Usage
- Nitrazepam is primarily prescribed for the short-term treatment of insomnia characterized by difficulty falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. It is also used in the management of myoclonic seizures, including infantile spasms, in children.
- Pharmacological Classification: Nitrazepam is classified as a benzodiazepine, a type of psychoactive drug with sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties.
- Mechanism of Action: Nitrazepam enhances the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system. This leads to increased chloride ion influx into neurons, resulting in hyperpolarization and decreased neuronal excitability.
Alternate Names
- Nitrazepam is also known internationally by its generic name.
- Brand Names: A common brand name is Mogadon.
How It Works
- Pharmacodynamics: Nitrazepam exerts its effects by binding to the benzodiazepine site on the GABAA receptor, a ligand-gated chloride channel. This binding allosterically modulates the receptor, increasing the frequency of channel opening in the presence of GABA. The resulting increase in chloride conductance inhibits neuronal firing.
- Pharmacokinetics:
- Absorption: Nitrazepam is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations reached in about 2-4 hours.
- Metabolism: It is primarily metabolized in the liver, mainly by hepatic cytochrome P450 (CYP) enzymes, specifically CYP3A4. No active metabolites are formed.
- Elimination: Nitrazepam has an elimination half-life of approximately 15–38 hours, with an average of 26 hours. This can be prolonged in elderly patients and those with hepatic or renal impairment. It is primarily excreted in the urine as inactive metabolites.
- Mode of Action: Nitrazepam’s mode of action involves allosteric modulation of the GABAA receptor, leading to enhanced GABAergic inhibition. This results in the various pharmacological effects mentioned earlier, including sedation, hypnosis, and anticonvulsant activity.
- Elimination pathways: The drug is metabolized by hepatic CYP enzymes, predominantly CYP3A4, and excreted renally as inactive metabolites.
Dosage
Standard Dosage
Adults:
- Insomnia: 5-10 mg orally once daily, immediately before bedtime. The dose may be increased if needed, up to a maximum of 20 mg/day in hospitalized patients. The lowest effective dose should be used.
- Myoclonic Seizures: As per specific clinical guidelines.
Children:
- Myoclonic Seizures: Dosages vary depending on age and weight, but typically range from 0.3 mg/kg/day to 1 mg/kg/day, divided into three doses. It is essential to start at the lower end of the range and titrate carefully, monitoring for adverse effects.
- Insomnia: Not recommended for children under 12.
Special Cases:
- Elderly Patients: Start with 2.5 mg orally once daily at bedtime. Increase to 5 mg only if necessary. Doses above 5 mg are generally not recommended.
- Patients with Renal Impairment: Dosage adjustments may be needed. Start at a lower dose and titrate cautiously.
- Patients with Hepatic Dysfunction: Start with 2.5 mg orally once daily. Increase with caution, monitoring for adverse events. Severe hepatic impairment is a contraindication.
- Patients with Comorbid Conditions: Patients with chronic pulmonary insufficiency may require dose reductions.
Clinical Use Cases
- Intubation, Surgical Procedures, Mechanical Ventilation, ICU Use, Emergency Situations: Dosage is highly context-dependent and requires careful consideration of the patient’s condition and other medications. Generally, nitrazepam is not the preferred agent in these acute settings. Consult specific guidelines and clinical resources.
Dosage Adjustments
- Dose adjustments are based on patient-specific factors such as age, weight, hepatic and renal function, and comorbid conditions. It is essential to monitor closely for efficacy and adverse effects and adjust the dose accordingly.
Side Effects
Common Side Effects
- Drowsiness, dizziness, lightheadedness, fatigue, ataxia, headache, impaired coordination, slurred speech, “hungover” feeling in the morning, and reduced alertness.
Rare but Serious Side Effects
- Paradoxical reactions (excitement, agitation, aggression, hallucinations), severe sedation, respiratory depression, amnesia, angioedema, and hepatotoxicity.
Long-Term Effects
- Cognitive impairment, dependence, tolerance, withdrawal symptoms (anxiety, insomnia, seizures) upon abrupt discontinuation.
Adverse Drug Reactions (ADR)
- Severe allergic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Contraindications
- Hypersensitivity to benzodiazepines, severe respiratory insufficiency, sleep apnea syndrome, myasthenia gravis, severe hepatic insufficiency, acute porphyria, phobic or obsessional states, chronic psychosis, and use in children for insomnia.
Drug Interactions
- CNS depressants: Alcohol, opioids, antihistamines, barbiturates, other benzodiazepines, antipsychotics, and antidepressants.
- CYP3A4 inhibitors: Azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (erythromycin, clarithromycin), cimetidine, grapefruit juice.
- CYP3A4 inducers: Rifampicin, carbamazepine, phenytoin.
- Hormonal contraceptives: Nitrazepam may reduce their effectiveness.
- Warfarin: Close monitoring of INR is required.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D (US FDA). Nitrazepam crosses the placenta and can cause fetal harm, including congenital malformations, neonatal withdrawal syndrome, and floppy infant syndrome. Avoid use during pregnancy, especially in the first trimester and near term.
- Breastfeeding: Nitrazepam is excreted in breast milk and can cause drowsiness and feeding difficulties in infants. Breastfeeding is not recommended while taking nitrazepam.
Drug Profile Summary
- Mechanism of Action: Enhances GABAergic inhibition by binding to the benzodiazepine site on the GABAA receptor.
- Side Effects: Drowsiness, dizziness, ataxia, cognitive impairment, dependence. Rarely: paradoxical reactions, respiratory depression, hepatotoxicity.
- Contraindications: Hypersensitivity, severe respiratory or hepatic insufficiency, sleep apnea, myasthenia gravis, pregnancy.
- Drug Interactions: CNS depressants, CYP3A4 inhibitors/inducers, hormonal contraceptives, warfarin.
- Pregnancy & Breastfeeding: Avoid during pregnancy and breastfeeding.
- Dosage: Adults: 5-10 mg orally at bedtime for insomnia. Elderly: Start 2.5 mg. Children: 0.3-1 mg/kg/day for myoclonic seizures.
- Monitoring Parameters: Respiratory rate, mental status, liver function tests.
Popular Combinations (Generally not recommended due to increased risk of adverse effects)
- Nitrazepam is usually prescribed as monotherapy. Combining it with other CNS depressants is generally avoided due to an increased risk of adverse effects.
Precautions
- General Precautions: Assess for respiratory and hepatic function, history of substance abuse, and risk of falls.
- Specific Populations: Avoid in pregnancy, breastfeeding, and children for insomnia. Use cautiously in elderly and patients with renal/hepatic impairment.
- Lifestyle Considerations: Avoid alcohol, operate machinery with caution, and be aware of potential daytime sedation.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Nitrazepam?
A: For adults, the initial dose for insomnia is 5 mg orally at bedtime, which can be increased to 10 mg if needed. Elderly patients should start with 2.5 mg. For children with myoclonic seizures, the dose ranges from 0.3-1 mg/kg/day divided into three doses.
Q2: What are the common side effects of Nitrazepam?
A: Common side effects include drowsiness, dizziness, lightheadedness, fatigue, and impaired coordination.
Q3: Is Nitrazepam safe to use during pregnancy?
A: No, Nitrazepam is contraindicated during pregnancy due to the risk of fetal harm.
Q4: Can I take Nitrazepam with alcohol?
A: No, alcohol potentiates the sedative effects of Nitrazepam and can be dangerous. Avoid alcohol while taking this medication.
Q5: How long can I take Nitrazepam?
A: Nitrazepam is generally prescribed for short-term use only (up to 4 weeks, including a tapering-off period) due to the risk of dependence and tolerance.
Q6: What should I do if I experience side effects?
A: Contact your doctor immediately if you experience any unusual or bothersome side effects, especially paradoxical reactions, severe sedation, or respiratory depression.
Q7: Can Nitrazepam interact with other medications?
A: Yes, Nitrazepam can interact with other CNS depressants, CYP3A4 inhibitors/inducers, hormonal contraceptives, and warfarin. Provide your doctor with a complete list of your medications.
Q8: What are the signs of Nitrazepam overdose?
A: Symptoms of overdose can include profound sedation, respiratory depression, coma, and hypotension. Seek immediate medical attention if overdose is suspected.
Q9: How should Nitrazepam be discontinued?
A: Nitrazepam should be tapered off gradually to avoid withdrawal symptoms. Do not discontinue abruptly, especially after prolonged use.
