Brotizolam for Insomnia

Overview:

Brotizolam is a derivative of thienodiazepine that is analogous to benzodiazepine. Brotizolam acts as a short-acting sedative (drug with calming effects) and hypnotic (can induce sleep). It is primarily used in patients with insomnia (sleep deficit disorder). It sedates and relaxes the neurons by mitigating the effects of gamma amino butyric acid (GABA). Brotizolam is a drug known for its quick onset of effect and comparatively brief duration of effects, making it suitable for the short-term management of insomnia. Brotizolam has not yet received approval from the US Food and Drug Administration (USFDA). It is available for usage only in countries like the Netherlands, Germany, Japan, Austria, and Spain.

Dosage and Route of Administration:

• The recommended dosage for Brotizolam to treat insomnia is 0.25 to 0.5 mg (milligrams).

• Brotizolam is available as a tablet and should be taken once daily at bedtime through the oral route.

This dose is modified based on the response and tolerance of the individual to Brotizolam.

For Patients:

What Is Insomnia?

Insomnia is considered to be a sleep disorder where individuals may feel difficulty falling asleep, staying asleep, or experiencing non-restorative sleep. This can cause impairment in daytime functions and puts the individual at risk of developing stress and anxiety. For such individuals, there is trouble in initiating sleep despite feeling tired. They also wake up frequently during the night or awaken too early in the morning and struggle to return to sleep.

Types of Insomnia:

• Acute Insomnia: Lasts for a very short time and occurs due to situational factors and lifestyle changes.

• Chronic Insomnia: Persists for at least three months and can be due to depression or anxiety (psychiatric disorders).

What Is the Impact of Insomnia?

The normal physical and mental health of patients is severely disrupted. Hence, there are several side effects seen in patients with insomnia.

• Since there is no sufficient time for the body's repair mechanisms, there can be continued inflammation within the body. This manifests as generalized fatigue and joint pain.

• Infectious diseases become very common due to dysfunctional immune systems.

• People with insomnia are susceptible to developing chronic morbidities like cardiovascular diseases (heart conditions), diabetes mellitus, and stroke.

• Cognitive functions are disturbed. This can affect the memory and decision-making capacities of the individual.

• Continued sleep deprivation also damages the social relationships of the individual, which can affect personal and professional work.

• Anxiety and substance abuse are very common among such individuals due to impaired judgemental skills.

How Is Insomnia Managed?

Measures used to manage insomnia are:

• Behavioral interventions.

• Stress relaxation and mindfulness techniques.

• Limitation of caffeine.

• Implementation of sleep hygiene practices.

Why Is Brotizolam Given for Insomnia?

Brotizolam is prescribed for insomnia primarily due to its properties of sedation and hypnosis. Brotizolam works by enhancing the action of gamma-aminobutyric acid (GABA). GABA is a very important neurotransmitter that is responsible for balancing the sleep-wake cycle. In individuals with insomnia, there may be disruptions in the normal functioning of GABAergic pathways, leading to difficulties falling or staying asleep. GABA acts as an inhibitory neurotransmitter, soothing the nervous system and facilitating relaxation, which is essential for the initiation and maintenance of sleep.

As a short-acting benzodiazepine derivative, Brotizolam works by enhancing the activity of gamma-aminobutyric acid that inhibits neuronal activity, resulting in sedation and relaxation. Brotizolam's rapid onset of action and short duration make it effective for inducing sleep quickly and maintaining sleep throughout the night. It is especially used in individuals where other treatments have been ineffective or when insomnia is extreme and leading to significant levels of distress in daily functioning. Brotizolam is indicated for short-term use as it can cause dependence in individuals using them for a chronic period of time.

How Should Brotizolam Be Taken?

Brotizolam should be taken orally at bedtime. The dosage is prescribed from 0.25 to 0.5 mg depending on the level of insomnia and the individual’s level of tolerance to Brotizolam. There are no restrictions on food intake. Brotizolam should never be taken more than the prescribed dosage. In case there is any activity that requires patients to wake up in between sleep, the drug should be avoided.

This course of therapy is generally given for two to four weeks and may be changed as per the individual's response.

Missed Dose: Patients can take a missed dose if there is a substantial amount of time between sleeping and waking up. If the period is short, patients can skip the dosage.

Drug Storage: Brotizolam should be stored at a temperature of 68 to 77 degrees Fahrenheit. Exposure to excessive heat and moisture should be strictly avoided.

What Are the Side Effects of Taking Brotizolam?

• Excessive drowsiness (especially after waking up).

• Dizziness.

• Generalized fatigue.

• Headache.

• Confusion.

• Memory impaired.

• Coordination and balance problems.

• Nausea.

• Vomiting.

• Constipation.

• Dry mouth.

• Blurry vision.

• Loss of appetite.

• Aggressive behavior.

• Disinterest in any activity.

• Agitation.

• Hallucinations.

• Slurred speech.

• Difficulty breathing (can result in respiratory depression).

• Chest pain.

• Palpitations.

• Ataxia (involuntary muscle movements due to lack of coordination).

In advanced cases, there can be dependence on the drug and exacerbation of insomnia.

What Are the Precautions to Be Taken Before Taking Brotizolam?

• Brotizolam carries the risk of developing drowsiness in the morning. Thus, patients should avoid working with heavy loads or machinery that require caution. Driving is also not advisable for such patients.

• Patients should inform the doctor if there is a history of substance use or alcohol. Such habits can cause dependence and misuse of Brotizolam. Hence, they should be avoided while taking Brotizolam.

• There can be impairment of cognitive and motor functions in patients taking Brotizolam. So, any activities that involve coordination should be completely avoided.

For Doctors:

Indications:

• Short-term management of insomnia. Brotizolam is prescribed to induce and maintain sleep, primarily in situations where other non-pharmacological interventions have been ineffective or insufficient. The dosage prescribed is 0.25 to 0.5 mg (milligrams) once daily for two to four weeks.

• A dosage of 0.25 mg is given occasionally as a part of pre-anesthetic medication.

Contraindications:

• People with hypersensitive responses to benzodiazepines should avoid Brotizolam.

• Brotizolam is contraindicated in individuals with myasthenia gravis (autoimmune condition with degenerative neuromuscular system) because of its potential to worsen muscle weakness associated with this condition. Brotizolam, like other benzodiazepines, acts on the central nervous system to produce its sedative and muscle-relaxing effects. However, these medications can also have muscle-relaxant properties, which can exacerbate the muscle weakness already present in individuals with myasthenia gravis. By further depressing muscle function, Brotizolam can worsen symptoms and lead to respiratory muscle weakness, which can be a serious complication in severe cases of myasthenia gravis.

• Respiratory insufficiency is a common side effect of Brotizolam. So, patients with respiratory disorders and failure are contraindicated for treatment with Brotizolam.

• Since Brotizolam is metabolized in the liver, patients with dysfunctional liver are not indicated for insomnia treatment with Brotizolam.

• Individuals with sleep apnea are also contraindicated. As Brotizolam can induce sedation and muscle relaxation, it may contribute to the collapse of the upper airway, which is already compromised in individuals with sleep apnea. This can further obstruct breathing during sleep, worsening the symptoms of sleep apnea.

Clinical Pharmacology:

Brotizolam is a benzodiazepine derivative with potent sedative, hypnotic, anxiolytic, and muscle relaxant properties. As a short-acting benzodiazepine, it acts by enhancing the inhibitory effects of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. By attaching to particular sites on the GABA-A receptor complex, Brotizolam potentiates the effects of GABA, leading to hyperpolarization of neuronal membranes and inhibition of neuronal excitability. This results in sedation, induction of sleep, anxiolysis, and muscle relaxation.

Half-Life:

The half-life of Brotizolam ranges from 3.6 to 7.9 hours (the average is 4.4 hours).

Ingredients:

• Active Ingredient: Brotizolam. The chemical name is 8-bromo-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine.

• Inactive Ingredient: Mannitol, glycine, and sodium monophosphate are used.

Pharmacokinetics:

Absorption:

After taking it orally, Brotizolam is readily absorbed through the intestine, and maximum plasma concentration is achieved within 1 to 2 hours post-dose. This swift absorption is facilitated by the compound's favorable physicochemical properties, including its lipophilicity and relatively low molecular weight.

Metabolism:

Oxidation and hydroxylation occur as soon as Brotizolam reaches the liver. Several metabolites, including 1-desmethyl Brotizolam, 1-hydroxy Brotizolam, and 1,4-dihydroxy Brotizolam, are produced. These metabolites may exhibit pharmacological activity to varying degrees, contributing to the overall effects of the drug. However, the primary metabolite, 1-desethyl Brotizolam, is believed to be pharmacologically inactive. Brotizolam and its metabolites are subsequently conjugated with glucuronic acid to form water-soluble metabolites.

Distribution:

Brotizolam reaches the central nervous system to exert its action and treat insomnia. Its distribution is facilitated by its lipophilic nature, allowing it to readily cross biological membranes, including the blood-brain barrier, and reach target tissues. Brotizolam's distribution is also influenced by plasma protein binding, primarily to albumin, which can limit its distribution to some extent. Once in the CNS, Brotizolam acts on gamma-aminobutyric acid (GABA) receptors and improves the inhibitory effects of GABA.

Excretion:

The water-soluble metabolites are mainly excreted through urine. A minimal portion of Brotizolam and its metabolites are excreted through feces.

Pharmacodynamics:

Brotizolam, a benzodiazepine derivative, exerts its pharmacodynamic effects primarily through the potentiation of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system (CNS). By attaching to particular sites on the GABA-A receptor complex, Brotizolam enhances the inhibitory effects of GABA, leading to increased chloride ion influx through the receptor channel. This results in hyperpolarization of neuronal membranes, suppression of neuronal excitability, and ultimately, the manifestation of pharmacological effects such as sedation, hypnotic induction, anxiolysis, and muscle relaxation. Brotizolam's selectivity for GABA-A receptors containing alpha-1 subunits contributes to its sedative and hypnotic properties, while its affinity for alpha-2 and alpha-3 subunits may contribute to its anxiolytic effects. Additionally, Brotizolam has a relatively short half-life and rapid onset of action, making it suitable for the management of insomnia.

Clinical Toxicity:

• Brotizolam can cause reduced heart rate and arterial pressure.

• Central nervous system depression occurs frequently. There can be drowsiness and confusion.

• Overdose can cause suppression of the respiratory system and lead to breathlessness.

• In advanced cases, coma is reported.

Drug Interactions:

• Since Brotizolam has the potential to depress the central nervous system, it should not be given along with other depressants like opioids, sedatives, or hypnotics.

• Brotizolam is primarily metabolized by the cytochrome P450 enzyme CYP3A4. Co-administration of potent CYP3A4 inhibitors, such as Ketoconazole, Clarithromycin, or Ritonavir, can increase Brotizolam plasma concentrations. This can predispose the patient to develop respiratory depression and coma.

• Conversely, CYP3A4 inducers, such as Rifampicin or Carbamazepine, may decrease Brotizolam plasma concentrations. This will, in turn, reduce the efficacy of Brotizolam and lead to failure of therapy.

• Brotizolam should not be given to patients taking oral contraceptives as estrogen can interact with the drug and increase the levels of Brotizolam in the circulation.

Precautions and Warnings:

• Since Brotizolam can cause depression in the respiratory system, it should be given with caution among patients with respiratory disorders.

• Benzodiazepines like Brotizolam have the potential for dependence and withdrawal reactions, particularly with prolonged use or abrupt discontinuation. Patients should be advised to use Brotizolam only as directed and to avoid abrupt cessation to minimize the risk of withdrawal symptoms.

• Tolerance to the sedative effects of Brotizolam may develop with prolonged use, necessitating dose adjustments or discontinuation of therapy. Thus, continuous monitoring of the dosage and tolerance of Brotizolam is necessary.

• Patients should be advised to avoid activities requiring mental alertness until they have established how Brotizolam affects them.

• Patients should also be advised to stop alcohol intake while on Brotizolam to prevent central nervous system depression.

Guidelines for Specific Population:

• Pregnant and Lactating Women: Brotizolam is not used in pregnant ladies as it can impair fetal growth. It is not given to lactating women as Brotizolam can excrete through breast milk and cause side effects.

• Geriatric Population: Brotizolam should be used with caution in elderly or debilitated patients, as they may be more susceptible to develop symptoms associated with sedative effects of Brotizolam and at higher risk of falls and cognitive impairment.

Overall, Brotizolam is a drug that acts as a sedative, hypnotic, and anxiolytic and is commonly used in short-term management of sleep disorders like insomnia in severe cases. It has a relatively rapid onset of action and a short half-life, making it suitable for individuals who require prompt relief from sleep disturbances.