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Tetrazepam

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Tetrazepam
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life3–26 hours
Identifiers
  • 7-chloro-5-(cyclohexen-1-yl)-1-methyl-3H-1,4-benzodiazepin-2-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.030.749 Edit this at Wikidata
Chemical and physical data
FormulaC16H17ClN2O
Molar mass288.77 g·mol−1
3D model (JSmol)
  • CN1C(=O)CN=C(C2=C1C=CC(=C2)Cl)C3=CCCCC3
  • InChI=1S/C16H17ClN2O/c1-19-14-8-7-12(17)9-13(14)16(18-10-15(19)20)11-5-3-2-4-6-11/h5,7-9H,2-4,6,10H2,1H3 checkY
  • Key:IQWYAQCHYZHJOS-UHFFFAOYSA-N checkY
  (verify)

Tetrazepam[2] (is marketed under the following brand names, Clinoxan, Epsipam, Myolastan, Musaril, Relaxam and Spasmorelax) is a benzodiazepine derivative with anticonvulsant, anxiolytic, muscle relaxant and slightly hypnotic properties. It was formerly used mainly in Austria, France, Belgium, Germany and Spain to treat muscle spasm, anxiety disorders such as panic attacks, or more rarely to treat depression, premenstrual syndrome or agoraphobia. Tetrazepam has relatively little sedative effect at low doses while still producing useful muscle relaxation and anxiety relief. The Co-ordination Group for Mutual Recognition and Decentralised Procedures-Human (CMD(h)) endorsed the Pharmacovigilance Risk Assessment Committee (PRAC) recommendation to suspend the marketing authorisations of tetrazepam-containing medicines across the European Union (EU) in April 2013.[3] The European Commission has confirmed the suspension of the marketing authorisations for Tetrazepam in Europe because of cutaneous toxicity, effective from the 1 August 2013.[4]

Delayed type 4 allergic hypersensitivity reactions including maculopapular exanthema, erythematous rash, urticarial eruption, erythema multiforme, photodermatitis, eczema and Stevens–Johnson syndrome can occasionally occur as a result of tetrazepam exposure. These hypersensitivity reactions to tetrazepam share no cross-reactivity with other benzodiazepines.[5]

Indications

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Tetrazepam is used therapeutically as a muscle relaxant.[6][7]

Availability

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The indicated adult dose for muscle spasm is 25 mg to 150 mg per day, increased if necessary to a maximum of 300 mg per day, in divided doses. Tetrazepam is not generally recommended for use in children, except on the advice of a specialist.

Tetrazepam is only available in one strength and formulation, 50 mg tablets. The benzodiazepine equivalent of tetrazepam is approximately 100 mg of tetrazepam = 10 mg of diazepam.[8]

Adverse effects

[edit]

Allergic reactions to tetrazepam occasionally occur involving the skin.[5]

Allergic reactions can develop to tetrazepam[9][10] and it is considered to be a potential allergen.[11][12] Drug rash and drug-induced eosinophilia with systemic symptoms is a known complication of tetrazepam exposure.[13][14] These hypersensitive allergic reactions can be of the delayed type.[15][16][17]

Toxic epidermal necrolysis has occurred from the use of tetrazepam[18][19] including at least one reported death.[20] Stevens–Johnson syndrome and erythema multiforme has been reported from use of tetrazepam. Cross-reactivity with other benzodiazepines does not typically occur in such patients.[21][22][23] Exanthema[24] and eczema may occur.[25] The lack of cross-reactivity with other benzodiazepines is believed to be due to the molecular structure of tetrazepam.[26][27] Photodermatitis[28] and phototoxicity have also been reported.[29] Occupational contact allergy can also develop from regularly handling tetrazepam.[30][31] Airborne contact dermatitis can also occur as an allergy which can develop from occupational exposure.[32]

Patch test

Patch testing has been used successfully to demonstrate tetrazepam allergy.[33][34] Oral testing can also be used. Skin prick tests are not always accurate and may produce false negatives.[35]

Drowsiness is a common side effect of tetrazepam.[36] A reduction in muscle force can occur.[37] Myasthenia gravis, a condition characterised by severe muscle weakness is another potential adverse effect from tetrazepam.[38] Cardiovascular and respiratory adverse effects can occur with tetrazepam similar to other benzodiazepines.[27]

Tolerance, dependence and withdrawal

[edit]
See also: Benzodiazepine withdrawal syndrome

Prolonged use, as with all benzodiazepines, should be avoided, as tolerance occurs and there is a risk of benzodiazepine dependence and a benzodiazepine withdrawal syndrome after stopping or reducing dosage.[27]

Overdose

[edit]
See also: Benzodiazepine overdose

Tetrazepam, like other benzodiazepines is a drug which is very frequently present in cases of overdose. These overdoses are often mixed overdoses, i.e. a mixture of other benzodiazepines or other drug classes with tetrazepam.[39][40]

Contraindications and special caution

[edit]

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.[41]

Pharmacology

[edit]

Tetrazepam is an unusual benzodiazepine in its molecular structure as it has cyclohexenyl group which has substituted the typical 5-phenyl moiety seen in other benzodiazepines.[42] Tetrazepam, is rapidly absorbed after oral administration, within 45 mins and reaches peak plasma levels in less than 2 hours. It is classed as an intermediate acting benzodiazepine with an elimination half-life of approximately 15 hours. It is primarily metabolised to the inactive metabolites 3-hydroxy-tetrazepam and nortetrazepam.[42][43] The pharmacological effects of tetrazepam are significantly less potent when compared against diazepam, in animal studies.[44] Tetrazepam is a benzodiazepine site agonist and binds unselectively to type 1 and type 2 benzodiazepine site types as well as to peripheral benzodiazepine receptors.[45] The muscle relaxant properties of tetrazepam are most likely due to a reduction of calcium influx.[46] Small amounts of diazepam as well as the active metabolites of diazepam are produced from metabolism of tetrazepam.[47][48] The metabolism of tetrazepam has led to false accusations of prisoners prescribed tetrazepam of taking illicit diazepam; this can lead to increased prison sentences for prisoners.[42]

Abuse

[edit]
See also: Drug-related crime and Benzodiazepine misuse

Tetrazepam as with other benzodiazepines is sometimes abused. It is sometimes abused to incapacitate a victim in order to carry out a drug-facilitated crime.[49] or abused in order to achieve a state of intoxication.[50] Tetrazepam's abuse for to carry out drug facilitated crimes may be less however, than other benzodiazepines due to its reduced hypnotic properties.[51]

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. ^ NL Patent 6600095
  3. ^ Recommendation to suspend tetrazepam-containing medicines endorsed by CMDh, European Medicines Agency, published 29 April 2013
  4. ^ Ruhen der Zuhlassung aller Tetrazepam-haltiger Arzneimittel, Sanofi-Avensis Deutschland GmbH (German), published June 2013
  5. ^ a b Thomas E, Bellón T, Barranco P, Padial A, Tapia B, Morel E, et al. (2008). "Acute generalized exanthematous pustulosis due to tetrazepam" (PDF). Journal of Investigational Allergology & Clinical Immunology. 18 (2): 119–22. PMID 18447141.
  6. ^ Simiand J, Keane PE, Biziere K, Soubrie P (January 1989). "Comparative study in mice of tetrazepam and other centrally active skeletal muscle relaxants". Archives Internationales de Pharmacodynamie et de Therapie. 297: 272–85. PMID 2567153.
  7. ^ Perez-Guerrero C, Herrera MD, Marhuenda E (November 1996). "Relaxant effect of tetrazepam on rat uterine smooth muscle: role of calcium movement". The Journal of Pharmacy and Pharmacology. 48 (11): 1169–73. doi:10.1111/j.2042-7158.1996.tb03915.x. PMID 8961167. S2CID 38144317.
  8. ^ "Benzodiazepine Names". non-benzodiazepines.org.uk. Archived from the original on 2008-12-08. Retrieved 2009-04-05.
  9. ^ Camarasa JG, Serra-Baldrich E (April 1990). "Tetrazepam allergy detected by patch test". Contact Dermatitis. 22 (4): 246. doi:10.1111/j.1600-0536.1990.tb01587.x. PMID 2140761. S2CID 26973793.
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  11. ^ Ortiz-Frutos FJ, Alonso J, Hergueta JP, Quintana I, Iglesias L (July 1995). "Tetrazepam: an allergen with several clinical expressions". Contact Dermatitis. 33 (1): 63–5. doi:10.1111/j.1600-0536.1995.tb00462.x. PMID 7493477. S2CID 41533643.
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