Chemistry:List of benzodiazepines

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Benzodiazepines
Chemical structure diagram of a benzene ring fused to a diazepine ring. Another benzene ring is attached to the bottom of the diazepine ring via a single line. Attached to the first benzene ring is a side chain labeled R7; to the second, a side chain labeled R2'; and attached to the diazepine ring, two side chains labeled R1 and R2.
The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties.

The below tables contain a sample list of benzodiazepines and benzodiazepine analogs that are commonly prescribed, with their basic pharmacological characteristics, such as half-life and equivalent doses to other benzodiazepines, also listed, along with their trade names and primary uses. The elimination half-life is how long it takes for half of the drug to be eliminated by the body. "Time to peak" refers to when maximum levels of the drug in the blood occur after a given dose. Benzodiazepines generally share the same pharmacological properties, such as anxiolytic, sedative, hypnotic, skeletal muscle relaxant, amnesic, and anticonvulsant effects. Variation in potency of certain effects may exist amongst individual benzodiazepines. Some benzodiazepines produce active metabolites. Active metabolites are produced when a person's body metabolizes the drug into compounds that share a similar pharmacological profile to the parent compound and thus are relevant when calculating how long the pharmacological effects of a drug will last. Long-acting benzodiazepines with long-acting active metabolites, such as diazepam and chlordiazepoxide, are often prescribed for benzodiazepine or alcohol withdrawal as well as for anxiety if constant dose levels are required throughout the day. Shorter-acting benzodiazepines are often preferred for insomnia due to their lesser hangover effect.[1][2][3][4][5]

It is fairly important to note that elimination half-life of diazepam and chlordiazepoxide, as well as other long half-life benzodiazepines, is twice as long in the elderly compared to younger individuals. Due to increased sensitivity and potentially dangerous adverse events among elderly patients, it is recommended to avoid prescribing them as specified by the 2015 American Geriatrics Society Beers Criteria.[6] Individuals with an impaired liver also metabolize benzodiazepines more slowly. Thus, the approximate equivalent of doses below may need to be adjusted accordingly in individuals on short acting benzodiazepines who metabolize long-acting benzodiazepines more slowly and vice versa. The changes are most notable with long acting benzodiazepines as these are prone to significant accumulation in such individuals and can lead to withdrawal symptoms.[citation needed] For example, the equivalent dose of diazepam in an elderly individual on lorazepam may be half of what would be expected in a younger individual.[7][8] Equivalent doses of benzodiazepines differ as much as 20 fold.[9][10][11]

Pharmacokinetic properties of various benzodiazepines

Equivalency data in the table below is taken from the Ashton "Benzodiazepine Equivalence Table".[4][12][13][14]

Drug Name Common Trade Names[lower-alpha 1] Year Approved

(US FDA)

Typical Oral Dosage Formulations

(mg)

Approx. Equivalent Oral Dose to 10 mg Diazepam[lower-alpha 2] (mg) Peak Onset of Action

(hours)

Elimination Half-life of Active Metabolite (hours) Primary Therapeutic Use
Adinazolam Deracyn Research chemical 1–2 3 anxiolytic, antidepressant
Alprazolam Xanax, Helex, Xanor, Trankimazin, Onax, Alprox, Misar, Restyl, Solanax, Tafil, Neurol, Frontin, Kalma, Ksalol, Farmapram 1981 0.25, 0.5, 1, 2 0.5-1 1–3[16] 11-13 [10–20][16] anxiolytic, antidepressant[17]
Bentazepam[lower-alpha 3] Thiadipona 25 1–3 2–4 anxiolytic
Bretazenil[18] 2.5 anxiolytic, anticonvulsant
Bromazepam Lexotanil, Lexotan, Lexilium, Lectopam, Lexaurin, Lexatin, Bromam 1981 1.5, 3, 6 6 1–5 20–40 anxiolytic,

hypnotic, muscle relaxant

Bromazolam Research chemical anxiolytic
Brotizolam[lower-alpha 4] Lendormin, Dormex, Sintonal, Noctilan 0.25 0.25-0.5 0.5–2 4–5 hypnotic
Camazepam Albego, Limpidon 40[19] 1–3 6–11 anxiolytic
Chlordiazepoxide Librium, Risolid, Elenium 1960 5, 10, 25 25 1.5–6 36–200 anxiolytic
Cinazepam Levana 0.5, 1, 2 2–4 60 hypnotic, anxiolytic
Cinolazepam Gerodorm 40 0.5–2 9 hypnotic
Clobazam Onfi, Frisium, Urbanol 2011 5, 10, 20 20 1–5 8–60 anxiolytic, anticonvulsant
Clonazepam Rivatril, Rivotril, Klonopin, Iktorivil, Paxam 1975 0.5, 1, 2 0.5-1 1–5 19.5–50 anticonvulsant, anxiolytic
Clonazolam Research chemical 0.25, 0.5 0.2 0.5-1 3-4[20] hypnotic, anticonvulsant
Clorazepate Tranxene, Tranxilium 1972 3.75, 5, 7.5 15 Variable 32–152 anxiolytic, anticonvulsant
Clotiazepam[lower-alpha 3] Veratran, Clozan, Rize 5, 10 10 1–3 4 anxiolytic
Cloxazolam Cloxam, Sepazon, Olcadil 1, 2, 4 1.5[19] 2–5 55–77[19] anxiolytic, anticonvulsant
Delorazepam Dadumir 0.5, 1, 2 1-1.5 1–2 79<[21] anxiolytic, amnesic
Deschloroetizolam[lower-alpha 4] Research chemical 1, 2 anxiolytic
Diazepam Antenex, Apaurin, Apzepam, Apozepam, Diazepan, Hexalid, Normabel, Pax, Stesolid, Stedon, Tranquirit, Valium, Vival, Valaxona 1963 2, 5, 10 10 1–1.5 32–205 anxiolytic, anticonvulsant, muscle relaxant, amnesic
Diclazepam[22] Research chemical 1, 2 1.5–3 42 anxiolytic, muscle relaxant
Estazolam ProSom, Nuctalon 1990 1, 2 2[19] 3–5 10–24 hypnotic, anxiolytic
Ethyl carfluzepate Not approved 2 1–5 11–24 hypnotic
Etizolam[lower-alpha 4] Etilaam, Etizest, Pasaden, Depas Often sold as a research chemical, but is approved for human use in many countries. Controlled substance in some US states, Canada, Germany, Austria, and others.[23][24] 1 2 1–3 5-7 anxiolytic, muscle relaxant, anticonvulsant
Ethyl loflazepate Victan, Meilax, Ronlax 2[19] 2.5–3 73–119 anxiolytic
Flualprazolam Research chemical 0.5, 1 0.25 1-2 12-22 anxiolytic, hypnotic
Flubromazepam[25] Templex Research chemical 4, 8, 12 4 1.5–8 100–220 anxiolytic, hypnotic, amnesic, muscle relaxant, anticonvulsant
Flubromazolam Remnon Research chemical 0.25, 0.5 0.075 0.5-5 10-20[26] hypnotic
Flubrotizolam[lower-alpha 4] Research chemical 0.5 anxiolytic
Fluclotizolam[lower-alpha 4] Research chemical 0.25-0.5 anxiolytic
Flunitrazepam Rohypnol, Hipnosedon, Vulbegal, Fluscand, Flunipam, Ronal, Rohydorm, Hypnodorm 1972 1, 2 1.5 0.5–3 18–200 hypnotic
Flunitrazolam Research chemical 0.25, 0.5 0.1 0.5-1 5-13 hypnotic
Flurazepam Dalmadorm, Dalmane, Fluzepam 1970 30 20-25 1–1.5 40–250 hypnotic
Flutazolam Coreminal 4 10 1-3 47-100 hypnotic
Flutemazepam Research chemical 1 0.5-5 8-20 hypnotic, anxiolytic, anticonvulsant, muscle relaxant[27]
Flutoprazepam Restas 1984 1, 2 2.5 0.5–9 87[28] hypnotic, anticonvulsant, muscle relaxant
Halazepam Alapryl, Paxipam 1981 20, 40 40 3–6 15-35 [30-100] anxiolytic
Ketazolam Anxon, Sedotime 1980 15, 30, 45 20 2.5–6 30-100 [36-200] anxiolytic
Loprazolam Dormonoct, Havlane 1983 1, 2 1.5 2–4 6–20[29] hypnotic
Lorazepam Ativan, Orfidal, Lorenin, Lorsilan, Temesta, Tavor, Lorabenz 1977 0.5, 1, 2, 2.5 1 2–4 10–20 anxiolytic, anticonvulsant, hypnotic, muscle relaxant[30][14][31]
Lormetazepam Loramet, Noctamid, Pronoctan 1984 1, 2 1.5 0.5–2 10-12 hypnotic, anxiolytic
Meclonazepam Research chemical 6 anxiolytic
Medazepam Nobrium, Ansilan, Mezapam, Rudotel, Raporan 10 10 4-8 36–200 anxiolytic
Metizolam[lower-alpha 4] Research chemical 1, 2, 4 2–4 12 anxiolytic
Mexazolam Melex, Sedoxil 0.5, 1 1–2 anxiolytic
Midazolam Dormicum, Flormidal, Versed, Hypnovel, Dormonid 1985 15, 30 10 (oral)

4 (IV)

0.5–1 1.8-6 hypnotic, anticonvulsant
Nifoxipam Research chemical 0.5, 1, 2 hypnotic
Nimetazepam Erimin, Lavol 1984 5 2.5-5 0.5–3 14–30 hypnotic
Nitemazepam Research chemical 2 0.5-5 10-27 hypnotic, anticonvulsant
Nitrazepam Mogadon, Alodorm, Pacisyn, Dumolid, Nitrazadon 1965 5, 10 5 0.5–7 17–48 hypnotic, anticonvulsant
Nitrazolam Research chemical 0.5, 1 hypnotic
Nordazepam Madar, Stilny 5, 7.5, 15 10-15 30–150 anxiolytic
Norflurazepam Research chemical 5 47-100 hypnotic
Oxazepam Seresta, Serax, Serenid, Serepax, Sobril, Oxabenz, Oxapax, Oxascand, Ox-Pam, Opamox, Alepam, Medopam, Murelax, Noripam, Purata 1965 10, 15, 30, 50 30 3–4 4–11 anxiolytic
Phenazepam Phenazepam, Phenzitat Research chemical 1.5–4 60 anxiolytic, anticonvulsant
Pinazepam Domar, Duna 5, 10 40–100 anxiolytic
Prazepam Demetrin, Lysanxia, Prazene, Centrax 1976 10, 20, 30 15-20 2–6 36–200 anxiolytic
Premazepam Not approved 15 2–6 10–13 anxiolytic
Pyrazolam Research chemical 0.25, 0.5, 1 1–1.5 16–18[32] anxiolytic, amnesic
Quazepam Doral, Quiedorm 1985 15 20 1–5 39–120 hypnotic
Rilmazafone Rhythmy 11 hypnotic
Temazepam Restoril, Normison, Euhypnos, Temaze, Tenox 1981 10, 20 15-20 0.5–3 4–11 hypnotic, anxiolytic, muscle relaxant
Tetrazepam Myolastan, Clinoxam, Epsipam, Musaril 50 1–3 3–26 muscle relaxant, anxiolytic
Triazolam Halcion, Rilamir, Notison, Somese 1980 0.125, 0.25 0.25-0.5 0.5–2 2 hypnotic
Drug Name Common Trade Names Year Approved Typical Dosages of Oral Tablets

(mg)

Approx. Equivalent Oral Dose to 10mg Diazepam (mg) Peak onset of action (hours) Elimination Half-life of Active Metabolite (hours) Primary Therapeutic Use

Atypical benzodiazepine receptor ligands

Drug Name Common Trade Names Year approved(US FDA) Elimination Half-life

of Active Metabolite (hours)

Primary Therapeutic Use
DMCM anxiogenic, convulsant
Flumazenil[lower-alpha 5] Anexate, Lanexat, Mazicon, Romazicon 1 antidote
Eszopiclone§ Lunesta 2004 6 hypnotic
Zaleplon§ Sonata, Starnoc 1999 1 hypnotic
Zolpidem§ Ambien, Nytamel, Sanval, Stilnoct, Stilnox, Sublinox (Canada), Xolnox, Zoldem, Zolnod 1992 2.6 hypnotic
Zopiclone§ Imovane, Rhovane, Ximovan; Zileze; Zimoclone; Zimovane; Zopitan; Zorclone, Zopiklone 4–6 hypnotic
  1. ↑ Not all trade names are listed.
  2. ↑ An alternative table published by the state of South Australia uses equivalent approximate oral dosages to 5 mg diazepam.[15]
  3. ↑ 3.0 3.1 Technically this is a thienodiazepine, but produces very similar effects as benzodiazepines.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Technically this is a thienotriazolodiazepine, but produces very similar effects as benzodiazepines.
  5. ↑ Flumazenil is an imidazobenzodiazepine derivative,[33] and in layman's terms, it is a benzodiazepine overdose antidote that is given intravenously in Intensive Care Units (ICUs) to reverse the effects of benzodiazepine overdoses, as well for overdoses of the non-benzodiazepine "Z-drugs" such as zolpidem.[34] Flumazenil is contraindicated for benzodiazepine-tolerant patients in overdose cases.[34] In such cases, the benefits are far outweighed by the risks, which include potential and severe seizures.[33][35] The method by which flumazenil acts to prevent non-benzodiazepine tolerant overdose from causing potential harm is via preventing the benzodiazepines and Z-drugs from binding to the GABAA receptors via competitive inhibition which the flumazenil creates. Clinical observation notating the patient's oxygen levels, respiratory, heart and blood pressure rates are used, as they are much safer than the potential seizure effects from flumazenil. Supportive care to mediate any problems resulting from abnormal rates of the pulmonary, respiratory, and cardiovascular systems is typically the only treatment that is required in benzodiazepine-only overdoses.[36] In most cases, activated charcoal/carbon is often used to prevent benzodiazepines from being absorbed by the gastrointestinal tract, and the use of stomach-pumping/gastric lavage is no longer commonly used nor suggested by some toxicologists.[37] Even in cases where other central nervous system (CNS) depressants (such as in combined benzodiazepine and tricyclic antidepressant/TCA overdoses) are detected and/or suspected, endotrachial intubation for the airway path and supportive oxygen are typically implemented and are much safer than flumazenil.[36]

Controversy

In 2015 the UK's House of Commons attempted to get a two to four week limit mandate for prescribing benzodiazepines to replace the two to four week benzodiazepine prescribing guidelines, which are merely recommended.[38]

Binding data and structure-activity relationship

A variety of Benzodiazepines along with their molecular structure.

A large number of benzodiazepine derivatives have been synthesised and their structure-activity relationships explored in detail.[39][40][41][42] This chart contains binding data for benzodiazepines and related drugs investigated by Roche up to the late 1990s (though in some cases the compounds were originally synthesised by other companies such as Takeda or Upjohn).[43][44][45][46][47][48] Other benzodiazepines are also listed for comparison purposes,[49][50][51] but it does not however include binding data for;

While binding or activity data are available for most of these compounds also, the assay conditions vary between sources, meaning that in many cases the values are not suitable for a direct comparison. Many older sources used animal measures of activity (i.e. sedation or anticonvulsant activity) but did not measure in vitro binding to benzodiazepine receptors.[57][58] See for instance Table 2 vs Table 11 in the Chem Rev paper, Table 2 lists in vitro pIC50 values matching those below, while Table 11 has pEC50 values derived from in vivo assays in mice, which show the same activity trends but cannot be compared directly, and includes data for compounds such as diclazepam and flubromazepam which are not available in the main data set.


Also note;

  • IC50 / pIC50 values represent binding affinity only and do not reflect efficacy or pharmacokinetics, and some compounds listed are GABAA antagonists rather than agonists (e.g. flumazenil).
  • Low IC50 or high pIC50 values indicate tighter binding (pIC50 of 8.0 = IC50 of 10nM, pIC50 of 9.0 = IC50 of 1nM, etc.)
  • These are non subtype selective IC50 values averaged across all GABAA receptor subtypes, so subtype selective compounds with strong binding at one subtype but weak at others will appear unusually weak due to averaging of binding values (see e.g. CL-218,872)
  • † indicates a predicted value from in silico modelling.[59]
  • Finally, note that the benzodiazepine core is a privileged scaffold, which has been used to derive drugs with diverse activity that is not limited to the GABAA modulatory action of the classical benzodiazepines,[60] such as devazepide and tifluadom, however these have not been included in the list below. 2,3-benzodiazepines such as tofisopam are also not listed, as these act primarily as AMPA receptor modulators, and are inactive at GABAA receptors.


See also

References

  1. ↑ "The psychopharmacological effects of premazepam, diazepam and placebo in healthy human subjects". British Journal of Clinical Pharmacology 18 (2): 127–133. August 1984. doi:10.1111/j.1365-2125.1984.tb02444.x. PMID 6148956. 
  2. ↑ "Biomarkers for the effects of benzodiazepines in healthy volunteers". British Journal of Clinical Pharmacology 55 (1): 39–50. January 2003. doi:10.1046/j.1365-2125.2002.t01-10-01714.x. PMID 12534639. 
  3. ↑ "Benzodiazepine Names". non-benzodiazepines.org.uk. http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html. 
  4. ↑ 4.0 4.1 "Benzodiazepine Equivalence Table". benzo.org.uk. March 2007. http://www.benzo.org.uk/bzequiv.htm. 
  5. ↑ "Benzodiazepine Equivalence Charts". dr-bob.org. July 1995. http://www.dr-bob.org/tips/bzd.html. 
  6. ↑ By the American Geriatrics Society 2015 Beers Criteria Update Expert Panel (November 2015). "American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults". Journal of the American Geriatrics Society 63 (11): 2227–2246. doi:10.1111/jgs.13702. PMID 26446832. 
  7. ↑ Clinical geriatric psychopharmacology (4th ed.). USA: Lippincott Williams & Wilkins. 15 May 2004. pp. 450–453. ISBN 978-0-7817-4380-8. https://books.google.com/books?id=RXvpjJ1Un2gC&pg=PA450. 
  8. ↑ "Dose adjustment in patients with liver disease". Drug Safety 28 (6): 529–545. 2005. doi:10.2165/00002018-200528060-00005. PMID 15924505. 
  9. ↑ "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics". Acta Neurologica Scandinavica 118 (2): 69–86. August 2008. doi:10.1111/j.1600-0404.2008.01004.x. PMID 18384456. 
  10. ↑ "Guidelines for the rational use of benzodiazepines. When and what to use". Drugs 48 (1): 25–40. July 1994. doi:10.2165/00003495-199448010-00004. PMID 7525193. 
  11. ↑ "benzo.org.uk : Benzodiazepines: How They Work & How to Withdraw, Prof C H Ashton DM, FRCP, 2002". https://benzo.org.uk/manual/bzcha01.htm#24. 
  12. ↑ "Benzodiazepine Equivalence Chart". http://www.mental-health-today.com/rx/benzo.htm. 
  13. ↑ "Benzodiazepine Equivalence Table". April 2007. http://www.bcnc.org.uk/equivalence.html. 
  14. ↑ 14.0 14.1 Benzodiazepine Equivalency Table. 31 July 2018. https://emedicine.medscape.com/article/2172250-overview. 
  15. ↑ "Benzodiazepines Information for GPs". Drug and Alcohol Services South Australia. https://www.sahealth.sa.gov.au/wps/wcm/connect/dbd6d500407749f193d6bb222b2948cf/Benzodiazepines+-+GPs+2017.pdf?MOD=AJPERES&CACHEID=ROOTWORKSPACE-dbd6d500407749f193d6bb222b2948cf-m08aBgI. 
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  17. ↑ Ashton Manual
  18. ↑ "Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol". British Journal of Clinical Pharmacology 41 (6): 565–573. June 1996. doi:10.1046/j.1365-2125.1996.38514.x. PMID 8799523. 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 "Benzodiazepine Names". non-benzodiazepines.org.uk. http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html. 
  20. ↑ N. Edinoff, Amber; A. Nix, Catherine; S. Odisho, Amira; P. Babin, Caroline; G. Derouen, Alyssa; C. Lutfallah, Salim; M. Cornett, Elyse; Murnane, Kevin S. et al. (22 August 2022). Müller, Thomas; Yamauchi, Junji. eds. "Novel Designer Benzodiazepines: Comprehensive Review of Evolving Clinical and Adverse Effects". Neurology International 14 (3): 652. doi:10.3390/neurolint14030053. PMID 35997362. 
  21. ↑ "NMS Labs Report". NMS Labs. https://www.nmslabs.com/sites/default/files/test-catalog/reports/0570B%40POS.roi_4.pdf. 
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  23. ↑ Health Santé Canada, Federal Government of Canada (January 20, 2012). "Status Decision of Controlled and Non-Controlled Substances". Controlled Drugs and Substances Act 1: 2. https://isomerdesign.com/Cdsa/HC/StatusDecisions/A-2013-00235%20-%20PDFs/C-Etizolam-23-08-04.pdf. 
  24. ↑ Indiana General Assembly. "House Bill 1019 - Controlled substances" (in en-US). https://iga.in.gov/legislative/2017/bills/house/1019. 
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  33. ↑ 33.0 33.1 "Romazicon 2 (flumazenil) 3 Injection". Genentech, Inc.. https://www.gene.com/download/pdf/romazicon_prescribing.pdf. 
  34. ↑ 34.0 34.1 "Flumazenil Injection, Solution [App Pharmaceuticals, Llc]". DailyMed. U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=11882e93-aa62-4d24-895c-6f01d97fc730. 
  35. ↑ Synopsis of pediatric emergency medicine.. Lippincott Williams & Wilkins.. 2002. p. 409. ISBN 978-0-7817-3274-1. 
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  48. ↑ "Chapter 7: Chemical and computer assisted development of the inclusive pharmacophore of benzodiazepine receptors.". Studies in Medicinal Chemistry. CRC Press. 1996. pp. 303. ISBN 9783718658794. 
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  52. ↑ "Designer benzodiazepines: A new challenge". World Psychiatry 14 (2): 248. June 2015. doi:10.1002/wps.20236. PMID 26043347. 
  53. ↑ "Designer Benzodiazepines: Another Class of New Psychoactive Substances". New Psychoactive Substances. Handbook of Experimental Pharmacology. 252. 2018. pp. 383–410. doi:10.1007/164_2018_154. ISBN 978-3-030-10560-0. 
  54. ↑ "The emergence of new psychoactive substance (NPS) benzodiazepines: A review". Drug Testing and Analysis 10 (1): 37–53. January 2018. doi:10.1002/dta.2211. PMID 28471096. https://rke.abertay.ac.uk/en/publications/9a280549-be8d-4907-b7d4-532fbfd8547a. 
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