. Shorter acting benzodiazepine compounds are generally associated with a more intense and immediate withdrawal reaction compared to longer acting benzodiazepines. For this reason it is generally recommended to cross from lormetazepam to an equivalent dose of diazepam to gradually taper the dosage.
The bioavailability of lormetazepam was found to be 80%.
Lormetazepam and other benzodiazepine drugs act as positive modulators at the GABAA benzodiazepine receptor complex. Lormetazepam binds to the benzodiazepine receptor which in turn enhances the effect of the GABAA receptor producing its therapeutic effects as well as adverse effects. When lormetazepam binds to the benzodiazepine receptor sites in sufficient quantities it produces sedation which is used clinically as a therapeutic treatment for insomnia. Lormetazepam alters the brain electrical activity which has been studied via EEG readings. Lormetazepam appears to be more selective in the type of benzodiazepine receptor it binds to showing a higher affinity for the omega 1 receptor which is responsible for sedation. Changes in EEG can therefore be used to measure the sedative sleep promoting properties of lormetazepam.
Trade names include Aldosomnil, Dilamet, Ergocalm, Loramet, Loretam, Metatop, Minias, Noctamid, Noctamide, Noctofer, Nocton, Pronoctan, Sedaben, and Stilaze.
Lormetazepam has a stereocenter and two enantiomers. Medications are racemates.
Book Title:
Doctoring the Mind: Why Psychiatric Treatments Fail.
Author(s): Richard P. Bentall.
Year: 2010.
Edition: First (1st).
Publisher: Penguin.
Type(s): Hardcover, Paperback and Kindle.
Synopsis:
Why is the Western world’s treatment of mental illness so flawed? Who really benefits from psychiatry? And why would a patient in Nigeria have a much greater chance of recovery than one in the UK?
In Doctoring the Mind, leading clinical psychologist Richard Bentall reveals the shocking truths behind the system of mental health care in the West. With a heavy dependence on pills and the profit they bring, psychiatry has been relying on myths and misunderstandings of madness for too long, and builds on methods which can often hinder rather than help the patient.
Bentall argues passionately for a new future of mental health, one that considers the patient as an individual and redefines our understanding and treatment of madness for the twenty-first century.
Tacrine is a centrally acting acetylcholinesterase inhibitor and indirect cholinergic agonist (parasympathomimetic).
It was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer’s disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the University of Sydney in 1949. It also acts as a histamine N-methyltransferase inhibitor.
Tacrine was the prototypical cholinesterase inhibitor for the treatment of Alzheimer’s disease. William K. Summers received a patent for this use in 1989. Studies found that it may have a small beneficial effect on cognition and other clinical measures, though study data was limited and the clinical relevance of these findings was unclear.
Tacrine has been discontinued in the US in 2013, due to concerns over safety.
Tacrine was also described as an analeptic agent used to promote mental alertness.
As stated above, overdosage of tacrine may give rise to severe side effects such as nausea, vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Atropine is a popular treatment for overdose.
Major form of metabolism is in the liver via hydroxylation of benzylic carbon by CYP1A2. This forms the major metabolite 1-hydroxy-tacrine (velnacrine) which is still active.
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