Nitrazepam
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| Non-proprietary name | Nitrazepam | ||||||||||||||||||
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| Molecular formula | C 15 H 11 N 3 O 3 | ||||||||||||||||||
| Brief description |
yellow, crystalline powder |
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| Molar mass | 281.27 g · mol -1 | ||||||||||||||||||
| Physical state |
firmly |
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| Melting point |
224-226 ° C |
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| pK s value |
3.2 |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||||||||
Nitrazepam ( trade name e.g. Mogadan; first manufacturer Hoffmann-La Roche ) is a drug from the group of benzodiazepines with pronounced hypnotic and anticonvulsant properties and is used for the symptomatic treatment of sleep disorders and in the treatment of juvenile epilepsy . Psychological and physical dependence can develop after only a short period of use .
Clinical information
Application areas (indications)
Nitrazepam is rapidly and extensively absorbed from the digestive tract into the systemic circulation . Due to the great hypnotic potency, it is therefore indicated for the symptomatic short-term treatment of insomnia (sleep disorders) of clinically significant severity, for example caused by overuse, fear, worry, etc. In the case of organically caused sleep disorders, causal therapy for the underlying disease must also be considered. Due to the medium-long plasma half - life (t 1/2 = 15–30 hours), hang-over effects (symptoms of tiredness during the day, especially after getting up) and a tendency to accumulate after repeated administration can occur. Nitrazepam induced sleep is different from normal sleep. While two stages of orthodox sleep are prolonged, one stage is shortened. In contrast, REM sleep is only slightly affected. Today, the so-called Z-drugs ( zopiclone , zolpidem and zaleplon ) are often prescribed as sleeping pills instead of benzodiazepines .
Nitrazepam is used in the adjuvant treatment of Blitz-Nick-Salaam attacks . It is also used in children with Lennox-Gastaut syndrome with myoclonic-astatic seizures. Overall , the epilepsy syndromes mentioned represent a therapeutic problem. An attempt at therapy, like the treatment of this epilepsy, should be reserved for specialists.
Contraindications (contraindications)
Nitrazepam is contraindicated in patients with known
- Hypersensitivity to the active substance and the pharmaceutical excipients
- in severe respiratory failure
- Sleep apnea
- severe chronic hypercapnia
- Myasthenia gravis pseudoparalytica (severe muscle weakness)
- Addicts; alcoholism
- severe hepatic insufficiency
- Cerebellar and spinal ataxias (disorders of balance regulation and movement coordination)
Drug interactions
With a few exceptions, nitrazepam does not generally show any clinically relevant interactions with other drugs when dosed correctly . In therapeutic doses, nitrazepam does not induce enzyme induction and can therefore be administered simultaneously with other drugs such as anticoagulants or oral antidiabetic agents .
Use during pregnancy and breastfeeding
Nitrazepam crosses the placental barrier and reaches the same concentrations in the fetal plasma as in the maternal plasma in late pregnancy. It may therefore only be used in exceptional cases for compelling reasons. With prolonged use of the drug by pregnant women, withdrawal symptoms can occur in newborns. Use towards the end of pregnancy or during childbirth can lead to hypothermia (decreased body temperature), hypotension (drop in blood pressure), depressed breathing, muscular hypotension (decreased muscle tension) and poor drinking in the newborn . Therefore, the use of nitrazepam in the last trimester of pregnancy is contraindicated . Nitrazepam crosses the placental barrier and is excreted in breast milk. It can accumulate there after repeated administration, so that repeated ingestion or high doses must be weaned .
Special patient groups (diabetics, kidney patients)
Since the Qo value of nitrazepam is high (Qo = 1), no dose adjustment is necessary in the case of impaired renal function. Many drugs with a high Qo value produce renally eliminated metabolites, the activity of which is not always known. Accordingly, caution should be exercised in the case of severe kidney function impairments.
Adverse effects (side effects)
Acute side effects:
- Among the acute side effects of oral therapy with nitrazepam, fatigue, drowsiness, poor concentration and impaired concentration and the ability to react are in the foreground. This affects the ability to drive and operate machines.
Side effects with chronic use:
- With chronic use of nitrazepam, there is a particular risk of tolerance and dependence on psychotropic substances.
Pharmacological properties
Mechanism of action (pharmacodynamics)
The psychotropic drug nitrazepam from the group of 1,4-benzodiazepines binds with high affinity to GABA receptors in the CNS. Nitrazepam strengthens the inhibitory effect of GABA-ergic transmission on different groups of neurons. This results in tension-relieving, arousal-dampening and anxiolytic (anxiety-suppressing) properties as well as sedating and hypnotic effects. In addition, Nitrazepam shows muscle relaxant (muscle tone depressant) and anticonvulsant properties.
Absorption and distribution in the body (pharmacokinetics)
Nitrazepam is absorbed from the gastrointestinal tract with individual differences (60–90%) . Approximately 40–80 minutes after taking 5 mg of nitrazepam, maximum values averaging 40 ng per ml are reached in the blood plasma . The volume of distribution in young patients is 2 liters / kg. The plasma protein binding is 90%. After oral administration, the bioavailability is 80%. The metabolic conversion in the liver consists of reduction to the 7-amino compound, which in turn is converted to 7-acetamidonitrazepam. The optimal effective concentration should be 40 ng nitrazepam per ml blood plasma . The elimination of nitrazepam from the blood is biphasic. The average elimination half-life is 30 hours. Under chronic administration of these elimination half-life does not change. In a continuous administration of 5 mg daily nitrazepam that is steady state ( steady state ) at concentrations of approximately 40-60 ng per ml of plasma nitrazepam achieved by the fourth day. Only a few percent of the orally administered doses appear in the urine as unchanged nitrazepam.
toxicology
Benzodiazepines have a wide therapeutic range , so overdose or accidental poisoning with nitrazepam is generally not life-threatening unless taken with other CNS-active substances, including alcohol . Benzodiazepine intoxications are usually characterized - depending on the dose absorbed - by various stages of central depression, which can range from somnolence, mental confusion, lethargy, visual disturbances and dystonia to ataxia, unconsciousness, central respiratory and circulatory depression and coma.
In the case of minor symptoms of intoxication, patients should sleep in while observing their vital functions (breathing and circulatory control). In more severe cases, further measures (gastric lavage, stabilization of the circulatory system, intensive monitoring) may be necessary. If you are conscious, it makes sense to induce vomiting beforehand. Due to the high plasma protein binding and the large volume of distribution, forced diuresis or hemodialysis should only be of little use in cases of pure nitrazepam poisoning.
The selective benzodiazepine antagonist flumazenil ( trade name Anexate ® ) is indicated to reverse the central depressant effects of nitrazepam . Flumazenil is an imidazobenzodiazepine that binds competitively and reversibly to the GABA receptors with a high specificity, thereby canceling the effects of benzodiazepines. Because of its structural chemical analogy to the benzodiazepines, flumazenil has a high affinity for the benzodiazepine binding site on the GABA A receptor. Flumazenil does not cause serious side effects and does not affect your heart rate or blood pressure.
Other Information
Chemical and pharmaceutical information
The chemical name of nitrazepam according to IUPAC nomenclature is: 7-nitro-5-phenyl-2,3-dihydro-1 H -1,4-benzodiazepin-2-one. It therefore belongs to the group of benzodiazepines . Nitrazepam is a yellow, crystalline powder with a melting point in the range of 224 to 226 ° C. The compound is soluble in ethanol , acetone , chloroform and ethyl acetate . In contrast, it is practically insoluble in water, diethyl ether and hexane . The verification of identity according to Ph.Eur.5. Output takes place with the help of infrared spectroscopy by comparing the spectrum of the substance with that of Nitrazepam CRS.
Statutory information
Germany: As a representative of the benzodiazepine active ingredient group , Nitrazepam is subject to the legislation of the Narcotics Act ( BtMG ) in the Federal Republic of Germany . Here it is included in Annex III (marketable and prescription narcotics). RESTRICTION BTM: except in preparations that contain up to 0.5 percent as a drip solution without another substance from Annexes I to III BtMG, but not more than 250 mg per packaging unit, or up to 10 mg nitrazepam per divided form.
Switzerland: Nitrazepam is subject to the Narcotics Act and is listed in the Narcotics Ordinance in Appendix b - List of substances and preparations containing narcotics that are partially excluded from the control - and is in the list of specialties without any limitation. This means that nitrazepam is classified in dispensing category B and can be prescribed on a normal prescription form. The prescription may not be repeated without the consent of the doctor. Nitrazepam is reimbursed normally by the compulsory basic insurance.
Trade names
- Dormo-Puren (D)
- Imeson (D)
- Mogadan (D)
- Mogadon (A, CH)
- Novanox (D)
- Radedorm (D)
- Somnibel N (D)
See also
literature
- Hermann J. Roth: Medicinal Chemistry: Targets and Drugs; 157 tables . German Apotheker-Verlag, Stuttgart 2005, ISBN 3-7692-3483-9
- European Pharmacopoeia Commission (Ed.): EUROPEAN PHARMACOPOE 5TH EDITION . tape 5.0-5.8 , 2006.
- W. Forth, D. Henschler, W. Rummel: General and special pharmacology and toxicology . 9th edition. URBAN & FISCHER, Munich 2005, ISBN 3-437-42521-8 .
- Patent US3121076 .
Web links
Individual evidence
- ↑ a b c d e f The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; ISBN 978-0-911910-00-1
- ↑ a b c Data sheet Nitrazepam from Sigma-Aldrich , accessed on April 16, 2011 ( PDF ).
- ↑ technical information Mogadon ®
- ↑ Dose adjustment in case of renal insufficiency with Dosing ( Memento of September 27, 2007 in the Internet Archive )
- ↑ Swissmedic: List of all substances and preparations containing narcotics ( Memento of December 21, 2015 in the Internet Archive ), as of August 2011.
