Tag: Triazolam

What is Flualprazolam?

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Introduction

Flualprazolam is a tranquiliser of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring.

Background

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.

What is Triazolobenzodiazepine?

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Introduction

Triazolobenzodiazepines (TBZD) are a class of benzodiazepine (BZD) derivative pharmaceutical drugs. Chemically, they differ from other benzodiazepines by having an additional fused triazole ring.

Examples include:

  • Adinazolam.
  • Alprazolam.
  • Bromazolam.
  • Clonazolam.
  • Estazolam.
  • Flualprazolam.
  • Flubromazolam.
  • Flunitrazolam.
  • Nitrazolam.
  • Pyrazolam.
  • Triazolam.
  • Zapizolam.

Synthesis

Synthesis of 1-methyltriazolobenzodiazepines (alprazolam type) is possible by heating 1,4-benzodiazepin-2-thiones with hydrazine and acetic acid in n-butanol under reflux.

What is the Rebound Effect?

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Introduction

The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage.

In the case of re-emergence, the severity of the symptoms is often worse than pre-treatment levels.

Examples

Sedative Hypnotics

Rebound Insomnia

Rebound insomnia is insomnia that occurs following discontinuation of sedative substances taken to relieve primary insomnia. Regular use of these substances can cause a person to become dependent on its effects in order to fall asleep. Therefore, when a person has stopped taking the medication and is ‘rebounding’ from its effects, he or she may experience insomnia as a symptom of withdrawal. Occasionally, this insomnia may be worse than the insomnia the drug was intended to treat.

Common medicines known to cause this problem are eszopiclone, zolpidem, and anxiolytics such as benzodiazepines and which are prescribed to people having difficulties falling or staying asleep.

Rebound Depression

Depressive symptoms may appear to arise in patients previously free of such an illness.

Daytime Rebound

Rebound phenomena do not necessarily only occur on discontinuation of a prescribed dosage. For example, daytime rebound effects of anxiety, metallic taste, perceptual disturbances which are typical benzodiazepine withdrawal symptoms can occur the next day after a short-acting benzodiazepine hypnotic wears off. Another example is early morning rebound insomnia which may occur when a rapidly eliminated hypnotic wears off which leads to rebounding awakeness forcing the person to become wide awake before he or she has had a full night’s sleep. One drug which seems to be commonly associated with these problems is triazolam, due to its high potency and ultra short half life, but these effects can occur with other short-acting hypnotic drugs. Quazepam, due to its selectivity for type1 benzodiazepine receptors and long half-life, does not cause daytime anxiety rebound effects during treatment, showing that half-life is very important for determining whether a night-time hypnotic will cause next-day rebound withdrawal effects or not. Daytime rebound effects are not necessarily mild but can sometimes produce quite marked psychiatric and psychological disturbances.

Stimulants

Rebound effects from stimulants such as methylphenidate or dextroamphetamine include stimulant psychosis, depression and a return of ADHD symptoms but in a temporarily exaggerated form. Up to a third of ADHD children experience a rebound effect when methylphenidate is withdrawn.

Antidepressants

Many antidepressants, including SSRIs, can cause rebound depression, panic attacks, anxiety, and insomnia when discontinued.

Antipsychotics

Sudden and severe emergence or re-emergence of psychosis may appear when antipsychotics are switched or discontinued too rapidly.

Alpha-2 Adrenergic Agents

Rebound hypertension, above pre-treatment level, was observed after clonidine, and guanfacine discontinuation.

Others

Other Rebound Effects

An example is the use of highly potent corticosteroids, such as clobetasol for psoriasis. Abrupt withdrawal can cause a much more severe case of the psoriasis to develop. Therefore, withdrawal should be gradual, diluting the medication with lotion perhaps, until very little actual medication is being applied.

Another example of pharmaceutical rebound is a rebound headache from painkillers when the dose is lowered, the medication wears off, or the drug is abruptly discontinued.

Continuous usage of topical decongestants (nasal sprays) can lead to constant nasal congestion, known as rhinitis medicamentosa.

What is Quazepam?

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Introduction

Quazepam (marketed under brand names Doral, Dormalin) is a relatively long-acting benzodiazepine derivative drug developed by the Schering Corporation in the 1970s.

Quazepam is indicated for the treatment of insomnia including sleep induction and sleep maintenance. Quazepam induces impairment of motor function and has relatively (and uniquely) selective hypnotic and anticonvulsant properties with considerably less overdose potential than other benzodiazepines (due to its novel receptor-subtype selectively). Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.

Brief History

It was patented in 1970 and came into medical use in 1985.

Medical Uses

Quazepam is used for short-term treatment of insomnia related to sleep induction or sleep maintenance problems and has demonstrated superiority over other benzodiazepines such as temazepam. It had a fewer incidence of side effects than temazepam, including less sedation, amnesia, and less motor-impairment. Usual dosage is 7.5 to 15 mg orally at bedtime.

Quazepam is effective as a premedication prior to surgery.

Side Effects

Quazepam has fewer side effects than other benzodiazepines and less potential to induce tolerance and rebound effects. There is significantly less potential for quazepam to induce respiratory depression or to adversely affect motor coordination than other benzodiazepines. The different side effect profile of quazepam may be due to its more selective binding profile to type 1 benzodiazepine receptors.

  • Ataxia.
  • Daytime somnolence.
  • Hypokinesia.
  • Cognitive and performance impairments.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance and Dependence

Tolerance may occur to quazepam but more slowly than seen with other benzodiazepines such as triazolam. Quazepam causes significantly less drug tolerance and less withdrawal symptoms including less rebound insomnia upon discontinuation compared to other benzodiazepines. Quazepam may cause less rebound effects than other type1 benzodiazepine receptor selective nonbenzodiazepine drugs due to its longer half-life. Short-acting hypnotics often cause next day rebound anxiety. Quazepam due to its pharmacological profile does not cause next day rebound withdrawal effects during treatment.

No firm conclusions can be drawn, however, whether long-term use of quazepam does not produce tolerance as few, if any, long-term clinical trials extending beyond 4 weeks of chronic use have been conducted. Quazepam should be withdrawn gradually if used beyond 4 weeks of use to avoid the risk of a severe benzodiazepine withdrawal syndrome developing. Very high dosage administration over prolonged periods of time, up to 52 weeks, of quazepam in animal studies provoked severe withdrawal symptoms upon abrupt discontinuation, including excitability, hyperactivity, convulsions and the death of two of the monkeys due to withdrawal-related convulsions. More monkeys died, however, in the diazepam-treated monkeys. In addition it has now been documented in the medical literature that one of the major metabolites of quazepam, N-desalkyl-2-oxoquazepam (N-desalkylflurazepam), which is long-acting and prone to accumulation, binds unselectively to benzodiazepine receptors, thus quazepam may not differ all that much pharmacologically from other benzodiazepines.

Special Precautions

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

Quazepam and its active metabolites are excreted into breast milk.

Accumulation of one of the active metabolites of quazepam, N-desalkylflurazepam, may occur in the elderly. A lower dose may be required in the elderly.

Elderly

Quazepam is more tolerable for elderly patients compared to flurazepam due to its reduced next day impairments. However, another study showed marked next day impairments after repeated administration due to accumulation of quazepam and its long-acting metabolites. Thus the medical literature shows conflicts on quazepam’s side effect profile. A further study showed significant balance impairments combined with an unstable posture after administration of quazepam in test subjects. 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 underutilised. Compared with the benzodiazepines including quazepam, the nonbenzodiazepine sedative/hypnotics 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 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.

Interactions

The absorption rate is likely to be significantly reduced if quazepam is taken in the fasted state reducing the hypnotic effect of quazepam. If 3 or more hours have passed since eating food then some food should be eaten before taking quazepam.

Pharmacology

Quazepam is a trifluoroalkyl type of benzodiazepine. Quazepam is unique amongst benzodiazepines in that it selectively targets the GABAA α1 subunit receptors which are responsible for inducing sleep. Its mechanism of action is very similar to zolpidem and zaleplon in its pharmacology and can successfully substitute for zolpidem and zaleplon in animal studies.

Quazepam is selective for type I benzodiazepine receptors containing the α1 subunit, similar to other drugs such as zaleplon and zolpidem. As a result, quazepam has little or no muscle relaxant properties. Most other benzodiazepines are unselective and bind to type1 GABAA receptors and type2 GABAA receptors. Type1 GABAA receptors include the α1 subunit containing GABAA receptors which are responsible for hypnotic properties of the drug. Type 2 receptors include the α2, α3 and α5 subunits which are responsible for anxiolytic action, amnesia and muscle relaxant properties. Thus quazepam may have less side effects than other benzodiazepines but, it has a very long half-life of 25 hours which reduces its benefits as a hypnotic due to likely next day sedation. It also has two active metabolites with half-lives of 28 and 79 hours. Quazepam may also cause less drug tolerance than other benzodiazepines such as temazepam and triazolam perhaps due to its subtype selectivity. The longer half-life of quazepam may have the advantage however, of causing less rebound insomnia than shorter acting subtype selective nonbenzodiazepines. However, one of the major metabolites of quazepam, the N-desmethyl-2-oxoquazepam (aka N-desalkylflurazepam), binds unselectively to both type1 and type2 GABAA receptors. The N-desmethyl-2-oxoquazepam metabolite also has a very long half-life and likely contributes to the pharmacological effects of quazepam.

Pharmacokinetics

Quazepam has an absorption half-life of 0.4 hours with a peak in plasma levels after 1.75 hours. It is eliminated both renally and through faeces. The active metabolites of quazepam are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. The N-desalkyl-2-oxoquazepam metabolite has only limited pharmacological activity compared to the parent compound quazepam and the active metabolite 2-oxoquazepam. Quazepam and its major active metabolite 2-oxoquazepam both show high selectivity for the type1 GABAA receptors. The elimination half-life range of quazepam is between 27 and 41 hours.

Mechanism of Action

Quazepam modulates specific GABAA receptors via the benzodiazepine site on the GABAA receptor. This modulation enhances the actions of GABA, causing an increase in opening frequency of the chloride ion channel which results in an increased influx of chloride ions into the GABAA receptors. Quazepam, unique amongst benzodiazepine drugs selectively targets type1 benzodiazepine receptors which results reduced sleep latency in promotion of sleep. Quazepam also has some anticonvulsant properties.

EEG and Sleep

Quazepam has potent sleep inducing and sleep maintaining properties. Studies in both animals and humans have demonstrated that EEG changes induced by quazepam resemble normal sleep patterns whereas other benzodiazepines disrupt normal sleep. Quazepam promotes slow wave sleep. This positive effect of quazepam on sleep architecture may be due to its high selectivity for type1 benzodiazepine receptors as demonstrated in animal and human studies. This makes quazepam unique in the benzodiazepine family of drugs.

Drug Misuse

Refer to Benzodiazepine Use Disorder.

Quazepam is a drug with the potential for misuse. Two types of drug misuse can occur, either recreational misuse where the drug is taken to achieve a high, or when the drug is continued long term against medical advice.

What is Triazolam?

Published on by Andrew Marshall5 Comments

Introduction

Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives.

It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties, triazolam’s amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced, as well. Due to its short half-life, triazolam is not effective for patients who experience frequent awakenings or early wakening.

Triazolam was initially patented in 1970 and went on sale in the United States in 1982. In 2017, it was the 280th most commonly prescribed medication in the United States, with more than one million prescriptions.

Medical Uses

Triazolam is usually used for short-term treatment of acute insomnia and circadian rhythm sleep disorders, including jet lag. It is an ideal benzodiazepine for this use because of its fast onset of action and short half-life. It puts a person to sleep for about 1.5 hours, allowing its user to avoid morning drowsiness. Triazolam is also sometimes used as an adjuvant in medical procedures requiring anaesthesia or to reduce anxiety during brief events, such as MRI scans and nonsurgical dental procedures. Triazolam is ineffective in maintaining sleep, however, due to its short half-life, with quazepam showing superiority.

Triazolam is frequently prescribed as a sleep aid for passengers travelling on short- to medium-duration flights. If this use is contemplated, the user avoiding the consumption of alcoholic beverages is especially important, as is trying a ground-based “rehearsal” of the medication to ensure that the side effects and potency of this medication are understood by the user prior to using it in a relatively more public environment (as disinhibition can be a common side effect, with potentially severe consequences). Triazolam causes anterograde amnesia, which is why so many dentists administer it to patients undergoing even minor dental procedures. This practice is known as sedation dentistry.

Side Effects

Adverse drug reactions associated with the use of triazolam include:

  • Relatively common (>1% of patients): somnolence, dizziness, feeling of lightness, coordination problems.
  • Less common (0.9% to 0.5% of patients): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances.
  • Rare (<0.5% of patients): constipation, taste alteration, diarrhoea, dry mouth, dermatitis/allergy, dreams/nightmares, insomnia, paraesthesia, tinnitus, dysesthesia, weakness, congestion.

Triazolam, although a short-acting benzodiazepine, may cause residual impairment into the next day, especially the next morning. A meta-analysis demonstrated that residual “hangover” effects after night-time administration of triazolam such as sleepiness, psychomotor impairment, and diminished 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. Confusion and amnesia have been reported.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance, Dependence, and Withdrawal

Refer to Benzodiazepine Withdrawal Syndrome.

A review of the literature found that long-term use of benzodiazepines, including triazolam, is associated with drug tolerance, drug dependence, rebound insomnia, and CNS-related adverse effects. Benzodiazepine hypnotics should be used at their lowest possible dose and for a short period of time. Nonpharmacological treatment options were found to yield sustained improvements in sleep quality. A worsening of insomnia (rebound insomnia) compared to baseline may occur after discontinuation of triazolam, even following short-term, single-dose therapy.

Other withdrawal symptoms can range from mild unpleasant feelings to a major withdrawal syndrome, including stomach cramps, vomiting, muscle cramps, sweating, tremor, and in rare cases, convulsions.

Contraindications

Benzodiazepines require special precautions if used in the elderly, during pregnancy, in children, in alcoholics, or in other drug-dependent individuals and individuals with comorbid psychiatric disorders. Triazolam belongs to the Pregnancy Category X of the FDA. It is known to have the potential to cause birth defects.

Elderly

Triazolam, similar to other benzodiazepines and nonbenzodiazepines, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments. Daytime withdrawal effects can occur.

An extensive review of the medical literature regarding the management of insomnia and the elderly found considerable evidence of the effectiveness and durability of nondrug treatments for insomnia in adults of all ages and that these interventions are underused. Compared with the benzodiazepines including triazolam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. Newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin 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. One study found no evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment for triazolam.

In addition, the effectiveness and safety of long-term use of these agents remain to be determined. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

Interactions

Ketoconazole and itraconazole have a profound effect on the pharmacokinetics of triazolam, leading to greatly enhanced effects. Anxiety, tremor, and depression have been documented in a case report following administration of nitrazepam and triazolam. Following administration of erythromycin, repetitive hallucinations and abnormal bodily sensations developed. The patient had, however, acute pneumonia, and kidney failure. Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in those with other physical complications. Caffeine reduces the effectiveness of triazolam. Other important interactions include cimetidine, diltiazem, fluconazole, grapefruit juice, isoniazid, itraconazole, nefazodone, rifampicin, ritonavir, and troleandomycin. Triazolam should not be administered to patients on Atripla.

Overdose

Refer to Benzodiazepine Overdose.

Symptoms of an overdose include:

  • Coma.
  • Hypoventilation (respiratory depression).
  • Somnolence (drowsiness).
  • Slurred speech.
  • Seizures.

Death can occur from triazolam overdose, but is more likely to occur in combination with other depressant drugs such as opioids, alcohol, or tricyclic antidepressants.

Pharmacology

The pharmacological effects of triazolam are similar to those of most other benzodiazepines. It does not generate active metabolites. Triazolam is a short-acting benzodiazepine, is lipophilic, and is metabolised hepatically via oxidative pathways. The main pharmacological effects of triazolam are the enhancement of the neurotransmitter GABA at the GABAA receptor. The half-life of triazolam is only 2 hours making it a very short acting benzodiazepine drug. It has anticonvulsant effects on brain function.

Society and Culture

Recreational Use

Refer to Benzodiazepine Drug Misuse.

Triazolam issued nonmedically: recreational use wherein the drug is taken to achieve a high or continued long-term dosing against medical advice.

Legal Status

Triazolam is a Schedule IV drug under the Convention on Psychotropic Substances and the US Controlled Substances Act.

Brandnames

The drug is marketed in English-speaking countries under the brand names Apo-Triazo, Halcion, Hypam, and Trilam. Other (designer) names include 2′-chloroxanax, chloroxanax, triclazolam, and chlorotriazolam.