Prazepam Explained

Watchedfields:changed
Verifiedrevid:464213409
Iupac Name:7-Chloro-1-(cyclopropylmethyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one
Width:180
Width2:140
Legal Br:B1
Legal Br Comment:[1]
Legal Ca:Schedule IV
Legal De:Rx-only/Anlage III
Legal Us:Schedule IV
Routes Of Administration:Oral
Metabolism:Hepatic
Elimination Half-Life:36–200 hours
Excretion:Renal
Iuphar Ligand:7275
Cas Number:2955-38-6
Atc Prefix:N05
Atc Suffix:BA11
Pubchem:4890
Drugbank:DB01588
Chemspiderid:4721
Unii:Q30VCC064M
Kegg:D00470
Chembl:969
C:19
H:17
Cl:1
N:2
O:1
Smiles:Clc4cc\1c(N(C(=O)C/N=C/1c2ccccc2)CC3CC3)cc4
Stdinchi:1S/C19H17ClN2O/c20-15-8-9-17-16(10-15)19(14-4-2-1-3-5-14)21-11-18(23)22(17)12-13-6-7-13/h1-5,8-10,13H,6-7,11-12H2
Stdinchikey:MWQCHHACWWAQLJ-UHFFFAOYSA-N
Synonyms:9-chloro-2-(cyclopropylmethyl)-6-phenyl-2,5-diazabicyclo[5.4.0]undeca-5,8,10,12-tetraen- 3-one

Prazepam is a benzodiazepine derivative drug developed by Warner-Lambert in the 1960s.[2] It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.[3] Prazepam is a prodrug for desmethyldiazepam which is responsible for the therapeutic effects of prazepam.[4]

Indications

Prazepam is indicated for the short-term treatment of anxiety. After short-term therapy, the dose is usually gradually tapered-off to reduce or avoid any withdrawal or rebound effects.[5] [6] Desmethyldiazepam, an active metabolite, has a very long half-life of 29 to 224 hours, which contributes to the therapeutic effects of prazepam.[7] [8]

Side effects

Side effects of prazepam are less profound than with other benzodiazepines.[9] Excessive drowsiness and with longer-term use, drug dependence, are the most common side effects of prazepam.[10] [11] Side effects such as fatigue or "feeling spacey" can also occur but less commonly than with other benzodiazepines. Other side effects include feebleness, clumsiness or lethargy, clouded thinking and mental slowness.[12] [13] [14]

Tolerance, dependence and withdrawal

See also: Benzodiazepine withdrawal syndrome. Tolerance and dependence can develop with long-term use of prazepam, and upon cessation or reduction in dosage, then a benzodiazepine withdrawal syndrome may occur with symptoms such as tremulousness, dysphoria, psychomotor agitation, tachycardia and sweating. In severe cases, hallucinations, psychosis and seizures can occur. Withdrawal-related psychosis is generally unresponsive to antipsychotic mediations. The risk and severity of the withdrawal syndrome increases the higher the dose and the longer prazepam is taken for.[15] Tolerance, dependence and withdrawal problems may be less severe than with other benzodiazepines, such as diazepam.[16] It may be because tolerance is slower to develop with prazepam than with other benzodiazepines.[17] Abrupt or over-rapid discontinuation of prazepam after long-term use, even at low dosage, may result in a protracted withdrawal syndrome.[18]

Benzodiazepines can induce serious problems of addiction, which is one of the main reasons for their use being restricted to short-term use. A survey in Senegal found that the majority of doctors believed that their training in this area was generally poor. It was recommended that national authorities take urgent action regarding the rational use of benzodiazepines. Almost one-fifth of doctors ignored prescription guidelines regarding short-term use of benzodiazepines, and almost three-quarters of doctors regarded their training and knowledge of benzodiazepines to be inadequate. More training regarding benzodiazepines has been recommended for doctors.[19] [20]

Contraindications and special caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.[21]

Mechanism of action

Prazepam exerts its therapeutic effects primarily via modulating the benzodiazepine receptor which in turn enhances GABA function in the brain.[22] Prazepam like other benzodiazepines has anticonvulsant properties, but its anticonvulsant properties are not as potent as other benzodiazepines when tested in animal studies.[23] [24] [25] [26]

Pharmacokinetics

Prazepam is metabolised into descyclopropylmethylprazepam (also known as desmethyldiazepam) and 3-hydroxyprazepam which is further metabolised into oxazepam.[27] [28] [29] [30] [31] Prazepam is a prodrug for descyclopropylmethylprazepam/desmethyldiazepam (also known as norprazepam or nordazepam) which is responsible for most of the therapeutic activity of prazepam rather than prazepam itself.[32] [33]

Interactions

Prazepam may interact with cimetidine.[34] Alcohol in combination with prazepam increases the adverse effects, particularly performance impairing side effects and drowsiness.[35]

Overdose

See also: Benzodiazepine overdose. The symptoms of an overdose of prazepam include sleepiness, agitation and ataxia. Hypotonia may also occur in severe cases. Overdoses in children typically result in more severe symptoms of overdose.[36]

Abuse potential

See also: Benzodiazepine drug misuse. Prazepam like other benzodiazepines has abuse potential and can be habit forming. However, its abuse potential may be lower than other benzodiazepines because it has a slow onset of action.[37]

Toxicity

Animal studies have found prazepam taken during pregnancy results in delayed growth and causes reproductive abnormalities.[38] [39] [40]

Trade names

Common trade names include Centrac, Centrax, Demetrin, Lysanxia, Mono Demetrin, Pozapam, Prasepine, Prazene, Reapam and Trepidan. Trade names vary depending on the country; Austria: Demetrin, Belgium: Lysanxia, France: Lysanxia, Germany: Demetrin; Mono Demetrin, Greece: Centrac, Ireland: Centrax, Italy: Prazene; Trepidan, Macedonia: Demetrin, Prazepam, Netherlands: Reapam, Portugal: Demetrin, South Africa: Demetrin, Switzerland: Demetrin, Thailand: Pozapam; Prasepine.[41]

See also

External links

Notes and References

  1. Web site: Anvisa . Brazilian Health Regulatory Agency . 2023-03-31 . RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial . Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control. live . 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 . 2023-08-03 . 2023-08-16 . . pt-BR . 2023-04-04.
  2. US Patent 3192199 – Process for the production of I-CYCLO- ALKYL derivatives of I,X-BENZODIAZEPINE
  3. Shader RI, Greenblatt DJ . Benzodiazepines: some aspects of their clinical pharmacology . Ciba Foundation Symposium . 1979 . 74 . 141–155 . 1979 . 45081 . 10.1002/9780470720578.ch9 . 9780470720578 . Novartis Foundation Symposia .
  4. Jacqmin P, Ansseau M . Comparison of sublingual and oral prazepam in normal subjects. II. Pharmacokinetic and pharmacodynamic data . Neuropsychobiology . 19 . 4 . 186–191 . 1988 . 2854609 . 10.1159/000118458 .
  5. Rickels K, Sablosky L, Silverman H, Case WG, Rial W, Mirman M, Gottlieb S . Prazepam in anxiety: a controlled clinical trial . Comprehensive Psychiatry . 18 . 3 . 239–249 . 1977 . 858240 . 10.1016/0010-440X(77)90018-9 .
  6. Ansseau M, Von Frenckell R . [Value of prazepam drops in the brief treatment of anxiety disorders] . fr . L'Encephale . 17 . 4 . 291–294 . 1991 . 1959497 . Value of prazepam drops in the brief treatment of anxiety disorders .
  7. Breimer DD, Jochemsen R, von Albert HH . Pharmacokinetics of benzodiazepines. Short-acting versus long-acting . Arzneimittel-Forschung . 30 . 5a . 875–881 . 1980 . 6106488 .
  8. Allen MD, Greenblatt DJ, Harmatz JS, Shader RI . Desmethyldiazepam kinetics in the elderly after oral prazepam . Clinical Pharmacology and Therapeutics . 28 . 2 . 196–202 . August 1980 . 6772370 . 10.1038/clpt.1980.150 . 7514074 .
  9. Greenblatt DJ, Harmatz JS, Dorsey C, Shader RI . Comparative single-dose kinetics and dynamics of lorazepam, alprazolam, prazepam, and placebo . Clinical Pharmacology and Therapeutics . 44 . 3 . 326–334 . September 1988 . 3138056 . 10.1038/clpt.1988.158 . 20150379 .
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  17. Saletu M, Saletu B, Grünberger J, Mader R, Karobath M . Clinical symptomatology and computer analyzed EEG before, during and after anxiolytic therapy of alcohol withdrawal patients . Neuropsychobiology . 9 . 2–3 . 119–134 . 1983 . 6353268 . 10.1159/000117949 .
  18. Soyka M, Lehle R, Hippius H . [Exacerbation of an affective psychosis after terminating a decade of benzodiazepine treatment. Which therapeutic procedure is sensible?] . de . Der Nervenarzt . 65 . 9 . 628–632 . September 1994 . 7991010 . Exacerbation of an affective psychosis after terminating a decade of benzodiazepine treatment. Which therapeutic procedure is sensible? .
  19. Dièye AM, Sylla M, Ndiaye A, Ndiaye M, Sy GY, Faye B . Benzodiazepines prescription in Dakar: a study about prescribing habits and knowledge in general practitioners, neurologists and psychiatrists . Fundamental & Clinical Pharmacology . 20 . 3 . 235–238 . June 2006 . 16671957 . 10.1111/j.1472-8206.2006.00400.x . 20619323 .
  20. Dièye AM, Sy AN, Sy GY, Diallo AA, Diarra M, Ndiaye M, Faye B . fr . Therapie . 62 . 2 . 163–168 . 2007 . 17582318 . 10.2515/therapie:2007018 . Prescription of benzodiazepines by general practitioners in the private sector of Dakar: survey on knowledge and attitudes. Prescription des benzodiazépines par les médecins généralistes du privé à Dakar : Enquête sur les connaissances et les attitudes.
  21. Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A . 6 . Benzodiazepine dependence: focus on withdrawal syndrome . Annales Pharmaceutiques Françaises . 67 . 6 . 408–413 . November 2009 . 19900604 . 10.1016/j.pharma.2009.07.001 .
  22. Quast U . [Molecular mechanism of action of benzodiazepines] . de . Fortschritte der Medizin . 99 . 20 . 788–794 . May 1981 . 6114911 . Molecular mechanism of action of benzodiazepines .
  23. De Sarro G, Gitto R, Rizzo M, Zappia M, De Sarro A . 1,4-Benzodiazepine derivatives as anticonvulsant agents in DBA/2 mice . General Pharmacology . 27 . 6 . 935–941 . September 1996 . 8909973 . 10.1016/0306-3623(95)02147-7 .
  24. De Sarro G, Chimirri A, Zappala M, Guisti P, Lipartiti M, De Sarro A . Azirino[1, 2-d][1, 4]benzodiazepine derivatives and related 1,4-benzodiazepines as anticonvulsant agents in DBA/2 mice . General Pharmacology . 27 . 7 . 1155–1162 . October 1996 . 8981061 . 10.1016/S0306-3623(96)00049-3 .
  25. De Sarro G, Chimirri A, McKernan R, Quirk K, Giusti P, De Sarro A . Anticonvulsant activity of azirino[1,2-d][1,4]benzodiazepines and related 1,4-benzodiazepines in mice . Pharmacology, Biochemistry, and Behavior . 58 . 1 . 281–289 . September 1997 . 9264104 . 10.1016/S0091-3057(96)00565-5 . 24492818 .
  26. Fukinaga M, Ishizawa K, Kamei C . Anticonvulsant properties of 1,4-benzodiazepine derivatives in amygdaloid-kindled seizures and their chemical structure-related anticonvulsant action . Pharmacology . 57 . 5 . 233–241 . November 1998 . 9742288 . 10.1159/000028247 . 25773207 .
  27. Viau JP, Epps JE, Di Carlo J . Prazepam metabolism after chronic administration to humans . Xenobiotica; the Fate of Foreign Compounds in Biological Systems . 3 . 9 . 581–587 . September 1973 . 4763144 . 10.3109/00498257309151546 .
  28. Valavani P, Atta-Politou J, Panderi I . Development and validation of a liquid chromatographic/electrospray ionization mass spectrometric method for the quantitation of prazepam and its main metabolites in human plasma . Journal of Mass Spectrometry . 40 . 4 . 516–526 . April 2005 . 15712230 . 10.1002/jms.824 . 2005JMSp...40..516V .
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  30. Greenblatt DJ, Shader RI . Prazepam, a precursor of desmethyldiazepam . Lancet . 1 . 8066 . 720 . April 1978 . 76260 . 10.1016/S0140-6736(78)90834-6 . 2179445 .
  31. Nau H, Liddiard C, Jesdinsky D, Wittfoht W . Quantitative analysis of prazepam and its metabolites by electron capture gas chromatography and selected ion monitoring. Application to diaplacetal passage and fetal hepatic metabolism in early human pregnancy . Journal of Chromatography . 146 . 2 . 227–239 . September 1978 . 701422 . 10.1016/S0378-4347(00)81889-7 .
  32. Kölle EU . [Pharmacokinetics of oral prazepam] . de . Fortschritte der Medizin . 99 . 22 . 874–879 . June 1981 . 6790396 . Pharmacokinetics of oral prazepam .
  33. Ochs HR, Greenblatt DJ, Verburg-Ochs B, Locniskar A . Comparative single-dose kinetics of oxazolam, prazepam, and clorazepate: three precursors of desmethyldiazepam . Journal of Clinical Pharmacology . 24 . 10 . 446–451 . October 1984 . 6150943 . 10.1002/j.1552-4604.1984.tb01817.x . dead . 24414335 . https://web.archive.org/web/20090720073318/http://jcp.sagepub.com/cgi/content/abstract/24/10/446 . 2009-07-20 .
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