Harmful effects of drugs, from overdose or sensitivity to regular doses. Many medicines are dangerous; the margin between dose and overdose is often narrow. A normally safe dose may be toxic in some people, over time, or in combination with certain foods, alcohol, or other drugs. Safeguards to prevent drug poisoning include testing in animals, then human volunteers, and then patients. Drugs unsafe for self-medication are available only to doctors or by prescription. Pharmacists advise the public on proper use.
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Nitrazepam is a type of benzodiazepine drug. It is a hypnotic drug with sedative and motor impairing properties, anxiolytic, amnestic, anticonvulsant, and skeletal muscle relaxant properties. Nitrazepam is available in 5mg and 10mg tablets. In Australia, Israel and the United Kingdom it is only available in 5mg tablets.
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-aminobutyric acid) to GABAA receptors. 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. 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 in mouse spinal cord cell cultures. The muscle relaxant properties of nitrazepam are produced via inhibition of polysynaptic pathways in the spinal cord of decerebrate cats. It is a full agonist of the benzodiazepine receptor. The endogenous opioid system may play a role in some of the pharmacological properties of nitrazepam in rats. Nitrazepam causes a decrease in the cerebral contents of the amino acids glycine and alanine in the mouse brain. The decrease may be due to activation of benzodiazepine receptors. At high doses decreases in histamine turnover occur as a result of nitrazepam's action at the benzodiazepine-GABA receptor complex in mouse brain. Nitrazepam has demonstrated cortisol suppressing properties in man. Nitrazepam is an agonist for both central benzodiazepine receptors, and to the peripheral type benzodiazepine receptors found in rat neuroblastoma cells.
Stage 2 NREM sleep is significantly increased by nitrazepam but SWS stage sleep is significantly decreased by nitrazepam. 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. Nitrazepam is reported to significantly affect stages of sleep: a decrease stage 1, 3 and 4 sleep and to increase stage 2. 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. 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. 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. 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.
After 6 days of use tolerance to nitrazepam's but not temazepams sleep inducing effects and performance impairing effects occurred in a study. One study demonstrated tolerance to the sleep promoting effects of nitrazepam and temazepam after 7 days nightly administration in 19 elderly inpatients. Self reported quality of sleep was found to be increased after the first nights administration of either nitrazepam or temazepam but by day 7 self reported quality of sleep was found to have returned to baseline in these patients, suggesting the development of tolerance after 7 days use. The effect was more pronounced in patients of lower intelligence. In mice tolerance to the anticonvulsant properties of nitrazepam developed profoundly and rapidly over 6 days, and then did not proceed. Some anticonvulsant effects were still apparent after 6 days administration. In humans tolerance to the anticonvulsant effects of nitrazepam is a frequent occurrence.
Benzodiazepine drugs such as nitrazepam can cause dependence and addiction and is what is known as the benzodiazepine withdrawal syndrome. Withdrawal from nitrazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen with alcohol and barbiturates, including delirium tremens. The higher the dose and the longer the drug is taken the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur at standard dosages and also after short term treatment. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.
Frequent use of nitrazepam may cause dependence and when the drug is reduced or stopped, withdrawal symptoms occur. Withdrawal symptoms including a worsening of insomnia compared to baseline typically occurs after discontinuation of nitrazepam even after short term single nightly dose therapy. Dependence on benzodiazepines such as nitrazepam or temazepam often occurs due to discharging patients from hospital on benzodiazepines who were started on benzodiazepine hypnotics in hospital. It is recommended that hypnotic use in hospital be limited to 5 days to avoid the development of drug dependence and withdrawal insomnia.
After discontinuation of nitrazepam a rebound effect may occur about 4 days after stopping medication. Nitrazepam has more side effects than other hypnotic drugs and tolerance to sedative properties and rebound insomnia after discontinuation occurs after only 7 days administration. Tolerance to the anticonvulsant and anxiolytic effects also develops rapidly during daily administration.
Abrupt withdrawal after long term use from therapeutic doses of nitrazepam may result in a severe benzodiazepine withdrawal syndrome. Reports in the medical literature report of two psychotic states developing after abrupt withdrawal from nitrazepam including delirium after abrupt withdrawal of 10 mg of nitrazepam and in another case auditory hallucinations and visual cognitive disorder developed after abrupt withdrawal from 5 mg of nitrazepam and 0.5 mg of triazolam. Gradual and careful reduction of the dosage was recommended to prevent severe withdrawal syndromes from developing. Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions. Depersonalisation has also been reported as a benzodiazepine withdrawal effect from nitrazepam.
Nitrazepam may be carcinogenic in hamster cells under the influence of UV-light and has been found to be both photogenotoxic and photocytotoxic in hamster cells under UV light. Some studies on some animals have demonstrated teratogenic and also carcinogenic effects of nitrazepam and some other benzodiazepines in these animals and the wide spread use of these drugs world wide was of major concern for human health. A review and update of existing results was therefore attempted. However, since 1996 no further research for this concern has been carried out. Genotoxic drugs have the potential to cause genetic mutations, DNA damage and promote the development of cancer including tumors.
Nitrazepam has been reported in the medical literature by researchers as a drug which is well known for inducing testicular and reproductive toxicities. Nitrazepam decreases the number of motile sperm, curilinear velocity, beat cross frequency, maximum and mean amplitude of lateral head displacement and causes testicular lesions. Nitrazepam may result in low fertility.
In studies of Sprague-Dawley rats, nitrazepam induced reproductive toxicity has been demonstrated after 2 weeks of therapy, with significant decreases in fertility in nitrazepam treated male rats. Testicular signs of toxicity, decrease in number of sperm heads in the testis and increase in number of sperm with abnormal heads was found after 2 weeks treatment with the higher dose nitrazepam and after 4 weeks in the lower dosed rats. The doses used however in the toxicology tests were significantly higher than standard therapeutic doses. Nitrazepam has also been shown at high doses to affect sperm motion in laboratory tests via causing lesions in spermatids.
Nitrazepam has been shown in Sprague-Dawley rats to cause testicular damage. A decrease in the weight of the testis, weight of the epididymis, number of sperm in the testis and sperm motility was shown in very high dose of nitrazepam treated rats, i.e. 20mg/kg to 80mg/kg. Rats treated with such extreme doses of nitrazepam show a significant decrease in pregnancy rate. Localised necrosis in the seminiferous epithelium and Leydig cell hyperplasia occurs in the testis of rats treated with nitrazepam and morphological changes occur in spermatocytes with necrosis of the cytoplasm. Laboratory tests assessing the toxicity of nitrazepam, diazepam and chlordiazepoxide on mice spermatozoa found that nitrazepam produced the most toxicities on sperm including abnormalities involving both shape and size of the sperm head.
In female rats nitrazepam has been shown to inhibit ovulation.
In a rat study nitrazepam showed much greater damage to the fetus than other benzodiazepines, as did nimetazepam. High levels of nitrazepam were found in the maternal serum and in the whole fetus which may account for the increased toxicity. Diazepam showed relatively weak fetal toxicities. Rats treated with a single very high dose of nitrazepam on day 12 of gestation significant increase in malformation in rats. However, mice seem more resistant to the teratogenic effects which may be related to differences in metabolism of nitrazepam between the two species. Exencephaly, cleft palate, micrognathia, short or kinky tail and limb reduction defects occurred in rats treated with a single very high dose of nitrazepam, with limb buds revealing hemorrhage and mesenchymal cell necrosis. Another fetal toxicity study in rats at 100mg/kg demonstrated that nitrazepam has embryocidal activity in vitro and that nitrazepam is teratogenic in vivo in rats. Nitrazepam is much more teratogenic in rats, but not mice, than other benzodiazepines probably due to its extensive nitro reduction to 7-aminonitrazepam by rat intestinal microflora. Nitrazepam undergoes enterocyte metabolism to form oxidative free radicals. Superoxide is intracellularly produced during nitrazepam metabolism and this oxidative metabolism can lead to cellular dysfunction.
Benzodiazepine usage for more than 1 - 6 months at prescribed doses is associated with an increased risk of the development of ovarian cancer. There have been 15 epidemiologic studies which have shown that hypnotic drug use is associated with increased mortality, mainly due to increased cancer deaths in humans. The cancers included cancer of the brain, lung, bowel, breast, and bladder, and other neoplasms. Not only are benzodiazepines associated with an increased risk of cancer, the benzodiazepine receptor agonist Z-drugs also are associated with cancer in humans in these studies. Initially FDA reviewers did not want to approve the Z drugs due to concerns of cancer but ultimately changed their mind and approved the drugs despite the concerns. The data shows that trial subjects receiving hypnotic drugs had an increased the risk of developing cancer. The review author concluded saying; "the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer". It has to be seen if other reviewers and the FDA come to the same result.
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. Nitrazepam may cause sudden death in children. Nitrazepam therapy can cause swallowing incoordination, high-peaked esophageal peristalsis, bronchospasm, delayed cricopharyngeal relaxation and severe respiratory distress necessitating ventilatory support in children. Nitrazepam may promote the development of parasympathetic overactivity or vagotonia leading to potentially fatal respiratory distress in children.
Nitrazepam in animal studies has been shown to increase reward seeking which may suggest increased risk of addictive behavioural patterns. A study found that nitrazepam caused significant euphoria as against placebos and was identified as an active drug by freshly detoxified experienced drug abusers of heroin and other drugs. Nitrazepam resembled diazepam (Valium), however, on certain parameters the effects produced by nitrazepam were more pronounced in these drug abusers. Nitrazepam was found to be an abusable drug and has similar abuse liability like diazepam, if not slightly higher in these drug abusers. Treatment with nitrazepam should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient. Prescriptions for nitrazepam should be written for short-term use (7 to 10 days) and it should not be prescribed in quantities exceeding a 1-month supply. Dependence can occur in as little as four weeks.
Benzodiazepines, including diazepam, nitrazepam and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines, suggesting benzodiazepines are a major prescription drug class of abuse.
Nitrazepam is detected frequently in cases of people suspected of driving under the influence of drugs in Sweden. Other benzodiazepines and zolpidem and zopiclone are also found in high numbers in suspected impaired drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone. In Northern Ireland in cases where drugs were found in tests on impaired drivers, benzodiazepines were found to be present in 87% of cases.
Impaired learning and memory occurs due to the action of the drug on benzodiazepine receptors which causes a dysfunction in the cholinergic neuronal system. Nitrazepam causes a reduced output of serotonin which is closely involved in regulating mood and may be the cause of feelings of depression in users of nitrazepam or other benzodiazepines.
Nitrazepam is a long acting benzodiazepine with an elimination half life of 15-38 (mean elimination half life 26 hours). Residual 'hangover' effects after nighttime administration of nitrazepam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may impair the ability of users to drive safely and increases the risk of falls and hip fractures. Significant impairment of visual perception and sedative effects persisting into the next day typically occurs with nitrazepam administration as was demonstrated in a human clinical trial assessing the effect of nitrazepam on peak saccade velocity.
Impairment of psychomotor function may especially occur after repeated administration, with the elderly being more vulnerable to this adverse effect. Overall accuracy of completing tasks is impaired after repeated administration of nitrazepam and is due to drug accumulation of nitrazepam. The elderly are more vulnerable to these side effects.
Caution in the elderly. Nitrazepam has been found to be dangerous in elderly patients due to a significant increased risk of falls. This increased risk is probably due to the persisting drug effects of nitrazepam well into the next day. Nitrazepam is a particularly unsuitable hypnotic for the elderly as it induces a disability characterised by general mental deterioration, inability to walk, incontinence, dysarthric, confusion, prone to stumbling, falls and disoriention which can occur from doses as low as 5 mg. The nitrazepam induced symptomatology can lead to a misdiagnosis of brain disease in the elderly eg dementia and can also lead to the symptoms of postural hypotension which may also get misdiagnosed. It was reported that a geriatric unit was seeing as many as 7 patients a month with nitrazepam induced disabilities and health problems. It was recommended that nitrazepam should join the barbiturates in not being prescribed to the elderly. Only nitrazepam and lorazepam were found to increase the risk of falls and fractures in the elderly. CNS depression occurs much more frequently in the elderly and is especially common in doses above 5 mg of nitrazepam. Both young and old patients report sleeping better after 3 nights use of nitrazepam however they also report feeling less awake and are slower on psychomotor testing up to 36 hours after intake of nitrazepam. The elderly showed cognitive deficits, making significantly more mistakes in psychomotor testing than younger patients despite similar plasma levels of the drug, suggesting that the elderly are more sensitive to nitrazepam due to increased sensitivity of the aging brain to nitrazepam. Confusion and disorientation can result from chronic nitrazepam administration to elderly subjects. Also the effects of a single dose of nitrazepam may last up to 60 hours after administration.
Caution in children. Nitrazepam is not recommended for use in those under 18. Use in very young children may be especially danagerous. 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 ataxia were common side effects in children with tuberous sclerosis treated with nitrazepam. The side effects of nitrazepam may impair the development of motor and cognitive skills in children treated with nitrazepam. Withdrawal of nitrazepam only occasionally resulted in a return of seizures and some children withdrawn from nitrazepam appeared to improve. Development, eg able to walk at 5 years was impaired in many children taking nitrazepam but was not impaired with several other non benzodiazepine antiepileptic agents. It has been recommended that children being treated with nitrazepam should be reviewed and have their nitrazepam gradually discontinued whenever appropriate.
Caution in hypotension. Caution in those suffering from hypotension, nitrazepam may worsen hypotension.
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.
Benzodiazepines are lipophilic and rapidly penetrate membranes and therefore rapidly penetrate the placenta with significant uptake of the drug. Use of benzodiazepines eg nitrazepam in late pregnancy especially high doses may result in floppy infant syndrome. Use in the third trimester stage of pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth.
Nitrazepam should be avoided in patients who drive or operate machinery. A study assessing driving skills of sedative hypnotic users found that users of nitrazepam were found 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.
Benzodiazepines were implicated in 39% of suicides by drug poisoning in Sweden, with nitrazepam and flunitrazepam accounting for 90% of benzodiazepine implicated suicides, in the elderly over a period of 2 decades. In three quarters of cases death was due to drowning, typically in the bath. Benzodiazepines were the predominant drug class in suicides in this review of Swedish death certificates. In 72% of the cases benzodiazepines were the only drug consumed. Benzodiazepines and in particular nitrazepam and flunitrazepam should therefore be prescribed with caution in the elderly. In a brain sample of a fatal nitrazepam poisoning high concentrations of nitrazepam and its metabolite were found in the brain of the deceased person.
In a retrospective study of deaths, 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. 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. 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.
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.