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Prazepam

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Not to be confused with Prazepine.
Prazepam
Clinical data
Other names9-chloro-2-(cyclopropylmethyl)-6-phenyl-2,5-diazabicyclo[5.4.0]undeca-5,8,10,12-tetraen- 3-one
AHFS/Drugs.comMicromedex Detailed Consumer Information
MedlinePlusa601036
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismHepatic
Elimination half-life36–200 hours
ExcretionRenal
Identifiers
  • 7-Chloro-1-(cyclopropylmethyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.019.069 Edit this at Wikidata
Chemical and physical data
FormulaC19H17ClN2O
Molar mass324.81 g·mol−1
3D model (JSmol)
  • Clc4cc\1c(N(C(=O)C/N=C/1c2ccccc2)CC3CC3)cc4
  • InChI=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 checkY
  • Key:MWQCHHACWWAQLJ-UHFFFAOYSA-N checkY
  (verify)

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

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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

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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

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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

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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

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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

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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.[15][22][32][33]

Interactions

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

Overdose

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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

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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.[15][37]

Toxicity

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

Trade names

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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

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References

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  1. ^ Anvisa (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] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ^ US Patent 3192199 – Process for the production of I-CYCLO- ALKYL derivatives of I,X-BENZODIAZEPINE
  3. ^ Shader RI, Greenblatt DJ (1979). "Benzodiazepines: Some Aspects of Their Clinical Pharmacology". Ciba Foundation Symposium 74 - Drug Concentrations in Neuropsychiatry. Novartis Foundation Symposia. Vol. 1979. pp. 141–155. doi:10.1002/9780470720578.ch9. ISBN 9780470720578. PMID 45081. {{cite book}}: |journal= ignored (help)
  4. ^ Jacqmin P, Ansseau M (1988). "Comparison of sublingual and oral prazepam in normal subjects. II. Pharmacokinetic and pharmacodynamic data". Neuropsychobiology. 19 (4): 186–191. doi:10.1159/000118458. PMID 2854609.
  5. ^ Rickels K, Sablosky L, Silverman H, Case WG, Rial W, Mirman M, Gottlieb S (1977). "Prazepam in anxiety: a controlled clinical trial". Comprehensive Psychiatry. 18 (3): 239–249. doi:10.1016/0010-440X(77)90018-9. PMID 858240.
  6. ^ Ansseau M, Von Frenckell R (1991). "[Value of prazepam drops in the brief treatment of anxiety disorders]" [Value of prazepam drops in the brief treatment of anxiety disorders]. L'Encephale (in French). 17 (4): 291–294. PMID 1959497.
  7. ^ Breimer DD, Jochemsen R, von Albert HH (1980). "Pharmacokinetics of benzodiazepines. Short-acting versus long-acting". Arzneimittel-Forschung. 30 (5a): 875–881. PMID 6106488.
  8. ^ Allen MD, Greenblatt DJ, Harmatz JS, Shader RI (August 1980). "Desmethyldiazepam kinetics in the elderly after oral prazepam". Clinical Pharmacology and Therapeutics. 28 (2): 196–202. doi:10.1038/clpt.1980.150. PMID 6772370. S2CID 7514074.
  9. ^ Greenblatt DJ, Harmatz JS, Dorsey C, Shader RI (September 1988). "Comparative single-dose kinetics and dynamics of lorazepam, alprazolam, prazepam, and placebo". Clinical Pharmacology and Therapeutics. 44 (3): 326–334. doi:10.1038/clpt.1988.158. PMID 3138056. S2CID 20150379.
  10. ^ Danion JM, Brion S, Escande M, Ropert R, Sacquepee L, Singer L, Scotto JC (1984). "[Treatment of anxiety with prazepam, 40 mg. A controlled study versus lorazepam]" [Treatment of anxiety with prazepam, 40 mg. A controlled study versus lorazepam]. L'Encephale (in French). 10 (3): 135–138. PMID 6389091.
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  13. ^ Ansseau M, von Frenckell R, Jacqmin P (1987). "Comparison of sublingual and oral prazepam in normal subjects. I. Clinical data". Neuropsychobiology. 18 (2): 77–82. doi:10.1159/000118397. hdl:2268/249065. PMID 3330182.
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  18. ^ Soyka M, Lehle R, Hippius H (September 1994). "[Exacerbation of an affective psychosis after terminating a decade of benzodiazepine treatment. Which therapeutic procedure is sensible?]" [Exacerbation of an affective psychosis after terminating a decade of benzodiazepine treatment. Which therapeutic procedure is sensible?]. Der Nervenarzt (in German). 65 (9): 628–632. PMID 7991010.
  19. ^ Dièye AM, Sylla M, Ndiaye A, Ndiaye M, Sy GY, Faye B (June 2006). "Benzodiazepines prescription in Dakar: a study about prescribing habits and knowledge in general practitioners, neurologists and psychiatrists". Fundamental & Clinical Pharmacology. 20 (3): 235–238. doi:10.1111/j.1472-8206.2006.00400.x. PMID 16671957. S2CID 20619323.
  20. ^ Dièye AM, Sy AN, Sy GY, Diallo AA, Diarra M, Ndiaye M, Faye B (2007). "Prescription des benzodiazépines par les médecins généralistes du privé à Dakar : Enquête sur les connaissances et les attitudes" [Prescription of benzodiazepines by general practitioners in the private sector of Dakar: survey on knowledge and attitudes]. Therapie (in French). 62 (2): 163–168. doi:10.2515/therapie:2007018. PMID 17582318.
  21. ^ Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Annales Pharmaceutiques Françaises. 67 (6): 408–413. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
  22. ^ a b Quast U (May 1981). "[Molecular mechanism of action of benzodiazepines]" [Molecular mechanism of action of benzodiazepines]. Fortschritte der Medizin (in German). 99 (20): 788–794. PMID 6114911.
  23. ^ De Sarro G, Gitto R, Rizzo M, Zappia M, De Sarro A (September 1996). "1,4-Benzodiazepine derivatives as anticonvulsant agents in DBA/2 mice". General Pharmacology. 27 (6): 935–941. doi:10.1016/0306-3623(95)02147-7. PMID 8909973.
  24. ^ De Sarro G, Chimirri A, Zappala M, Guisti P, Lipartiti M, De Sarro A (October 1996). "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. doi:10.1016/S0306-3623(96)00049-3. PMID 8981061.
  25. ^ De Sarro G, Chimirri A, McKernan R, Quirk K, Giusti P, De Sarro A (September 1997). "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. doi:10.1016/S0091-3057(96)00565-5. PMID 9264104. S2CID 24492818.
  26. ^ Fukinaga M, Ishizawa K, Kamei C (November 1998). "Anticonvulsant properties of 1,4-benzodiazepine derivatives in amygdaloid-kindled seizures and their chemical structure-related anticonvulsant action". Pharmacology. 57 (5): 233–241. doi:10.1159/000028247. PMID 9742288. S2CID 25773207.
  27. ^ Viau JP, Epps JE, Di Carlo J (September 1973). "Prazepam metabolism after chronic administration to humans". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 3 (9): 581–587. doi:10.3109/00498257309151546. PMID 4763144.
  28. ^ Valavani P, Atta-Politou J, Panderi I (April 2005). "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. Bibcode:2005JMSp...40..516V. doi:10.1002/jms.824. PMID 15712230.
  29. ^ Lu XL, Guengerich FP, Yang SK (1991). "Stereoselective metabolism of prazepam and halazepam by human liver microsomes". Drug Metabolism and Disposition. 19 (3): 637–642. PMID 1680631.
  30. ^ Greenblatt DJ, Shader RI (April 1978). "Prazepam, a precursor of desmethyldiazepam". Lancet. 1 (8066): 720. doi:10.1016/S0140-6736(78)90834-6. PMID 76260. S2CID 2179445.
  31. ^ Nau H, Liddiard C, Jesdinsky D, Wittfoht W (September 1978). "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. doi:10.1016/S0378-4347(00)81889-7. PMID 701422.
  32. ^ Kölle EU (June 1981). "[Pharmacokinetics of oral prazepam]" [Pharmacokinetics of oral prazepam]. Fortschritte der Medizin (in German). 99 (22): 874–879. PMID 6790396.
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  34. ^ Ruffalo RL, Thompson JF, Segal J (September 1981). "Cimetidine-benzodiazepine drug interaction". American Journal of Hospital Pharmacy. 38 (9): 1365–1366. PMID 6116430.
  35. ^ Girre C, Hirschhorn M, Bertaux L, Palombo S, Fournier PE (1991). "Comparison of performance of healthy volunteers given prazepam alone or combined with ethanol. Relation to drug plasma concentrations". International Clinical Psychopharmacology. 6 (4): 227–238. doi:10.1097/00004850-199100640-00004. PMID 1816280.
  36. ^ Pulce C, Mollon P, Pham E, Frantz P, Descotes J (April 1992). "Acute poisonings with ethyle loflazepate, flunitrazepam, prazepam and triazolam in children". Veterinary and Human Toxicology. 34 (2): 141–143. PMID 1354907.
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  38. ^ Fox KA, Guerriero FJ (July 1978). "Effect of benzodiazepines on age of vaginal perforation and first estrus in mice". Research Communications in Chemical Pathology and Pharmacology. 21 (1): 181–184. PMID 28555.
  39. ^ Guerriero FJ, Fox KA (April 1976). "Benzodiazepines and reproduction of swiss-webster mice". Research Communications in Chemical Pathology and Pharmacology. 13 (4): 601–610. PMID 4863.
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