NITREST 10 TABLETS

Indications

• Insomnia
• Difficulty in sleep onset
• Short-term treatment of sleep disorders

Dosage

Children: Zolpidem is not recommended for use in

Adults: The recommended dose for adults is 10 mg taken orally immediately before bedtime. In older patients or those with hepatic impairment, a lower dose of 5 mg is advised.

Mechanism of action

Zolpidem exerts its effects by selectively binding to the benzodiazepine site of the GABA-A receptor, enhancing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This action results in increased neuronal inhibition, facilitating sleep onset and reducing wakefulness. Zolpidem's selectivity for certain GABA-A receptor subtypes is believed to contribute to its favorable side effect profile compared to traditional benzodiazepines.

Pharmacodynamics

The pharmacodynamic effects of zolpidem include sedation, anxiolysis, and muscle relaxation. It has a rapid onset of action that allows for effective sleep induction, with studies indicating that it can decrease sleep latency and increase total sleep time. Due to its short half-life, zolpidem is particularly effective for initiating sleep rather than maintaining it.

Pharmacokinetics

Zolpidem is rapidly absorbed following oral administration, with peak plasma concentrations occurring approximately 1.5 to 2 hours post-dose. Its bioavailability is about 70%, and it exhibits a volume of distribution of approximately 1.2 L/kg. The drug is primarily metabolized in the liver by cytochrome P450 enzymes, particularly CYP3A4, and has a half-life of about 2 to 3 hours, leading to minimal accumulation with repeated dosing. Zolpidem is excreted mainly in the urine as metabolites, with less than 1% excreted unchanged.

Adverse effects

• Abdominal pain
• Anterograde amnesia
• Anxiety
• Back pain
• Diarrhoea
• Dizziness
• Fatigue
• Hallucination
• Headache
• Increased risk of infection
• Nausea
• Sleep disorders
• Vomiting
• Confusion
• Diplopia
• Irritability
• Angioedema
• Behavioural abnormality
• Depression
• Skin reactions
• Speech disorder
• Withdrawal syndrome

Precautions

• Use with caution in elderly patients due to potential for protracted daytime sedation and/or ataxia.
• Caution in hepatic impairment due to risk of decreased clearance.
• Use with caution in renal impairment.

Pregnancy

Avoid regular use due to the risk of neonatal withdrawal symptoms; high doses during late pregnancy or labour may cause neonatal hypothermia, hypotonia, and respiratory depression.

Breast-feeding

Small amounts present in milk-avoid.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Modified-release tablets
• Oral solution
• Capsules

Indications

• Acidity regulator
• Stabilizing agent in pharmaceutical formulations
• Potential use in metabolic processes

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations, as pediatric dosing should be based on individual clinical scenarios.

Adults: Refer to specific guidelines for formulations containing tartarate, as dosing may vary based on the therapeutic context.

Mechanism of action

Tartarate acts as a salt that can influence the solubility and stability of various pharmaceutical compounds. It is known to interact with calcium ions and may affect the crystallization processes of certain compounds. In metabolic pathways, tartarate may participate in the citric acid cycle, contributing to energy production and various enzymatic reactions.

Pharmacodynamics

The pharmacodynamics of tartarate are largely related to its role as a buffering agent and stabilizer in formulations. It does not have direct pharmacological effects in the way that active drugs do but can influence the solubility and bioavailability of co-administered medications. Its effects on metabolic pathways can indirectly influence physiological responses.

Pharmacokinetics

The pharmacokinetics of tartarate, particularly potassium tartrate, involve absorption in the gastrointestinal tract, where it dissociates into potassium and tartrate ions. These ions can be absorbed and utilized in various biochemical processes. Excretion primarily occurs via the kidneys. The pharmacokinetic profile may vary based on the formulation and route of administration.

Indications

• Insomnia characterized by difficulty in falling asleep
• Short-term management of sleep disorders

Dosage

Adults: The recommended starting dose for adults is 10 mg taken immediately before bedtime, with a maximum dose of 10 mg. For women, the initial dose is often reduced to 5 mg due to differences in pharmacokinetics. It is advised to ensure at least 7-8

Mechanism of action

Zolpidem interacts with the GABA-A receptor complex, specifically binding to the BZ1 receptor subtype. This selective binding leads to an enhancement of GABAergic transmission, resulting in sedative, anxiolytic, and muscle relaxant effects. Unlike benzodiazepines, which are non-selective, zolpidem primarily affects the alpha 1, 2, and 3 subunits of the GABA receptor, which are associated with sleep induction and anxiolytic properties.

Pharmacodynamics

Zolpidem exhibits CNS depressant effects, which include somnolence, sedation, decreased alertness, and drowsiness. It acts quickly, typically inducing sleep within 30 minutes of administration, and is designed for short-term use due to potential dependence and tolerance. While it is effective for sleep initiation, there is evidence of anterograde amnesia, especially at higher doses, suggesting caution with dosing and use in certain populations.

Pharmacokinetics

Zolpidem is rapidly absorbed, with peak plasma concentrations occurring approximately 1.5 hours after oral administration. The drug has a half-life of about 2.5 hours, allowing it to be effective without causing prolonged sedation. It is metabolized primarily by the liver via cytochrome P450 enzymes, and its elimination may be affected by drugs that induce or inhibit these enzymes, potentially leading to altered exposure.

Adverse effects

• somnolence
• decreased alertness
• sedation
• drowsiness
• dizziness
• anterograde amnesia

Interactions

• carbamazepine+zolpidem: Unknown (decreases exposure)
• rifampicin+zolpidem: Unknown (decreases exposure)

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Zolpidem is excreted in human milk. Caution should be exercised when administering to a nursing woman.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Zolpidem tartrate tablets

Mechanism of action

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic substance with a chemical structure that is not related to the structure benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines or other drugs exerting hypnotic effects. It interacts with a _GABA-BZ_ receptor complex and shares various pharmacological properties with the _benzodiazepine_ class of drugs. Subunit binding of the _GABAA_ receptor chloride channel macromolecular complex is thought to lead to the sedative, anticonvulsant, anxiolytic, and myorelaxant drug effects of zolpidem. The main regulatory site of the GABAA receptor complex can be found on its _alpha (α) subunit_ and is called the _benzodiazepine_ (BZ) or _omega (ω)_ receptor. At least three different subtypes of the (ω) receptor have been identified to this date. In contrast to benzodiazepine drugs, which are found to modulate all benzodiazepine receptor subtypes in a non-selective fashion, zolpidem binds the (BZ1) receptor specifically with a potent affinity for the alpha 1/alpha 5 subunits (in vitro). More recent studies suggest that zolpidem binds primarily to the alpha 1, 2, and 3 subunits of the GABA receptor,,, and not the alpha 5 subunit. The (_BZ1_) receptor is found primarily on the Lamina IV of the brain sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. Specific and selective binding of zolpidem on the (BZ1) receptor is not considered absolute, however, this binding could potentially explain the relative lack of myorelaxant and anticonvulsant activity in animal studies in addition to the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses.

Pharmacodynamics

**Effects on the central nervous system (CNS)** This drug has CNS depressant effects, which may include somnolence, decreased alertness, sedation, drowsiness, dizziness, and other changes in psychomotor function. Due to the above effects, the FDA has recommended an initial dose of zolpidem (immediate-acting) is a single dose of 5 mg for women and a single dose of 5 or 10 mg for men, immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening. Refer to product labeling for detailed information,. **Effects on memory** Controlled studies in adults using objective measures of memory demonstrated no significant evidence of next-day memory impairment after the administration of zolpidem. On the contrary, in a clinical study involving the administration of zolpidem doses of 10 and 20 mg, a marked reduction in a next-morning recall of information relayed to subjects during peak drug effect (90 minutes after dosing) was observed. These subjects experienced a condition known as _anterograde amnesia_. Subjective evidence from adverse event data has suggested that anterograde amnesia may occur after zolpidem administration, mainly at doses above 10 mg. **Effects on psychomotor function** This drug may cause decreased psychomotor performance. Additive psychomotor effects may occur with other drugs that cause depression of psychomotor function, including alcohol. Patients taking zolpidem should be cautioned against participating in hazardous activities or occupations requiring complete mental alertness or motor coordination, including operating machinery or driving a motor vehicle after ingesting the drug. Potential impairment of the performance of the above types of activities may also occur the day after zolpidem ingestion, especially at higher doses and ingestion of the extended-release form,. **Effects on insomnia and sleep stages** Evidence suggests that this drug is associated with minimal rebound insomnia. During clinical trials with patients using zolpidem on an ‘as-needed’ basis, zolpidem use resulted in global improvements in sleep. Zolpidem has been demonstrated to decrease sleep latency (the time it takes to fall asleep) for up to 35 days in controlled clinical studies. In studies measuring the percentage of sleep time spent in each sleep stage, zolpidem has primarily been shown to preserve sleep stages. Sleep time spent in stages 3 and 4 (deep sleep) was measured as similar to placebo with only minor and inconsistent changes in REM (paradoxical) sleep at the recommended dose. **Next-day residual effects** In 2013, the FDA issued a statement warning that patients who take zolpidem extended-release (Ambien CR)―either 6.25 mg or 12.5 mg―should not drive or participate in other activities requiring full mental alertness the day after taking the drug, due to the fact that zolpidem concentrations can remain increased the next day, and impair the ability to perform these activities,. Patients may decrease their risk of next-morning impairment by taking the lowest dose of their insomnia medicine that treats their symptoms, according to the FDA. Specific dosing recommendations for both men and women are included in this statement. This information is also available on product labeling,. **Rebound effects** There was no polysomnographic (objective) evidence of rebound insomnia at normal doses, in studies evaluating sleep on the nights following discontinuation of zolpidem tartrate. Subjective evidence of impaired sleep in the elderly on the first post-treatment night was observed at doses higher than the recommended 5mg dose for elderly patients.