Nitrazepam

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Nitrazepam is a benzodiazepine derivative with a nitro group at the 7 position of the benzodiazepine ring.

Oral bioavailability is about 78%. Peak concentrations are reached in about 1.5 hours. Nitrazepam is 85-88% protein bound. The volume of distribution is 2.4 l/kg, and is higher in the elderly. The plasma half-life is about 27 hours, but the drug is rapidly taken up into the CSF and brain tissue and the CSF elimination half-life is 68 hours. Nitrazepam is metabolized in the liver by nitro-reduction to the inactive aromatic amine (7-aminonitrazepam), followed by acetylation to 7-acetoamidonitrazepam. Excretion occurs in both urine (45-65%) and faeces (14-20%), with the remainder bound in tissues for prolonged periods.

Like most benzodiazepines, nitrazepam can produce sedation, disorientation, sleep disturbance, nightmares, confusion, drowsiness and ataxia. Hypotonia, weakness, hypersalivation, drooling, and impaired swallowing and aspiration seem to particularly common with nitrazepam, particularly in young children. Confusion and pseudodementia can occur in the elderly. Withdrawal symptoms include delirium, mood and behavioural change, insomnia, involuntary movements, paraesthesia and confusion. The tolerability profile of many other AEDs differs in children compared with adults. There is a risk of sudden death in young children due to nitrazepam therapy, probably because of pharyngeal hypotonia in children given nitrazepam doses over 0.7 mg/kg. In a retrospective analysis of 302 patients treated for periods ranging from 3 days to 10 years, 21 patients died, 14 of whom were taking nitrazepam at the time of death. In patients younger than 3.4 years, the death rate was 3.98 per 100 patient-years, compared with 0.26 deaths per 100 patient-years in patients not taking nitrazepam. Conversely, nitrazepam had a slight protective effect (death rate of 0.50 vs 0.86) in children older than 3.4 years. Nitrazepam is in FDA pregnancy category C (teratogenic effects demonstrated in animals but no studies in humans).

Nitrazepam has been used mainly in West syndrome, febrile seizures, Lennox-Gastaut syndrome and myoclonic epilepsy, and as adjunctive therapy for refractory epilepsy, particularly in children. Its main residual use is in refractory childhood epilepsy. One study showed a reduction in average daily seizure number from 17.7 to 7.2 in 36 infants and children (aged 3 months to 12 years) when nitrazepam was added to existing therapy. Myoclonic seizures particularly improved. In another study, of 31 children with learning disability aged between 2 months and 15 years, complete control of seizures was obtained in seven patients and moderate control in 10. In West syndrome, a study of 52 patients (aged 1-24 months) demonstrated similar efficacy when nitrazepam (0.2-0.4 mg/kg/day in two divided doses) and adrenocorticotropic hormone (ACTH, 40 IU intramuscularly daily) were compared. Both regimens resulted in a reduction in seizure frequency of 75-100% in 50-60% of patients.

The usual initial dose is 1-6 mg/day, and the maintenance dose is usually 0.25-10 mg/day in children. Optimal seizure control has been related to a mean plasma concentration of 114 ng/ml. Occasionally, very high maintenance doses have been used (up to 60 mg/day). There was also a common practice among paediatricians of using very small doses (1.25-5 mg a day), sometimes on alternate days— a practice which seems to have no published evidential support. In view of the alarming suggestion of increased mortality rates, nitrazepam should be used with extreme caution, if at all, in children younger than 4 years.

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