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Nitrazepam [UPD]

Intraday precision and accuracy of the proposed methods were evaluated by replicate analysis () of calibration standards at three different concentration levels in the same day. Precision and accuracy of interday were measured by performing the calibration standards at cited three concentrations on five consecutive days. Both precision and accuracy were based on the calculated percent relative standard deviation (RSD, %) and percent relative error (RE, %) of found concentration compared to the theoretical one, respectively (Table 2). The result shows that these methods have reasonable precision Table 2. The proposed methods were successfully applied to the determination of nitrazepam in pharmaceutical dosage forms.



In order to check the validity of the proposed methods, we applied the standard addition technique by adding nitrazepam to the previously analyzed tablets. The recovery of each drug was calculated by comparing the concentration obtained from the spiked mixtures with those of pure drugs. The results are summarized in Table 3.

The absorption of nitrazepam from the gastrointestinal tract is fairly rapid (tmax ranging 0.5 to 7 hours). The bioavailability after oral intake averages about 80%. Maximum plasma concentrations after a single 5mg dose are of the order of 40ng/ml. As a lipophilic drug, nitrazepam is distributed rapidly in the body. The plasma levels can be fitted to a 2-compartment open model. The α-phase is rather rapid and the elimination phase is characterised by a long half-life of about 30 hours; accumulation with daily use therefore occurs. Marked interindividual variation (up to 10-fold) is found in all pharmacokinetic parameters. Age and immobilising diseases may influence the parameters, evidently increasing Vdβ and t1/2β

Nitrazepam has no clinically active metabolites. It is excreted mainly as conjugated and non-conjugated 7-aminonitrazepam and 7-acetamidonitrazepam. Polymorphic acetylation is not likely to be of clinical importance. Enzyme induction or significant loss of efficacy have not been found with long term use.

There is no significant correlation between plasma concentrations and clinical effects (or side effects) of nitrazepam. Plasma level monitoring is therefore of no benefit clinically (except for special cases, e.g. in epileptic patients). Increased responsiveness in terms of therapeutic effects and side effects is evident in the elderly. Therefore, small doses not exceeding 5mg daily should be prescribed for geriatric patients.

People who suffer from depression should avoid nitrazepam. Patients with prior history of drug abuse, or kidney and liver problems should inform their doctor prior to using this drug. Do not drive or do any activity requiring mental alertness within three hours of taking nitrazepam. Pregnant women and breastfeeding mothers should avoid taking nitrazepam. Alcohol should not be taken during treatment with nitrazepam.

Nitrazepam has a risk for abuse and addiction, which can lead to overdose and death. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems (especially opioid medications such as codeine, hydrocodone) may cause very serious side effects, including death. To lower your risk, your doctor should have you take the smallest dose of nitrazepam that works, and take it for the shortest possible time. Be sure you know how to take nitrazepam and what other drugs you should avoid taking with it. See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up.

Rarely, after taking this drug, people have gotten out of bed and driven vehicles while not fully awake ("sleep-driving"). People have also sleepwalked, prepared/eaten food, made phone calls, or had sex while not fully awake. Often, these people do not remember these events. This problem can be dangerous to you or to others. If you find out that you have done any of these activities after taking this medication, tell your doctor right away. Your risk is increased if you use alcohol or other medications that can make you drowsy while taking nitrazepam.

Before taking nitrazepam, tell your doctor or pharmacist if you are allergic to it; or to other benzodiazepines (such as diazepam, temazepam); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Poor sleep (insomnia) is fairly common but does not usually last for long. If you have problems sleeping, it may mean that you have difficulty getting off to sleep, or you may wake up for long periods during the night, or you may wake up too early in the morning. 'Sleeping tablets' like nitrazepam are considered a last resort, but are sometimes prescribed for a short period of time to help with a particularly bad spell of insomnia.

In addition, you may become addicted to nitrazepam. Addiction is different from dependence. You have an overwhelming craving for a drug, so that you feel compelled to take it even though it is harming you physically or affecting your life and relationships.

Some medicines are not suitable for people with certain conditions, and sometimes a medicine can only be used if extra care is taken. For these reasons, before you start taking nitrazepam it is important that your doctor knows:

Along with their useful effects, most medicines can cause unwanted side-effects although not everyone experiences them. The table below contains some of the more common ones associated with nitrazepam. The best place to find a full list of the side-effects which can be associated with your medicine, is from the manufacturer's printed information leaflet supplied with the medicine. Alternatively, you can find an example of a manufacturer's information leaflet in the reference section below. Speak with your doctor or pharmacist if any of the following continue or become troublesome.

It is long acting, is lipophilic and is metabolised hepatically via oxidative pathways. It acts on benzodiazepine receptors in the brain which are associated with the GABA receptors, causing an enhanced binding of GABA (gamma amino butyric acid) to GABAA receptors.[4] GABA is a major inhibitory neurotransmitter in the brain, involved in inducing sleepiness, muscular relaxation and control of anxiety and seizures, and slows down the central nervous system. The mechanism of action of nitrazepam is the same as other benzodiazepine drugs and zopiclone.[5] The anticonvulsant properties of nitrazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.[6] The muscle relaxant properties of nitrazepam are produced via inhibition of polysynaptic pathways in the spinal cord.[7] It is a full agonist of the benzodiazepine receptor.[8] The endogenous opioid system may play a role in some of the pharmacological properties of nitrazepam in rats.[9] Nitrazepam causes a decrease in the cerebral contents of the amino acids glycine and aspartic acid in the mouse brain. The decrease may be due to activation of benzodiazepine receptors.[10] At high doses decreases in histamine turnover occur as a result of nitrazepam's action at the benzodiazepine-GABA receptor complex in mouse brain. [11] Nitrazepam possesses antipruritic properties. It possesses antipruritic properties, which are believed to be due to a central mechanism of action rather than a peripheral mechanism of action.[12] Nitrazepam has demonstrated cortisol suppressing properties in man.[13]Nitrazepam is an agonist for both central and peripheral type benzodiazepine receptors in rat neuroblastoma cells.[14]

In sleep laboratory studies, nitrazepam decreased sleep onset latency. In psychogeriatric in-patients nitrazepam was found to be no more effective than placebo tablets in increasing total time spent asleep, was found to significantly impair trial subjects abilities to move and carry out everyday activities the next day and it was concluded that nitrazepam should not be used as a sleep aid in psychogeriatric in-patients.[15]

Stage 2 NREM sleep is significantly increased by nitrazepam but SWS stage sleep is significantly decreased by nitrazepam.[16] There is delay in the onset, and decrease in the duration of REM sleep. Following discontinuation of the drug, REM sleep rebound has been reported in some studies.[17] Nitrazepam is reported to significantly affect stages of sleep: a decrease stage 1, 3 and 4 sleep and to increase stage 2.[18] In young volunteers the pharmacological properties of nitrazepam was found to produce sedation, impaired psychomotor performance and standing steadiness. EEG tests showed a decrease of alpha activity and increased the beta activity. These effects increased according to blood plasma levels of nitrazepam.[19] Performance was significantly impaired 13 hours after dosing with nitrazepam as was decision-making skills. EEG tests show more drowsiness and light sleep 18 hours after nitrazepam intake more so than amylobarbitone. Fast activity was recorded via EEG 18 hours after nitrazepam dosing.[20] An animal study demonstrated that nitrazepam induces a drowsy pattern of spontaneous EEG including high voltage slow waves and spindle bursts increase in the cortex and amygdala, while the hippocampal theta rhythm is desynchronized. Also low voltage fast waves occur particularly in the cortical EEG. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus is significantly suppressed. The photic driving response elicited by a flash light in the visual cortex is also suppressed by nitrazepam. Estazolam was found to be more potent however.[21] Nitrazepam increases the slow wave light sleep (SWLS) in a dose-dependent manner whilst suppressing deep sleep stages. Less time is spent in stages 3 and 4 which are the deep sleep stages, when benzodiazepines such as nitrazepam are used. Benzodiazepines are therefore not good hypnotics in the treatment of insomnia. The suppression of deep sleep stages by benzodiazepines may be especially problematic to the elderly as they naturally spend less time in the deep sleep stage.[22] 350c69d7ab


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