List of benzodiazepines

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]

Benzodiazepines
The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties.

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. Individuals with an impaired liver also metabolize benzodiazepines more slowly. Many doctors make the mistake of not adjusting benzodiazepine dosage according to age in elderly patients. 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. 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.[6][7] Equivalencies between individual benzodiazepines can differ by 400 fold on a mg per mg basis; awareness of this fact is necessary for the safe and effective use of benzodiazepines.[8]

A variety of Benzodiazepines along with their molecular structure.

Pharmacokinetic properties of various benzodiazepines

Data in the table below is taken from the Ashton "Benzodiazepine Equivalency Table".[4][9][10][11]

Drug nameCommon trade names[lower-alpha 1]Year approved (US FDA)Approx. equivalent oral doses to 10 mg diazepam[lower-alpha 2] (mg)Time to peak onset of action

(hours)

 Elimination half-life of active metabolite (hours)Therapeutic use
Adinazolam DeracynResearch chemical 1–23anxiolytic, antidepressant
Alprazolam Xanax, Helex, Xanor, Trankimazin, Onax, Alprox, Misar, Restyl, Solanax, Tafil, Neurol, Frontin, Kalma, Ksalol1981 0.51–210–20anxiolytic, antidepressant
Bentazepam[lower-alpha 3] Thiadipona 1–32–4anxiolytic
Bretazenil[13] 2.5anxiolytic, anticonvulsant
Bromazepam Lectopam, Lexaurin, Lexatin, Lexotanil, Lexotan, Bromam1981 61–320–40anxiolytic,

hypnotic

Bromazolam Research chemical anxiolytic
Brotizolam[lower-alpha 4] Lendormin, Dormex, Sintonal, Noctilan 0.5–24–5hypnotic
Camazepam Albego, Limpidon, Paxor 0.5–26–29anxiolytic
Chlordiazepoxide Librium, Risolid, Elenium1960 251.5–45–200anxiolytic
Cinazepam Levana 2–460hypnotic, anxiolytic
Cinolazepam Gerodorm 0.5–29hypnotic
Clobazam Onfi, Frisium, Urbanol2011 1–38–60anxiolytic, anticonvulsant
Clonazepam Rivatril, Rivotril, Klonopin, Iktorivil, Paxam1975 0.51–4 19.5–50anticonvulsant, anxiolytic, muscle relaxant
Clonazolam Research chemical 0.20.5–1.510–18anxiolytic, anticonvulsant, hypnotic, muscle relaxant
Clorazepate Tranxene, Tranxilium1972 20Variable32–152anxiolytic, anticonvulsant
Clotiazepam[lower-alpha 3] Veratran, Clozan, Rize 1–34anxiolytic
Cloxazolam Sepazon, Olcadil 2–580–105anxiolytic, anticonvulsant
Delorazepam Dadumir 1–280–105anxiolytic, amnesic
Deschloroetizolam[lower-alpha 4] Research chemical anxiolytic
Diazepam Antenex, Apaurin, Apzepam, Apozepam, Diazepan, Hexalid, Normabel, Pax, Stesolid, Stedon, Tranquirit, Valium, Vival, Valaxona1963 101–1.532–205anxiolytic, anticonvulsant, muscle relaxant, amnesic
Diclazepam[14] Research chemical 1.5–342anxiolytic, amnesic, anticonvulsant, hypnotic, muscle relaxant
Estazolam ProSom, Nuctalon1990 1–510–31hypnotic, anxiolytic
Ethyl carfluzepate Not approved 1–511–24hypnotic
Etizolam[lower-alpha 4] Etilaam, Etizest, Pasaden, DepasOften 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.[15][16] 1–2 1–26anxiolytic, hypnotic, amnesic, muscle relaxant, anticonvulsant
Ethyl loflazepate Victan, Meilax, Ronlax 2.5–373–119anxiolytic
Flualprazolam Research chemical hypnotic, anxiolytic
Flubromazepam[17] Research chemical 1.5–8100–220anxiolytic, hypnotic, amnesic, muscle relaxant, anticonvulsant
Flubromazolam Research chemical hypnotic
Fluclotizolam[lower-alpha 4] Research chemical hypnotic
Flunitrazepam Rohypnol, Hipnosedon, Vulbegal, Fluscand, Flunipam, Ronal, Rohydorm, HypnodormNot approved 1 0.5–318–200hypnotic
Flunitrazolam Research chemical hypnotic
Flurazepam Dalmadorm, Dalmane, Fluzepam1970 151–1.540–250hypnotic
Flutazolam Coreminal 3.5hypnotic
Flutoprazepam RestasResearch chemical 0.5–960–90hypnotic, anticonvulsant
Halazepam Paxipam1981 20 1–330–100anxiolytic
Ketazolam AnxonNot approved 202.5–330–200anxiolytic
Loprazolam Dormonoct 1.5 0.5–43–15hypnotic
Lorazepam Ativan, Orfidal, Lorenin, Lorsilan, Temesta, Tavor, Lorabenz1977 1 2–410–20anxiolytic, amnesic, anticonvulsant, hypnotic, muscle relaxant[18][11][19]
Lormetazepam Loramet, Noctamid, Pronoctan 1 0.5–210hypnotic
Meclonazepam Research chemical anxiolytic
Medazepam Nobrium, Ansilan, Mezapam, Rudotel, Raporan 10 1–1.536–200anxiolytic
Metizolam[lower-alpha 4] Research chemical 2–4 12anxiolytic, hypnotic, amnesic, muscle relaxant, anticonvulsant
Mexazolam Melex, Sedoxil 1–2anxiolytic
Midazolam Dormicum, Versed, Hypnovel, Dormonid1985 10 (oral)

4 (IV)

 0.5–11.5–2.5hypnotic, anticonvulsant, amnesic
Nifoxipam Research chemical hypnotic
Nimetazepam Erimin 0.5–314–30hypnotic
Nitemazepam Research chemical
Nitrazepam Mogadon, Alodorm, Pacisyn, Dumolid, Nitrazadon1965 100.5–317–48hypnotic, anticonvulsant
Nitrazolam Research chemical hypnotic
Nordiazepam Madar, Stilny 30–150anxiolytic
Norflurazepam Research chemical hypnotic
Oxazepam Seresta, Serax, Serenid, Serepax, Sobril, Oxabenz, Oxapax, Oxascand, Ox-Pam, Opamox, Alepam, Medopam, Murelax, Noripam, Purata1965 253–44–11anxiolytic
Phenazepam PhenazepamResearch chemical 1.5–460anxiolytic, anticonvulsant
Pinazepam Domar 40–100anxiolytic
Prazepam Lysanxia, CentraxNot approved 15 2–636–200anxiolytic
Premazepam Not approved 2–610–13anxiolytic
Pyrazolam Research chemical 1–1.516–18[20]anxiolytic, amnesic
Quazepam Doral1985 201–539–120hypnotic
Rilmazafone Rhythmy 11hypnotic
Temazepam Restoril, Normison, Euhypnos, Temaze, Tenox1981 200.5–34–11hypnotic, anxiolytic, muscle relaxant
Tetrazepam Myolastan 1–33–26muscle relaxant
Triazolam Halcion, Rilamir1982 0.250.5–22hypnotic

Atypical benzodiazepine receptor ligands
Drug nameCommon trade namesYear approved (US FDA)Elimination half-life

of active metabolite (hours)

 Therapeutic use
DMCManxiogenic, convulsant
Flumazenil[lower-alpha 5]Anexate, Lanexat, Mazicon, Romazicon1antidote
Eszopiclone§Lunesta20046hypnotic
Zaleplon§Sonata, Starnoc19991hypnotic
Zolpidem§Ambien, Nytamel, Sanval, Stilnoct, Stilnox, Sublinox (Canada), Xolnox, Zoldem, Zolnod19922.6hypnotic
Zopiclone§Imovane, Rhovane, Ximovan; Zileze; Zimoclone; Zimovane; Zopitan; Zorclone, Zopiklone4–6hypnotic
  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.[12]
  3. Technically this is a thienodiazepine, but produces very similar effects as benzodiazepines.
  4. Technically this is a thienotriazolodiazepine, but produces very similar effects as benzodiazepines.
  5. Flumazenil is an imidazobenzodiazepine derivative,[21] 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.[22] Flumazenil is contraindicated for benzodiazepine-tolerant patients in overdose cases.[23] In such cases, the benefits are far outweighed by the risks, which include potential and severe seizures.[21][24] 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.[25] 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.[26] 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.[25]

Controversy

The UK's House of Commons has 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.[27]

Binding data and structure-activity relationship

A large number of benzodiazepine derivatives have been synthesised and their structure-activity relationships explored in detail.[28][29] 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).[30][31][32][33][34][35] Other benzodiazepines are also listed for comparison purposes,[36][37][38] but it does not however include binding data for;

While binding or activity data is 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.[44][45] 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)
  • 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,[46] 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
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