| Medication Name: | Nitrazepam / Mogadon |
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What are the main pharmacological effects of nitrazepam besides its hypnotic action?
Abstract
Nitrazepam (NTZ), chemically identified as 1,3-dihydro-1-nitro-2-oxo-5-phenyl-2H-1,4-benzodiazepine-2-one, is a benzodiazepine derivative widely recognized for its hypnotic properties and therapeutic role in stress-related disorders. According to the British Pharmacopoeia, its determination is routinely performed by non-aqueous titrimetry. Additional reported analytical methods include high-performance liquid chromatography (HPLC), complexometry with cadmium-2-methyl-5-nitrobenzenesulphonate, and derivative UV spectrophotometry. Many of these approaches require multiple preparation steps, making them less convenient for routine pharmaceutical analysis. In contrast, spectrophotometric techniques remain a practical and cost-effective choice for estimating active compounds in both pure substances and dosage forms. In this study, orcinol was employed as a coupling agent to optimize a spectrophotometric method based on the diazo-coupling reaction. The developed procedure offers a simple, sensitive, and accurate means for quantifying nitrazepam in raw materials as well as in pharmaceutical formulations.
Keywords: Nitrazepam, benzodiazepine, HPLC, UV spectrophotometry, titrimetry, diazo-coupling.
Introduction
Nitrazepam is a 1,4-benzodiazepinone derivative characterized by nitro and phenyl substitutions at positions 5 and 7, respectively. Also referred to as 1,3-dihydro-2H-1,4-benzodiazepin-2-one, this compound is widely used as a hypnotic and anticonvulsant. Clinically, it is prescribed for the short-term management of severe insomnia and anxiety, as well as for the treatment of infantile epileptic spasms (West syndrome). Nitrazepam exerts multiple pharmacological actions, including sedative, anticonvulsant, skeletal muscle relaxant, and amnestic effects. Its administration reduces sleep latency and alters sleep duration, while also demonstrating efficacy in controlling myoclonic seizures.
Medical Uses
Nitrazepam is indicated for the short-term treatment of insomnia, including difficulty initiating sleep, frequent nighttime awakenings, and early morning arousals. Beyond its hypnotic application, the drug is occasionally prescribed in epilepsy cases resistant to first-line therapies. Clinical evidence suggests that nitrazepam is particularly effective in managing West syndrome, a rare, age-dependent epilepsy of infancy, where it has shown superior outcomes compared to clonazepam.
However, long-term therapy is limited due to the development of tolerance to its anticonvulsant effects, as well as adverse outcomes such as drowsiness and hypotonia. As a result, nitrazepam is generally reserved as a secondary or last-line option when other anti-seizure medications fail to achieve adequate control.
Side Effects
More Common
Nitrazepam may cause central nervous system (CNS) depression, which manifests as drowsiness, vertigo, headache, fatigue, ataxia, depression, impaired memory, reduced motor coordination, and a characteristic “morning hangover” effect. Other reported reactions include inattention, muscle weakness, double vision, decreased alertness, and emotional blunting. Some patients experience rebound insomnia and unpleasant dreams.
Because of its relatively long elimination half-life (15–38 hours, mean ~26 hours), nitrazepam is classified as a long-acting benzodiazepine. Taken at night, it may still cause residual effects the following day, such as prolonged drowsiness and reduced psychomotor performance. These side effects can impair driving ability, increase accident risk, and contribute to falls and hip fractures, particularly in elderly patients.
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Less Common
Less frequent adverse effects include hypotension, palpitations, gastrointestinal disturbances, skin rash or pruritus, and changes in libido. There are also reports of hypothermia, delirium tremens, retrograde amnesia, increased dreaming, depression, disorientation, and severe sedation.
Contraindications
Nitrazepam is contraindicated in patients with chronic obstructive pulmonary disease (COPD), especially during acute exacerbations, due to the risk of severe respiratory depression. Like other hypnotics, nitrazepam increases the risk of motor vehicle accidents. In controlled studies, significant driving impairment was observed up to 17 hours after dosing with nitrazepam, while no comparable deficits were noted with temazepam. This highlights the prolonged sedative activity of nitrazepam compared to shorter-acting alternatives.
Pharmacology
Nitrazepam is a lipophilic benzodiazepine with a long half-life, metabolized hepatically through oxidative pathways. It enhances the binding of gamma-aminobutyric acid (GABA) to GABAA receptors via benzodiazepine receptor sites, thereby potentiating inhibitory neurotransmission. GABA, the primary inhibitory neurotransmitter, reduces central nervous system activity, promoting sleep, muscle relaxation, anxiolysis, and seizure suppression.
Its pharmacological profile resembles that of z-drugs such as zopiclone. Some evidence suggests that nitrazepam’s anticonvulsant effects may also involve interactions with voltage-dependent sodium channels, limiting repetitive neuronal firing. Animal studies indicate that nitrazepam reduces polysynaptic activity in the spinal cord and acts as a full agonist at benzodiazepine receptors. Additional findings include:
- Modulation of the endogenous opioid system in rodents.
- Reduction of cerebral glycine and alanine concentrations.
- Suppression of histamine turnover at high doses.
- Inhibition of cortisol secretion in humans.
- Agonistic activity at both central and peripheral benzodiazepine receptors.
Pharmacokinetics
- Absorption: Nitrazepam is rapidly absorbed after oral administration, reaching peak plasma concentrations within 0.5–5 hours (average ~2 hours). Food intake does not significantly alter absorption or bioavailability.
- Distribution: Highly lipophilic; approximately 90% bound to plasma proteins with extensive penetration into cerebral tissue.
- Metabolism: Undergoes hepatic oxidative metabolism.
- Half-life: Ranges between 16.5 and 48.3 hours. Average half-life is ~29 hours in young adults and ~40 hours in elderly patients. In cerebrospinal fluid, the half-life is extremely prolonged (~68 hours).
- Endocrine effects: Both low (5 mg) and higher doses (10 mg) significantly increase circulating human growth hormone levels.
Overall, nitrazepam is a long-acting benzodiazepine with prolonged sedative effects, requiring cautious use due to next-day residual activity and increased risk of tolerance, dependence, and adverse reactions in sensitive populations.
Metabolism
The metabolic pathways of nitrazepam in both humans and rats have been extensively studied. With the exception of compound IV (first described by Beyer and Sadee) and compound X (still hypothetical), all other metabolites identified in urine have been confirmed as genuine biotransformation products by Rieder and Wendt.
These metabolites were isolated using extraction procedures, column chromatography, and thin-layer chromatography. Their chemical structures were elucidated through chemical reactions, comparison with authentic reference samples, and analytical techniques including mass spectrometry, nuclear magnetic resonance (NMR) spectroscopy, ultraviolet (UV), and infrared (IR) spectroscopy.
The primary metabolic route involves the reduction of the nitro group to the corresponding amino compound (II), followed by acetylation to form the acetamide derivative (III), which represents the major metabolite. A small fraction of compounds II and III undergo hydroxylation at position III, yielding derivatives IV and V.
Precautions
- Elderly patients: Nitrazepam should be prescribed at the lowest effective dose. Excessive sedation in older adults increases the risk of falls and other unintentional accidents.
- History of substance or alcohol abuse: Use with extreme caution, as benzodiazepines may trigger dependence.
- Treatment-resistant insomnia: If symptoms persist beyond 7–10 days, underlying psychiatric or medical conditions should be investigated. Worsening insomnia or new cognitive/behavioral abnormalities may indicate such conditions, and some of these adverse effects are associated with benzodiazepine receptor blockade.
- Paradoxical reactions: Patients with a history of unusual or paradoxical responses to alcohol or sedatives should be closely monitored when prescribed nitrazepam.
Drug Abuse and Withdrawal
Abrupt discontinuation of benzodiazepines can result in withdrawal symptoms similar to those seen with alcohol or barbiturates. These may include:
- Convulsions, tremors, abdominal or muscle cramps
- Vomiting, sweating, dysphoria
- Perceptual disturbances, insomnia, headache
- Severe anxiety, irritability, tension, confusion
In severe cases, nitrazepam withdrawal may lead to derealization, depersonalization, hyperacusis, paresthesias, hypersensitivity to sensory input, hallucinations, and epileptic seizures.
Risk factors for severe withdrawal include higher dosages, long-term use, previous seizures, and underlying personality disorders. Importantly, even therapeutic use for as little as 1–2 weeks may trigger withdrawal symptoms such as daytime anxiety between doses. Gradual tapering is strongly recommended, especially for patients with prior seizure history or substance dependence.
Conclusion
Nitrazepam is a potent sedative with additional antipsychotic potential. Its synthesis process is relatively straightforward and allows for efficient large-scale production. However, due to the risk of dependence, tolerance, and withdrawal, careful clinical supervision is essential.