Perth and Nitrazepam: Difference between pages

{{Short description|Benzodiazepine sedative}}

<!-- {{lead too short|date=March 2012}} -->{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 461743504

| IUPAC_name = 7-nitro-5-phenyl-1''H''-benzo[''e''][1,4]diazepin-2(3''H'')-one

| image = Nitrazepam.svg

| width = 222

| image2 = Nitrazepam-from-xtal-3D-balls.png

<!--Clinical data-->| tradename = Alodorm, Apodorm, Arem, Cerson, Insoma, Insomin, Mogadon, Nitrados, Nitrazadon, Nitrosun, Nitravet, Ormodon, Paxadorm, Remnos, Epam, and Somnite

| Drugs.com = {{drugs.com|international|nitrazepam}}

| dependency_liability = [[Physical dependence|Physical]]: High [[Psychological dependence|Psychological]]: Moderate

| addiction_liability = Moderate

| pregnancy_US = D

| legal_BR = B1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Schedule IV

| legal_AU = Schedule 4

| legal_DE = Rx-only/Anlage III

| legal_UN = Psychotropic Schedule IV

| routes_of_administration = Oral

<!--Pharmacokinetic data-->| bioavailability = 53–94%

| metabolism = [[Liver|Hepatic]]

| elimination_half-life = 16–38 hours

| excretion = [[Kidney|Renal]]

<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 146-22-5

| ATC_prefix = N05

| ATC_suffix = CD02

| PubChem = 4506

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB01595

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4350

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 9CLV70W7HS

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D00531

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 7581

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 13209

<!--Chemical data-->| C = 15

| H = 11

| N = 3

| O = 3

| smiles = [O-][N+](C1=CC2=C(C=C1)NC(CN=C2C3=CC=CC=C3)=O)=O

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C15H11N3O3/c19-14-9-16-15(10-4-2-1-3-5-10)12-8-11(18(20)21)6-7-13(12)17-14/h1-8H,9H2,(H,17,19)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = KJONHKAYOJNZEC-UHFFFAOYSA-N

<!-- Definition and medical uses -->

'''Nitrazepam''', sold under the brand name '''Mogadon''' among others,<ref>{{cite web| url=http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html| title=Benzodiazepine Names| access-date=2008-12-29| publisher=non-benzodiazepines.org.uk| url-status=dead| archive-url=https://web.archive.org/web/20081208054743/http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html| archive-date=2008-12-08}}</ref><ref>{{cite web| url= http://www.laakeinfo.fi/Medicine.aspx?m=680&i=ORION+PHARMA_INSOMIN | title = INSOMIN tabletti 5 mg | publisher = laaketietokeskus.fi }}</ref> is a [[Hypnotic|hypnotic drug]] of the [[benzodiazepine]] class used for short-term relief from severe, disabling [[anxiety]] and [[insomnia]].<ref>{{cite web| url= http://www.bnf.org| title=Hypnotics and anxiolytics| access-date=2014-08-14| publisher=BNF}}</ref> It also has [[sedative]] (calming) properties,<ref>{{cite journal | vauthors = Yasui M, Kato A, Kanemasa T, Murata S, Nishitomi K, Koike K, Tai N, Shinohara S, Tokomura M, Horiuchi M, Abe K | display-authors = 6 | title = [Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes] | journal = Nihon Shinkei Seishin Yakurigaku Zasshi = Japanese Journal of Psychopharmacology | volume = 25 | issue = 3 | pages = 143–151 | date = June 2005 | pmid = 16045197 | oclc = 111086408 }}</ref> as well as [[amnestic]] (inducing forgetfulness), [[anticonvulsant]], and [[skeletal muscle relaxant]] effects.

<!-- Society and culture -->

It was first synthesized in the late 1950s by a team of researchers at [[Hoffmann-La Roche]] in Switzerland.<ref>{{Cite web |date=2013-04-09 |title=Benzodiazepines |url=https://www.release.org.uk/drugs/benzodiazepines |access-date=2023-03-22 |website=Release |language=en}}</ref> It was patented in 1961 and came into medical use in 1965.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=537 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA537 |language=en}}</ref>

{{TOC limit}}

==Medical use==

[[File:Nitraz-Mogadon-5mg.jpg|thumb|A box of Mogadon pills containing 5mg of Nitrazepam.]]

Nitrazepam is used to treat short-term sleeping problems ([[insomnia]]),<ref name="Tanaka-2008">{{cite journal | vauthors = Tanaka M, Suemaru K, Watanabe S, Cui R, Li B, Araki H | title = Comparison of short- and long-acting benzodiazepine-receptor agonists with different receptor selectivity on motor coordination and muscle relaxation following thiopental-induced anesthesia in mice | journal = Journal of Pharmacological Sciences | volume = 107 | issue = 3 | pages = 277–284 | date = July 2008 | pmid = 18603831 | doi = 10.1254/jphs.FP0071991 | doi-access = free }}</ref> 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 [[clonazepam]] in the treatment of [[West syndrome]], which is an age-dependent epilepsy, affecting the very young. In uncontrolled studies, nitrazepam has shown effectiveness in infantile spasms and is sometimes considered when other anti-seizure drugs have failed.<ref name="Tsao-2009"/> However, [[hypotonia|drowsiness, hypotonia]], and most significantly [[Drug tolerance|tolerance]] to anti-seizure effects typically develop with long-term treatment, generally limiting Nitrazepam to acute seizure management.<ref>{{cite journal | vauthors = Isojärvi JI, Tokola RA | title = Benzodiazepines in the treatment of epilepsy in people with intellectual disability | journal = Journal of Intellectual Disability Research | volume = 42 Suppl 1 | issue = 1 | pages = 80–92 | date = December 1998 | pmid = 10030438 }}</ref>

A light-activated derivative of nitrazepam (fulgazepam) has been developed for research purposes.<ref name="Rustler_2020">{{cite journal | vauthors = Rustler K, Maleeva G, Gomila AM, Gorostiza P, Bregestovski P, König B | title = Optical Control of GABAA Receptors with a Fulgimide-Based Potentiator | journal = Chemistry: A European Journal | volume = 26 | issue = 56 | pages = 12722–12727 | date = October 2020 | pmid = 32307732 | pmc = 7589408 | doi = 10.1002/chem.202000710 }}</ref>

==Side effects==

===More common===

More common side effects may include: [[central nervous system]] depression, including [[somnolence]], [[dizziness]], [[Depression (mood)|depressed mood]], [[Fatigue (medical)|fatigue]], [[ataxia]], [[headache]], [[Vertigo (medical)|vertigo]], impairment of memory, impairment of motor functions, a "hungover" feeling in the morning, slurred speech, decreased physical performance,{{clarify|date=June 2023}} [[Reduced affect display|numbed emotions]], reduced alertness, muscle weakness, [[Diplopia|double vision]], and inattention have been reported. Unpleasant dreams and rebound insomnia have also been reported.

Nitrazepam is a long-acting benzodiazepine with an [[elimination half-life]] of 15–38 hours (mean elimination half-life 26 hours).<ref>{{cite web |url=http://www.non-benzodiazepines.org.uk/equivalents.html |title=Benzodiazepine Equivalents Table - A list of Equivalent Doses of Benzodiazepines |website=www.non-benzodiazepines.org.uk |access-date=11 January 2022 |archive-url=https://web.archive.org/web/20070717073909/http://www.non-benzodiazepines.org.uk/equivalents.html |archive-date=17 July 2007 |url-status=dead}}</ref> 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]].<ref>{{cite journal | vauthors = Vermeeren A | title = Residual effects of hypnotics: epidemiology and clinical implications | journal = CNS Drugs | volume = 18 | issue = 5 | pages = 297–328 | year = 2004 | pmid = 15089115 | doi = 10.2165/00023210-200418050-00003 | s2cid = 25592318 }}</ref>

===Less common===

Less common side effects may include: [[Hypotension]],<ref name="nithypotension">{{cite journal | vauthors = Hossmann V, Maling TJ, Hamilton CA, Reid JL, Dollery CT | title = Sedative and cardiovascular effects of clonidine and nitrazepam | journal = Clinical Pharmacology and Therapeutics | volume = 28 | issue = 2 | pages = 167–176 | date = August 1980 | pmid = 7398184 | doi = 10.1038/clpt.1980.146 | s2cid = 71760513 }}</ref> faintness, [[palpitation]], rash or [[pruritus]], gastrointestinal disturbances, and changes in [[libido]] are less common. Very infrequently, [[paradoxical reaction]]s may occur, for example, excitement, stimulation, hallucinations, hyperactivity, and insomnia. Also, depressed or increased dreaming, disorientation, severe sedation, [[retrograde amnesia]], headache, [[hypothermia]], and [[delirium tremens]] are reported.<ref>{{cite journal | vauthors = Impallomeni M, Ezzat R | title = Letter: Hypothermia associated with nitrazepam administration | journal = British Medical Journal | volume = 1 | issue = 6003 | pages = 223–224 | date = January 1976 | pmid = 1247796 | pmc = 1638481 | doi = 10.1136/bmj.1.2665.223 }}</ref> Severe liver toxicity has also been reported.<ref name="Mizuno-2009"/>

===Cancer===

Benzodiazepine use is associated with an increased risk of developing cancer.<ref name="pmid27667780">{{cite journal | vauthors = Kim HB, Myung SK, Park YC, Park B | title = Use of benzodiazepine and risk of cancer: A meta-analysis of observational studies | journal = International Journal of Cancer | volume = 140 | issue = 3 | pages = 513–525 | date = February 2017 | pmid = 27667780 | doi = 10.1002/ijc.30443 | doi-access = free }}</ref>

However, conflicting evidence implies that further research is needed in order to conclude that products of this class really do induce cancer.<ref>{{cite journal | vauthors = Brandt J, Leong C | title = Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research | journal = Drugs in R&D | volume = 17 | issue = 4 | pages = 493–507 | date = December 2017 | pmid = 28865038 | pmc = 5694420 | doi = 10.1007/s40268-017-0207-7 }}</ref>

===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.<ref>{{cite journal | vauthors = Rintahaka PJ, Nakagawa JA, Shewmon DA, Kyyronen P, Shields WD | title = Incidence of death in patients with intractable epilepsy during nitrazepam treatment | journal = Epilepsia | volume = 40 | issue = 4 | pages = 492–496 | date = April 1999 | pmid = 10219277 | doi = 10.1111/j.1528-1157.1999.tb00746.x | s2cid = 10133690 | doi-access = free }}</ref> Nitrazepam may cause sudden death in children. It can cause swallowing incoordination, high-peaked [[esophagus|esophageal]] [[peristalsis]], [[bronchospasm]], delayed cricopharyngeal relaxation, and severe [[Labored breathing|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.<ref>{{cite journal | vauthors = Lim HC, Nigro MA, Beierwaltes P, Tolia V, Wishnow R | title = Nitrazepam-induced cricopharyngeal dysphagia, abnormal esophageal peristalsis and associated bronchospasm: probable cause of nitrazepam-related sudden death | journal = Brain & Development | volume = 14 | issue = 5 | pages = 309–314 | date = September 1992 | pmid = 1456385 | doi = 10.1016/s0387-7604(12)80149-5 | s2cid = 23523653 }}</ref>

===Liver===

Nitrazepam has been associated with severe hepatic disorders, similar to other nitrobenzodiazepines. Nitrobenzodiazepines such as nitrazepam, [[nimetazepam]], [[flunitrazepam]], and [[clonazepam]] are more toxic to the liver than other benzodiazepines as they are metabolically activated by [[CYP3A4]] which can result in [[cytotoxicity]]. This activation can lead to the generation of [[free radicals]] and oxidation of thiol, as well as covalent binding with endogenous macromolecules; this results, then, in oxidation of cellular components or inhibition of normal cellular function. Metabolism of a nontoxic drug to reactive metabolites has been causally connected with a variety of adverse reactions.<ref name="Mizuno-2009">{{cite journal | vauthors = Mizuno K, Katoh M, Okumura H, Nakagawa N, Negishi T, Hashizume T, Nakajima M, Yokoi T | display-authors = 6 | title = Metabolic activation of benzodiazepines by CYP3A4 | journal = Drug Metabolism and Disposition | volume = 37 | issue = 2 | pages = 345–351 | date = February 2009 | pmid = 19005028 | doi = 10.1124/dmd.108.024521 | s2cid = 5688931 }}</ref>

===Other long-term effects===

{{Main|Long-term effects of benzodiazepines}}

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.<ref name="tdamobd2004">{{cite journal | vauthors = Ashton H | title = The diagnosis and management of benzodiazepine dependence | journal = Current Opinion in Psychiatry | volume = 18 | issue = 3 | pages = 249–255 | date = May 2005 | pmid = 16639148 | doi = 10.1097/01.yco.0000165594.60434.84 | s2cid = 1709063 }}</ref><ref name="asapdacg">{{cite book|title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |publisher=Oxford University Press |year=2004 |isbn=978-0-19-852748-0 |pages=239–60 |chapter=Benzodiazepine dependence |veditors=Haddad P, Dursun S, Deakin B| vauthors = Ashton H }}</ref>

Some other sources however seem to indicate that there is no relation between the use of benzodiazepine medication and dementia.<ref>{{cite journal | vauthors = Grossi CM, Richardson K, Fox C, Maidment I, Steel N, Loke YK, Arthur A, Myint PK, Campbell N, Boustani M, Robinson L, Brayne C, Matthews FE, Savva GM | display-authors = 6 | title = Anticholinergic and benzodiazepine medication use and risk of incident dementia: a UK cohort study | journal = BMC Geriatrics | volume = 19 | issue = 1 | pages = 276 | date = October 2019 | pmid = 31638906 | pmc = 6802337 | doi = 10.1186/s12877-019-1280-2 | doi-access = free }}</ref> Further research is needed in order to assert that this class of medication does really induce cognitive decline.

===Abuse potential===

{{See also|Benzodiazepine drug misuse}}

Recreational use of nitrazepam is common.{{Citation needed|date=June 2016}}

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."<ref>{{cite web |author=Hoffmann–La Roche |author-link=Hoffmann–La Roche |title=Mogadon |url=http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20M)/MOGADON.html |publisher=RxMed |access-date=26 May 2009}}</ref>

===Tolerance===

Tolerance to nitrazepam's effects often appears with regular use. Increased levels of [[GABA]] in [[Cerebrum|cerebral]] tissue and alterations in the activity state of the serotoninergic system occur as a result of nitrazepam tolerance.{{Citation needed|date=June 2016}}

[[Drug tolerance|Tolerance]] to the sleep-inducing effects of nitrazepam can occur after about seven days;{{Citation needed|date=June 2016}} tolerance also frequently occurs to its anticonvulsant effects.{{Citation needed|date=June 2016}}

However, other sources indicate that continuous use does not necessarily lead to reduced effectiveness,<ref>{{cite journal | vauthors = Adam K, Adamson L, Brezinová V, Hunter WM | title = Nitrazepam: lastingly effective but trouble on withdrawal | journal = British Medical Journal | volume = 1 | issue = 6025 | pages = 1558–1560 | date = June 1976 | pmid = 179657 | pmc = 1640482 | doi = 10.1136/bmj.1.6025.1558 }}</ref><ref>{{cite journal | vauthors = Oswald I, French C, Adam K, Gilham J | title = Benzodiazepine hypnotics remain effective for 24 weeks | journal = British Medical Journal | volume = 284 | issue = 6319 | pages = 860–863 | date = March 1982 | pmid = 6121605 | pmc = 1496323 | doi = 10.1136/bmj.284.6319.860 }}</ref><ref>{{cite journal | vauthors = Kangas L, Kanto J, Lehtinen V, Salminen J | title = Long-term nitrazepam treatment in psychiatric out-patients with insomnia | journal = Psychopharmacology | volume = 63 | issue = 1 | pages = 63–66 | date = May 1979 | pmid = 112623 | doi = 10.1007/BF00426923 | s2cid = 27388443 }}</ref> which implies that tolerance is not automatic and that not all patients exhibit tolerance to the same extent.

====Dependence and withdrawal====

{{See also|Benzodiazepine withdrawal syndrome}}

Nitrazepam can cause dependence, addiction, and benzodiazepine withdrawal syndrome. Withdrawal from nitrazepam may lead to withdrawal symptoms which are similar to those seen with [[alcohol (drug)|alcohol]] and [[barbiturates]]. Common withdrawal symptoms include [[anxiety]], [[insomnia]], concentration problems, and [[Fatigue (medical)|fatigue]].<ref name="Străulea-">{{cite journal | vauthors = Străulea AO, Chiriţă V | title = [The withdrawal syndrome in benzodiazepine dependence and its management] | language = Romanian | journal = Revista Medico-Chirurgicala a Societatii de Medici Si Naturalisti Din Iasi | volume = 113 | issue = 3 | pages = 879–884 | date = July–September 2009 | pmid = 20191849 | url = https://www.revmedchir.ro/index.php/revmedchir/issue/view/42/3%202009 | trans-title = The withdrawal syndrome in benzodiazepine dependence and its management }}</ref> Discontinuation of nitrazepam produced rebound insomnia after short-term single nightly dose therapy.<ref>{{cite journal | vauthors = Kales A, Scharf MB, Kales JD, Soldatos CR | title = Rebound insomnia. A potential hazard following withdrawal of certain benzodiazepines | journal = JAMA | volume = 241 | issue = 16 | pages = 1692–1695 | date = April 1979 | pmid = 430730 | doi = 10.1001/jama.241.16.1692 }}</ref>

==Special precautions==

Benzodiazepines require special precautions if used in alcohol- or drug-dependent individuals and individuals with [[comorbid]] [[psychiatric disorders]].<ref name="Authier-2009">{{cite journal | vauthors = Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A | display-authors = 6 | title = Benzodiazepine dependence: focus on withdrawal syndrome | journal = Annales Pharmaceutiques Françaises | volume = 67 | issue = 6 | pages = 408–413 | date = November 2009 | pmid = 19900604 | doi = 10.1016/j.pharma.2009.07.001 }}</ref> Caution should be exercised in prescribing nitrazepam to anyone who is of working age due to the significant impairment of psychomotor skills; this impairment is greater when the higher dosages are prescribed.<ref>{{cite journal | vauthors = Lahtinen U, Lahtinen A, Pekkola P | title = The effect of nitrazepam on manual skill, grip strength, and reaction time with special reference to subjective evaluation of effects on sleep | journal = Acta Pharmacologica et Toxicologica | volume = 42 | issue = 2 | pages = 130–134 | date = February 1978 | pmid = 343500 | doi = 10.1111/j.1600-0773.1978.tb02180.x }}</ref>

Nitrazepam in doses of 5&nbsp;mg or more causes significant deterioration in [[vigilance (psychology)|vigilance]] performance combined with increased feelings of sleepiness.<ref>{{cite journal | vauthors = Kozená L, Frantik E, Horváth M | title = Vigilance impairment after a single dose of benzodiazepines | journal = Psychopharmacology | volume = 119 | issue = 1 | pages = 39–45 | date = May 1995 | pmid = 7675948 | doi = 10.1007/BF02246052 | s2cid = 2618084 }}</ref> Nitrazepam at doses of 5&nbsp;mg or higher impairs driving skills<ref name="Törnros-1990"/> and like other [[hypnotic]] drugs, it is associated with an increased risk of traffic accidents.<ref name="Gustavsen-2008"/> In the elderly, nitrazepam is associated with an increased risk of falls and hip fractures due to impairments of body balance.<ref name="Mets-2010"/> The [[elimination half-life]] of nitrazepam is 40 hours in the elderly and 29 hours in younger adults.<ref name="Kangas-1979"/><ref name="Vozeh-1981"/> Nitrazepam is commonly taken in [[benzodiazepine overdose|overdose]] by drug abusers or suicidal individuals, sometimes leading to death.<ref name="Ericsson-1993"/><ref name="Drummer-1996"/><ref name="Carlsten-2003"/> Nitrazepam is [[teratology|teratogenic]] if taken in overdose during pregnancy with 30% of births showing congenital abnormalities.<ref name="Gidai-2010"/> It is a popular drug of abuse in countries where it is available.<ref name="ba2002">{{cite web|url=http://www.benzo.org.uk/ashbzab.htm|title=BENZODIAZEPINE ABUSE|year=2002|publisher=Harwood Academic Publishers|work=Drugs and Dependence|access-date=September 25, 2007 | vauthors = Ashton CH }}</ref><ref name="Garretty-1997">{{cite journal | vauthors = Garretty DJ, Wolff K, Hay AW, Raistrick D | title = Benzodiazepine misuse by drug addicts | journal = Annals of Clinical Biochemistry | volume = 34 ( Pt 1) | issue = Pt 1 | pages = 68–73 | date = January 1997 | pmid = 9022890 | doi = 10.1177/000456329703400110 | s2cid = 42665843 | doi-access = free }}</ref><ref name="Chatterjee-1996">{{cite journal | vauthors = Chatterjee A, Uprety L, Chapagain M, Kafle K | title = Drug abuse in Nepal: a rapid assessment study | journal = Bulletin on Narcotics | volume = 48 | issue = 1–2 | pages = 11–33 | year = 1996 | pmid = 9839033 }}</ref>

Doses as low as 5&nbsp;mg can impair driving skills.<ref name="Törnros-1990">{{cite journal | vauthors = Törnros J, Laurell H | title = Acute and carry-over effects of brotizolam compared to nitrazepam and placebo in monotonous simulated driving | journal = Pharmacology & Toxicology | volume = 67 | issue = 1 | pages = 77–80 | date = July 1990 | pmid = 2395820 | doi = 10.1111/j.1600-0773.1990.tb00786.x | url = http://urn.kb.se/resolve?urn=urn:nbn:se:vti:diva-2939 }}</ref> Therefore, people driving or conducting activities which require vigilance should exercise caution in using nitrazepam or possibly avoid it altogether.<ref>{{cite journal | vauthors = Hindmarch I, Parrott AC | title = The effects of combined sedative and anxiolytic preparations on subjective aspects of sleep and objective measures of arousal and performance the morning following nocturnal medication. I: Acute doses | journal = Arzneimittel-Forschung | volume = 30 | issue = 6 | pages = 1025–1028 | year = 1980 | pmid = 6106498 }}</ref>

===Elderly===

Nitrazepam, similar to other benzodiazepines and [[nonbenzodiazepines]], causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. Combination with alcohol increases these impairments. Partial but incomplete tolerance develops to these impairments.<ref name="Mets-2010">{{cite journal | vauthors = Mets MA, Volkerts ER, Olivier B, Verster JC | title = Effect of hypnotic drugs on body balance and standing steadiness | journal = Sleep Medicine Reviews | volume = 14 | issue = 4 | pages = 259–267 | date = August 2010 | pmid = 20171127 | doi = 10.1016/j.smrv.2009.10.008 }}</ref> Nitrazepam has been found to be dangerous in elderly patients due to a significantly increased risk of falls.<ref name="Shats-1995">{{cite journal | vauthors = Shats V, Kozacov S | title = [Falls in the geriatric department: responsibility of the care-giver and the hospital] | journal = Harefuah | volume = 128 | issue = 11 | pages = 690–3, 743 | date = June 1995 | pmid = 7557666 }}</ref> This increased risk is probably due to the drug effects of nitrazepam persisting well into the next day.<ref>{{cite journal | vauthors = Borland RG, Nicholson AN | title = Comparison of the residual effects of two benzodiazepines (nitrazepam and flurazepam hydrochloride) and pentobarbitone sodium on human performance | journal = British Journal of Clinical Pharmacology | volume = 2 | issue = 1 | pages = 9–17 | date = February 1975 | pmid = 10941 | pmc = 1402497 | doi = 10.1111/j.1365-2125.1975.tb00465.x }}</ref> Nitrazepam is a particularly unsuitable hypnotic for the [[elderly]] as it induces a disability characterised by general mental deterioration, inability to walk, [[Urinary incontinence|incontinence]], dysarthria, [[confusion]], [[stumbling]], [[falling (accident)|falls]], and disoriention which can occur from doses as low as 5&nbsp;mg. The nitrazepam-induced symptomatology can lead to a misdiagnosis of brain disease in the elderly, for example [[dementia]], and can also lead to the symptoms of [[postural hypotension]] which may also be misdiagnosed. A [[geriatric]] unit reportedly was seeing as many as seven patients a month with nitrazepam-induced disabilities and health problems. The drug was recommended to join the barbiturates in not being prescribed to the elderly.<ref>{{cite journal | vauthors = Evans JG, Jarvis EH | title = Nitrazepam and the elderly | journal = British Medical Journal | volume = 4 | issue = 5838 | pages = 487 | date = November 1972 | pmid = 4653884 | pmc = 1786736 | doi = 10.1136/bmj.4.5838.487-a }}</ref> Only nitrazepam and [[lorazepam]] were found to increase the risk of falls and fractures in the elderly.<ref>{{cite journal | vauthors = Trewin VF, Lawrence CJ, Veitch GB | title = An investigation of the association of benzodiazepines and other hypnotics with the incidence of falls in the elderly | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 17 | issue = 2 | pages = 129–133 | date = April 1992 | pmid = 1349894 | doi = 10.1111/j.1365-2710.1992.tb00750.x | doi-access = free }}</ref> [[Central nervous system|CNS]] depression occurs much more frequently in the elderly and is especially common in doses above 5&nbsp;mg of nitrazepam.<ref>{{cite journal | vauthors = Greenblatt DJ, Allen MD | title = Toxicity of nitrazepam in the elderly: a report from the Boston Collaborative Drug Surveillance Program | journal = British Journal of Clinical Pharmacology | volume = 5 | issue = 5 | pages = 407–413 | date = May 1978 | pmid = 656280 | pmc = 1429343 | doi = 10.1111/j.1365-2125.1978.tb01646.x }}</ref> Both young and old patients report sleeping better after three nights' use of nitrazepam, but they also reported feeling less awake and were 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 the elderly are more sensitive to nitrazepam due to increased sensitivity of the aging brain to it. 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.<ref>{{cite journal | vauthors = Castleden CM, George CF, Marcer D, Hallett C | title = Increased sensitivity to nitrazepam in old age | journal = British Medical Journal | volume = 1 | issue = 6052 | pages = 10–12 | date = January 1977 | pmid = 318894 | pmc = 1603636 | doi = 10.1136/bmj.1.157.10 }}</ref>

===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 [[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 only occasionally resulted in a return of seizures and some children withdrawn from nitrazepam appeared to improve. Development, for example the ability to walk at five years of age, was impaired in many children taking nitrazepam, but was not impaired with several other nonbenzodiazepine [[antiepileptic]] agents. Children being treated with nitrazepam have been recommended to be reviewed and have their nitrazepam gradually discontinued whenever appropriate.<ref name="Dennis-1985">{{cite journal | vauthors = Dennis J, Hunt A | title = Prolonged use of nitrazepam for epilepsy in children with tuberous sclerosis | journal = British Medical Journal | volume = 291 | issue = 6497 | pages = 692–693 | date = September 1985 | pmid = 3929902 | pmc = 1416679 | doi = 10.1136/bmj.291.6497.692 }}</ref> Excess sedation, [[hypersalivation]], swallowing difficulty, and high incidence of [[aspiration pneumonia]], as well as several deaths, have been associated with nitrazepam therapy in children.<ref name="Tsao-2009">{{cite journal | vauthors = Tsao CY | title = Current trends in the treatment of infantile spasms | journal = Neuropsychiatric Disease and Treatment | volume = 5 | pages = 289–299 | date = May 20, 2009 | pmid = 19557123 | pmc = 2695218 | doi = 10.2147/ndt.s4488 | doi-access = free }}</ref>

===Pregnancy===

Nitrazepam is not recommended during pregnancy as it is associated with causing a [[neonatal withdrawal syndrome]]<ref name="McElhatton-"/> and is not generally recommended in alcohol- or drug-dependent individuals or people with comorbid psychiatric disorders.<ref name="Authier-2009"/> The Dutch, British and French system called the System of Objectified Judgement Analysis for assessing whether drugs should be included in drug formularies based on clinical efficacy, [[adverse effects]], [[pharmacokinetic]] properties, [[toxicity]], and [[drug interactions]] was used to assess nitrazepam. A Dutch analysis using the system found nitrazepam to be unsuitable in drug-prescribing formularies.<ref>{{cite journal | vauthors = Janknegt R, van der Kuy A, Declerck G, Idzikowski C | title = Hypnotics. Drug selection by means of the System of Objectified Judgement Analysis (SOJA) method | journal = PharmacoEconomics | volume = 10 | issue = 2 | pages = 152–163 | date = August 1996 | pmid = 10163418 | doi = 10.2165/00019053-199610020-00007 }}</ref>

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. [[Breast feeding]] by mothers using nitrazepam is not recommended.<ref name="Serreau-2010">{{cite journal | vauthors = Serreau R | title = [Drugs during preeclampsia. Fetal risks and pharmacology] | journal = Annales Françaises d'Anesthésie et de Réanimation | volume = 29 | issue = 4 | pages = e37–e46 | date = April 2010 | pmid = 20347563 | doi = 10.1016/j.annfar.2010.02.016 }}</ref> Nitrazepam is a long-acting benzodiazepine with a risk of drug accumulation, though no active metabolites are formed during metabolism. Accumulation can occur in various body organs, including the heart; accumulation is even greater in babies. Nitrazepam rapidly crosses the placenta and is present in breast milk in high quantities. Therefore, benzodiazepines including nitrazepam should be avoided during pregnancy.<ref>{{cite journal | vauthors = Olive G, Dreux C | title = [Pharmacologic bases of use of benzodiazepines in peréinatal medicine] | journal = Archives Françaises de Pédiatrie | volume = 34 | issue = 1 | pages = 74–89 | date = January 1977 | pmid = 851373 }}</ref> In early pregnancy, nitrazepam levels are lower in the baby than in the mother, and in the later stages of pregnancy, nitrazepam is found in equal levels in both the mother and the unborn child.<ref>{{cite journal | vauthors = Kangas L, Kanto J, Erkkola R | title = Transfer of nitrazepam across the human placenta | journal = European Journal of Clinical Pharmacology | volume = 12 | issue = 5 | pages = 355–357 | date = December 1977 | pmid = 598407 | doi = 10.1007/BF00562451 | s2cid = 21227168 }}</ref> Internationally benzodiazepines are known to cause harm when used during pregnancy and nitrazepam is a category D drug during pregnancy.

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 [[floppy infant syndrome]].<ref>{{cite journal | vauthors = Kanto JH | title = Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations | journal = Drugs | volume = 23 | issue = 5 | pages = 354–380 | date = May 1982 | pmid = 6124415 | doi = 10.2165/00003495-198223050-00002 | s2cid = 27014006 }}</ref> Use in the [[third trimester]] 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 suckle, to [[apnoeic]] spells, [[cyanosis]], and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth.<ref name="McElhatton-">{{cite journal | vauthors = McElhatton PR | title = The effects of benzodiazepine use during pregnancy and lactation | journal = Reproductive Toxicology | volume = 8 | issue = 6 | pages = 461–475 | date = November–December 1994 | pmid = 7881198 | doi = 10.1016/0890-6238(94)90029-9 | bibcode = 1994RepTx...8..461M }}</ref>

===Other precautions===

====Caution in hypotension====

Caution in those suffering from [[hypotension]], nitrazepam may worsen hypotension.<ref name="nithypotension"/>

====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.<ref>{{cite journal | vauthors = Kenny RA, Kafetz K, Cox M, Timmers J, Impallomeni M | title = Impaired nitrazepam metabolism in hypothyroidism | journal = Postgraduate Medical Journal | volume = 60 | issue = 702 | pages = 296–297 | date = April 1984 | pmid = 6728755 | pmc = 2417841 | doi = 10.1136/pgmj.60.702.296 }}</ref>

==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.<ref>{{cite journal | vauthors = Midgren B, Hansson L, Ahlmann S, Elmqvist D | title = Effects of single doses of propiomazine, a phenothiazine hypnotic, on sleep and oxygenation in patients with stable chronic obstructive pulmonary disease | journal = Respiration; International Review of Thoracic Diseases | volume = 57 | issue = 4 | pages = 239–242 | year = 1990 | pmid = 1982774 | doi = 10.1159/000195848 }}</ref>

As with other hypnotic drugs, nitrazepam is associated with an increased risk of traffic accidents.<ref name="Gustavsen-2008">{{cite journal | vauthors = Gustavsen I, Bramness JG, Skurtveit S, Engeland A, Neutel I, Mørland J | title = Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam | journal = Sleep Medicine | volume = 9 | issue = 8 | pages = 818–822 | date = December 2008 | pmid = 18226959 | doi = 10.1016/j.sleep.2007.11.011 | hdl-access = free | hdl = 10852/34650 }}</ref> 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.<ref>{{cite journal | vauthors = O'Hanlon JF, Volkerts ER | title = Hypnotics and actual driving performance | journal = Acta Psychiatrica Scandinavica. Supplementum | volume = 332 | pages = 95–104 | year = 1986 | pmid = 3554901 | doi = 10.1111/j.1600-0447.1986.tb08985.x | s2cid = 44982782 }}</ref>

== 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.<ref>{{cite journal | vauthors = Luurila H, Olkkola KT, Neuvonen PJ | title = Interaction between erythromycin and nitrazepam in healthy volunteers | journal = Pharmacology & Toxicology | volume = 76 | issue = 4 | pages = 255–258 | date = April 1995 | pmid = 7617555 | doi = 10.1111/j.1600-0773.1995.tb00139.x }}</ref> 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.<ref>{{cite journal | vauthors = Tokinaga N, Kondo T, Kaneko S, Otani K, Mihara K, Morita S | title = Hallucinations after a therapeutic dose of benzodiazepine hypnotics with co-administration of erythromycin | journal = Psychiatry and Clinical Neurosciences | volume = 50 | issue = 6 | pages = 337–339 | date = December 1996 | pmid = 9014234 | doi = 10.1111/j.1440-1819.1996.tb00577.x | s2cid = 22742117 }}</ref>

Oral contraceptive pills reduce the clearance of nitrazepam, which may lead to increased plasma levels of nitrazepam and accumulation.<ref>{{cite journal | vauthors = Back DJ, Orme ML | title = Pharmacokinetic drug interactions with oral contraceptives | journal = Clinical Pharmacokinetics | volume = 18 | issue = 6 | pages = 472–484 | date = June 1990 | pmid = 2191822 | doi = 10.2165/00003088-199018060-00004 | s2cid = 32523973 }}</ref>

[[Rifampin]] significantly increases the clearance of nitrazepam, while [[probenecid]] significantly decreases its clearance.<ref>{{cite journal | vauthors = Brockmeyer NH, Mertins L, Klimek K, Goos M, Ohnhaus EE | title = Comparative effects of rifampin and/or probenecid on the pharmacokinetics of temazepam and nitrazepam | journal = International Journal of Clinical Pharmacology, Therapy, and Toxicology | volume = 28 | issue = 9 | pages = 387–393 | date = September 1990 | pmid = 2228325 }}</ref> [[Cimetidine]] slows down the elimination rate of nitrazepam, leading to more prolonged effects and increased risk of accumulation.<ref>{{cite journal | vauthors = Ochs HR, Greenblatt DJ, Gugler R, Müntefering G, Locniskar A, Abernethy DR | title = Cimetidine impairs nitrazepam clearance | journal = Clinical Pharmacology and Therapeutics | volume = 34 | issue = 2 | pages = 227–230 | date = August 1983 | pmid = 6872417 | doi = 10.1038/clpt.1983.157 | s2cid = 97229669 }}</ref> Alcohol in combination with nitrazepam may cause a synergistic enhancement of the hypotensive properties of both benzodiazepines and alcohol.<ref>{{cite journal | vauthors = Zácková P, Kvĕtina J, Nĕmec J, Nĕmcová J | title = Cardiovascular effects of diazepam and nitrazepam in combination with ethanol | journal = Die Pharmazie | volume = 37 | issue = 12 | pages = 853–856 | date = December 1982 | pmid = 7163374 }}</ref> Benzodiazepines including nitrazepam may inhibit the [[glucuronidation]] of [[morphine]], leading to increased levels and prolongation of the effects of morphine in rat experiments.<ref>{{cite journal | vauthors = Pacifici GM, Gustafsson LL, Säwe J, Rane A | title = Metabolic interaction between morphine and various benzodiazepines | journal = Acta Pharmacologica et Toxicologica | volume = 58 | issue = 4 | pages = 249–252 | date = April 1986 | pmid = 2872767 | doi = 10.1111/j.1600-0773.1986.tb00103.x }}</ref>

==Pharmacology==

Nitrazepam is a nitrobenzodiazepine.<ref>{{cite journal | vauthors = Robertson MD, Drummer OH | title = Postmortem drug metabolism by bacteria | journal = Journal of Forensic Sciences | volume = 40 | issue = 3 | pages = 382–386 | date = May 1995 | pmid = 7782744 | doi = 10.1520/JFS13791J }}</ref><ref>{{cite journal | vauthors = Danneberg P, Weber KH | title = Chemical structure and biological activity of the diazepines | journal = British Journal of Clinical Pharmacology | volume = 16 | issue = Suppl 2 | pages = 231S–244S | year = 1983 | pmid = 6140944 | pmc = 1428206 | doi = 10.1111/j.1365-2125.1983.tb02295.x }}</ref> 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, [[lipophilic]], and metabolised hepatically by oxidative pathways. It acts on benzodiazepine receptors in the brain which are associated with the GABA receptors, causing an enhanced binding of GABA to GABA_A receptors.<ref>{{cite journal | vauthors = Skerritt JH, Johnston GA | title = Enhancement of GABA binding by benzodiazepines and related anxiolytics | journal = European Journal of Pharmacology | volume = 89 | issue = 3–4 | pages = 193–198 | date = May 1983 | pmid = 6135616 | doi = 10.1016/0014-2999(83)90494-6 }}</ref> 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. Nitrazepam is similar in action to the z-drug [[zopiclone]] prescribed for insomnia.<ref>{{cite journal | vauthors = Sato K, Hong YL, Yang MS, Shibuya T, Kawamoto H, Kitagawa H | title = Pharmacologic studies of central actions of zopiclone: influence on brain monoamines in rats under stressful condition | journal = International Journal of Clinical Pharmacology, Therapy, and Toxicology | volume = 23 | issue = 4 | pages = 204–210 | date = April 1985 | pmid = 2860074 }}</ref> 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.<ref>{{cite journal | vauthors = McLean MJ, Macdonald RL | title = Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 244 | issue = 2 | pages = 789–795 | date = February 1988 | pmid = 2450203 }}</ref> The muscle relaxant properties of nitrazepam are produced via inhibition of polysynaptic pathways in the spinal cord of decerebrate cats.<ref>{{cite journal | vauthors = Date SK, Hemavathi KG, Gulati OD | title = Investigation of the muscle relaxant activity of nitrazepam | journal = Archives Internationales de Pharmacodynamie et de Thérapie | volume = 272 | issue = 1 | pages = 129–139 | date = November 1984 | pmid = 6517646 }}</ref> It is a [[full agonist]] of the benzodiazepine receptor.<ref name="Podhorna-2000">{{cite journal | vauthors = Podhorna J, Krsiak M | title = Behavioural effects of a benzodiazepine receptor partial agonist, Ro 19-8022, in the social conflict test in mice | journal = Behavioural Pharmacology | volume = 11 | issue = 2 | pages = 143–151 | date = April 2000 | pmid = 10877119 | doi = 10.1097/00008877-200004000-00006 | s2cid = 27601469 }}</ref> The endogenous opioid system may play a role in some of the pharmacological properties of nitrazepam in rats.<ref>{{cite journal | vauthors = Nowakowska E, Chodera A | title = Studies on the involvement of opioid mechanism in the locomotor effects of benzodiazepines in rats | journal = Pharmacology, Biochemistry, and Behavior | volume = 38 | issue = 2 | pages = 265–266 | date = February 1991 | pmid = 1676167 | doi = 10.1016/0091-3057(91)90276-8 | s2cid = 35953710 }}</ref> Nitrazepam causes a decrease in the [[Cerebrum|cerebral]] contents of the [[amino acids]] [[glycine]] and [[alanine]] in the [[mouse brain]]. The decrease may be due to activation of benzodiazepine receptors.<ref>{{cite journal | vauthors = Tomono S, Kuriyama K | title = Effect of 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative, on cerebral content of neuroactive amino acids | journal = Japanese Journal of Pharmacology | volume = 39 | issue = 4 | pages = 558–561 | date = December 1985 | pmid = 2869172 | doi = 10.1254/jjp.39.558 | doi-access = free }}</ref> At high doses decreases in histamine turnover occur as a result of nitrazepam's action at the benzodiazepine-GABA receptor complex in mouse brain.<ref>{{cite journal | vauthors = Oishi R, Nishibori M, Itoh Y, Saeki K | title = Diazepam-induced decrease in histamine turnover in mouse brain | journal = European Journal of Pharmacology | volume = 124 | issue = 3 | pages = 337–342 | date = May 1986 | pmid = 3089825 | doi = 10.1016/0014-2999(86)90236-0 }}</ref> Nitrazepam has demonstrated cortisol-suppressing properties in humans.<ref>{{cite journal | vauthors = Christensen P, Lolk A, Gram LF, Kragh-Sørensen P | title = Benzodiazepine-induced sedation and cortisol suppression. A placebo-controlled comparison of oxazepam and nitrazepam in healthy male volunteers | journal = Psychopharmacology | volume = 106 | issue = 4 | pages = 511–516 | year = 1992 | pmid = 1349754 | doi = 10.1007/BF02244823 | s2cid = 29331503 }}</ref>

It is an agonist for both central benzodiazepine receptors and to the peripheral-type benzodiazepine receptors found in rat neuroblastoma cells.<ref>{{cite journal | vauthors = Watabe S, Yoshii M, Ogata N, Tsunoo A, Narahashi T | title = Differential inhibition of transient and long-lasting calcium channel currents by benzodiazepines in neuroblastoma cells | journal = Brain Research | volume = 606 | issue = 2 | pages = 244–250 | date = March 1993 | pmid = 8387860 | doi = 10.1016/0006-8993(93)90991-U | s2cid = 40892187 }}</ref>

==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.<ref>{{cite journal | vauthors = Linnoila M, Viukari M | title = Efficacy and side effects of nitrazepam and thioridazine as sleeping aids in psychogeriatric in-patients | journal = The British Journal of Psychiatry | volume = 128 | issue = 6 | pages = 566–569 | date = June 1976 | pmid = 776314 | doi = 10.1192/bjp.128.6.566 | s2cid = 45948499 }}</ref>

<!--explain abbreviations Stage 2 NREM sleep is significantly increased by nitrazepam, but SWS stage sleep is significantly decreased by nitrazepam.<ref>{{cite journal | vauthors = Nakazawa Y, Kotorii M, Oshima M, Horikawa S, Tachibana H | title = Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives | journal = Psychopharmacologia | volume = 44 | issue = 2 | pages = 165–171 | date = October 1975 | pmid = 709 | doi = 10.1007/BF00421005 | author = Nakazawa Y }}</ref> -->The drug causes a delay in the onset, and decrease in the duration of [[Rapid eye movement sleep|REM sleep]]. Following discontinuation of the drug, REM sleep rebound has been reported in some studies.<ref>{{cite journal | vauthors = Adam K, Oswald I | title = A comparison of the effects of chlormezanone and nitrazepam on sleep | journal = British Journal of Clinical Pharmacology | volume = 14 | issue = 1 | pages = 57–65 | date = July 1982 | pmid = 7104168 | pmc = 1427586 | doi = 10.1111/j.1365-2125.1982.tb04934.x }}</ref> Nitrazepam is reported to significantly affect [[NREM|stages of sleep]] - a decrease in stage 1, 3, and 4 sleep and an increase in stage 2.<ref>{{cite journal | vauthors = Mizuki Y, Suetsugi M, Hotta H, Ushijima I, Yamada M | title = Stimulatory effect of butoctamide hydrogen succinate on REM sleep in normal humans | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 19 | issue = 3 | pages = 385–401 | date = May 1995 | pmid = 7624490 | doi = 10.1016/0278-5846(95)00020-V | s2cid = 25074381 }}</ref> In young volunteers, the pharmacological properties of nitrazepam were found to produce sedation and impaired psychomotor performance and standing steadiness. EEG tests showed decreased alpha activity and increased the beta activity, according to blood plasma levels of nitrazepam.<ref>{{cite journal | vauthors = Tazaki T, Tada K, Nogami Y, Takemura N, Ishikawa K | title = Effects of butoctamide hydrogen succinate and nitrazepam on psychomotor function and EEG in healthy volunteers | journal = Psychopharmacology | volume = 97 | issue = 3 | pages = 370–375 | year = 1989 | pmid = 2497487 | doi = 10.1007/BF00439453 | s2cid = 24330487 }}</ref> Performance was significantly impaired 13 hours after dosing with nitrazepam, as were 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.<ref>{{cite journal | vauthors = Malpas A, Rowan AJ, Boyce CR, Scott DF | title = Persistent behavioural and electroencephalographic changes after single doses of nitrazepam and amylobarbitone sodium | journal = British Medical Journal | volume = 2 | issue = 5712 | pages = 762–764 | date = June 1970 | pmid = 4913785 | pmc = 1700857 | doi = 10.1136/bmj.2.3382.762 }}</ref> An animal study demonstrated that nitrazepam induces a drowsy pattern of spontaneous EEG including high-voltage slow waves and spindle bursts increase in the [[Cerebral cortex|cortex]] and [[amygdala]], while the [[hippocampal]] theta rhythm is desynchronized. Also low-voltage fast waves occur particularly in the [[Cerebral cortex|cortical]] EEG. The EEG arousal response to [[Sound|auditory]] stimulation and to electric stimulation of the mesencephalic reticular formation, [[Posterior (anatomy)|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.<ref>{{cite journal | vauthors = Watanabe S, Ohta H, Sakurai Y, Takao K, Ueki S | title = [Electroencephalographic effects of 450191-S and its metabolites in rabbits with chronic electrode implants] | journal = Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica | volume = 88 | issue = 1 | pages = 19–32 | date = July 1986 | pmid = 3758874 | doi = 10.1254/fpj.88.19 | doi-access = free }}</ref> 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. 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.<ref name="Noguchi-2004">{{cite journal | vauthors = Noguchi H, Kitazumi K, Mori M, Shiba T | title = Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats | journal = Journal of Pharmacological Sciences | volume = 94 | issue = 3 | pages = 246–251 | date = March 2004 | pmid = 15037809 | doi = 10.1254/jphs.94.246 | doi-access = free }}</ref>

==Pharmacokinetics==

Nitrazepam is largely bound to plasma proteins.<ref>{{cite journal | vauthors = Tokola RA, Neuvonen PJ | title = Pharmacokinetics of antiepileptic drugs | journal = Acta Neurologica Scandinavica. Supplementum | volume = 97 | pages = 17–27 | year = 1983 | pmid = 6143468 | doi = 10.1111/j.1600-0404.1983.tb01532.x | s2cid = 25137468 | doi-access = free }}</ref> Benzodiazepines such as nitrazepam are [[Lipophilicity|lipid-soluble]] and have a high cerebral uptake.<ref>{{cite journal | vauthors = Hertz MM, Paulson OB | title = Heterogeneity of cerebral capillary flow in man and its consequences for estimation of blood-brain barrier permeability | journal = The Journal of Clinical Investigation | volume = 65 | issue = 5 | pages = 1145–1151 | date = May 1980 | pmid = 6988458 | pmc = 371448 | doi = 10.1172/JCI109769 }}</ref> 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.<ref name="Kangas-1979">{{cite journal | vauthors = Kangas L, Iisalo E, Kanto J, Lehtinen V, Pynnönen S, Ruikka I, Salminen J, Sillanpää M, Syvälahti E | display-authors = 6 | title = Human pharmacokinetics of nitrazepam: effect of age and diseases | journal = European Journal of Clinical Pharmacology | volume = 15 | issue = 3 | pages = 163–170 | date = April 1979 | pmid = 456400 | doi = 10.1007/bf00563100 | s2cid = 19791755 }}</ref><ref name="Vozeh-1981">{{cite journal | vauthors = Vozeh S | title = [Pharmacokinetic of benzodiazepines in old age] | journal = Schweizerische Medizinische Wochenschrift | volume = 111 | issue = 47 | pages = 1789–1793 | date = November 1981 | pmid = 6118950 }}</ref> Both low dose (5&nbsp;mg) and high dose (10&nbsp;mg) of nitrazepam significantly increases [[growth hormone]] levels in humans.<ref>{{cite journal | vauthors = Kangas L, Kanto J, Syvälahti E | title = Plasma nitrazepam concentrations after an acute intake and their correlation to sedation and serum growth hormone levels | journal = Acta Pharmacologica et Toxicologica | volume = 41 | issue = 1 | pages = 65–73 | date = July 1977 | pmid = 331868 | doi = 10.1111/j.1600-0773.1977.tb02124.x }}</ref>

Nitrazepam's half-life in the [[cerebrospinal fluid]], 68 hours, indicates that nitrazepam is eliminated extremely slowly from the cerebrospinal fluid.<ref>{{cite journal | vauthors = Kangas L, Kanto J, Siirtola T, Pekkarinen A | title = Cerebrospinal-fluid concentrations of nitrazepam in man | journal = Acta Pharmacologica et Toxicologica | volume = 41 | issue = 1 | pages = 74–79 | date = July 1977 | pmid = 578380 | doi = 10.1111/j.1600-0773.1977.tb02125.x }}</ref> 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.<ref>{{cite journal | vauthors = Holm V, Melander A, Wåhlin-Boll E | title = Influence of food and of age on nitrazepam kinetics | journal = Drug-Nutrient Interactions | volume = 1 | issue = 4 | pages = 307–311 | year = 1982 | pmid = 6926838 }}</ref>

==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]].<ref>{{cite journal | vauthors = Lai SH, Yao YJ, Lo DS | title = A survey of buprenorphine related deaths in Singapore | journal = Forensic Science International | volume = 162 | issue = 1–3 | pages = 80–86 | date = October 2006 | pmid = 16879940 | doi = 10.1016/j.forsciint.2006.03.037 }}</ref> Nitrobenzodiazepines such as nitrazepam can result in a severe neurological effects.<ref name="Linwu-2009">{{cite journal | vauthors = Linwu SW, Syu CJ, Chen YL, Wang AH, Peng FC | title = Characterization of Escherichia coli nitroreductase NfsB in the metabolism of nitrobenzodiazepines | journal = Biochemical Pharmacology | volume = 78 | issue = 1 | pages = 96–103 | date = July 2009 | pmid = 19447228 | doi = 10.1016/j.bcp.2009.03.019 | url = http://ntur.lib.ntu.edu.tw//handle/246246/163394 }}</ref> 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.<ref name="Gidai-2010">{{cite journal | vauthors = Gidai J, Acs N, Bánhidy F, Czeizel AE | title = Congenital abnormalities in children of 43 pregnant women who attempted suicide with large doses of nitrazepam | journal = Pharmacoepidemiology and Drug Safety | volume = 19 | issue = 2 | pages = 175–182 | date = February 2010 | pmid = 19998314 | doi = 10.1002/pds.1885 | s2cid = 25856700 }}</ref>

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.<ref>{{cite journal | vauthors = Carroll WM, Mastiglia FL | title = Alpha and beta coma in drug intoxication | journal = British Medical Journal | volume = 2 | issue = 6101 | pages = 1518–1519 | date = December 1977 | pmid = 589310 | pmc = 1632784 | doi = 10.1136/bmj.2.6101.1518-a }}</ref><ref>{{cite journal | vauthors = Rumpl E, Prugger M, Battista HJ, Badry F, Gerstenbrand F, Dienstl F | title = Short latency somatosensory evoked potentials and brain-stem auditory evoked potentials in coma due to CNS depressant drug poisoning. Preliminary observations | journal = Electroencephalography and Clinical Neurophysiology | volume = 70 | issue = 6 | pages = 482–489 | date = December 1988 | pmid = 2461282 | doi = 10.1016/0013-4694(88)90146-0 }}</ref>

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.<ref name="Carlsten-2003">{{cite journal | vauthors = Carlsten A, Waern M, Holmgren P, Allebeck P | title = The role of benzodiazepines in elderly suicides | journal = Scandinavian Journal of Public Health | volume = 31 | issue = 3 | pages = 224–228 | year = 2003 | pmid = 12850977 | doi = 10.1080/14034940210167966 | s2cid = 24102880 }}</ref> 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.<ref>{{cite journal | vauthors = Moriya F, Hashimoto Y | title = Tissue distribution of nitrazepam and 7-aminonitrazepam in a case of nitrazepam intoxication | journal = Forensic Science International | volume = 131 | issue = 2–3 | pages = 108–112 | date = January 2003 | pmid = 12590048 | doi = 10.1016/S0379-0738(02)00421-8 }}</ref>

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.<ref name="Ericsson-1993">{{cite journal | vauthors = Ericsson HR, Holmgren P, Jakobsson SW, Lafolie P, De Rees B | title = [Benzodiazepine findings in autopsy material. A study shows interacting factors in fatal cases] | journal = Läkartidningen | volume = 90 | issue = 45 | pages = 3954–3957 | date = November 1993 | pmid = 8231567 }}</ref> 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.<ref name="Drummer-1996">{{cite journal | vauthors = Drummer OH, Ranson DL | title = Sudden death and benzodiazepines | journal = The American Journal of Forensic Medicine and Pathology | volume = 17 | issue = 4 | pages = 336–342 | date = December 1996 | pmid = 8947361 | doi = 10.1097/00000433-199612000-00012 }}</ref>

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.<ref>{{cite journal | vauthors = Brødsgaard I, Hansen AC, Vesterby A | title = Two cases of lethal nitrazepam poisoning | journal = The American Journal of Forensic Medicine and Pathology | volume = 16 | issue = 2 | pages = 151–153 | date = June 1995 | pmid = 7572872 | doi = 10.1097/00000433-199506000-00015 | s2cid = 11306468 }}</ref>

==Synthesis==

Reaction of 2-amino-5-nitrobenzophenone ('''1''') with [[bromoacetyl bromide]] forms the amide '''2'''. Ring closure in [[liquid ammonia]] affords nitrazepam ('''3'''). More simply, [[diazepinone]] ('''4''') can be nitrated directly at the more reactive C₇ position with [[potassium nitrate]] in [[sulfuric acid]].

[[File:Nitrazepam synthesis.svg|thumb|center|700px|Nitrazepam synthesis:<ref>{{cite journal | vauthors = Sternbach LH, Fryer RI, Keller O, Metlesics W, Sach G, Steiger N | title = Quinazolines and 1,4-Benzodiazepines. X. Nitro-Substituted 5-Phenyl-1,4-Benzodiazepine Derivatives | journal = Journal of Medicinal Chemistry | volume = 6 | issue = 3 | pages = 261–265 | date = May 1963 | pmid = 14185980 | doi = 10.1021/jm00339a010 }}</ref><ref>{{cite patent | country = US | number = 3121076 | status = patent | pubdate = 11 February 1964 | title = Benzodiazepinones and Processes | assign1 = [[Hoffmann-La Roche]] | inventor = Keller O }}</ref>]]

== 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<ref name="Rustler_2020" /> - light-activated derivative of benzodiazepine based on photoisomerizable fulgimide

== References ==

{{Reflist}}

== External links ==

* [https://web.archive.org/web/20120328101755/http://www.betterhealth.vic.gov.au/bhcv2/bhcmed.nsf/pages/afcalodo/$File/afcalodo.pdf Patient information sheet 1]

* [https://web.archive.org/web/20070928050201/http://www.pbs.gov.au/pi/afpalodo10705.pdf Patient information sheet 2]

* [http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20M)/MOGADON.html RxMed - Nitrazepam]

* [http://www.inchem.org/documents/pims/pharm/pim675.htm Inchem - Nitrazepam]

{{Benzodiazepines}}

{{Anticonvulsants}}

{{Hypnotics and sedatives}}

{{GABAAR PAMs}}

[[Category:GABAA receptor positive allosteric modulators]]

[[Category:Lactams]]

[[Category:Nitrobenzodiazepines]]