Nitrazepam
Clinical data | |
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Trade names | Alodorm, Apodorm, Arem, Cerson, Insoma, Insomin, Mogadon, Nitrados, Nitrazadon, Nitrosun, Nitravet, Ormodon, Paxadorm, Remnos, Epam, and Somnite |
AHFS/Drugs.com | International Drug Names |
Dependence liability | Psychological: Moderate[1] |
Addiction liability | Moderate[1] |
Routes of administration | Oral |
ATC code | |
Legal status | |
Legal status |
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Pharmacokinetic data | |
Bioavailability | 53–94% |
Metabolism | Hepatic |
Elimination half-life | 16–38 hours |
Excretion | Renal |
Identifiers | |
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Nitrazepam, sold under the brand name Mogadon among others,
It was first synthesized in the late 1950s by a team of researchers at
Medical use
Nitrazepam is used to treat short-term sleeping problems (insomnia),[9] namely difficulty falling asleep, frequent awakening, early awakening, or a combination of each.
Nitrazepam is sometimes tried to treat epilepsy when other medications fail. It has been found to be more effective than
A light-activated derivative of nitrazepam (fulgazepam) has been developed for research purposes.[12]
Side effects
More common
More common side effects may include:
Nitrazepam is a long-acting benzodiazepine with an
Less common
Less common side effects may include:
Cancer
Benzodiazepine use is associated with an increased risk of developing cancer.[18] However, conflicting evidence implies that further research is needed in order to conclude that products of this class really do induce cancer.[19]
Mortality
Nitrazepam therapy, compared with other drug therapies, increases risk of death when used for intractable epilepsy in an analysis of 302 patients. The risk of death from nitrazepam therapy may be greater in younger patients (children below 3.4 years in the study) with intractable epilepsy. In older children (above 3.4 years), the tendency appears to be reversed in this study.
Liver
Nitrazepam has been associated with severe hepatic disorders, similar to other nitrobenzodiazepines. Nitrobenzodiazepines such as nitrazepam,
Other long-term effects
Long-term use of nitrazepam may carry mental and physical health risks, such as the development of cognitive deficits. These adverse effects show improvement after a period of abstinence.[22][23] Some other sources however seem to indicate that there is no relation between the use of benzodiazepine medication and dementia.[24] Further research is needed in order to assert that this class of medication does really induce cognitive decline.
Abuse potential
Recreational use of nitrazepam is common.[citation needed]
A monograph for the drug says: "Treatment with nitrazepam should usually not exceed seven to ten consecutive days. Use for more than two to three consecutive weeks requires complete re-evaluation of the patient. Prescriptions for nitrazepam should be written for short-term use (seven to ten days) and it should not be prescribed in quantities exceeding a one-month supply. Dependence can occur in as little as four weeks."[25]
Tolerance
Tolerance to nitrazepam's effects often appears with regular use. Increased levels of
However, other sources indicate that continuous use does not necessarily lead to reduced effectiveness,[26][27][28] which implies that tolerance is not automatic and that not all patients exhibit tolerance to the same extent.
Dependence and withdrawal
Nitrazepam can cause dependence, addiction, and benzodiazepine withdrawal syndrome. Withdrawal from nitrazepam may lead to withdrawal symptoms which are similar to those seen with
Special precautions
Benzodiazepines require special precautions if used in alcohol- or drug-dependent individuals and individuals with
Nitrazepam in doses of 5 mg or more causes significant deterioration in
Doses as low as 5 mg can impair driving skills.[34] Therefore, people driving or conducting activities which require vigilance should exercise caution in using nitrazepam or possibly avoid it altogether.[46]
Elderly
Nitrazepam, similar to other benzodiazepines and
Children
Nitrazepam is not recommended for use in those under 18 years of age. Use in very young children may be especially dangerous. Children treated with nitrazepam for epilepsies may develop tolerance within months of continued use, with dose escalation often occurring with prolonged use. Sleepiness, deterioration in motor skills and
Pregnancy
Nitrazepam is not recommended during pregnancy as it is associated with causing a
The use of nitrazepam during pregnancy can lead to intoxication of the newborn. A neonatal withdrawal syndrome can also occur if nitrazepam or other benzodiazepines are used during pregnancy with symptoms such as hyperexcitability, tremor, and gastrointestinal upset (diarrhea or vomiting) occurring.
Benzodiazepines are lipophilic and rapidly penetrate membranes, so rapidly penetrate the placenta with significant uptake of the drug. Use of benzodiazepines such as nitrazepam in late pregnancy in especially high doses may result in
Other precautions
Caution in hypotension
Caution in those suffering from hypotension, nitrazepam may worsen hypotension.[15]
Caution in hypothyroidism
Caution should be exercised by people who have hypothyroidism, as this condition may cause a long delay in the metabolism of nitrazepam leading to significant drug accumulation.[60]
Contraindications
Nitrazepam should be avoided in patients with chronic obstructive pulmonary disease (COPD), especially during acute exacerbations of COPD, because serious respiratory depression may occur in patients receiving hypnotics.[61]
As with other hypnotic drugs, nitrazepam is associated with an increased risk of traffic accidents.[35] Nitrazepam is recommended to be avoided in patients who drive or operate machinery. A study assessing driving skills of sedative hypnotic users found the users of nitrazepam to be significantly impaired up to 17 hours after dosing, whereas users of temazepam did not show significant impairments of driving ability. These results reflect the long-acting nature of nitrazepam.[62]
Interactions
Nitrazepam interacts with the antibiotic erythromycin, a strong inhibitor of CYP3A4, which affects concentration peak time. Alone, this interaction is not believed to be clinically important.[63] However, anxiety, tremor, and depression were documented in a case report involving a patient undergoing treatment for acute pneumonia and renal failure. Following administration of nitrazepam, triazolam, and subsequently erythromycin, the patient experienced repetitive hallucinations and abnormal bodily sensations. Coadministration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in persons with other, significant physical complications.[64]
Oral contraceptive pills reduce the clearance of nitrazepam, which may lead to increased plasma levels of nitrazepam and accumulation.[65]
Pharmacology
Nitrazepam is a nitrobenzodiazepine.[70][71] It is a 1,4 benzodiazepine, with the chemical name 1,3-Dihydro-7-nitro-5-phenyl-2H-1,4- benzodiazepin-2-one.
It is long acting,
EEG and sleep
In sleep laboratory studies, nitrazepam decreased sleep onset latency. In psychogeriatric inpatients, it was found to be no more effective than placebo tablets in increasing total time spent asleep and to significantly impair trial subjects' abilities to move and carry out everyday activities the next day, and it should not be used as a sleep aid in psychogeriatric inpatients.[82]
The drug causes a delay in the onset, and decrease in the duration of
Pharmacokinetics
Nitrazepam is largely bound to plasma proteins.[89] Benzodiazepines such as nitrazepam are lipid-soluble and have a high cerebral uptake.[90] The time for nitrazepam to reach peak plasma concentrations following oral administration is about 2 hours (0.5 to 5 hours). The half-life of nitrazepam is between 16.5 and 48.3 hours. In young people, nitrazepam has a half-life of about 29 hours and a much longer half-life of 40 hours in the elderly.[37][38] Both low dose (5 mg) and high dose (10 mg) of nitrazepam significantly increases growth hormone levels in humans.[91]
Nitrazepam's half-life in the cerebrospinal fluid, 68 hours, indicates that nitrazepam is eliminated extremely slowly from the cerebrospinal fluid.[92] Concomitant food intake has no influence on the rate of absorption of nitrazepam nor on its bioavailability. Therefore, nitrazepam can be taken with or without food.[93]
Overdose
Nitrazepam overdose may result in stereotypical symptoms of benzodiazepine overdose including intoxication, impaired balance and slurred speech. In cases of severe overdose this may progress to a comatose state with the possibility of death. The risk of nitrazepam overdose is increased significantly if nitrazepam is abused in conjunction with opioids, as was highlighted in a review of deaths of users of the opioid buprenorphine.[94] Nitrobenzodiazepines such as nitrazepam can result in a severe neurological effects.[95] Nitrazepam taken in overdose is associated with a high level of congenital abnormalities (30 percent of births). Most of the congentital abnormalities were mild deformities.[42]
Severe nitrazepam overdose resulting in coma causes the central somatosensory conduction time (CCT) after median nerve stimulation to be prolonged and the N20 to be dispersed. Brain-stem auditory evoked potentials demonstrate delayed interpeak latencies (IPLs) I-III, III-V and I-V. Toxic overdoses therefore of nitrazepam cause prolonged CCT and IPLs. An alpha pattern coma can be a feature of nitrazepam overdose with alpha patterns being most prominent in the frontal and central regions of the brain.[96][97]
Benzodiazepines were implicated in 39% of suicides by drug poisoning in
In a retrospective study of deaths in Sweden, when benzodiazepines were implicated in the deaths, the benzodiazepines nitrazepam and flunitrazepam were the most common benzodiazepines involved. Benzodiazepines were a factor in all deaths related to drug addiction in this study of causes of deaths. In Sweden, nitrazepam and flunitrazepam were significantly more commonly implicated in suicide related deaths than natural deaths. In four of the cases benzodiazepines alone were the only cause of death.[39] In Australia, nitrazepam and temazepam were the benzodiazepines most commonly detected in overdose drug related deaths. In a third of cases benzodiazepines were the sole cause of death.[40]
Individuals with chronic illnesses are much more vulnerable to lethal overdose with nitrazepam, as fatal overdoses can occur at relatively low doses in these individuals.[99]
Synthesis
Reaction of 2-amino-5-nitrobenzophenone (1) with
See also
- Benzodiazepine
- Benzodiazepine dependence
- Benzodiazepine withdrawal syndrome
- Long-term effects of benzodiazepines
- Nimetazepam — methylamino derivative of nitrazepam
- Flunitrazepam — fluorinated methylamino derivative
- Clonazepam — chlorinated derivative
- Fulgazepam[12] - light-activated derivative of benzodiazepine based on photoisomerizable fulgimide
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