Prazepam

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Prazepam
Clinical data
Synonyms9-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
Pregnancy
category
  • ?
Routes of
administration		Oral
ATC code
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Legal status
Pharmacokinetic data
Bioavailability?
MetabolismHepatic
Elimination half-life36-200 hours
ExcretionRenal
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CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
E number{{#property:P628}}
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Chemical and physical data
FormulaC19H17ClN2O
Molar mass324.8
3D model (JSmol)
  (verify)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Prazepam is a benzodiazepine derivative drug developed by Warner-Lambert in the 1960s.[1] It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.[2] Prazepam is a prodrug for desmethyldiazepam which is responsible for the therapeutic effects of prazepam.[3]

Prazepam is marketed for anxiolytic use under various trade names: Centrac, Centrax, Demetrin, Lysanxia, Mono Demetrin, Pozapam, Prasepine, Prazene, Reapam and Trepidan.

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.[4][5] Desmethyldiazepam, an active metabolite, has a very long half-life of 29 to 224 hours, which contributes to the therapeutic effects of prazepam.[6][7]

Side effects

Side effects of prazepam are less profound than with other benzodiazepines.[8] Excessive drowsiness and with longer-term use, drug dependence, are the most common side effects of prazepam.[9][10] 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 lethargic, clouded thinking and mental slowness.[11][12][13]

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.[14] Tolerance, dependence and withdrawal problems may be less severe than with other benzodiazepines, such as diazepam.[15] It may be because tolerance is slower to develop with prazepam than with other benzodiazepines.[16] Abrupt or over-rapid discontinuation of prazepam after long-term use, even at low dosage, may result in a protracted withdrawal syndrome.[17]

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. Recommendations for national authorities to take urgent action regarding the rational use of benzodiazepines.[18] Another study in Dakar found that 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]

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.[20]

Mechanism of action

Prazepam exerts its therapeutic effects primarily via modulating the benzodiazepine receptor which in turn enhances GABA function in the brain.[21] Prazepam like other benzodiazepines has anticonvulsant properties, but its anticonvulsant properties are not as potent as other benzodiazepines when tested in animal studies.[22][23][24][25]

Pharmacokinetics

Prazepam is metabolised into descyclopropylmethylprazepam (also known as desmethyldiazepam) and 3-hydroxyprazepam which is further metabolised into oxazepam.[26][27][28][29][30] Prazepam is a prodrug for descyclopropylmethylprazepam/desmethyldiazepam (also known as norprazepam or nordiazepam) which is responsible for most of the therapeutic activity of prazepam rather than prazepam itself.[14][21][31][32]

Interactions

Prazepam may interact with cimetidine.[33] Alcohol in combination with prazepam increases the adverse effects, particularly performance impairing side effects and drowsiness.[34]

Trade names

Prazepam is available under different trade names in the following countries; 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.[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.[14][37]

Toxicity

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

Synthesis

Prazepam differs from diazepam in that it has a substituent on the nitrogen atom in the first position of the benzodiazepine system.

This drug is made according to a scheme very similar to that of diazepam. It is derived from the same initial 2-amino-5-chlorobenzophenone, which undergoes acylation by cyclopropancarboxylic acid chloride. The resulting 2-cyclopropylcarbonylamino-5-chlorobenzophenone is reduced by lithium aluminum hydride into 2-cyclopropylmethylamino-5-chlorobenzhydrol, and the resulting product is oxidized by manganese dioxide into 2-cyclopropylmethylamino-5-chlorobenzophenone. This is acylated by phthalimidoacetic acid chloride. The phthalimide protecting group in the resulting product is removed by treatment with hydrazine, during which an intramolecular reaction of imino formation occurs under the conditions of synthesis, leading to the formation of the desired product, prazepam.

I. Pattison, F.H. McMillan, Template:US Patent (1965). Warner-Lambert Pharmaceutical Company, FR 1394287  (1965).

In the second, simpler scheme, synthesis begins with 7-chloro-5-phenyl-2,3-dihydro-1H- 1,4-benzodiazepin-2-one, which is alkylated by cyclopropylmethylbromide in the presence of sodium hydride into prazepam.

  • H.M. Wuest, Template:US Patent (1965).
  • S. Inaba, T. Hirohashi, H. Yamamoto, Chem. Pharm. Bull., 17, 1263 (1969).

See also


References

  1. ↑ US Patent 3192199 - Process for the production of I-CYCLO- ALKYL derivatives of I,X-BENZODIAZEPINE
  2. ↑ Shader RI, Greenblatt DJ (1979). "Benzodiazepines: some aspects of their clinical pharmacology". Ciba Found. Symp. 1979 (74): 141–55. PMID 45081.
  3. ↑ Jacqmin P, Ansseau M (1988). "Comparison of sublingual and oral prazepam in normal subjects. II. Pharmacokinetic and pharmacodynamic data". Neuropsychobiology. 19 (4): 186–91. doi:10.1159/000118458. PMID 2854609.
  4. ↑ Rickels K, Sablosky L, Silverman H; et al. (1977). "Prazepam in anxiety: a controlled clinical trial". Compr Psychiatry. 18 (3): 239–49. doi:10.1016/0010-440X(77)90018-9. PMID 858240.
  5. ↑ Ansseau M, Von Frenckell R (1991). "(title in French)". Encephale (in French). 17 (4): 291–294. PMID 1959497. Unknown parameter |trans_title= ignored (help)
  6. ↑ Breimer DD, Jochemsen R, von Albert HH (1980). "Pharmacokinetics of benzodiazepines. Short-acting versus long-acting". Arzneimittelforschung. 30 (5a): 875–81. PMID 6106488.
  7. ↑ Allen MD, Greenblatt DJ, Harmatz JS, Shader RI (August 1980). "Desmethyldiazepam kinetics in the elderly after oral prazepam". Clin. Pharmacol. Ther. 28 (2): 196–202. doi:10.1038/clpt.1980.150. PMID 6772370.
  8. ↑ Greenblatt DJ, Harmatz JS, Dorsey C, Shader RI (September 1988). "Comparative single-dose kinetics and dynamics of lorazepam, alprazolam, prazepam, and placebo". Clin. Pharmacol. Ther. 44 (3): 326–34. doi:10.1038/clpt.1988.158. PMID 3138056.
  9. ↑ Danion JM, Brion S, Escande M; et al. (1984). "(title in French)". Encephale (in French). 10 (3): 135–138. PMID 6389091. Unknown parameter |trans_title= ignored (help)
  10. ↑ Dièye AM, Sy B, Diarra M, Faye B (March 2004). "(title in French)". Ann Pharm Fr (in French). 62 (2): 133–137. PMID 15107731. Unknown parameter |trans_title= ignored (help)
  11. ↑ Shader RI, Pary RJ, Harmatz JS, Allison S, Locniskar A, Greenblatt DJ (October 1984). "Plasma concentrations and clinical effects after single oral doses of prazepam, clorazepate, and diazepam". J Clin Psychiatry. 45 (10): 411–3. PMID 6148339.
  12. ↑ 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. PMID 3330182.
  13. ↑ Chabannes JP, Lemoine P (1990). "(title in French)". Therapie (in French). 45 (6): 467–470. PMID 2080484. Unknown parameter |trans_title= ignored (help)
  14. ↑ 14.0 14.1 14.2 Shader RI, Greenblatt DJ (1981). "The use of benzodiazepines in clinical practice". Br J Clin Pharmacol. 11. Suppl 1: 5S–9S. doi:10.1111/j.1365-2125.1981.tb01832.x. PMC 1401641. PMID 6133535.
  15. ↑ Dorman T (1983). "A multi-centre comparison of prazepam and diazepam in the treatment of anxiety". Pharmatherapeutica. 3 (6): 433–40. PMID 6353434.
  16. ↑ Saletu M, Saletu B, Grünberger J, Mader R, Karobath M (1983). "Clinical symptomatology and computer analyzed EEG before, during and after anxiolytic therapy of alcohol withdrawal patients". Neuropsychobiology. 9 (2–3): 119–34. doi:10.1159/000117949. PMID 6353268.
  17. ↑ Soyka M, Lehle R, Hippius H (September 1994). "(title in German)". Nervenarzt (in German). 65 (9): 628–32. PMID 7991010. Unknown parameter |trans_title= ignored (help)
  18. ↑ 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". Fundam Clin Pharmacol. 20 (3): 235–8. doi:10.1111/j.1472-8206.2006.00400.x. PMID 16671957.
  19. ↑ Dièye AM, Sy AN, Sy GY; et al. (2007). "(title in French)". Therapie (in French). 62 (2): 163–168. doi:10.2515/therapie:2007018. PMID 17582318. Unknown parameter |trans_title= ignored (help)
  20. ↑ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (Nov 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr. 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
  21. ↑ 21.0 21.1 Quast U (May 1981). "(title in German)". Fortschr. Med. (in German). 99 (20): 788–94. PMID 6114911. Unknown parameter |trans_title= ignored (help)
  22. ↑ 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". Gen. Pharmacol. 27 (6): 935–41. doi:10.1016/0306-3623(95)02147-7. PMID 8909973.
  23. ↑ 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". Gen. Pharmacol. 27 (7): 1155–1162. doi:10.1016/S0306-3623(96)00049-3. PMID 8981061.
  24. ↑ 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". Pharmacol. Biochem. Behav. 58 (1): 281–289. doi:10.1016/S0091-3057(96)00565-5. PMID 9264104.
  25. ↑ 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.
  26. ↑ Viau JP, Epps JE, Di Carlo J (September 1973). "Prazepam metabolism after chronic administration to humans". Xenobiotica. 3 (9): 581–587. doi:10.3109/00498257309151546. PMID 4763144.
  27. ↑ 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". J Mass Spectrom. 40 (4): 516–26. doi:10.1002/jms.824. PMID 15712230.
  28. ↑ Lu XL, Guengerich FP, Yang SK (1991). "Stereoselective metabolism of prazepam and halazepam by human liver microsomes". Drug Metab. Dispos. 19 (3): 637–642. PMID 1680631.
  29. ↑ 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.
  30. ↑ 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". J. Chromatogr. 146 (2): 227–239. doi:10.1016/S0378-4347(00)81889-7. PMID 701422.
  31. ↑ Kölle EU (June 1981). "(title in German)". Fortschr. Med. (in German). 99 (22): 874–879. PMID 6790396. Unknown parameter |trans_title= ignored (help)
  32. ↑ Ochs HR, Greenblatt DJ, Verburg-Ochs B, Locniskar A (October 1984). "Comparative single-dose kinetics of oxazolam, prazepam, and clorazepate: three precursors of desmethyldiazepam". J Clin Pharmacol. 24 (10): 446–51. doi:10.1002/j.1552-4604.1984.tb01817.x. PMID 6150943.
  33. ↑ Ruffalo RL, Thompson JF, Segal J (September 1981). "Cimetidine-benzodiazepine drug interaction". Am J Hosp Pharm. 38 (9): 1365–1366. PMID 6116430.
  34. ↑ 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". Int Clin Psychopharmacol. 6 (4): 227–238. doi:10.1097/00004850-199100640-00004. PMID 1816280.
  35. ↑ "Benzodiazepine Names". non-benzodiazepines.org.uk. Retrieved 2009-05-31.
  36. ↑ Pulce C, Mollon P, Pham E, Frantz P, Descotes J (April 1992). "Acute poisonings with ethyle loflazepate, flunitrazepam, prazepam and triazolam in children". Vet Hum Toxicol. 34 (2): 141–143. PMID 1354907.
  37. ↑ Hakuba A; Matysiakiewicz J (1986). "Uzalezniajace właściwości prazepamu". Psychiatr. Pol. (in Polish). 20 (3): 232–234. PMID 3797537. Unknown parameter |trans_title= ignored (help)
  38. ↑ Fox KA, Guerriero FJ (July 1978). "Effect of benzodiazepines on age of vaginal perforation and first estrus in mice". Res. Commun. Chem. Pathol. Pharmacol. 21 (1): 181–184. PMID 28555.
  39. ↑ Guerriero FJ, Fox KA (April 1976). "Benzodiazepines and reproduction of swiss-webster mice". Res. Commun. Chem. Pathol. Pharmacol. 13 (4): 601–10. PMID 4863.
  40. ↑ Guerriero FJ, Fox KA (May 1975). "Benzodiazepine-induced suppression of estrous cycles in C57BL/6J mice". Res. Commun. Chem. Pathol. Pharmacol. 11 (1): 155–158. PMID 239442.

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