Tag: Benzodiazepine

What is Chlordiazepoxide?

Published on by Andrew Marshall2 Comments

Introduction

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs.

Chlordiazepoxide has a medium to long half-life but its active metabolite has a very long half-life. The drug has amnesic, anticonvulsant, anxiolytic, hypnotic, sedative and skeletal muscle relaxant properties.

Chlordiazepoxide was patented in 1958 and approved for medical use in 1960. It was the first benzodiazepine to be synthesized and the discovery of chlordiazepoxide was by pure chance. Chlordiazepoxide and other benzodiazepines were initially accepted with widespread public approval but were followed with widespread public disapproval and recommendations for more restrictive medical guidelines for its use.

Brief History

Chlordiazepoxide (initially called methaminodiazepoxide) was the first benzodiazepine to be synthesized in the mid-1950s. The synthesis was derived from work on a class of dyes, quinazolone-3-oxides. It was discovered by accident when in 1957 tests revealed that the compound had hypnotic, anxiolytic, and muscle relaxant effects. “The story of the chemical development of Librium and Valium was told by Sternbach. The serendipity involved in the invention of this class of compounds was matched by the trials and errors of the pharmacologists in the discovery of the tranquilising activity of the benzodiazepines. The discovery of Librium in 1957 was due largely to the dedicated work and observational ability of a gifted technician, Beryl Kappell. For some seven years she had been screening compounds by simple animal tests for muscle relaxant activity…” Three years later chlordiazepoxide was marketed as a therapeutic benzodiazepine medication under the brand name Librium. Following chlordiazepoxide, in 1963 diazepam hit the market under the brand name Valium – and was followed by many further benzodiazepine compounds over the subsequent years and decades.

In 1959 it was used by over 2,000 physicians and more than 20,000 patients. It was described as “chemically and clinically different from any of the tranquilisers, psychic energizers or other psychotherapeutic drugs now available.” During studies, chlordiazepoxide induced muscle relaxation and a quieting effect on laboratory animals like mice, rats, cats, and dogs. Fear and aggression were eliminated in much smaller doses than those necessary to produce hypnosis. Chlordiazepoxide is similar to phenobarbital in its anticonvulsant properties. However, it lacks the hypnotic effects of barbiturates. Animal tests were conducted in the Boston Zoo and the San Diego Zoo. Forty-two hospital patients admitted for acute and chronic alcoholism, and various psychoses and neuroses were treated with chlordiazepoxide. In a majority of the patients, anxiety, tension, and motor excitement were “effectively reduced.” The most positive results were observed among alcoholic patients. It was reported that ulcers and dermatologic problems, both of which involved emotional factors, were reduced by chlordiazepoxide.

In 1963, approval for use was given to diazepam (Valium), a “simplified” version of chlordiazepoxide, primarily to counteract anxiety symptoms. Sleep-related problems were treated with nitrazepam (Mogadon), which was introduced in 1972, temazepam (Restoril), which was introduced in 1979, and flurazepam (Dalmane), which was introduced in 1975.

Medical Uses

Chlordiazepoxide is indicated for the short-term (2-4 weeks) treatment of anxiety that is severe and disabling or subjecting the person to unacceptable distress. It is also indicated as a treatment for the management of acute alcohol withdrawal syndrome.

It can sometimes be prescribed to ease symptoms of irritable bowel syndrome combined with clidinium bromide as a fixed dose medication, Librax.

Contraindications

Use of chlordiazepoxide should be avoided in individuals with the following conditions:

  • Myasthenia gravis.
  • Acute intoxication with alcohol, narcotics, or other psychoactive substances.
  • Ataxia.
  • Severe hypoventilation.
  • Acute narrow-angle glaucoma.
  • Severe liver deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of 2).
  • Severe sleep apnoea.
  • Hypersensitivity or allergy to any drug in the benzodiazepine class.

Chlordiazepoxide is generally considered an inappropriate benzodiazepine for the elderly due to its long elimination half-life and the risks of accumulation. Benzodiazepines require special precaution if used in the elderly, pregnancy, children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.

Pregnancy

The research into the safety of benzodiazepines during pregnancy is limited and it is recommended that use of benzodiazepines during pregnancy should be based on whether the benefits outweigh the risks. If chlordiazepoxide is used during pregnancy the risks can be reduced via using the lowest effective dose and for the shortest time possible. Benzodiazepines should generally be avoided during the first trimester of pregnancy. Chlordiazepoxide and diazepam are considered to be among the safer benzodiazepines to use during pregnancy in comparison to other benzodiazepines. Possible adverse effects from benzodiazepine use during pregnancy include, abortion, malformation, intrauterine growth retardation, functional deficits, carcinogenesis and mutagenesis. Caution is also advised during breast feeding as chlordiazepoxide passes into breast milk.

Adverse Effects

Sedative drugs and sleeping pills, including chlordiazepoxide, have been associated with an increased risk of death. The studies had many limitations: possibly tending to overestimate risk, such as possible confounding by indication with other risk factors; confusing hypnotics with drugs having other indications. Common side-effects of chlordiazepoxide include:

  • Confusion.
  • Constipation.
  • Drowsiness.
  • Fainting.
  • Altered sex drive.
  • Liver problems.
  • Lack of muscle coordination.
  • Minor menstrual irregularities.
  • Nausea.
  • Skin rash or eruptions.
  • Swelling due to fluid retention.
  • Yellow eyes and skin.

Chlordiazepoxide in laboratory mice studies impairs latent learning. Benzodiazepines impair learning and memory via their action on benzodiazepine receptors, which causes a dysfunction in the cholinergic neuronal system in mice. It was later found that scopolamine impairment in learning was caused by an increase in benzodiazepine/GABA activity (and that benzodiazepines were not associated with the cholinergic system). In tests of various benzodiazepine compounds, chlordiazepoxide was found to cause the most profound reduction in the turnover of 5HT (serotonin) in rats. Serotonin is closely involved in regulating mood and may be one of the causes of feelings of depression in rats using chlordiazepoxide or other benzodiazepines.

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

Chronic use of benzodiazepines, such as chlordiazepoxide, leads to the development of tolerance, with a decrease in number of benzodiazepine binding sites in mouse forebrain. The Committee of Review of Medicines, who carried out an extensive review of benzodiazepines including chlordiazepoxide, found – and were in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the US National Institute on Drug Abuse – that there was little evidence that long-term use of benzodiazepines were beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep-promoting properties within 3-14 days of continuous use, and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months’ continuous use due to the development of tolerance.

Dependence

Chlordiazepoxide can cause physical dependence and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from chlordiazepoxide or other benzodiazepines often leads to withdrawal symptoms that are similar to those seen with alcohol and barbiturates. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can, however, occur at standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible through a slow and gradual dose-reduction regime.

Chlordiazepoxide taken during pregnancy can cause a postnatal benzodiazepine withdrawal syndrome.

Overdose

Refer to Benzodiazepine Overdose.

An individual who has consumed excess chlordiazepoxide may display some of the following symptoms:

  • Somnolence (difficulty staying awake).
  • Mental confusion.
  • Hypotension.
  • Hypoventilation.
  • Impaired motor functions:
    • Impaired reflexes.
    • Impaired coordination.
    • Impaired balance.
    • Dizziness.
    • Muscle weakness.
  • Coma.

Chlordiazepoxide is a drug that is very frequently involved in drug intoxication, including overdose. Chlordiazepoxide overdose is considered a medical emergency and, in general, requires the immediate attention of medical personnel. The antidote for an overdose of chlordiazepoxide (or any other benzodiazepine) is flumazenil. Flumazenil should be given with caution as it may precipitate severe withdrawal symptoms in benzodiazepine-dependent individuals.

Pharmacology

Chlordiazepoxide acts on benzodiazepine allosteric sites that are part of the GABAA receptor/ion-channel complex and this results in an increased binding of the inhibitory neurotransmitter GABA to the GABAA receptor thereby producing inhibitory effects on the central nervous system and body similar to the effects of other benzodiazepines. Chlordiazepoxide is anticonvulsant. There is preferential storage of chlordiazepoxide in some organs including the heart of the neonate. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate. The withdrawal of chlordiazepoxide during pregnancy and breast feeding is recommended, as chlordiazepoxide rapidly crosses the placenta and also is excreted in breast milk. Chlordiazepoxide also decreases prolactin release in rats. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in animal nerve terminal preparations. Chlordiazepoxide inhibits acetylcholine release in mouse hippocampal synaptosomes in vivo. This has been found by measuring sodium-dependent high affinity choline uptake in vitro after pre-treatment of the mice in vivo with chlordiazepoxide. This may play a role in chlordiazepoxide’s anticonvulsant properties.

Pharmacokinetics

Chlordiazepoxide is a long-acting benzodiazepine drug. The half-life of Chlordiazepoxide is 5-30 hours but has an active benzodiazepine metabolite (desmethyldiazepam), which has a half-life of 36-200 hours. The half-life of chlordiazepoxide increases significantly in the elderly, which may result in prolonged action as well as accumulation of the drug during repeated administration. Delayed body clearance of the long half-life active metabolite also occurs in those over 60 years of age, which further prolongs the effects of the drugs with additional accumulation after repeated dosing.

Despite its name, chlordiazepoxide is not an epoxide; they are formed from different roots.

Recreational Use

Refer to Benzodiazepine Use Disorder.

In 1963, Carl F. Essig of the Addiction Research Centre of the National Institute of Mental Health stated that meprobamate, glutethimide, ethinamate, ethchlorvynol, methyprylon and chlordiazepoxide as drugs whose usefulness “can hardly be questioned.” However, Essig labelled these “newer products” as “drugs of addiction,” like barbiturates, whose habit-forming qualities were more widely known. He mentioned a 90-day study of chlordiazepoxide, which concluded that the automobile accident rate among 68 users was 10 times higher than normal. Participants’ daily dosage ranged from 5 to 100 milligrams.

Chlordiazepoxide is a drug of potential misuse and is frequently detected in urine samples of drug users who have not been prescribed the drug.

Internationally, chlordiazepoxide is a Schedule IV controlled drug under the Convention on Psychotropic Substances.

Toxicity

Animal

Laboratory tests assessing the toxicity of chlordiazepoxide, nitrazepam and diazepam on mice spermatozoa found that chlordiazepoxide produced toxicities in sperm including abnormalities involving both the shape and size of the sperm head. Nitrazepam, however, caused more profound abnormalities than chlordiazepoxide.

Availability

Chlordiazepoxide is available in various dosage forms, alone or in combination with other drugs, worldwide. In combination with Clidinium as NORMAXIN-CC and in combination with dicyclomine as NORMAXIN for IBS, and with the anti-depressant Amitriptyline as Limbitrol.

What is Alprazolam?

Published on by Andrew Marshall8 Comments

Introduction

Alprazolam, sold under the brand name Xanax, among others, is a fast-acting tranquiliser of medium duration in the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring.

It is most commonly used in short-term management of anxiety disorders, specifically panic disorder or generalised anxiety disorder (GAD). Other uses include the treatment of chemotherapy-induced nausea, together with other treatments. GAD improvement occurs generally within a week. Alprazolam is generally taken by mouth.

Common side effects include sleepiness, depression, headaches, feeling tired, dry mouth, and memory problems. Some of the sedation and tiredness may improve within a few days. Due to concerns about misuse, some do not recommend alprazolam as an initial treatment for panic disorder. Withdrawal or rebound symptoms may occur if use is suddenly decreased; gradually decreasing the dose over weeks or months may be required. Other rare risks include suicide, and a two fold increased risk of all cause mortality. Alprazolam, like other benzodiazepines, acts through the GABAA receptor.

Alprazolam was patented in 1971 and approved for medical use in the United States in 1981. Alprazolam is a Schedule IV controlled substance and is a common drug of abuse. It is available as a generic medication. In 2019, it was the 41st most commonly prescribed medication in the United States, with more than 17 million prescriptions.

Medical Uses

Alprazolam is mostly used in short term management of anxiety disorders, panic disorders, and nausea due to chemotherapy. Alprazolam may also be indicated for the treatment of GAD, as well as for the treatment of anxiety conditions with co-morbid depression. The US Food and Drug Administration (FDA) label advises that the physician should periodically reassess the usefulness of the drug.

Panic Disorder

Alprazolam is effective in the relief of moderate to severe anxiety and panic attacks. However, it is not a first line treatment since the development of selective serotonin reuptake inhibitors. Alprazolam is no longer recommended in Australia for the treatment of panic disorder due to concerns regarding tolerance, dependence, and abuse. Most evidence shows that the benefits of alprazolam in treating panic disorder last only 4 to 10 weeks. However, people with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit.

In the United States, alprazolam is FDA-approved for the treatment of panic disorder with or without agoraphobia. Alprazolam is recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) for treatment-resistant cases of panic disorder where there is no history of tolerance or dependence.

Anxiety Disorders

Anxiety associated with depression is responsive to alprazolam. Clinical studies have shown that the effectiveness is limited to 4 months for anxiety disorders. However, the research into antidepressant properties of alprazolam is poor and has only assessed its short-term effects against depression. In one study, some long term, high-dosage users of alprazolam developed reversible depression. In the US, alprazolam is FDA-approved for the management of anxiety disorders (a condition corresponding most closely to the Diagnostic and Statistical Manual DSM-IV-TR diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. In the UK, alprazolam is recommended for the short-term treatment (2-4 weeks) of severe acute anxiety.

Nausea due to Chemotherapy

Alprazolam may be used in combination with other medications for chemotherapy-induced nausea and vomiting.

Contraindications

Benzodiazepines require special precaution if used in children and in alcohol- or drug-dependent individuals. Particular care should be taken in pregnant or elderly people, people with substance use disorder history (particularly alcohol dependence), and people with comorbid psychiatric disorders. The use of alprazolam should be avoided or carefully monitored by medical professionals in individuals with: myasthenia gravis, acute narrow-angle glaucoma, severe liver deficiencies (e.g. cirrhosis), severe sleep apnoea, pre-existing respiratory depression, marked neuromuscular respiratory, acute pulmonary insufficiency, chronic psychosis, hypersensitivity or allergy to alprazolam or other benzodiazepines, and borderline personality disorder (where it may induce suicidality and dyscontrol).

Like all central nervous system depressants, alprazolam in larger-than-normal doses can cause significant deterioration in alertness and increase drowsiness, especially in those unaccustomed to the drug’s effects.

Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side-effects, especially loss of coordination and drowsiness.

Side Effects

Sedative drugs, including alprazolam, have been associated with an increased risk of death.

Possible side effects include:

  • Anterograde amnesia and concentration problems.
  • Ataxia, slurred speech.
  • Disinhibition.
  • Drowsiness, dizziness, lightheadedness, fatigue, unsteadiness, and impaired coordination, vertigo.
  • Dry mouth (infrequent).
  • Hallucinations (rare).
  • Jaundice (very rare).
  • Seizures (less common).
  • Skin rash, respiratory depression, constipation.
  • Suicidal ideation or suicide.
  • Urinary retention (infrequent).
  • Muscle weakness.

In September 2020, the 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.

Paradoxical Reactions

Although unusual, the following paradoxical reactions have been shown to occur:

  • Aggression.
  • Mania, agitation, hyperactivity, and restlessness.
  • Rage, hostility.
  • Twitches and tremor.

Food and Drug Interactions

Alprazolam is primarily metabolised via CYP3A4. Combining CYP3A4 inhibitors such as cimetidine, erythromycin, norfluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene, and ritonavir delay the hepatic clearance of alprazolam, which may result in its accumulation and increased severity of its side effects.

Imipramine and desipramine have been reported to increase an average of 31% and 20% respectively by the concomitant administration of alprazolam tablets. Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.

Alcohol is one of the most common interactions; alcohol and alprazolam taken in combination have a synergistic effect on one another, which can cause severe sedation, behavioural changes, and intoxication. The more alcohol and alprazolam taken, the worse the interaction. Combination of alprazolam with the herb kava can result in the development of a semi-comatose state. Plants in the genus Hypericum (including St. John’s wort) conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.

Pregnancy and Breastfeeding

Benzodiazepines cross the placenta, enter the foetus, and are also excreted in breast milk. Chronic administration of diazepam, another benzodiazepine, to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.

The use of alprazolam during pregnancy is associated with congenital abnormalities, and use in the last trimester may cause foetal drug dependence and withdrawal symptoms in the post-natal period as well as neonatal flaccidity and respiratory problems. However, in long-term users of benzodiazepines, abrupt discontinuation due to concerns of teratogenesis has a high risk of causing extreme withdrawal symptoms and a severe rebound effect of the underlying mental health disorder. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications, including benzodiazepines.

Overdose

Refer to Benzodiazepine Overdose.

The maximum recommended daily dose is 10 milligrams per day.

Overdoses of alprazolam can be mild to severe depending on the quantity ingested and if other drugs are taken in combination.

Alprazolam overdoses cause excess central nervous system (CNS) depression and may include one or more of the following symptoms:

  • Coma and death if alprazolam is combined with other substances.
  • Fainting.
  • Hypotension (low blood pressure).
  • Hypoventilation (shallow breathing).
  • Impaired motor functions.
  • Dizziness.
  • Impaired balance.
  • Impaired or absent reflexes.
  • Muscle weakness.
  • Orthostatic hypotension (fainting while standing up too quickly).
  • Somnolence (drowsiness).

Dependence and Withdrawal

Refer to Benzodiazepine Dependence and Benzodiazepine Withdrawal Syndrome.

The potential for misuse among those taking it for medical reasons is controversial, with some expert reviews stating that the risk is low and similar to that of other benzodiazepine drugs. Others state that there is a substantial risk of misuse and dependence in both patients and non-medical users and that the short half-life and rapid onset of action may increase the risk of misuse. Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in drug-seeking behaviour.

Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA (gamma-aminobutyric acid) receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABAA receptors and, thus, of GABAergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and thus making the drugs less potent.

Withdrawal and rebound symptoms commonly occur and necessitate a gradual reduction in dosage to minimise withdrawal effects when discontinuing.

Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pre-treatment levels. If the symptoms are more severe or frequent, the person may be experiencing a rebound effect due to the removal of the drug. Either of these can occur without the person actually being drug dependent.

Alprazolam and other benzodiazepines may also cause the development of physical dependence, tolerance, and benzodiazepine withdrawal symptoms during rapid dose reduction or cessation of therapy after long-term treatment. There is a higher chance of withdrawal reactions if the drug is administered in a higher dosage than recommended, or if a person stops taking the medication altogether without slowly allowing the body to adjust to a lower-dosage regimen.

In 1992, Romach and colleagues reported that dose escalation is not a characteristic of long-term alprazolam users and that the majority of long-term alprazolam users change their initial pattern of regular use to one of symptom control only when required.

Some common symptoms of alprazolam discontinuation include malaise, weakness, insomnia, tachycardia, lightheadedness, and dizziness.

Those taking more than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms upon abrupt withdrawal or rapid tapering, which in some cases have been known to cause seizures, as well as marked delirium similar to that produced by the anticholinergic tropane alkaloids of Datura (scopolamine and atropine). The discontinuation of this medication may also cause a reaction called rebound anxiety.

In a 1983 study, only 5% of patients who had abruptly stopped taking long-acting benzodiazepines after less than 8 months demonstrated withdrawal symptoms, but 43% of those who had been taking them for more than 8 months did. With alprazolam – a short-acting benzodiazepine – taken for 8 weeks, 65% of patients experienced significant rebound anxiety. To some degree, these older benzodiazepines are self-tapering.

The benzodiazepines diazepam and oxazepam have been found to produce fewer withdrawal reactions than alprazolam, temazepam, or lorazepam. Factors that determine the risk of psychological dependence or physical dependence and the severity of the benzodiazepine withdrawal symptoms during dose reduction of alprazolam include: dosage used, length of use, frequency of dosing, personality characteristics of the individual, previous use of cross-dependent/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), current use of cross-dependent/-tolerant drugs, use of other short-acting, high-potency benzodiazepines, and method of discontinuation.

Pharmacology

Alprazolam is a positive allosteric modulator of the GABA type A receptor. When it binds to the receptor, effects of GABA are enhanced leading to inhibition of neurones in the brain. This results in effects including reduced anxiety, muscle relaxant, antidepressant and anticonvulsant activity. The activity of alprazolam in the central nervous system is dose dependent.

Mechanism of Action

Alprazolam is classed as a high-potency triazolobenzodiazepine: a benzodiazepine with a triazole ring attached to its structure. As a benzodiazepine, alprazolam produces a variety of therapeutic and adverse effects by binding to the GABAA benzodiazepine receptor site and modulating its function; GABA receptors are the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates inhibitory or calming effects of alprazolam on the nervous system. Binding of alprazolam to the GABAA receptor, a chloride ion channel, enhances the effects of GABA, a neurotransmitter. When GABA binds the GABAA receptor the channel opens and chloride enters the cell which makes it more resistant to depolarisation. Therefore, alprazolam has a depressant effect on synaptic transmission to reduce anxiety.

The GABAA receptor is made up of 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain, and, importantly, different activities with regard to benzodiazepines. Alprazolam and other triazolobenzodiazepines such as triazolam that have a triazole ring fused to their diazepine ring appear to have antidepressant properties. This is perhaps due to the similarities shared with tricyclic antidepressants, as they have two benzene rings fused to a diazepine ring. Alprazolam causes a marked suppression of the hypothalamic-pituitary-adrenal axis. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic, anticonvulsant, muscle relaxant, hypnotic and amnesic; however, it is used mainly as an anxiolytic.

Giving alprazolam, as compared to lorazepam, has been demonstrated to elicit a statistically significant increase in extracellular dopamine D1 and D2 concentrations in the striatum.

Pharmacokinetics

Alprazolam is taken orally, and is absorbed well – 80% of alprazolam binds to proteins in the serum (the majority binding to albumin). The concentration of alprazolam peaks after one to two hours.

Alprazolam is metabolised in the liver, mostly by the enzyme cytochrome P450 3A4 (CYP3A4). Two major metabolites are produced: 4-hydroxyalprazolam and α-hydroxyalprazolam, as well as an inactive benzophenone. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they have little to no contribution to the effects of alprazolam.

The metabolites, as well as some unmetabolised alprazolam, are filtered out by the kidneys and are excreted in the urine.

Chemistry

Physical Properties

Alprazolam is a triazole and benzodiazepine derivative substituted with a phenyl group at position 6, with a chlorine atom at position 8 and with a methyl group at position 1. It is an analogue of triazolam, the difference between them being the absence of a chlorine atom in the ‘ortho’ position of the phenyl ring. It is slightly soluble in chloroform, soluble in alcohol, slightly soluble in acetone and insoluble in water. It has a melting point in the temperature range 228-229.5 °C.

Synthesis

For the synthesis of alprazolam the same method can be used as for triazolam, excepting that it starts from 2-amino-5-chlorobenzophenone. However, an alternative easier synthesis starting with 2,6-dichloro-4-phenylquinoline has been suggested, in which it reacts with hydrazine giving 6-chloro-2-hydrazino-4-phenylquinoline. Boiling the mixture with triethyl orthoacetate results in cyclization with the formation of the triazole ring. The product undergoes oxidative degradation in the presence of periodate and ruthenium dioxide in acetone solution, giving 2-[4-(3′-methyl-1,2,4-triazolo)]-5-chlorobenzophenone. Oxy-methylation with formaldehyde results in a product that is treated with phosphorus tribromide, when 2-[4-(3′-methyl-5′-bromomethyl-1,2,4-triazolo)]-5-chlorobenzophenone is obtained. By substituting the bromine atom with an amino group conferred by ammonia, it forms alprazolam triazolobenzophenone, following which an intermolecular heterocyclisation takes place to obtain alprazolam.

Detection

Quantification of alprazolam in blood and plasma samples may be necessary to confirm a diagnosis of intoxication in hospitalised patients, or to provide evidence in the case of crimes e.g., impaired driving arrest, or to assist in a thorough forensic investigation, e.g. in a medicolegal death investigation. Blood or plasma alprazolam concentrations are usually in a range of 10-100 μg/L in persons receiving the drug therapeutically, 100-300 μg/L in those arrested for impaired driving, and 300–2000 μg/L in victims of acute overdosage. Most of the commercial immunoassays used for the benzodiazepine class of drugs cross-react with alprazolam, but confirmation and quantitative determination are usually done by chromatographic techniques.

Forms of Alprazolam

Alprazolam regular release and orally disintegrating tablets are available as 0.25 mg, 0.5 mg, 1 mg, and 2 mg tablets, while extended release tablets are available as 0.5 mg, 1 mg, 2 mg, and 3 mg. Liquid alprazolam is available in a 1 mg/mL oral concentrate. Inactive ingredients in alprazolam tablets and solutions include microcrystalline cellulose, corn starch, docusate sodium, povidone, sodium starch glycollate, lactose monohydrate, magnesium stearate, colloidal silicon dioxide, and sodium benzoate. In addition, the 0.25 mg tablet contains D&C Yellow No. 10 and the 0.5 mg tablet contains FD&C Yellow No. 6 and D&C Yellow No. 10.

Society and Culture

Patent

Alprazolam is covered under US Patent 3,987,052, which was filed on 29 October 1969, granted on 19 October 1976, and expired in September 1993.

Recreational Use

Refer to Benzodiazepine Use Disorder.

There is a risk of misuse and dependence in both patients and non-medical users of alprazolam; alprazolam’s high affinity binding, high potency, and rapid onset increase its abuse potential. The physical dependence and withdrawal syndrome of alprazolam also add to its addictive nature. In the small subgroup of individuals who escalate their doses there is usually a history of alcohol or other substance use disorders. Despite this, most prescribed alprazolam users do not use their medication recreationally, and the long-term use of benzodiazepines does not generally correlate with the need for dose escalation. However, based on US findings from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance abuse treatment facilities in the United States, admissions due to “primary tranquiliser” (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002, suggesting that misuse of benzodiazepines may be on the rise. In 2011, The New York Times reported, “The Centres for Disease Control and Prevention last year reported an 89 percent increase in emergency room visits nationwide related to nonmedical benzodiazepine use between 2004 and 2008.”

Alprazolam is one of the most commonly prescribed and misused benzodiazepines in the United States. A large-scale nationwide US government study conducted by SAMHSA found that, in the US, benzodiazepines are recreationally the most frequently used pharmaceuticals due to their widespread availability, accounting for 35% of all drug-related visits to hospital emergency and urgent care facilities. Men and women are equally likely to use benzodiazepines recreationally. The report found that alprazolam is the most common benzodiazepine for recreational use, followed by clonazepam, lorazepam, and diazepam. The number of emergency department visits due to benzodiazepines increased by 36% between 2004 and 2006.

Regarding the significant increases detected, it is worthwhile to consider that the number of pharmaceuticals dispensed for legitimate therapeutic uses may be increasing over time, and DAWN estimates are not adjusted to take such increases into account. Nor do DAWN estimates take into account the increases in the population or in ED use between 2004 and 2006.

Those at a particularly high risk for misuse and dependence are people with a history of alcoholism or drug abuse and/or dependence and people with borderline personality disorder.

Alprazolam, along with other benzodiazepines, is often used with other recreational drugs. These uses include aids to relieve the panic or distress of dysphoric (“bad trip”) reactions to psychedelic drugs, such as LSD, and the drug-induced agitation and insomnia in the “comedown” stages of stimulant use, such as amphetamine, cocaine, and MDMA allowing sleep. Alprazolam may also be used with other depressant drugs, such as ethanol, heroin, and other opioids, in an attempt to enhance their psychological effects. Alprazolam may be used in conjunction with cannabis, with users citing a synergistic effect achieved after consuming the combination.

The poly-drug use of powerful depressant drugs poses the highest level of health concerns due to a significant increase in the likelihood of experiencing an overdose, which may cause fatal respiratory depression.

A 1990 study found that diazepam has a higher misuse potential relative to many other benzodiazepines and that some data suggest that alprazolam and lorazepam resemble diazepam in this respect.

Anecdotally, injection of alprazolam has been reported, causing dangerous damage to blood vessels, closure of blood vessels (embolisation) and decay of muscle tissue (rhabdomyolysis). Alprazolam is not very soluble in water – when crushed in water it does not fully dissolve (40 µg/ml of H2O at pH 7). There have also been anecdotal reports of alprazolam being snorted.[111] Due to the low weight of a dose, alprazolam, in one case, was distributed on blotter paper in a manner similar to LSD.

Slang terms for alprazolam vary from place to place. Some of the more common terms are modified versions of the trade name “Xanax”, such as Xannies (or Xanies) and the phonetic equivalent of Zannies; references to their drug classes, such as benzos or downers; or remark upon their shape or colour (most commonly a straight, perforated tablet or an oval-shaped pill): bars, ladders, Xanbars, Xans, Z-bars, handle bars, beans, footballs, planks, poles, sticks, blues, or blue footballs.

Availability

Alprazolam is available in English-speaking countries under the following brand names:

  • Alprax, Alprocontin, Alzam, Alzolam, Anzilum, Apo-Alpraz, Helex, Kalma, Mylan-Alprazolam, Niravam, Novo-Alprazol, Nu-Alpraz, Pacyl, Restyl, Tranax, Trika, Xycalm, Xanax, Xanor, Zolam, Zopax.

In December 2013, in anticipation of the rescheduling of alprazolam to Schedule 8 in Australia, Pfizer Australia announced they would be discontinuing the Xanax brand in Australia as it was no longer commercially viable.

Alprazolam has varied legal status depending on jurisdiction:

  • In the United States, alprazolam is a prescription drug and is assigned to Schedule IV of the Controlled Substances Act by the Drug Enforcement Administration.
  • Under the UK drug misuse classification system, benzodiazepines are Class C drugs (Schedule 4).
    • In the UK, alprazolam is not available on the NHS and can only be obtained on a private prescription.
  • In Ireland, alprazolam is a Schedule 4 medicine.
  • In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).
  • In the Netherlands, alprazolam is a List 2 substance of the Opium Law and is available for prescription.
  • In Germany, alprazolam can be prescribed normally in doses up to 1 mg.
    • Higher doses are scheduled as Anlage III drugs and require a special prescription form.
  • In Australia, alprazolam was originally a Schedule 4 (Prescription Only) medication; however, as of February 2014, it has become a Schedule 8 medication, subjecting it to more rigorous prescribing requirements.
  • In the Philippines, alprazolam is legally classified as a “dangerous drug” under the Comprehensive Dangerous Drugs Act of 2002, along with other schedule drugs listed in the 1971 Convention on Psychotropic Substances.
    • The importation of dangerous drugs including alprazolam, requires authorisation from the Philippine Drug Enforcement Agency.
  • Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.

What is Triazolobenzodiazepine?

Published on by Andrew Marshall7 Comments

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 Lormetazepam?

Published on by Andrew Marshall4 Comments

Introduction

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.

Medical Uses

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

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:

  • Somnolence.
  • Paradoxical increase in aggression.
  • Lightheadedness.
  • Confusion.
  • Muscle weakness.
  • Ataxia (particularly in the elderly).
  • Anterograde amnesia.
  • Headache.
  • Vertigo.
  • Hypotension.
  • Salivation changes.
  • Gastro-intestinal disturbances.
  • Visual disturbances.
  • Dysarthria.
  • Tremor.
  • Changes in libido.
  • Incontinence.
  • Urinary retention.
  • Blood disorders and jaundice.
  • Skin reactions.
  • Dependence and withdrawal reactions.

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.

Tolerance, Dependence, and Withdrawal

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:

  • Rebound insomnia and nightmares.
  • Anxiety, panic attacks, and agoraphobia.
  • Clinical depression.
  • Malaise.
  • Lack of concentration.
  • Abdominal discomfort.
  • Depersonalisation and feelings of unreality.
  • Emotional lability.
  • Cognitive impairment.
  • Tinnitus.
  • Paraesthesiae, tingling, numbness, and pain.
  • Muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, blepharospasm.
  • Excitability, jumpiness, and restlessness.
  • Stiffness.
  • Sweats.

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.

Pharmacology

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

Trade names include Aldosomnil, Dilamet, Ergocalm, Loramet, Loretam, Metatop, Minias, Noctamid, Noctamide, Noctofer, Nocton, Pronoctan, Sedaben, and Stilaze.

Stereochemistry

Lormetazepam has a stereocenter and two enantiomers. Medications are racemates.

What is Flurazepam?

Published on by Andrew Marshall5 Comments

Introduction

Flurazepam (marketed under the brand names Dalmane and Dalmadorm) is a drug which is a benzodiazepine derivative.

It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It produces a metabolite with a long half-life, which may stay in the bloodstream for days. Flurazepam was patented in 1968 and came into medical use the same year. Flurazepam, developed by Roche Pharmaceuticals was one of the first benzo hypnotics (sleeping pills) to be marketed.

Medical Uses

Flurazepam is officially indicated for mild to moderate insomnia and as such it is used for short-term treatment of patients with mild to moderate insomnia such as difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Flurazepam is a long-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep, though benzodiazepines with intermediate half-lives such as loprazolam, lormetazepam, and temazepam are also indicated for patients with difficulty maintaining sleep.

Flurazepam was temporarily unavailable in the United States when its sole producer, Mylan Pharmaceuticals, discontinued making it in January 2019. In October of 2019, the US Food and Drug Administration (FDA) informed pharmacies that they could expect to be resupplied by manufacturers in early to mid December 2019. As of this date, Flurazepam is now again available in the United States.

Side Effects

The most common adverse effects are dizziness, drowsiness, light-headedness, and ataxia. Flurazepam has abuse potential and should never be used with alcoholic beverages or any other substance that can cause drowsiness. Addictive and possibly fatal results may occur. Flurazepam users should only take this drug strictly as prescribed, and should only be taken directly before the user plans on sleeping a full night. Next day drowsiness is common and may increase during the initial phase of treatment as accumulation occurs until steady-state plasma levels are attained.

A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking hypnotic drugs compared to those taking a placebo.

In September 2020, the 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 paper found that long-term use of flurazepam is associated with drug tolerance, drug dependence, rebound insomnia and central nervous system (CNS) related adverse effects. Flurazepam is best used for a short time period and at the lowest possible dose to avoid complications associated with long-term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality. Flurazepam and other benzodiazepines such as fosazepam, and nitrazepam lost some of their effect after seven days administration in psychogeriatric patients. Flurazepam shares cross tolerance with barbiturates and barbiturates can easily be substituted by flurazepam in those who are habituated to barbiturate sedative hypnotics.

After discontinuation of flurazepam a rebound effect or benzodiazepine withdrawal syndrome may occur about four days after discontinuation of medication.

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.

Elderly

Flurazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs 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. 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 flurazepam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy in elderly persons. Tolerability in elderly patients, however, is improved marginally in that benzodiazepines have moderately higher risks of falls, memory problems, and disinhibition (“paradoxical agitation”) when compared to non-benzodiazepine sedatives. 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. Chronic use of sedative-hypnotic drugs for the management of insomnia does not have an evidence base and has been discouraged due to concerns including 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 sedative hypnotics has been determined to be no better than placebo after 3 months of therapy and worse than placebo after 6 months of therapy.

Pharmacology

Flurazepam is a “classical” benzodiazepine; some other classical benzodiazepines include diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam, and clorazepate. Flurazepam generates an active metabolite, N-desalkylflurazepam, with a very long elimination half-life. Flurazepam could be therefore unsuitable as a sleeping medication for some individuals due to next-day sedation; however, this same effect may also provide next-day anxiety relief. Residual ‘hangover’ effects after nighttime administration of flurazepam, 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.

Flurazepam is lipophilic, is metabolised hepatically via oxidative pathways. The main pharmacological effect of flurazepam is to increase the effect of GABA at the GABAA receptor via binding to the benzodiazepine site on the GABAA receptor causing an increase influx of chloride ions into the GABAA neuron.

Flurazepam is contraindicated in pregnancy. It is recommended to withdraw flurazepam during breast feeding, as flurazepam is excreted in breast milk.

Society and Culture

Drug Misuse

Refer to Benzodiazepine Use Disorder.

Flurazepam is a drug with 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.

Flurazepam is a Schedule IV drug under the Convention on Psychotropic Substances.

What is Emotional Lability?

Published on by Andrew Marshall1 Comment

Introduction

In medicine and psychology, emotional lability is a sign or symptom typified by exaggerated changes in mood or affect in quick succession.

Background

Sometimes the emotions expressed outwardly are very different from how the person feels on the inside. These strong emotions can be a disproportionate response to something that happened, but other times there might be no trigger at all. The person experiencing emotional lability usually feels like they do not have control over their emotions. For example, someone might cry uncontrollably in response to any strong emotion even if they do not feel sad or unhappy.

Emotional lability is seen or reported in various conditions including borderline personality disorder, histrionic personality disorder, hypomanic or manic episodes of bipolar disorder, and neurological disorders or brain injury (where it is termed pseudobulbar affect), such as after a stroke. It has sometimes been found to have been a harbinger, or early warning, of certain forms of thyroid disease. Emotional lability also results from intoxication with certain substances, such as alcohol and benzodiazepines. It can also be an associated feature of ADHD.

Children who display a high degree of emotional lability generally have low frustration tolerance and frequent crying spells or tantrums. During preschool, ADHD with emotional lability is associated with increased impairment and may be a sign of internalising problems or multiple comorbid disorders. Children who are neglected are more likely to experience emotional dysregulation, including emotional lability.

Potential triggers of emotional lability may be: excessive tiredness, stress or anxiety, over-stimulated senses (too much noise, being in large crowds, etc.), being around others exhibiting strong emotions, very sad or funny situations (such as jokes, movies, certain stories or books), death of a loved one, or other situations that elicit stress or strong emotions.

What is Flunitrazepam?

Published on by Andrew Marshall5 Comments

Introduction

Flunitrazepam, also known as Rohypnol among other names, is a benzodiazepine used to treat severe insomnia and assist with anaesthesia.

As with other hypnotics, flunitrazepam has been advised to be prescribed only for short-term use or by those with chronic insomnia on an occasional basis. It is said to be 10 times as potent as diazepam.

It was patented in 1962 and came into medical use in 1974. Flunitrazepam, nicknamed “roofies”, is widely known for its use as a date rape drug.

Brief History

Flunitrazepam was discovered at Roche as part of the benzodiazepine work led by Leo Sternbach; the patent application was filed in 1962 and it was first marketed in 1974.

Due to use of the drug for date rape and recreation, in 1998 Roche modified the formulation to give lower doses, make it less soluble, and add a blue dye for easier detection in drinks. It was never marketed in the United States, and by 2016 had been withdrawn from the markets in Spain, France, Norway, Germany, and the United Kingdom.

Use

In countries where this drug is used, it is used for treatment of severe cases of sleeping problems, and in some countries as a preanesthetic agent. These were also the uses for which it was originally studied.

It has also been administered as a concurrent dose for patients that are taking ketamine. Rohypnol lowers the side effects of the anaesthetic (ketamine), resulting in less confusion in awakening states, less negative influence on pulse rate, and fewer fluctuations in blood pressure.

It has also been shown to have therapeutic use in polysubstance use when combined with anaesthetics, opioids, ethanol, cocaine, and methamphetamine.

Adverse Effects

Adverse effects of flunitrazepam include dependency, both physical and psychological; reduced sleep quality resulting in somnolence; and overdose, resulting in excessive sedation, impairment of balance and speech, respiratory depression or coma, and possibly death. Because of the latter, flunitrazepam is commonly used in suicide. When used in late pregnancy, it might cause hypotonia of the foetus.

Dependence

Flunitrazepam, as with other benzodiazepines, can lead to drug dependence. Discontinuation may result in benzodiazepine withdrawal syndrome, characterised by seizures, psychosis, insomnia, and anxiety. Rebound insomnia, worse than baseline insomnia, typically occurs after discontinuation of flunitrazepam even from short-term single nightly dose therapy.

Paradoxical Effects

Flunitrazepam may cause a paradoxical reaction in some individuals, including anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behaviour, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour.

Hypotonia

Benzodiazepines such as flunitrazepam are lipophilic and rapidly penetrate membranes and, therefore, rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including flunitrazepam in late pregnancy, especially high doses, may result in hypotonia, also known as floppy baby syndrome.

Other

Flunitrazepam impairs cognitive functions. This may appear as lack of concentration, confusion and anterograde amnesia – the inability to create memories while under the influence. It can be described as a hangover-like effect which can persist to the next day. It also impairs psychomotor functions similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs; falls and hip fractures were frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.

Other adverse effects include:

  • Slurred speech.
  • Gastrointestinal disturbances, lasting 12 or more hours.
  • Vomiting.
  • Respiratory depression in higher doses.

Special Precautions

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

Impairment of driving skills with a resultant increased risk of road traffic accidents is probably the most important adverse effect. This side-effect is not unique to flunitrazepam but also occurs with other hypnotic drugs. Flunitrazepam seems to have a particularly high risk of road traffic accidents compared to other hypnotic drugs. Extreme caution should be exercised by drivers after taking flunitrazepam.

Interactions

The use of flunitrazepam in combination with alcoholic beverages synergizes the adverse effects, and can lead to toxicity and death.

Overdose

Refer to Benzodiazepine Overdose.

Flunitrazepam is a drug that is frequently involved in drug intoxication, including overdose. Overdose of flunitrazepam may result in excessive sedation, or impairment of balance or speech. This may progress in severe overdoses to respiratory depression or coma and possibly death. The risk of overdose is increased if flunitrazepam is taken in combination with CNS depressants such as ethanol (alcohol) and opioids. Flunitrazepam overdose responds to the GABAA receptor antagonist flumazenil, which thus can be used as a treatment.

Detection

As of 2016, blood tests can identify flunitrazepam at concentrations of as low as 4 nanograms per millilitre; the elimination half life of the drug is 11-25 hours. For urine samples, metabolites can be identified for 60 hours to 28 days, depending on the dose and analytical method used. Hair and saliva can also be analysed; hair is useful when a long time has transpired since ingestion, and saliva for workplace drug tests.

Flunitrazepam can be measured in blood or plasma to confirm a diagnosis of poisoning in hospitalised patients, provide evidence in an impaired driving arrest, or assist in a medicolegal death investigation. Blood or plasma flunitrazepam concentrations are usually in a range of 5-20 μg/L in persons receiving the drug therapeutically as a nighttime hypnotic, 10-50 μg/L in those arrested for impaired driving and 100-1000 μg/L in victims of acute fatal overdosage. Urine is often the preferred specimen for routine substance use monitoring purposes. The presence of 7-aminoflunitrazepam, a pharmacologically-active metabolite and in vitro degradation product, is useful for confirmation of flunitrazepam ingestion. In postmortem specimens, the parent drug may have been entirely degraded over time to 7-aminoflunitrazepam. Other metabolites include desmethylflunitrazepam and 3-hydroxydesmethylflunitrazepam.

Pharmacology

The main pharmacological effects of flunitrazepam are the enhancement of GABA, an inhibitory neurotransmitter, at various GABA receptors.

While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%.

Flunitrazepam has a long half-life of 18-26 hours, which means that flunitrazepam’s effects after nighttime administration persist throughout the next day. This is due to the production of active metabolites. These metabolites further increase the duration of drug action compared to benzodiazepines that produce nonactive metabolites.

Flunitrazepam is lipophilic and is metabolised by the liver via oxidative pathways. The enzyme CYP3A4 is the main enzyme in its phase 1 metabolism in human liver microsomes.

Chemistry

Flunitrazepam is classed as a nitro-benzodiazepine. It is the fluorinated N-methyl derivative of nitrazepam. Other nitro-benzodiazepines include nitrazepam (the parent compound), nimetazepam (methylamino derivative) and clonazepam (2ʹ-chlorinated derivative).

Society and Culture

Recreational and Illegal Uses

Recreational Use

A 1989 article in the European Journal of Clinical Pharmacology reports that benzodiazepines accounted for 52% of prescription forgeries, suggesting that benzodiazepines was a major prescription drug class of abuse. Nitrazepam accounted for 13% of forged prescriptions.

Flunitrazepam and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other benzodiazepines and nonbenzodiazepines (anxiolytic or hypnotic) such as zolpidem and zopiclone (as well as cyclopyrrolones, imidazopyridines, and pyrazolopyrimidines) are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range, suggesting a high degree of potential for addiction for benzodiazepines and similar drugs.

Suicide

In studies in Sweden, flunitrazepam was the second most common drug used in suicides, being found in about 16% of cases. In a retrospective Swedish study of 1,587 deaths, in 159 cases benzodiazepines were found. In suicides when benzodiazepines were implicated, the benzodiazepines flunitrazepam and nitrazepam were occurring in significantly higher concentrations, compared to natural deaths. In 4 of the 159 cases, where benzodiazepines were found, benzodiazepines alone were the only cause of death. It was concluded that flunitrazepam and nitrazepam might be more toxic than other benzodiazepines.

Drug-Facilitated Sexual Assault

Flunitrazepam is known to induce anterograde amnesia in sufficient doses; individuals are unable to remember certain events that they experienced while under the influence of the drug, which complicates investigations. This effect could be particularly dangerous if flunitrazepam is used to aid in the commission of sexual assault; victims may be unable to clearly recall the assault, the assailant, or the events surrounding the assault.

While use of flunitrazepam in sexual assault has been prominent in the media, as of 2015 appears to be fairly rare, and use of alcohol and other benzodiazepine drugs in date rape appears to be a larger but underreported problem.

Drug-Facilitated Robbery

In the United Kingdom, the use of flunitrazepam and other “date rape” drugs have also been connected to stealing from sedated victims. An activist quoted by a British newspaper estimated that up to 2,000 individuals are robbed each year after being spiked with powerful sedatives, making drug-assisted robbery a more commonly reported problem than drug-assisted rape.

Regional Use

Flunitrazepam is a Schedule III drug under the international Convention on Psychotropic Substances of 1971.

  • In Australia, as of 2013 the drug was authorised for prescribing for severe cases of insomnia but was restricted as a Schedule 8 medicine.
  • In France, as of 2016 flunitrazepam was not marketed.
  • In Germany, as of 2016 flunitrazepam is an Anlage III Betäubungsmittel (controlled substance which is allowed to be marketed and prescribed by physicians under specific provisions) and is available on a special narcotic drug prescription as the Rohypnol 1 mg film-coated tablets and several generic preparations (November 2016).
  • In Ireland, flunitrazepam is a Schedule 3 controlled substance with strict restrictions.
  • In Japan, flunitrazepam is marketed by Japanese pharmaceutical company Chugai under the trade name Rohypnol and is indicated for the treatment of insomnia as well as used for preanesthetic medication.
  • In Mexico, Rohypnol is legally available and approved for medical use.
  • In Norway, on 01 January 2003, flunitrazepam was moved up one level in the schedule of controlled drugs and, on 01 August 2004, the manufacturer Roche removed Rohypnol from the market there altogether.
  • In South Africa, Rohypnol is classified as a Schedule 6 drug. It is available by prescription only, and restricted to 1 mg doses.
  • In Iceland, Flunitrazepam is a controlled substance available from Mylan. It is prescribed for severe insomnia and is sometimes used before surgery to induce a calm, relaxed state of mind for the patient.
  • In Sweden, flunitrazepam was previously available from Mylan, but has been removed from the market in January 2020. It is listed as a List II (Schedule II) under the Narcotics Control Act (1968).
  • In the United Kingdom, flunitrazepam is not licensed for medical use and is a controlled drug under Schedule 3 and Class C.
  • In the United States, the drug has not been approved by the Food and Drug Administration and is considered to be an illegal drug; as of 2016 it is Schedule IV. 21 U.S.C. § 841 and 21 U.S.C. § 952 provide for punishment for the importation and distribution of up to 20 years in prison and a fine; possession is punishable by three years and a fine. Travelers travelling into the United States are limited to a 30-day supply. The drug must be declared to US Customs upon arrival. If a valid prescription cannot be produced, the drug may be subject to Customs search and seizure, and the traveller may face criminal charges or deportation.

Names

Flunitrazepam is marketed under many brand names in the countries where it is legal. It also has many street names, including “roofie” and “ruffie”. It is also known as Circles, Forget Me Pill, La Rocha, Lunch Money Drug, Mexican Valium, Pingus, R2, and Roach 2.

What is Bretazenil?

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Introduction

Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988.

It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5 GABAA benzodiazepine receptor complexes.

Brief History

Bretazenil was originally developed as an anti-anxiety drug and has been studied for its use as an anticonvulsant but has never commercialised. It is a partial agonist for GABAA receptors in the brain. David Nutt from the University of Bristol has suggested bretazenil as a possible base from which to make a better social drug, as it displays several of the positive effects of alcohol intoxication such as relaxation and sociability, but without the bad effects such as aggression, amnesia, nausea, loss of coordination, liver disease and brain damage. The effects of bretazenil can also be quickly reversed by the action of flumazenil, which is used as an antidote to benzodiazepine overdose, in contrast to alcohol for which there is no effective and reliable antidote.

Traditional benzodiazepines are associated with side effects such as drowsiness, physical dependence and abuse potential. It was hoped that bretazenil and other partial agonists would be an improvement on traditional benzodiazepines which are full agonists due to preclinical evidence that their side effect profile was less than that of full agonist benzodiazepines. For a variety of reasons however, bretazenil and other partial agonists such as pazinaclone and abecarnil were not clinically successful. However, research continues into other compounds with partial agonist and compounds which are selective for certain GABAA benzodiazepine receptor subtypes.

Tolerance and Dependence

In a study in rats, cross-tolerance between the benzodiazepine drug chlordiazepoxide and bretazenil has been demonstrated. In a primate study bretazenil was found to be able to replace the full agonist diazepam in diazepam dependent primates without precipitating withdrawal effects, demonstrating cross tolerance between bretazenil and benzodiazepine agonists, whereas other partial agonists precipitated a withdrawal syndrome. The differences are likely due to differences in intrinsic properties between different benzodiazepine partial agonists. Cross-tolerance has also been shown between bretazenil and full agonist benzodiazepines in rats. In rats tolerance is slower to develop to the anticonvulsant effects compared to the benzodiazepine site full agonist diazepam. However, tolerance developed to the anticonvulsant effects of bretazenil partial agonist more quickly than they developed to imidazenil.

Pharmacology

Bretazenil has a more broad spectrum of action than traditional benzodiazepines as it has been shown to have low affinity binding to α4 and α6 GABAA receptors in addition to acting on α1, α2, α3 and α5 subunits which traditional benzodiazepine drugs work on. The partial agonist imidazenil does not, however, act at these subunits. 0.5mg of bretazenil is approximately equivalent in its psychomotor-impairing effect to 10 mg of diazepam. Bretazenil produces marked sedative-hypnotic effects when taken alone and when combined with alcohol. This human study also indicates that bretazenil is possibly more sedative than diazepam. The reason is unknown, but the study suggests the possibility that a full-agonist metabolite may be generated in humans but not animals previously tested or else that there are significant differences in benzodiazepine receptor population in animals and humans.

In a study of monkeys bretazenil has been found to antagonize the effects of full agonist benzodiazepines. However, bretazenil has been found to enhance the effects of neurosteroids acting on the neurosteroid binding site of the GABAA receptor. Another study found that bretazenil acted as an antagonist provoking withdrawal symptoms in monkeys who were physically dependent on the full agonist benzodiazepine triazolam.

Partial agonists of benzodiazepine receptors have been proposed as a possible alternative to full agonists of the benzodiazepine site to overcome the problems of tolerance, dependence and withdrawal which limits the role of benzodiazepines in the treatment of anxiety, insomnia and epilepsy. Such adverse effects appear to be less problematic with bretazenil than full agonists. Bretazenil has also been found to have less abuse potential than benzodiazepine full agonists such as diazepam and alprazolam, however long-term use of bretazenil would still be expected to result in dependence and addiction.

Bretazenil alters the sleep EEG profile and causes a reduction in cortisol secretion and increases significantly the release of prolactin. Bretazenil has effective hypnotic properties but impairs cognitive ability in humans. Bretazenil causes a reduction in the number of movements between sleep stages and delays movement into REM sleep. At a dosage of 0.5 mg of bretazenil REM sleep is decreased and stage 2 sleep is lengthened.

What is Nitemazepam?

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Introduction

Nitemazepam (or 3-hydroxynimetazepam) is a benzodiazepine derivative which was first synthesised in the 1970s but was never marketed.

It is the 7-nitro instead of 7-chloro analogue of temazepam, and also the 3-hydroxy derivative of nimetazepam, and an active metabolite.

It has in more recent years been sold as a designer drug, first being definitively identified in Europe in 2017.

Not to be confused with Nimetazepam or Nitrazepam.

What is Nitrazepam?

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Introduction

Nitrazepam, sold under the brand name Mogadon among others, is a hypnotic drug of the benzodiazepine class used for short-term relief from severe, disabling anxiety and insomnia. It also has sedative (calming) properties, as well as amnestic (inducing forgetfulness), anticonvulsant, and skeletal muscle relaxant effects.

It was patented in 1961 and came into medical use in 1965.

Not to be confused with Nimetazepam and Nitemazepam.

Medical Use

Nitrazepam is used to treat short-term sleeping problems (insomnia), namely difficulty falling asleep, frequent awakening, early awakening, or a combination of each. Nitrazepam is sometimes tried to treat epilepsy when other medications fail. It has been found to be more effective than clonazepam in the treatment of West syndrome, which is an age-dependent epilepsy, affecting the very young. In uncontrolled studies, nitrazepam has shown effectiveness in infantile spasms and is sometimes considered when other anti-seizure drugs have failed. However, drowsiness, hypotonia, and most significantly tolerance to anti-seizure effects typically develop with long-term treatment, generally limiting Nitrazepam to acute seizure management.

Side Effects

More Common

More common side effects may include: Central nervous system depression, including somnolence, dizziness, depressed mood, fatigue, ataxia, headache, vertigo, impairment of memory, impairment of motor functions, hangover feeling in the morning, slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, double vision, and inattention have been reported. Unpleasant dreams and rebound insomnia have also been reported.

Nitrazepam is a long-acting benzodiazepine with an elimination half-life of 15-38 hours (mean elimination half-life 26 hours). Residual “hangover” effects after nighttime administration of nitrazepam 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 increases the risk of falls and hip fractures.

Less Common

Less common side effects may include: Hypotension, faintness, palpitation, rash or pruritus, gastrointestinal disturbances, and changes in libido are less common. Very infrequently, paradoxical reactions may occur, for example, excitement, stimulation, hallucinations, hyperactivity, and insomnia. Also, depressed or increased dreaming, disorientation, severe sedation, retrograde amnesia, headache, hypothermia, and delirium tremens are reported. Severe liver toxicity has also been reported.

Cancer

Benzodiazepine use is associated with an increased risk of developing cancer. However, conflicting evidence implies that further research is needed in order to conclude that products of this class really do induce cancer.

Mortality

Nitrazepam therapy, compared with other drug therapies, increases risk of death when used for intractable epilepsy in an analysis of 302 patients. The risk of death from nitrazepam therapy may be greater in younger patients (children below 3.4 years in the study) with intractable epilepsy. In older children (above 3.4 years), the tendency appears to be reversed in this study. Nitrazepam may cause sudden death in children. It can cause swallowing incoordination, high-peaked oesophageal peristalsis, bronchospasm, delayed cricopharyngeal relaxation, and severe respiratory distress necessitating ventilatory support in children. Nitrazepam may promote the development of parasympathetic overactivity or vagotonia, leading to potentially fatal respiratory distress in children.

Liver

Nitrazepam has been associated with severe hepatic disorders, similar to other nitrobenzodiazepines. Nitrobenzodiazepines such as nitrazepam, nimetazepam, flunitrazepam, and clonazepam are more toxic to the liver than other benzodiazepines as they are metabolically activated by CYP3A4 which can result in cytotoxicity. This activation can lead to the generation of free radicals and oxidation of thiol, as well as covalent binding with endogenous macromolecules; this results, then, in oxidation of cellular components or inhibition of normal cellular function. Metabolism of a nontoxic drug to reactive metabolites has been causally connected with a variety of adverse reactions

Other Long-Term Effects

Refer to Effects Long-Term Benzodiazepine Use.

Long-term use of nitrazepam may carry mental and physical health risks, such as the development of cognitive deficits. These adverse effects show improvement after a period of abstinence. Some other sources however seem to indicate that there is no relation between the use of benzodiazepine medication and dementia. Further research is needed in order to assert that this class of medication does really induce cognitive decline.

Abuse Potential

Refer to Benzodiazepine Use Disorder.

Recreational use of nitrazepam is common.

A monograph for the drug says: “Treatment with nitrazepam should usually not exceed seven to ten consecutive days. Use for more than two to three consecutive weeks requires complete re-evaluation of the patient. Prescriptions for nitrazepam should be written for short-term use (seven to ten days) and it should not be prescribed in quantities exceeding a one-month supply. Dependence can occur in as little as four weeks.”

Tolerance

Tolerance to nitrazepam’s effects often appears with regular use. Increased levels of GABA in cerebral tissue and alterations in the activity state of the serotoninergic system occur as a result of nitrazepam tolerance. Tolerance to the sleep-inducing effects of nitrazepam can occur after about seven days; tolerance also frequently occurs to its anticonvulsant effects.

However, other sources indicate that continuous use does not necessarily lead to reduced effectiveness, which implies that tolerance is not automatic and that not all patients exhibit tolerance to the same extent.

Dependence and Withdrawal

Refer to Benzodiazepine Withdrawal Syndrome.

Nitrazepam can cause dependence, addiction, and benzodiazepine withdrawal syndrome. Withdrawal from nitrazepam may lead to withdrawal symptoms which are similar to those seen with alcohol and barbiturates. Common withdrawal symptoms include anxiety, insomnia, concentration problems, and fatigue. Discontinuation of nitrazepam produced rebound insomnia after short-term single nightly dose therapy.

Special Precautions

Benzodiazepines require special precautions if used in alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders. Caution should be exercised in prescribing nitrazepam to anyone who is of working age due to the significant impairment of psychomotor skills; this impairment is greater when the higher dosages are prescribed.

Nitrazepam in doses of 5 mg or more causes significant deterioration in vigilance performance combined with increased feelings of sleepiness. Nitrazepam at doses of 5 mg or higher impairs driving skills and like other hypnotic drugs, it is associated with an increased risk of traffic accidents. In the elderly, nitrazepam is associated with an increased risk of falls and hip fractures due to impairments of body balance. The elimination half-life of nitrazepam is 40 hours in the elderly and 29 hours in younger adults. Nitrazepam is commonly taken in overdose by drug abusers or suicidal individuals, sometimes leading to death. Nitrazepam is teratogenic if taken in overdose during pregnancy with 30% of births showing congenital abnormalities. It is a popular drug of abuse in countries where it is available.

Doses as low as 5 mg can impair driving skills. Therefore, people driving or conducting activities which require vigilance should exercise caution in using nitrazepam or possibly avoid it altogether.

Elderly

Nitrazepam, 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. Combination with alcohol increases these impairments. Partial but incomplete tolerance develops to these impairments. Nitrazepam has been found to be dangerous in elderly patients due to a significantly increased risk of falls. This increased risk is probably due to the drug effects of nitrazepam persisting well into the next day. Nitrazepam is a particularly unsuitable hypnotic for the elderly as it induces a disability characterised by general mental deterioration, inability to walk, incontinence, dysarthria, confusion, stumbling, falls, and disorientation which can occur from doses as low as 5 mg. The nitrazepam-induced symptomatology can lead to a misdiagnosis of brain disease in the elderly, for example dementia, and can also lead to the symptoms of postural hypotension which may also be misdiagnosed. A geriatric unit reportedly was seeing as many as seven patients a month with nitrazepam-induced disabilities and health problems. The drug was recommended to join the barbiturates in not being prescribed to the elderly. Only nitrazepam and lorazepam were found to increase the risk of falls and fractures in the elderly. CNS depression occurs much more frequently in the elderly and is especially common in doses above 5 mg of nitrazepam. Both young and old patients report sleeping better after three nights’ use of nitrazepam, but they also reported feeling less awake and were slower on psychomotor testing up to 36 hours after intake of nitrazepam. The elderly showed cognitive deficits, making significantly more mistakes in psychomotor testing than younger patients despite similar plasma levels of the drug, suggesting the elderly are more sensitive to nitrazepam due to increased sensitivity of the aging brain to it. Confusion and disorientation can result from chronic nitrazepam administration to elderly subjects. Also, the effects of a single dose of nitrazepam may last up to 60 hours after administration.

Children

Nitrazepam is not recommended for use in those under 18 years of age. Use in very young children may be especially dangerous. Children treated with nitrazepam for epilepsies may develop tolerance within months of continued use, with dose escalation often occurring with prolonged use. Sleepiness, deterioration in motor skills and ataxia were common side effects in children with tuberous sclerosis treated with nitrazepam. The side effects of nitrazepam may impair the development of motor and cognitive skills in children treated with nitrazepam. Withdrawal only occasionally resulted in a return of seizures and some children withdrawn from nitrazepam appeared to improve. Development, for example the ability to walk at five years of age, was impaired in many children taking nitrazepam, but was not impaired with several other nonbenzodiazepine antiepileptic agents. Children being treated with nitrazepam have been recommended to be reviewed and have their nitrazepam gradually discontinued whenever appropriate. Excess sedation, hypersalivation, swallowing difficulty, and high incidence of aspiration pneumonia, as well as several deaths, have been associated with nitrazepam therapy in children.

Pregnancy

Nitrazepam is not recommended during pregnancy as it is associated with causing a neonatal withdrawal syndrome and is not generally recommended in alcohol- or drug-dependent individuals or people with comorbid psychiatric disorders. The Dutch, British and French system called the System of Objectified Judgement Analysis for assessing whether drugs should be included in drug formularies based on clinical efficacy, adverse effects, pharmacokinetic properties, toxicity, and drug interactions was used to assess nitrazepam. A Dutch analysis using the system found nitrazepam to be unsuitable in drug-prescribing formularies.

The use of nitrazepam during pregnancy can lead to intoxication of the newborn. A neonatal withdrawal syndrome can also occur if nitrazepam or other benzodiazepines are used during pregnancy with symptoms such as hyperexcitability, tremor, and gastrointestinal upset (diarrhoea or vomiting) occurring. Breast feeding by mothers using nitrazepam is not recommended. Nitrazepam is a long-acting benzodiazepine with a risk of drug accumulation, though no active metabolites are formed during metabolism. Accumulation can occur in various body organs, including the heart; accumulation is even greater in babies. Nitrazepam rapidly crosses the placenta and is present in breast milk in high quantities. Therefore, benzodiazepines including nitrazepam should be avoided during pregnancy. In early pregnancy, nitrazepam levels are lower in the baby than in the mother, and in the later stages of pregnancy, nitrazepam is found in equal levels in both the mother and the unborn child. Internationally benzodiazepines are known to cause harm when used during pregnancy and nitrazepam is a category D drug during pregnancy.

Benzodiazepines are lipophilic and rapidly penetrate membranes, so rapidly penetrate the placenta with significant uptake of the drug. Use of benzodiazepines such as nitrazepam in late pregnancy in especially high doses may result in floppy infant syndrome. Use in the third trimester of pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, and reluctance to suckle, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth.

Other Precautions

Caution in Hypotension

Caution in those suffering from hypotension, nitrazepam may worsen hypotension.

Caution in Hypothyroidism

Caution should be exercised by people who have hypothyroidism, as this condition may cause a long delay in the metabolism of nitrazepam leading to significant drug accumulation.

Contraindications

Nitrazepam should be avoided in patients with chronic obstructive pulmonary disease (COPD), especially during acute exacerbations of COPD, because serious respiratory depression may occur in patients receiving hypnotics.

As with other hypnotic drugs, nitrazepam is associated with an increased risk of traffic accidents. Nitrazepam is recommended to be avoided in patients who drive or operate machinery. A study assessing driving skills of sedative hypnotic users found the users of nitrazepam to be significantly impaired up to 17 hours after dosing, whereas users of temazepam did not show significant impairments of driving ability. These results reflect the long-acting nature of nitrazepam.

Interactions

Nitrazepam interacts with the antibiotic erythromycin, a strong inhibitor of CYP3A4, which affects concentration peak time. Alone, this interaction is not believed to be clinically important. However, anxiety, tremor, and depression were documented in a case report involving a patient undergoing treatment for acute pneumonia and renal failure. Following administration of nitrazepam, triazolam, and subsequently erythromycin, the patient experienced repetitive hallucinations and abnormal bodily sensations. Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in persons with other, significant physical complications.

Oral contraceptive pills reduce the clearance of nitrazepam, which may lead to increased plasma levels of nitrazepam and accumulation. Rifampin significantly increases the clearance of nitrazepam, while probenecid significantly decreases its clearance. Cimetidine slows down the elimination rate of nitrazepam, leading to more prolonged effects and increased risk of accumulation. Alcohol in combination with nitrazepam may cause a synergistic enhancement of the hypotensive properties of both benzodiazepines and alcohol. Benzodiazepines including nitrazepam may inhibit the glucuronidation of morphine, leading to increased levels and prolongation of the effects of morphine in rat experiments.

Pharmacology

Nitrazepam is a nitrobenzodiazepine. It is a 1,4 benzodiazepine, with the chemical name 1,3-Dihydro-7-nitro-5-phenyl-2H-1,4- benzodiazepin-2-one.

It is long acting, lipophilic, and metabolised hepatically by oxidative pathways. It acts on benzodiazepine receptors in the brain which are associated with the GABA receptors, causing an enhanced binding of GABA to GABAA receptors. GABA is a major inhibitory neurotransmitter in the brain, involved in inducing sleepiness, muscular relaxation, and control of anxiety and seizures, and slows down the central nervous system. Nitrazepam is similar in action to the z-drug zopiclone prescribed for insomnia. The anticonvulsant properties of nitrazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation in mouse spinal cord cell cultures. The muscle relaxant properties of nitrazepam are produced via inhibition of polysynaptic pathways in the spinal cord of decerebrate cats. It is a full agonist of the benzodiazepine receptor. The endogenous opioid system may play a role in some of the pharmacological properties of nitrazepam in rats. Nitrazepam causes a decrease in the cerebral contents of the amino acids glycine and alanine in the mouse brain. The decrease may be due to activation of benzodiazepine receptors. At high doses decreases in histamine turnover occur as a result of nitrazepam’s action at the benzodiazepine-GABA receptor complex in mouse brain. Nitrazepam has demonstrated cortisol-suppressing properties in humans. It is an agonist for both central benzodiazepine receptors and to the peripheral-type benzodiazepine receptors found in rat neuroblastoma cells.

EEG and Sleep

In sleep laboratory studies, nitrazepam decreased sleep onset latency. In psychogeriatric inpatients, it was found to be no more effective than placebo tablets in increasing total time spent asleep and to significantly impair trial subjects’ abilities to move and carry out everyday activities the next day, and it should not be used as a sleep aid in psychogeriatric inpatients.

The drug causes a delay in the onset, and decrease in the duration of REM sleep. Following discontinuation of the drug, REM sleep rebound has been reported in some studies. Nitrazepam is reported to significantly affect stages of sleep – a decrease in stage 1, 3, and 4 sleep and an increase in stage 2. In young volunteers, the pharmacological properties of nitrazepam were found to produce sedation and impaired psychomotor performance and standing steadiness. EEG tests showed decreased alpha activity and increased the beta activity, according to blood plasma levels of nitrazepam. Performance was significantly impaired 13 hours after dosing with nitrazepam, as were decision-making skills. EEG tests show more drowsiness and light sleep 18 hours after nitrazepam intake, more so than amylobarbitone. Fast activity was recorded via EEG 18 hours after nitrazepam dosing. An animal study demonstrated that nitrazepam induces a drowsy pattern of spontaneous EEG including high-voltage slow waves and spindle bursts increase in the cortex and amygdala, while the hippocampal theta rhythm is desynchronised. Also low-voltage fast waves occur particularly in the cortical EEG. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus is significantly suppressed. The photic driving response elicited by a flash light in the visual cortex is also suppressed by nitrazepam. Estazolam was found to be more potent however. Nitrazepam increases the slow wave light sleep (SWLS) in a dose-dependent manner whilst suppressing deep sleep stages. Less time is spent in stages 3 and 4 which are the deep sleep stages, when benzodiazepines such as nitrazepam are used. The suppression of deep sleep stages by benzodiazepines may be especially problematic to the elderly as they naturally spend less time in the deep sleep stage.

Pharmacokinetics

Nitrazepam is largely bound to plasma proteins. Benzodiazepines such as nitrazepam are lipid-soluble and have a high cerebral uptake. The time for nitrazepam to reach peak plasma concentrations following oral administration is about 2 hours (0.5 to 5 hours). The half-life of nitrazepam is between 16.5 and 48.3 hours. In young people, nitrazepam has a half-life of about 29 hours and a much longer half-life of 40 hours in the elderly. Both low dose (5 mg) and high dose (10 mg) of nitrazepam significantly increases growth hormone levels in humans.

Nitrazepam’s half-life in the cerebrospinal fluid, 68 hours, indicates that nitrazepam is eliminated extremely slowly from the cerebrospinal fluid. Concomitant food intake has no influence on the rate of absorption of nitrazepam nor on its bioavailability. Therefore, nitrazepam can be taken with or without food.

Overdose

Nitrazepam overdose may result in stereotypical symptoms of benzodiazepine overdose including intoxication, impaired balance and slurred speech. In cases of severe overdose this may progress to a comatose state with the possibility of death. The risk of nitrazepam overdose is increased significantly if nitrazepam is abused in conjunction with opioids, as was highlighted in a review of deaths of users of the opioid buprenorphine. Nitrobenzodiazepines such as nitrazepam can result in a severe neurological effects. Nitrazepam taken in overdose is associated with a high level of congenital abnormalities (30% of births). Most of the congenital abnormalities were mild deformities.

Severe nitrazepam overdose resulting in coma causes the central somatosensory conduction time (CCT) after median nerve stimulation to be prolonged and the N20 to be dispersed. Brain-stem auditory evoked potentials demonstrate delayed interpeak latencies (IPLs) I-III, III-V and I-V. Toxic overdoses therefore of nitrazepam cause prolonged CCT and IPLs. An alpha pattern coma can be a feature of nitrazepam overdose with alpha patterns being most prominent in the frontal and central regions of the brain.

Benzodiazepines were implicated in 39% of suicides by drug poisoning in Sweden, with nitrazepam and flunitrazepam accounting for 90% of benzodiazepine implicated suicides, in the elderly over a period of 2 decades. In three quarters of cases death was due to drowning, typically in the bath. Benzodiazepines were the predominant drug class in suicides in this review of Swedish death certificates. In 72% of the cases benzodiazepines were the only drug consumed. Benzodiazepines and in particular nitrazepam and flunitrazepam should therefore be prescribed with caution in the elderly. In a brain sample of a fatal nitrazepam poisoning high concentrations of nitrazepam and its metabolite were found in the brain of the deceased person.

In a retrospective study of deaths, when benzodiazepines were implicated in the deaths, the benzodiazepines nitrazepam and flunitrazepam were the most common benzodiazepines involved. Benzodiazepines were a factor in all deaths related to drug addiction in this study of causes of deaths. Nitrazepam and flunitrazepam were significantly more commonly implicated in suicide related deaths than natural deaths. In four of the cases benzodiazepines alone were the only cause of death. In Australia, nitrazepam and temazepam were the benzodiazepines most commonly detected in overdose drug related deaths. In a third of cases benzodiazepines were the sole cause of death.

Individuals with chronic illnesses are much more vulnerable to lethal overdose with nitrazepam, as fatal overdoses can occur at relatively low doses in these individuals.