Altamura AC, Moliterno D, Paletta S, et al. Understanding the pharmacokinetics of anxiolytic drugs. Expert Opin Drug Metab Toxicol. 2013;9(4):423-40. Abstract

Aouizerate B, Martin-Guehl C, Tignol J. Neurobiology and pharmacotherapy of social phobia. Encephale. 2004;30(4):301-13. Abstract

Greenblatt DJ, Shader RI, Divoll M, Harmatz JS. Benzodiazepines: a summary of pharmacokinetic properties. Br J Clin Pharmacol. 1981;11 Suppl 1:11S-16S. Article

12.2 Pharmacology

Griffin CE, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013;13(2):214-23. Article

Binding

Müller WE. The influence of plasma protein binding on distribution and pharmacological activity of tranquilizers of the benzodiazepine group (author’s transl). Klin Wochenschr. 1977;55(3):105-10. Abstract

Bioavailability

Buccal

Intranasal

Oral

Rectal

Sublingual / Buccal

Vaginal

Blockade

Flumazenil

Dunton AW, Schwam E, Pitman V, et al. Flumazenil: US clinical pharmacology studies. Eur J Anaesthesiol Suppl. 1988;2:81-95. Abstract

Brand Name v Generic

Desmarais JE, Beauclair L, Margolese HC. Switching from brand-name to generic psychotropic medications: a literature review. CNS Neurosci Ther. 2011;17(6):750-60. Abstract

Distribution

Brain

Greenblatt DJ, Sethy VH. Benzodiazepine concentrations in brain directly reflect receptor occupancy: studies of diazepam, lorazepam, and oxazepam. Psychopharmacology (Berl). 1990;102(3):373-8. Abstract

Miller LG, Greenblatt DJ, Abernethy DR, et al. Kinetics, brain uptake, and receptor binding characteristics of flurazepam and its metabolites. Psychopharmacology (Berl). 1988;94(3):386-91. Abstract

Elimination

Arnold J. Determinants of pharmacologic effects and toxicity of benzodiazepine hypnotics: role of lipophilicity and plasma elimination rates. J Clin Psychiatry. 1991;52 Suppl:11-4. Abstract

Duration of Action

Breimer DD, Jochemsen R, von Albert HH. Pharmacokinetics of benzodiazepines. Short-acting versus long-acting. Arzneimittelforschung. 1980;30(5a):875-81. Abstract

Mendelson WB. Clinical distinctions between long-acting and short-acting benzodiazepines. J Clin Psychiatry. 1992;53(suppl):4-7. Abstract

Preskorn SH. A way of conceptualizing benzodiazepines to guide clinical use. J Psychiatr Pract. 2015;21(6):436-41. Abstract

Soldatos CR, Dikeos DG, Whitehead A. Tolerance and rebound insomnia with rapidly eliminated hypnotics: a meta-analysis of sleep laboratory studies. Int Clin Psychopharmacol. 1999;14(5):287-303. Abstract

Immediate Release

Onset of Action

Time to Cmax

Duration of Action

Half Life

Extended Release

Glue P, Fang A, Gandelman K, Klee B. Pharmacokinetics of an extended release formulation of alprazolam (Xanax XR) in healthy normal adolescent and adult volunteers. Am J Ther. 2006;13(5):418-22. Abstract

Sheehan DV, Sheehan KH, Raj BA. The speed of onset of action of alprazolam-XR compared to alprazolam-CT in panic disorder. Psychopharmacol Bull. 2007;40(2):63-81. Abstract

Onset of Action

Time to Cmax

Duration of Action

Half Life

IR v ER

Interactions

Drug – Alcohol

Aguayo LG, Peoples RW, Yeh HH, Yevenes GE. GABA(A) receptors as molecular sites of ethanol action. Direct or indirect actions? Curr Top Med Chem. 2002;2(8):869-85. Abstract

Cosgrove KP, McKay R, Esterlis I, et al. Tobacco smoking interferes with GABAA receptor neuroadaptations during prolonged alcohol withdrawal. Proc Natl Acad Sci U S A. 2014;111(50):18031-6. Article

Criswell HE, Breese GR. A conceptualization of integrated actions of ethanol contributing to its GABAmimetic profile: a commentary. Neuropsychopharmacology. 2005;30(8):1407-25. Abstract

Darke S, Duflou J, Torok M, Prolov T. Characteristics, circumstances and toxicology of sudden or unnatural deaths involving very high-range alcohol concentrations. Addiction. 2013;108(8):1411-7. Abstract

Fraser AG. Pharmacokinetic interactions between alcohol and other drugs. Clin Pharmacokinet. 1997;33(2):79-90. Abstract

Hollister LE. Interactions between alcohol and benzodiazepines. Recent Dev Alcohol. 1990;8:233-9. Abstract

Hoyumpa AM. Alcohol interactions with benzodiazepines and cocaine. Adv Alcohol Subst Abuse. 1984;3(4):21-34. Abstract

Jones CM, Paulozzi LJ, Mack KM. Alcohol involvement in opioid pain reliever and benzodiazepine drug abuse-related emergency department visits and drug-related deaths – United States, 2010. MMWR. 2014;63(40):881-5. Article

Linnoila MI. Benzodiazepines and alcohol. J Psychiatr Res. 1990;24 Suppl 2:121-7. Abstract

Tanaka E. Toxicological interactions between alcohol and benzodiazepines. J Toxicol Clin Toxicol. 2002;40(1):69-75. Abstract

Tanaka E, Misawa S. Pharmacokinetic interactions between acute alcohol ingestion and single doses of benzodiazepines, and tricyclic and tetracyclic antidepressants – an update. J Clin Pharm Ther. 1998;23(5):331-6. Abstract

Drug – Drug

Abernethy DR, Greenblatt DJ, Ochs HR, Shader RI. Benzodiazepine drug-drug interactions commonly occurring in clinical practice. Curr Med Res Opin. 1984;8 Suppl 4:80-93. Abstract

Korpi ER, Gründer G, Lüddens H. Drug interactions at GABA(A) receptors. Prog Neurobiol. 2002;67(2):113-59. Abstract

Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-herbal interactions. Life Sci. 2006;78(18):2131-45. Abstract

Antibiotics

Ito K, Ogihara K, Kanamitsu S, Itoh T. Prediction of the in vivo interaction between midazolam and macrolides based on in vitro studies using human liver microsomes. Drug Metab Dispos. 2003;31(7):945-54. Article

Mattila MJ, Vanakoski J, Idänpään-Heikkilä JJ. Azithromycin does not alter the effects of oral midazolam on human performance. Eur J Clin Pharmacol. 1994;47(1):49-52. Abstract

Mattila MJ, Idänpään-Heikkilä JJ, Törnwall M, Vanakoski J. Oral single doses of erythromycin and roxithromycin may increase the effects of midazolam on human performance. Pharmacol Toxicol. 1993;73(3):180-5. Abstract

Yeates RA, Laufen H, Zimmermann T, et al. Pharmacokinetic and pharmacodynamic interaction study between midazolam and the macrolide antibiotics, erythromycin, clarithromycin, and the azalide azithromycin. Int J Clin Pharmacol Ther. 1997;35(12):577-9. Abstract

Yeates RA, Laufen H, Zimmermann T. Interaction between midazolam and clarithromycin: comparison with azithromycin. Int J Clin Pharmacol Ther. 1996;34(9):400-5. Abstract

Zimmermann T, Yeates RA, Laufen H, et al. Influence of the antibiotics erythromycin and azithromycin on the pharmacokinetics and pharmacodynamics of midazolam. Arzneimittelforschung. 1996;46(2):213-7. Abstract

Anti-Fungals

Vanakoski J, Mattila MJ, Vainio P, et al. 150 mg fluconazole does not substantially increase the effects of 10 mg midazolam or the plasma midazolam concentrations in healthy subjects. Int J Clin Pharmacol Ther. 1995;33(9):518-23. Abstract

Yamano K, Yamamoto K, Kotaki H, et al. Quantitative prediction of metabolic inhibition of midazolam by itraconazole and ketoconazole in rats: implication of concentrative uptake of inhibitors into liver. Drug Metab Dispos. 1999;27(3):395-402. Article

Caffeine

Ghoneim MM, Hinrichs JV, Chiang CK, Loke WH. Pharmacokinetic and pharmacodynamic interactions between caffeine and diazepam. J Clin Psychopharmacol. 1986;6(2):75-80. Abstract

Loke WH, Hinrichs JV, Ghoneim MM. Caffeine and diazepam: separate and combined effects on mood, memory, and psychomotor performance. Psychopharmacology (Berl). 1985;87(3):344-50. Abstract

Mattila MJ, Vainio P, Nurminen ML, et al. Midazolam 12 mg is moderately counteracted by 250 mg caffeine in man. Int J Clin Pharmacol Ther. 2000;38(12):581-7. Abstract

Mattila MJ, Nuotto E. Caffeine and theophylline counteract diazepam effects in man. Med Biol. 1983;61(6):337-43. Abstract

Roache JD, Griffiths RR. Interactions of diazepam and caffeine: behavioral and subjective dose effects in humans. Pharmacol Biochem Behav. 1987;26(4):801-12. Abstract

Cannabinoids

Andó RD, Bíró J, Csölle C, et al. The inhibitory action of exo- and endocannabinoids on [³H]GABA release are mediated by both CB₁and CB₂receptors in the mouse hippocampus. Neurochem Int. 2012;60(2):145-52. Abstract

Lile JA, Kelly TH, Hays LR. Separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ⁹-THC in humans discriminating Δ⁹-THC. Drug Alcohol Depend. 2014;143:141-8. Article

Lile JA, Kelly TH, Pinsky DJ, Hays LR. Substitution profile of Delta9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Delta9-tetrahydrocannabinol. Psychopharmacology (Berl). 2009;203(2):241-50. Article

Steiner MA, Wotjak CT. Role of the endocannabinoid system in regulation of the hypothalamic-pituitary-adrenocortical axis. Prog Brain Res. 2008;170:397-432. Abstract

Cimetidine

Greenblatt DJ, Abernethy DR, Koepke HH, Shader RI. Interaction of cimetidine with oxazepam, lorazepam, and flurazepam. J Clin Pharmacol. 1984;24(4):187-93. Abstract

Hines LE, Murphy JE. Potentially harmful drug-drug interactions in the elderly: a review. Am J Geriatr Pharmacother. 2011;9(6):364-77. Abstract

Nivoix Y, Ubeaud-Sequier G, Engel P, et al. Drug-drug interactions of triazole antifungal agents in multimorbid patients and implications for patient care. Curr Drug Metab. 2009;10(4):395-409. Abstract

Otani K. Cytochrome P450 3A4 and benzodiazepines. Seishin Shinkeigaku Zasshi. 2003;105(5):631-42. Abstract

Patwardhan RV, Yarborough GW, Desmond PV, et al. Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology. 1980;79(5 Pt 1):912-6. Abstract

Ruffalo RL, Thompson JF, Segal JL. Diazepam-cimetidine drug interaction: a clinically significant effect. South Med J. 1981;74(9):1075-8. Abstract

Tanaka E. Clinically significant pharmacokinetic drug interactions with benzodiazepines. J Clin Pharm Ther. 1999;24(5):347-55. Abstract

Wynn GH, Cozza KL, Zapor MJ, et al. Med-psych drug-drug interactions update. Antiretrovirals, part III: antiretrovirals and drugs of abuse. Psychosomatics. 2005;46(1):79-87. Abstract

Cocaine

Smelson D, Yu L, Buyske S, et al. Genetic association of GABA-A receptor alpha-2 and mu opioid receptor with cocaine cue-reactivity: evidence for inhibitory synaptic neurotransmission involvement in cocaine dependence. Am J Addict. 2012;21(5):411-5. Article

Mono-Amine Reuptake Inhibitors

Kroboth PD, Folan MM, Lush RM, et al. Coadministration of nefazodone and benzodiazepines: I. Pharmacodynamic assessment. J Clin Psychopharmacol. 1995;15(5):306-19. Abstract

Opioids: See also Benzodiazepines + Opioids

Horsfall JT, Sprague JE. The pharmacology and toxicology of the ‘Holy Trinity’. Basic Clin Pharmacol Toxicol. 2017;120(2):115-119. Abstract

Lintzeris N, Nielsen S. Benzodiazepines, methadone and buprenorphine: interactions and clinical management. Am J Addict. 2010;19(1):59-72. Abstract

Maurer PM, Bartkowski RR. Drug interactions of clinical significance with opioid analgesics. Drug Saf. 1993;8(1):30-48. Abstract

Shyer KM, Oertel BG, Geisslinger G. Drug interactions in pain therapy. Schmerz. 2015;29(6):595-603. Abstract

Opioids: Naloxone

Agmo A, Galvan A, Heredia A, Morales M. Naloxone blocks the antianxiety but not the motor effects of benzodiazepines and pentobarbital: experimental studies and literature review. Psychopharmacology (Berl). 1995;120:186-94. Abstract

Belzung C, Barreau S, Agmo A. Naloxone potentiates anxiolytic-like actions of diazepam, pentobarbital and meprobamate but not those of Ro19-8022 in the rat. Eur J Pharmacol. 2000;394:289-94. Abstract

Belzung C, Dubreuil D. Naloxone potentiates the anxiolytic but not the amnestic action of chlordiazepoxide in C57BL/6 mice. Behav Pharmacol. 1998;9:691-8. Abstract

Belzung C, Agmo A. Naloxone blocks anxiolytic-like effects of benzodiazepines in Swiss but not in Balb/c mice. Psychopharmacology ( Berl ). 1997;132:195-201. Abstract

Coiro V, Volpi R, Casti A, et al. Naloxone decreases the inhibitory effect of alprazolam on the release of adrenocorticotropin/cortisol induced by physical exercise in man. Br J Clin Pharmacol. 2011;71(6):951-5. Article

Dingledine R, Inversen LL, Breuker E. Naloxone as a GABA antagonist: evidence from iontophoretic, receptor binding and convulsant studies. Eur J Pharmacol. 1978;47:19-27. Abstract

Duka T, Cumin R, Haefely W, Herz A. Naloxone blocks the effect of diazepam and meprobamate on conflict behaviour in rats. Pharmacol Biochem Behav. 1981;15:115-7. Abstract

Svensson AI , Berntsson A., Eirefelt M., Söderpalm B. Naloxone antagonizes GABA(A)/benzodiazepine receptor function in rat corticohippocampal synaptoneurosomes. J Neural Transm. 2000;107:261-70. Abstract

Wolkowitz OM, Tinklenberg JR. Naloxone’s effect on cognitive functioning in drug-free and diazepam-treated normal humans. Psychopharmacology (Berl). 1985;85:221-3. Abstract

Oral Contraceptives

Abernethy DR, Greenblatt DJ, Ochs HR, et al. Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives. Clin Pharmacol Ther. 1983;33(5):628-32. Abstract

Babalonis S, Lile JA, Martin CA, Kelly TH. Physiological doses of progesterone potentiate the effects of triazolam in healthy, premenopausal women. Psychopharmacology (Berl). 2011;215(3):429-39. Abstract

Kroboth PD, Smith RB, Stoehr GP, Juhl RP. Pharmacodynamic evaluation of the benzodiazepine-oral contraceptive interaction. Clin Pharmacol Ther. 1985;38(5):525-32. Abstract

Patwardhan RV, Mitchell MC, Johnson RF, Schenker S. Differential effects of oral contraceptive steroids on the metabolism of benzodiazepines. Hepatology. 1983;3(2):248-53. Abstract

Roberts RK, Desmond PV, Wilkinson GR, Schenker S. Disposition of chlordiazepoxide: sex differences and effects of oral contraceptives. Clin Pharmacol Ther. 1979;25(6):826-31. Abstract

Drug – Food

Lilja JJ, Kivistö KT, Backman JT, Neuvonen PJ. Effect of grapefruit juice dose on grapefruit juice-triazolam interaction: repeated consumption prolongs triazolam half-life. Eur J Clin Pharmacol. 2000;56(5):411-5. Abstract

Otani K. Cytochrome P450 3A4 and benzodiazepines. Seishin Shinkeigaku Zasshi. 2003;105(5):631-42. Abstract

Sugimoto K, Araki N, Ohmori M, et al. Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam. Eur J Clin Pharmacol. 2006;62(3):209-15. Abstract

Vanakoski J, Mattila MJ, Seppälä T. Grapefruit juice does not enhance the effects of midazolam and triazolam in man. Eur J Clin Pharmacol. 1996;50(6):501-8. Abstract

Drug – Tobacco

Cosgrove KP, McKay R, Esterlis I, et al. Tobacco smoking interferes with GABAA receptor neuroadaptations during prolonged alcohol withdrawal. Proc Natl Acad Sci U S A. 2014;111(50):18031-6. Article

Huybrechts I. The pharmacology of alprazolam: a review. Clin Ther. 1991;13(1):100-17. Abstract

Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest. 1975;55(2):347-59. Article

Norman TR, Fulton A, Burrows GD, Maguire KP. Pharmacokinetics of N-desmethyldiazepam after a single oral dose of clorazepate: the effect of smoking. Eur J Clin Pharmacol. 1981;21(3):229-33. Abstract

Levels

Blood

Lipophilicity

Arendt RM, Greenblatt DJ, Liebisch DC, et al. Determinants of benzodiazepine brain uptake: lipophilicity versus binding affinity. Psychopharmacology (Berl). 1987;93(1):72-6. Abstract

Mechanism of Action

Metabolism

Chouinard G, Lefko-Singh K, Teboul E. Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem. Cell Mol Neurobiol. 1999;19(4):533-52. Abstract

Jochemsen R, Breimer DD. Pharmacokinetics of benzodiazepines: metabolic pathways and plasma level profiles. Curr Med Res Opin. 1984;8 Suppl 4:60-79. Abstract

Mandrioli R, Mercolini L, Raggi MA. Metabolism of benzodiazepine and non-benzodiazepine anxiolytic-hypnotic drugs: an analytical point of view. Curr Drug Metab. 2010;11(9):815-29. Abstract

First Pass

Phase I: P 450: See enzymes below

Phase II: UDP glucuronysyl Transferase Metabolism: See enzymes below

Pharmacokinetics: See also Pharmacokinetic / Pharmacodynamic Enzymes below

Breimer DD, Pharmacokinetics and metabolism of various benzodiazepines used as hypnotics. Br J Clin Pharmacol. 1979;8(1):7S-13S. Article

Chouinard G, Lefko-Singh K, Teboul E. Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem. Cell Mol Neurobiol. 1999;19(4):533-52. Abstract

DeVane CL, Ware MR, Lydiard RB. Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam. Psychopharmacol Bull. 1991;27(4):463-73. Abstract

Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part I). Clin Pharmacokinet. 1991;21(3):165-77. Abstract

Greenblatt DJ. Benzodiazepine hypnotics: sorting the pharmacokinetic facts. J Clin Psychiatry. 1991;52 Suppl:4-10. Abstract

Greenblatt DJ, Shader RI. Effects of age and other drugs on benzodiazepine kinetics. Arzneimittelforschung. 1980;30(5a):886-90. Abstract

Jochemsen R, Breimer DD. Pharmacokinetics of temazepam compared with other benzodiazepine hypnotics–some clinical consequences. Acta Psychiatr Scand Suppl. 1986;332:20-31. Abstract

Jochemsen R, Van Boxtel CJ, Breimer DD. Comparative pharmacokinetics of 5 hypnotic benzodiazepines in healthy volunteers. Nouv Presse Med. 1982;11(40):2965-6. Abstract

Mandrioli R, Mercolini L, Raggi MA. Metabolism of benzodiazepine and non-benzodiazepine anxiolytic-hypnotic drugs: an analytical point of view. Curr Drug Metab. 2010;11(9):815-29. Abstract

Vinkers CH, Tijdink JK, Luykx JJ, Vis R. Choosing the correct benzodiazepine: mechanism of action and pharmacokinetics. Ned Tijdschr Geneeskd. 2012;155(35):A4900. Abstract

Vozeh S. Pharmacokinetic of benzodiazepines in old age. Schweiz Med Wochenschr. 1981;111(47):1789-93. Abstract

Wang JS, DeVane CL. Pharmacokinetics and drug interactions of the sedative hypnotics. Psychopharmacol Bull. 2003;37(1):10-29. Abstract

Protein Binding

Solubility

Storage in Body

Pharmacodynamics

Potency

Tolerance

Busto U, Sellers EM. Pharmacologic aspects of benzodiazepine tolerance and dependence. J Subst Abuse Treat. 1991;8(1-2):29-33. Abstract

Fernandes C, Arnot MI, Irvine EE, et al. The effect of treatment regimen on the development of tolerance to the sedative and anxiolytic effects of diazepam. Psychopharmacology (Berl). 1999;145(3):251-9. Abstract

File SE. Tolerance to the behavioral actions of benzodiazepines. Neurosci Biobehav Rev. 1985;9(1):113-21. Abstract

Higgitt A, Fonagy P, Lader M. The natural history of tolerance to the benzodiazepines. Psychol Med Monogr Suppl. 1988;13:1-55. Abstract

Hriscu A, Gherase F, Năstasă V, Hriscu E. An experimental study of tolerance to benzodiazepines. Rev Med Chir Soc Med Nat Iasi. 2002;106(4):806-11. Abstract

Rosenberg HC, Chiu TH. Time course for development of benzodiazepine tolerance and physical dependence. Neurosci Biobehav Rev. 1985;9(1):123-31. Abstract

van Steveninck AL, Wallnöfer AE, Schoemaker RC, et al. A study of the effects of long-term use on individual sensitivity to temazepam and lorazepam in a clinical population. Br J Clin Pharmacol. 1997;44(3):267-75. Article

Vinkers CH, Olivier B. Mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective GABA(A) receptor modulators? Adv Pharmacol Sci. 2012;2012:416864. Article

Toxicity

Switching Benzodiazepines

Ashton: Benzodiazepine Equivalency Table

Benzodiazpeine Equivalency Charts

12.3 Pharmacology: Alprazolam

Ciraulo DA, Barnhill JG, Boxenbaum HG, et al. Pharmacokinetics and clinical effects of alprazolam following single and multiple oral doses in patients with panic disorder. J Clin Pharmacol. 1986;26(4):292-8. Abstract

DeVane CL, Ware MR, Lydiard RB. Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam. Psychopharmacol Bull. 1991;27(4):463-73. Abstract

Dawson GW, Jue SG, Brogden RN. Alprazolam: a review of its pharmacodynamic properties and efficacy in the treatment of anxiety and depression. Drugs. 1984;27(2):132-47. Abstract

Fawcett JA, Kravitz HM. Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action. Pharmacotherapy. 1982;2(5):243-54. Abstract

Greenblatt DJ, Harmatz JS, Shader RI. Plasma alprazolam concentrations. Relation to efficacy and side effects in the treatment of panic disorder. Arch Gen Psychiatry. 1993;50(9):715-22. Abstract

Huybrechts I. The pharmacology of alprazolam: a review. Clin Ther. 1991;13(1):100-17. Abstract

Kaplan GB, Greenblatt DJ, Ehrenberg BL, et al. Differences in pharmacodynamics but not pharmacokinetics between subjects with panic disorder and healthy subjects after treatment with a single dose of alprazolam. J Clin Psychopharmacol. 2000;20(3):338-46. Abstract

Scavone JM, Greenblatt DJ, Locniskar A, Shader RI. Alprazolam pharmacokinetics in women on low-dose oral contraceptives. J Clin Pharmacol. 1988;28(5):454-7. Abstract

Sheehan DV, Sheehan KH, Raj BA. The speed of onset of action of alprazolam-XR compared to alprazolam-CT in panic disorder. Psychopharmacol Bull. 2007;40(2):63-81. Abstract

Stoehr GP, Kroboth PD, Juhl RP, et al. Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics. Clin Pharmacol Ther. 1984;36(5):683-90. Abstract

Venkatakrishnan K, Culm KE, Ehrenberg BL, et al. Kinetics and dynamics of intravenous adinazolam, N-desmethyl adinazolam, and alprazolam in healthy volunteers. J Clin Pharmacol. 2005;45(5):529-37. Abstract

12.4 Pharmacology: Chlorazepate

Bertler A, Lindgren S, Malmgren H. Pharmacokinetics of dipotassium chlorazepate in patients after repeated 50 mg oral doses. Psychopharmacology (Berl). 1980;71(2):165-7. Abstract

Duguay R, Le Lorier J, Rochefort JG, et al. Efficacy and kinetics of chlorazepate administered to anxious patients in a single daily dose. Can J Psychiatry. 1985;30(6):414-7. Abstract

Greenblatt DJ, Divoll MK, Soong MH, et al. Desmethyldiazepam pharmacokinetics: studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam. J Clin Pharmacol. 1988;28(9):853-9. Abstract

Guentert TW. Time-dependence in benzodiazepine pharmacokinetics. Mechanisms and clinical significance. Clin Pharmacokinet. 1984;9(3):203-10. Abstract

Norman TR, Fulton A, Burrows GD, Maguire KP. Pharmacokinetics of N-desmethyldiazepam after a single oral dose of clorazepate: the effect of smoking. Eur J Clin Pharmacol. 1981;21(3):229-33. Abstract

Ochs HR, Steinhaus E, Locniskar A, et al. Desmethyldiazepam kinetics after intravenous, intramuscular, and oral administration of clorazepate dipotassium. Klin Wochenschr. 1982;60(8):411-5. Abstract

Post C, Lindgren S, Bertler A, Malmgren H. Pharmacokinetics of N-desmethyldiazepam in healthy volunteers after single daily doses of dipotassium chlorazepate. Psychopharmacology (Berl). 1977;53(2):105-9. Abstract

Shader RI, Greenblatt DJ, Ciraulo DA, et al. Effect of age and sex on disposition of desmethyldiazepam formed from its precursor clorazepate. Psychopharmacology (Berl). 1981;75(2):193-7. Abstract

12.5 Pharmacology: Chlordiazepoxide

Greenblatt DJ, Shader RI, Franke K, Harmatz JS. Pharmacokinetics of chlordiazepoxide and metabolites following single and multiple oral doses. Int J Clin Pharmacol Biopharm. 1978;16(10):486-93. Abstract

Greenblatt DJ, Shader RI, MacLeod SM, Sellers EM. Clinical pharmacokinetics of chlordiazepoxide. Clin Pharmacokinet. 1978;3(5):381-94. Abstract

Greenblatt DJ, Harmatz JS, Stanski DR, et al. Factors influencing blood concentrations of chlordiazepoxide: a use of multiple regression analysis. Psychopharmacology (Berl). 1977;54(3):277-82. Abstract

Ruffalo RL, Thompson JF, Segal JL. Diazepam-cimetidine drug interaction: a clinically significant effect. South Med J. 1981;74(9):1075-8. Abstract

12.6 Pharmacology: Clonazepam

DeVane CL, Ware MR, Lydiard RB. Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam. Psychopharmacol Bull. 1991;27(4):463-73. Abstract

Greenblatt DJ, Miller LG, Shader RI. Clonazepam pharmacokinetics, brain uptake, and receptor interactions. J Clin Psychiatry. 1987;48 Suppl:4-11. Abstract

Guentert TW. Time-dependence in benzodiazepine pharmacokinetics. Mechanisms and clinical significance. Clin Pharmacokinet. 1984;9(3):203-10. Abstract

12.7 Pharmacology: Diazepam

Greenblatt DJ, Ehrenberg BL, Gunderman J, et al. Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo. Clin Pharmacol Ther. 1989;45(4):356-65. Abstract

Greenblatt DJ, Ehrenberg BL, Gunderman J, et al. Kinetic and dynamic study of intravenous lorazepam: comparison with intravenous diazepam. J Pharmacol Exp Ther. 1989;250(1):134-40. Abstract

Greenblatt DJ, Abernethy DR, Koepke HH, Shader RI. Interaction of cimetidine with oxazepam, lorazepam, and flurazepam. J Clin Pharmacol. 1984;24(4):187-93. Abstract

Guentert TW. Time-dependence in benzodiazepine pharmacokinetics. Mechanisms and clinical significance. Clin Pharmacokinet. 1984;9(3):203-10. Abstract

Klotz U, Reimann I. Influence of cimetidine on the pharmacokinetics of desmethyldiazepam and oxazepam. Eur J Clin Pharmacol. 1980;18(6):517-20. Abstract

Klotz U. Clinical pharmacokinetics of diazepam and its biologically active metabolites (author’s transl). Klin Wochenschr. 1978;56(18):895-904. Abstract

Klotz U. Important factors determining human distribution and elimination of diazepam. Fortschr Med. 1977;95(32):1958-64. Abstract

Klotz U, Antonin KH, Brügel H, Bieck PR. Disposition of diazepam and its major metabolite desmethyldiazepam in patients with liver disease. Clin Pharmacol Ther. 1977;21(4):430-6. Abstract

Klotz U. Important factors determining human distribution and elimination of diazepam. Fortschr Med. 1977;95(32):1958-64. Abstract

Klotz U, Antonin KH, Bieck PR. Comparison of the pharmacokinetics of diazepam after single and subchronic doses. Eur J Clin Pharmacol. 1976;10(2):121-6. Abstract

Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest. 1975;55(2):347-59. Article

Lauven PM, Stoeckel H, Schwilden H, Schüttler J. Clinical pharmacokinetics of midazolam, flunitrazepam and diazepam. Anasth Intensivther Notfallmed. 1981;16(3):135-42. Abstract

Mould DR, DeFeo TM, Reele S, et al. Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam. Clin Pharmacol Ther. 1995;58(1):35-43. Abstract

Ruffalo RL, Thompson JF, Segal JL. Diazepam-cimetidine drug interaction: a clinically significant effect. South Med J. 1981;74(9):1075-8. Abstract

12.8 Pharmacology: Flurazepam

12.9 Pharmacology: Lorazepam

Greenblatt DJ, Ehrenberg BL, Gunderman J, et al. Kinetic and dynamic study of intravenous lorazepam: comparison with intravenous diazepam. J Pharmacol Exp Ther. 1989;250(1):134-40. Abstract

Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet. 1981;6(2):89-105. Abstract

Greenblatt DJ, Allen MD, Locniskar A. Lorazepam kinetics in the elderly. Clin Pharmacol Ther. 1979;26(1):103-13. Abstract

Greenblatt DJ, Knowles JA, Comer WH, et al. Clinical pharmacokinetics of lorazepam. IV. Long-term oral administration. J Clin Pharmacol. 1977;17(8-9):495-500. Abstract

Greenblatt DJ, et al. Clinical pharmacokinetics of lorazepam. Clin Pharmacol Ther. 1976;20:329-39. Abstract

Greenblatt DJ, Schillings RT, Kyriakopoulos AA, et al. Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam. Clin Pharmacol Ther. 1976;20(3):329-41. Abstract

Patwardhan RV, Yarborough GW, Desmond PV, et al. Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology. 1980;79(5 Pt 1):912-6. Abstract

12.10 Pharmacology: Midazolam

12.11 Pharmacology: Oxazepam

Greenblatt DJ, Abernethy DR, Koepke HH, Shader RI. Interaction of cimetidine with oxazepam, lorazepam, and flurazepam. J Clin Pharmacol. 1984;24(4):187-93. Abstract

Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet. 1981;6(2):89-105. Abstract

Patwardhan RV, Yarborough GW, Desmond PV, et al. Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology. 1980;79(5 Pt 1):912-6. Abstract

12.12 Pharmacology: Triazolam

12.13 By Receptor

Acetylcholine Receptor

Muscarinic

Nicotinic

Alpha₄ Beta₂

Alpha₆ Beta₂

Adrenoreceptor

Alpha₂

Giovannitti JA, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015;62(1):31-9. Article

AMPA Receptor

Qneibi MS, Micale N, Grasso S, Niu L. Mechanism of inhibition of GluA2 AMPA receptor channel opening by 2,3-benzodiazepine derivatives: functional consequences of replacing a 7,8-methylenedioxy with a 7,8-ethylenedioxy moiety. Biochemistry. 2012;51(8):1787-95. Article

Calcium Channel

Earl DE, Tietz EI. Inhibition of recombinant L-type voltage-gated calcium channels by positive allosteric modulators of GABAA receptors. J Pharmacol Exp Ther. 2011;337(1):301-11. Article

Gallos G, Yocum GT, Siviski ME, et al. Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling. Am J Physiol Lung Cell Mol Physiol. 2015;308(9):L931-42. Article

Alpha₂ Delta

Metabotropic

Cannabinoid Receptor

CB₁

CB₂

GPR55

Chemokine Receptor

Chloride Channel Receptor

Cholecystokinin Receptor

Cortioctropin Receptor

Dopamine Receptor

DRD1

DRD2

DRD3

GABA Receptor

Allison C, Pratt JA. Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence. Pharm Ther. 2003;98(3):171-95. Abstract

Atack JR. GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics. Curr Top Med Chem. 2011;11(9):1176-202. Abstract

Atack JR. The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics. Expert Opin Investig Drugs. 2005;14(5):601-18. Abstract

Atack JR, Hutson PH, Collinson N, et al. Anxiogenic properties of an inverse agonist selective for alpha3 subunit-containing GABA A receptors. Br J Pharmacol. 2005;144(3):357-66. Article

Atack JR. Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Curr Drug Targets CNS Neurol Disord. 2003;2(4):213-32. Abstract

Bartenstein P, Koepp M. Benzodiazepine receptor imaging with positron emission tomography and single photon emission tomography. Nervenarzt. 1995;66(6):412-21. Abstract

Crestani F, Löw K, Keist R, et al. Molecular targets for the myorelaxant action of diazepam. Mol Pharmacol. 2001;59(3):442-5. Article

Dingledine R, Iversen LL, Breuker E. Naloxone as a GABA antagonist: evidence from iontophoretic, receptor binding and convulsant studies. Eur J Pharmacol. 1978;47:19-27. Abstract

Da Settimo F, Taliani S, Trincavelli ML, et al. GABA A/Bz receptor subtypes as targets for selective drugs. Curr Med Chem. 2007;14(25):2680-701. Abstract

Dias R, Sheppard WF, Fradley RL, et al. Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines. J Neurosci. 2005;25(46):10682-8. Article

Emmanouil DE, Quock RM. Advances in understanding the actions of nitrous oxide. Anesth Prog. 2007;54(1):9-18. Article

Engin E, Rudolph U. α2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders. Pharmacol Ther. 2012;136(2):142-52. Article

Fahey JM, Pritchard GA, Grassi JM, et al. Pharmacodynamic and receptor binding changes during chronic lorazepam administration. Pharmacol Biochem Behav. 2001;69(1-2):1-8. Abstract

Farb DH, Ratner MH. Targeting the modulation of neural circuitry for the treatment of anxiety disorders. Pharmacol Rev. 2014;66(4):1002-32. Article

Fischer BD, Teixeira LP, van Linn ML, et al. Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation. Psychopharmacology (Berl). 2013;227(2):347-54. Article

Fradley RL, Guscott MR, Bull S, et al. Differential contribution of GABA(A) receptor subtypes to the anticonvulsant efficacy of benzodiazepine site ligands. J Psychopharmacol. 2007;21(4):384-91. Abstract

Galpern WR, Miller LG, Greenblatt DJ, Shader RI. Differential effects of chronic lorazepam and alprazolam on benzodiazepine binding and GABAA-receptor function. Br J Pharmacol. 1990;101(4):839-42. Article

Gavish M, Bachman, I, Shoukrun R, et al. Enigma of the Peripheral Benzodiazepine Receptor. Pharm Rev. 1999;51(4):630-48. Article

Griebel G, Perrault G, Tan S, et al. Comparison of the pharmacological properties of classical and novel BZ-omega receptor ligands. Behav Pharmacol. 1999;10(5):483-95. Abstract

Griebel G, Perrault G, Letang V, et al. New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZ (omega) receptor subtypes. Psychopharmacology (Berl). 1999;146(2):205-13. Abstract

Hanson SM, Czajkowski C. Structural mechanisms underlying benzodiazepine modulation of the GABA(A) receptor. J Neurosci. 2008;28(13):3490-9. Article

Harrison NL. Mechanisms of sleep induction by GABA(A) receptor agonists. J Clin Psychiatry. 2007;68 Suppl 5:6-12. Abstract

Hevers W, Lüddens H. The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes. Mol Neurobiol. 1998;18(1):35-86. Abstract

Kralic JE, O’Buckley TK, Khisti RT, et al. GABA(A) receptor alpha-1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology. 2002;43(4):685-94. Abstract

Lader M. Biological processes in benzodiazepine dependence. Addiction. 1994;89(11):1413-8. Abstract

Leonard BE. Sleep disorders and anxiety: biochemical antecedents and pharmacological consequences. J Psychosom Res. 1994;38 Suppl 1:69-87. Abstract

Leonard BE. Commentary on the mode of action of benzodiazepines. J Psychiatr Res. 1993;27 Suppl 1:193-207. Abstract

Licata SC, Platt DM, Cook JM, et al. Contribution of GABAA receptor subtypes to the anxiolytic-like, motor, and discriminative stimulus effects of benzodiazepines: studies with the functionally selective ligand SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one]. J Pharmacol Exp Ther. 2005;313(3):1118-25. Article

Lopez F, Miller LG, Greenblatt DJ, et al. Chronic low-dose alprazolam augments gamma-aminobutyric acid(A) receptor function. J Clin Psychopharmacol. 1992;12(2):119-23. Abstract

Luscher B, Fuchs T, Kilpatrick CL. GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron. 2011;70(3):385-409. Abstract

Masneuf S, Buetler J, Koester C, Crestani F. Role of α1- and α2-GABA(A) receptors in mediating the respiratory changes associated with benzodiazepine sedation. Br J Pharmacol. 2012;166(1):339-48. Abstract

McKernan RM, Rosahl TW, Reynolds DS, et al. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat Neurosci. 2000;3(6):587-92. Abstract

Mihic SJ, Kalant H, Liu JF, Wu PH. Role of the gamma-aminobutyric acid receptor/chloride channel complex in tolerance to ethanol and cross-tolerance to diazepam and pentobarbital. J Pharmacol Exp Ther. 1992;261(1):108-13. Abstract

Miller LG, Greenblatt DJ, Barnhill JG, Shader RI. Chronic benzodiazepine administration. I. Tolerance is associated with benzodiazepine receptor downregulation and decreased gamma-aminobutyric acidA receptor function. J Pharmacol Exp Ther. 1988;246(1):170-6. Abstract

Miller LG, Woolverton S, Greenblatt DJ, et al. Chronic benzodiazepine administration. IV. Rapid development of tolerance and receptor downregulation associated with alprazolam administration. Biochem Pharmacol. 1989;38(21):3773-7. Abstract

Morimoto K. Benzodiazepine receptor imaging in the brain: recent developments and clinical validity. Kaku Igaku. 1999;36(4):307-13. Abstract

Paul SM, Marangos PJ, Skolnick P, Goodwin FK. Biological substrates of anxiety: benzodiazepine receptors and endogenous ligands. Encephale. 1982;8(2):131-44. Abstract

Paul SM, Marangos PJ, Skolnick P. The benzodiazepine-GABA-chloride ionophore receptor complex: common site of minor tranquilizer action. Biol Psychiatry. 1981;16(3):213-29. Article

Pélissolo A. The benzodiazepine receptor: the enigma of the endogenous ligand. Encephale. 1995;21(2):133-40. Abstract

Rowlett JK, Cook JM, Duke AN, Platt DM. Selective antagonism of GABAA receptor subtypes: an in vivo approach to exploring the therapeutic and side effects of benzodiazepine-type drugs. CNS Spectr. 2005;10(1):40-8. Abstract

Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov. 2011;10(9):685-97. Article

Rudolph U, Crestani F, Benke D, et al. Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature. 1999;401(6755):796-800. Abstract

Saari TI, Uusi-Oukari M, Ahonen J, Olkkola KT. Enhancement of GABAergic activity: neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology. Pharmacol Rev. 2011;63(1):243-67. Article

Sanger DJ, Griebel G, Perrault G, et al. Discriminative stimulus effects of drugs acting at GABA(A) receptors: differential profiles and receptor selectivity. Pharmacol Biochem Behav. 1999;64(2):269-73. Abstract

Sanger DJ, Benavides J, Perrault G, et al. Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes. Neurosci Biobehav Rev. 1994;18(3):355-72. Abstract

Shen G, Mohamed MS, Das P, Tietz EI. Positive allosteric activation of GABAA receptors bi-directionally modulates hippocampal glutamate plasticity and behavior. Biochem Soc Trans. 2009;37(Pt 6):1394-8. Abstract

Shulman A, Strashun AM, Seibyl JP, er al. Benzodiazepine receptor deficiency and tinnitus. Int Tinnitus J. 2000;6(2):98-111. Abstract

Sigel E, Lüscher BP. A closer look at the high affinity benzodiazepine binding site on GABAA receptors. Curr Top Med Chem. 2011;11(2):241-6. Abstract

Sigel E. Mapping of the benzodiazepine recognition site on GABA(A) receptors. Curr Top Med Chem. 2002;2(8):833-9. Abstract

Smith TA. Type A gamma-aminobutyric acid (GABAA) receptor subunits and benzodiazepine binding: significance to clinical syndromes and their treatment. Br J Biomed Sci. 2001;58(2):111-21. Abstract

Song J, Shen G, Greenfield LJ, Tietz EI. Benzodiazepine withdrawal-induced glutamatergic plasticity involves up-regulation of GluR1-containing alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in Hippocampal CA1 neurons. J Pharmacol Exp Ther. 2007;322(2):569-81. Article

Teuber L, Wätjens F, Jensen LH. Ligands for the benzodiazepine binding site – a survey. Curr Pharm Des. 1999;5(5):317-43. Abstract

Trincavelli ML, Da Pozzo E, Daniele S, Martini C. The GABAA-BZR complex as target for the development of anxiolytic drugs. Curr Top Med Chem. 2012;12(4):254-69. Abstract

Twyman RE, Rogers CJ, Macdonald RL. Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital. Ann Neurol. 1989;25(3):213-20. Abstract

Williams M. Molecular aspects of the action of benzodiazepine and non-benzodiazepine anxiolytics: a hypothetical allosteric model of the benzodiazepine receptor complex. Prog Neuropsychopharmacol Biol Psychiatry. 1984;8(2):209-47. Abstract

GABA_B

Glucagon Receptor

Glycine Receptor

Histamine Receptor

H₁

H₂

Kainate Receptor

Melatonin Receptor

Motilin Receptor

Neurokinin Receptor

NK₁

Neuropeptide Y Receptor

NMDA Receptor

Metabotropic

Opioid Receptor

Mu₁

Mu₂

Kappa

Kappa₁

Kappa₂

Kappa₃

Delta

Primeaux SD, Wilson SP, McDonald AJ, et al. The role of delta opioid receptors in the anxiolytic actions of benzodiazepines. Pharmacol Biochem Behav. 2006;85(3):545-54. Article

Nociceptin (Orphanin, ORL-1)

Oxytocin Receptor

P2X Receptor

Potassium Channel Receptor

PPAR-a (Peroxisome Proliferator-Activated Receptor-alpha) Receptor

Secretin Receptor

Serine Receptor

Serotonin Receptor

5-HT_1a

5-HT_1b

5-HT_1d

5-HT_2a

5-HT_2b

5-HT_2c

5-HT₃

5-HT₄

5-HT_5a

5-HT₆

5-HT₇

Sigma Receptor

Sodium Channel Receptor

Somatostatin Receptor

TRPV₁ (Transient Receptor Potential Vanillioid₁) channel Receptor

Vasoactive Intestinal Peptide Receptor

Vasopressin Receptor

12.14 By Pharmacokinetic / Pharmacodynamic Enzymes – Genetics

Amitai M, Kronenberg S, Cohen T, et al. Pharmacogenetics and anxiety disorders: analysis of recent findings. Harefuah. 2014;153(3-4):210-4, 236. Abstract

Schosser A, Kasper S. The role of pharmacogenetics in the treatment of depression and anxiety disorders. Int Clin Psychopharmacol. 2009;24(6):277-88. Abstract

Tiwari AK, Souza RP, Müller DJ. Pharmacogenetics of anxiolytic drugs. J Neural Transm (Vienna). 2009;116(6):667-77. Abstract

Walubo A. The role of cytochrome P450 in antiretroviral drug interactions. Expert Opin Drug Metab Toxicol. 2007;3(4):583-98. Abstract

1A2

2A6

2B6

2C8

2C9

Ham AC, Ziere G, Broer L, et al. CYP2C9 genotypes modify benzodiazepine-related fall risk: original results from three studies with meta-analysis. J Am Med Dir Assoc. 2017;18(1):88.e1-88.e15. Abstract

2C19

2E1

3A4

Bossaer JB, Chakraborty K. Drug interaction between idelalisib and diazepam resulting in altered mental status and respiratory failure. J Oncol Pharm Pract. 2016 May 26. [Epub ahead of print] Abstract

Otani K. Cytochrome P450 3A4 and benzodiazepines. Seishin Shinkeigaku Zasshi. 2003;105(5):631-42. Abstract

Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-herbal interactions. Life Sci. 2006;78(18):2131-45. Abstract

Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-drug interactions. J Neuroimmune Pharmacol. 2006;1(3):323-39. Abstract

Sugimoto K, Araki N, Ohmori M, et al. Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam. Eur J Clin Pharmacol. 2006;62(3):209-15. Abstract

Yamano K, Yamamoto K, Katashima M, et al. Prediction of midazolam-CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data. Drug Metab Dispos. 2001;29(4 Pt 1):443-52. Article

3A5

Yu KS, Cho JY, Jang IJ, et al. Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states. Clin Pharmacol Ther. 2004;76(2):104-12. Abstract

3A7

APO-E

Pomara N, Belzer KD, Silva R, et al. The apolipoprotein E epsilon4 allele and memory performance in HIV-1 seropositive subjects: differences at baseline but not after acute oral lorazepam challenge. Psychopharmacology (Berl). 2008;201(1):125-35. Abstract

Pomara N, Willoughby L, Wesnes K, et al. Apolipoprotein E epsilon4 allele and lorazepam effects on memory in high-functioning older adults. Arch Gen Psychiatry. 2005;62(2):209-16. Abstract

UGT

Abernethy DR, Greenblatt DJ, Divoll M, Shader RI. Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen. J Lab Clin Med. 1983;101(6):873-80. Abstract

Court MH, Duan SX, Guillemette C, et al. Stereoselective conjugation of oxazepam by human UDP-glucuronosyltransferases (UGTs): S-oxazepam is glucuronidated by UGT2B15, while R-oxazepam is glucuronidated by UGT2B7 and UGT1A9. Drug Metab Dispos. 2002;30(11):1257-65. Article

Guillemette C, Lévesque E, Harvey M, et al. UGT genomic diversity: beyond gene duplication. Drug Metab Rev. 2010;42(1):24-44. Abstract

Kiang TK, Ensom MH, Chang TK. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther. 2005;106(1):97-132. Abstract

Lampe JW, Bigler J, Bush AD, Potter JD. Prevalence of Polymorphisms in the Human UDP-Glucuronosyltransferase 2B Family: UGT2B4(D458E), UGT2B7(H268Y), and UGT2B15(D85Y). Cancer Epidemiol Biomarkers Prevent. 2000;9(3) Article

Stingl JC, Bartels H, Viviani R, et al. Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: A quantitative systematic review. Pharmacol Ther. 2014;141(1):92-116. Abstract

Uchaipichat V, Suthisisang C, Miners JO. The glucuronidation of R- and S-lorazepam: human liver microsomal kinetics, UDP-glucuronosyltransferase enzyme selectivity, and inhibition by drugs. Drug Metab Dispos. 2013;41(6):1273-84. Article

UGT 1A4

UGT 1A6

UGT 2B7

Chung JY, Cho JY, Yu KS, et al. Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin Pharmacol Ther. 2008;83(4):595-600. Abstract

Patel M, Tang BK, Kalow W. (S)oxazepam glucuronidation is inhibited by ketoprofen and other substrates of UGT2B7. Pharmacogenetics. 1995;5(1):43-9. Abstract

UGT 2B15

Chung JY, Cho JY, Yu KS, et al. Effect of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers. Clin Pharmacol Ther. 2005;77(6):486-94. Abstract

UGT 2B17

COMT

Epigenetics

Gräff J, Joseph NF, Horn ME, et al. Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell. 2014;156(1-2):261-76. Article

12.15 By Endogenous Neuro Transmitters

Adenosine

Agouti-Related Peptide

ATP

BDNF

Bombesin

Calcitonin Gene-Related Peptide

α-CGRP

β-CGRP

Cannabinoids

Andanamide

Cytokines

Elements

Calcium

Chloride

Magnesium

Sodium

Zinc

GABA

Roy-Byrne PP, Cowley DS, Hommer D, et al. Effect of acute and chronic benzodiazepines on plasma GABA in anxious patients and controls. Psychopharmacology (Berl). 1992;109(1-2):153-6. Abstract

Galanin

Ghrelin

Glutamate

Stephens DN. A glutamatergic hypothesis of drug dependence: extrapolations from benzodiazepine receptor ligands. Behav Pharmacol. 1995;6(5 And 6):425-46. Abstract

Hormones

Giordano R, Grottoli S, Brossa P, et al. Alprazolam (a benzodiazepine activating GABA receptor) reduces the neuroendocrine responses to insulin-induced hypoglycaemia in humans. Clin Endocrinol (Oxf). 2003;59(3):314-20. Abstract

Graeff FG. Anxiety, panic and the hypothalamic-pituitary-adrenal axis. Rev Bras Psiquiatr. 2007;29 Suppl 1:S3-6. Abstract

Heberlein A, Bleich S, Kornhuber J, Hillemacher T. Neuroendocrine pathways in benzodiazepine dependence: new targets for research and therapy. Hum Psychopharmacol. 2008;23(3):171-81. Abstract

Adrenocorticotropic hormone

Anabolic Steroids

DHEA

Testosterone

Corticosteroids

Estrogens

Growth Hormone

Oxytocin

Prolactin

Somatostatin

Thyroid Hormone

Vasopressin

Leptin

Monoamines

Acetyl – choline (ACh)

Aspartate

Dopamine

Epinephrine

GABA – See GABA Receptor Above

Glutamate

Glycine

Histamine

N – acetyl – aspartyl – glutamate (NAAG)

Melatonin

Norepinephrine

Octopamine

Serine

Serotonin

Tyramine

Gastrins

Gastrin

Cholecystokinin

Bradwejn J, Koszycki D, Couëtoux du Tertre A, et al. Effects of flumazenil on cholecystokinin-tetrapeptide-induced panic symptoms in healthy volunteers Psychopharmacology. 1994;114: 257-61. Abstract

Zwanzger P, Eser D, Aicher S, et al. Effects of alprazolam on cholecystokinin-tetrapeptide-induced panic and hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study. Neuropsychopharmacology. 2003;28(5):979-84. Article

Gastrin Releasing Peptide

Neurohypophyseals

Neurophysin I

Neurophysin II

Neurokinins

Neurokinin A

Neurokinin B

Neuropeptide Y

Neuromedin U

Neurotensin

Orexin

Johnson PL, Truitt W, Fitz SD, et al. A key role for orexin in panic anxiety. Nat Med. 2010;16(1):111-5. Abstract

Neurotrophins

Brain-Derived Neurotrophic Factor (BDNF)

Nerve Growth Factor

Neurotrophin-3 (NT-3)

Neurotrophin 4/5 (NT-4/5)

Pancreatic polypeptide

Peptide YY

Secretins

Glucagon

Growth Hormone – Releasing Factor

Motilin

Secretin

Vasoactive intestinal peptide

Nitric oxide

Opioid

Dynorphin

Endorphin

Enkephalin

Tachykinins

Neurokinin A

Neurokinin B

Substance P

12.16 By Neuro-Chemical Action

Agonists

Partial Agonists

Inverse Agonists

Antagonists

Agonist – Antagonists

Reverse Agonists

12.17 By CNS Loci

Streeter CC, Ciraulo DA, Harris GJ, et al. Functional magnetic resonance imaging of alprazolam-induced changes in humans with familial alcoholism. Psychiatry Res. 1998;82(2):69-82. Abstract

Amygdala

Kang W, Wilson SP, Wilson MA. Overexpression of proenkephalin in the amygdala potentiates the anxiolytic effects of benzodiazepines. Neuropsychopharmacology. 2000;22(1):77-88. Abstract

Core

Shell

Anterior Cingulate

Palomero-Gallagher N, Mohlberg H, Zilles K, Vogt B. Cytology and receptor architecture of human anterior cingulate cortex. J Comp Neurol. 2008;508(6):906-26. Article

Arcuate Nucleus

Basal Optic Nucleus of Meynert

Cerebrospinal Fluid Spaces

Schmauss C, Krieg JC. Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine abusers. Psychol Med. 1987;17(4):869-73. Abstract

Cortex

Dentate gyrus

Boldrini M, Butt TH, Santiago AN, et al. Benzodiazepines and the potential trophic effect of antidepressants on dentate gyrus cells in mood disorders. Int J Neuropsychopharmacol. 2014;17(12):1923-33. Article

Hippocampus

Arcuate nucleus

Hypothalamus

Insula

Anterior Insula

Posterior Insula

Locus ceruleus

Hellsten KS, Sinkkonen ST, Hyde TM, et al. Human locus coeruleus neurons express the GABA(A) receptor gamma2 subunit gene and produce benzodiazepine binding. Neurosci Lett. 2010;477(2):77-81. Article

Medial Septal Nucleus

Nucleus accumbens

Wolf DH, Pinkham AE, Satterthwaite TD, et al. Oral alprazolam acutely increases nucleus accumbens perfusion. Mol Psychiatry. 2013;18(9):960-1. Article

Core

Shell

Pallidum (Globus Pallidus)

Prefrontal Cortex

Kuikka JT, Pitkänen A, Lepola U, et al. Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder. Nucl Med Commun. 1995;16(4):273-80. Abstract

Medial Prefrontal

Orbital Frontal

Raphe Nucleus

Caudal Dorsal

Rostral Dorsal

Spinal Cord

Chemoreceptor Trigger Zone

Dorsal Horn

Tegmental Area

Heikkinen AE, Möykkynen TP, Korpi ER. Long-lasting modulation of glutamatergic transmission in VTA dopamine neurons after a single dose of benzodiazepine agonists. Neuropsychopharmacology. 2009;34(2):290-8. Article

Lateral

Ventral

12.18 By CNS Neural Pathways

Cholinergic System

Ponto – mesen – cephalo – tegmental complex

Dopamine System

Mesocortico – pathway

Mesolimbic – pathway

Nigrostriatal – pathway

Tuberofundibular – pathway

Noradrenal System

Lateral tegmental field

12.19 By Neurophysiologic Function

Ability

Appetite

Coordination

Endurance

Energy

Enjoyment

Gastrointestinal Function

Jembrek MJ, Auteri M, Serio R, Vlainić J. GABAergic system in action: connection to gastrointestinal stress-related disorders. Curr Pharm Des. 2017 Feb 9. [Epub ahead of print] Abstract

Mood

Palomero-Gallagher N, Mohlberg H, Zilles K, Vogt B. Cytology and receptor architecture of human anterior cingulate cortex. J Comp Neurol. 2008;508(6):906-26. Article

Anger

Anxiety

Fear

Baas JM, Grillon C, Böcker KB, et al. Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology (Berl). 2002;161(3):233-47. Abstract

Sadness

Motor Activity / Relaxation

Kaplan GB, Tai NT, Greenblatt DJ, Shader RI. Separate and combined effects of caffeine and alprazolam on motor activity and benzodiazepine receptor binding in vivo. Psychopharmacology (Berl). 1990;101(4):539-44. Abstract

Outlook

Sexual Function

Sleep

Da Settimo F, Taliani S, Trincavelli ML, et al. GABA A/Bz receptor subtypes as targets for selective drugs. Curr Med Chem. 2007;14(25):2680-701. Abstract

Social Life

Somnolence

Strength

Weight

Withdrawal: See Benzodiazepine Withdrawal

12.20 Benzodiazepine Pharmacology By Subpopulation

Armed Services / Veterans

Addiction

Alcoholism

Laukkanen V, Storvik M, Häkkinen M, et al. Decreased GABA(A) benzodiazepine binding site densities in postmortem brains of Cloninger type 1 and 2 alcoholics. Alcohol. 2013;47(2):103-8. Abstract

Behavioral Addiction

Cannabis Addiction: See Cannabis Non-medical use

Nicotine Addiction

Smith RB, Gwilt PR, Wright CE. Single- and multiple-dose pharmacokinetics of oral alprazolam in healthy smoking and nonsmoking men. Clin Pharm. 1983;2(2):139-43. Abstract

Opioid Addiction

Stimulant Addiction

Cocaine Addiction

Cancer

Cardiovascular Disease

Cognitive Dysfunction

Criminal Justice

Elderly

Dreyfuss D, Shader RI, Harmatz JS, et al. Kinetics and dynamics of single doses of oxazepam in the elderly: implications of absorption rate. J Clin Psychiatry. 1986;47(10):511-4. Abstract

Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part I). Clin Pharmacokinet. 1991;21(3):165-77. Abstract

Greenblatt DJ, Divoll M, Abernethy DR, et al. Alprazolam kinetics in the elderly. Relation to antipyrine disposition. Arch Gen Psychiatry. 1983;40(3):287-90. Abstract

Greenblatt DJ, Shader RI. Effects of age and other drugs on benzodiazepine kinetics. Arzneimittelforschung. 1980;30(5a):886-90. Abstract

Greenblatt DJ, Allen MD, Locniskar A. Lorazepam kinetics in the elderly. Clin Pharmacol Ther. 1979;26(1):103-13. Abstract

Hines LE, Murphy JE. Potentially harmful drug-drug interactions in the elderly: a review. Am J Geriatr Pharmacother. 2011;9(6):364-77. Abstract

Jacobs JR, Reves JG, Marty J, et al. Aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam. Anesth Analg. 1995;80(1):143-8. Abstract

Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest. 1975;55(2):347-59. Article

Salzman C. Anxiety in the elderly: treatment strategies. J Clin Psychiatry. 1990;51 Suppl:18-21; discussion 29-32. Abstract

Salzman C, Shader RI, Greenblatt DJ, Harmatz JS. Long v short half-life benzodiazepines in the elderly. Kinetics and clinical effects of diazepam and oxazepam. Arch Gen Psychiatry. 1983;40(3):293-7. Abstract

Stern RG, Duffelmeyer ME, Zemishlani Z, Davidson M. The use of benzodiazepines in the management of behavioral symptoms in demented patients. Psychiatr Clin North Am. 1991;14(2):375-84. Abstract

Vozeh S. Pharmacokinetic of benzodiazepines in old age. Schweiz Med Wochenschr. 1981;111(47):1789-93. Abstract

Ethnicity

African-American

Asian

Caucasian

Hispanic

Native American

Pacific Island

Health Care Providers

Hepatic Disease

Klotz U, Antonin KH, Brügel H, Bieck PR. Disposition of diazepam and its major metabolite desmethyldiazepam in patients with liver disease. Clin Pharmacol Ther. 1977;21(4):430-6. Abstract

Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest. 1975;55(2):347-59. Article

HIV / AIDS

LGBT

Men

Greenblatt DJ, Divoll M, Abernethy DR, et al. Alprazolam kinetics in the elderly. Relation to antipyrine disposition. Arch Gen Psychiatry. 1983;40(3):287-90. Abstract

Neurologic Disease

Dementia

Carlson MD, Penney JB, Young AB. NMDA, AMPA, and benzodiazepine binding site changes in Alzheimer’s disease visual cortex. Neurobiol Aging. 1993;14(4):343-52. Article

TBI

Hashimoto K, Abo M. Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with mild traumatic brain injury. J Rehabil Med. 2009;41(8):661-5. Abstract

Pain

DeFeudis FV. Gamma-Aminobutyric acid-ergic analgesia: implications for gamma-aminobutyric acid-ergic therapy for drug addictions. Drug Alcohol Depend. 1984;14(2):101-11. Abstract

Enna SJ, McCarson KE. The role of GABA in the mediation and perception of pain. Adv Pharmacol. 2006;54:1-27. Abstract

Ignatov IuD, Andreev BV. Role of opioid and adrenergic mechanisms in the analgesic action of GABA-positive drugs. Biull Eksp Biol Med. 1988;105(5):556-8. Abstract

Sawynok J, GABAergic mechanisms of analgesia: an update. Pharmacol Biochem Behav. 1987;26(2):463-74. Abstract

Sivam SP, Ho IK. GABA in morphine analgesia and tolerance. Life Sci. 1985;37(3):199-208. Abstract

Palliative Care – End of Life

Pediatric

Pulmonary Disease

Renal Disease

Crone CC, Gabriel GM. Treatment of anxiety and depression in transplant patients: pharmacokinetic considerations. Clin Pharmacokinet. 2004;43(6):361-94. Abstract

Sleep Disorders

Sleep Apnea

Surgery

Swallowing Disorders

Weight

Abernethy DR, Greenblatt DJ, Divoll M, et al. The influence of obesity on the pharmacokinetics of oral alprazolam and triazolam. Clin Pharmacokinet. 1984;9(2):177-83. Abstract

Abernethy DR, Greenblatt DJ, Divoll M, Shader RI. Prolonged accumulation of diazepam in obesity. J Clin Pharmacol. 1983;23(8-9):369-76. Abstract

Abernethy DR, Greenblatt DJ, Divoll M, Shader RI. Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen. J Lab Clin Med. 1983;101(6):873-80. Abstract

Hasnain M, Vieweg WV. Weight considerations in psychotropic drug prescribing and switching. Postgrad Med. 2013;125(5):117-29. Abstract

Women

Abernethy DR, Greenblatt DJ, Ochs HR, et al. Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives. Clin Pharmacol Ther. 1983;33(5):628-32. Abstract

Stoehr GP, Kroboth PD, Juhl RP, et al. Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics. Clin Pharmacol Ther. 1984;36(5):683-90. Abstract

Perinatal

Nursing

Library 12 Benzodiazepine Pharmacology – Neuropharmacology

12 Benzodiazepine Pharmacology – Neuropharmacology

12.1 Reviews

12.2 Pharmacology

12.3 Pharmacology: Alprazolam

12.4 Pharmacology: Chlorazepate

12.5 Pharmacology: Chlordiazepoxide

12.6 Pharmacology: Clonazepam

12.7 Pharmacology: Diazepam

12.8 Pharmacology: Flurazepam

12.9 Pharmacology: Lorazepam

12.10 Pharmacology: Midazolam

12.11 Pharmacology: Oxazepam

12.12 Pharmacology: Triazolam

12.13 By Receptor

12.14 By Pharmacokinetic / Pharmacodynamic Enzymes – Genetics

12.15 By Endogenous Neuro Transmitters

12.16 By Neuro-Chemical Action

12.17 By CNS Loci

12.18 By CNS Neural Pathways

12.19 By Neurophysiologic Function

12.20 Benzodiazepine Pharmacology By Subpopulation

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