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Clinical Pharmacokinetics and Pharmacodynamics of Anxiolytics and Sedative/Hypnotics

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Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents

Abstract

Medications to promote sedation and reduce anxiety and its associated symptoms have been sought since recorded history. The development of the benzodiazepines represented a major therapeutic endeavor due to their safety profile especially when taken in overdose situations compared to the barbiturates and early non-barbiturates such as meprobamate. Benzodiazepines continue to be one of the most commonly prescribed agents available in a variety of dosage formulations used for all age groups. Their pharmacokinetic (PK) and pharmacodynamic (PD) profiles have been extensively studied in adult healthy volunteers, the elderly, and patients with hepatic and renal impairment. Most benzodiazepines are metabolized by the phase I oxidative CYP enzyme system and the remaining agents by the phase II glucuronidation. Many long-acting benzodiazepines are metabolized to an active metabolite desmethyldiazepam. Alprazolam and buspirone were FDA approved for panic and generalized anxiety disorders, respectively. Various sedative-hypnotic non-benzodiazepine agents have been developed that are agonists of the alpha-1 GABA-A subreceptor site and the melatonin receptors type 1 and 2. All of these agents produce common PD effects such as sedation and psychomotor impairment. Benzodiazepines also produce antiepileptic actions, muscle relaxation, and anterograde amnesia. PK-PD modeling has been conducted for benzodiazepines and non-benzodiazepines that mainly focus on sedation and psychomotor impairment. The elderly have more pronounced sedative and psychomotor impairment from these agents compared to the adult population. Gender can be another significant factor as females were found to have significantly higher zolpidem plasma concentrations than males and when given comparative doses also displayed more pronounced psychomotor impairment which led to the FDA recommendation of lower doses prescribed.

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References

  1. Ban TA (2001) Pharmacotherapy of mental illness. A historical analysis. Prog Neuropsychopharmacol Biol Psychiatry 25:709–727

    Article  CAS  PubMed  Google Scholar 

  2. Wick JY (2013) The history of benzodiazepines. Consult Pharm 28:538–548

    Article  PubMed  Google Scholar 

  3. Greenblatt DJ, Shader RI, Divoll M, Harmatz JS (1981) Benzodiazepines: a summary of pharmacokinetic properties. Br J Clin Pharmacol 11(suppl):11–16

    Article  Google Scholar 

  4. Garzone PD, Kroboth PD (1989) Pharmacokinetics of the newer benzodiazepines. Clin Pharmacokinet 16:337–364

    Article  CAS  PubMed  Google Scholar 

  5. Wang JS, DeVane CL (2003) Pharmacokinetics and drug interactions of the sedative hypnotics. Psychopharmacol Bull 37:10–29

    PubMed  Google Scholar 

  6. Strang J, Griffiths P, Gossop M (1997) Heroin smoking by chasing the dragon: origins and history. Addiction 92:673–684

    Article  CAS  PubMed  Google Scholar 

  7. Sourkes TL (1992) Early clinical neurochemistry of CNS-active drugs Chloral hydrate. Mol Chem Neuropathol 17:21–30

    Article  CAS  PubMed  Google Scholar 

  8. Lopez-Munoz F, Ucha-Udabe R, Alamo C (2005) The history of barbiturates a century after their clinical introduction. Neuropsychiatr Dis Treat 1(4):329–343

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Welsh-Huggins A. Key death penalty drug discontinued by US maker. NBC News, 21 Jan 2011. www.nbcnews.com/id/41196734. Accessed 20 Aug 2015

  10. Morselli PL, Franco-Morselli R (1980) Clinical pharmacokinetics of antiepileptic drugs in adults. Pharmacol Ther 10:65–101

    Article  CAS  PubMed  Google Scholar 

  11. Solomon F, White CC, Parron DL et al (1979) Sleeping pills, insomnia and medical practice. N Engl J Med 300:803–808

    Article  CAS  PubMed  Google Scholar 

  12. Allen MD, Greenblatt DJ, Noel BJ (1977) Meprobamate overdosage: a continuing problem. Clin Toxicol 11:501–515

    Article  CAS  PubMed  Google Scholar 

  13. Powell LW, Mann GT, Kaye S (1958) Acute meprobamate poisoning. N Eng J Med 259:716–718

    Article  Google Scholar 

  14. Elsohly MA, Salamone SJ (1999) Prevalence of drugs used in cases of alleged sexual assault. J Anal Toxicol 23:141–146

    Article  CAS  PubMed  Google Scholar 

  15. Tietz EL, Rosenberg HC, Chiu TH (1969) A comparison of the anticonvulsant effects of 1,4- and 1,5-benzodiazepines in the amygdala-kindled rats and their effects on motor function. Epilepsy Res 3:31–43

    Article  Google Scholar 

  16. Gable RS (1993) Toward a comparative overview of dependence potential and acute toxicity of psychoactive substances used nonmedically. Am J Drug Alcohol Abuse 19:263–281

    Article  CAS  PubMed  Google Scholar 

  17. World Health Organization, Essential medicines. Accessed 123 May 2015. http://www.who.int/medicines/publications/essentialmedicines/en/index.html

  18. DeVane CL (2008) Principles of pharmacokinetics and pharmacodynamics. In: Schatzberg AF, Nemeroff CB (eds) Textbook of psychopharmacology, 4th ed. American Psychiatric Publishing, Inc, Washington DC.

    Google Scholar 

  19. Dusci LJ, Good SM, Hall RW, Iiett KF (1990) Excretion of diazepam and its metabolites in human milk during withdrawal from combination high dose diazepam and oxazepam. Br J Clin Pharmacol 29:123–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Squires RF, Braestrup C (1977) Benzodiazepine receptors in rat brain. Nature 266:732–734

    Article  CAS  PubMed  Google Scholar 

  21. Johnstone GA (1996) GABA-A receptor pharmacology. Pharmacol Ther 69:173–198

    Article  Google Scholar 

  22. Schraf MB, Fletcher K, Graham JP (1988) Comparative amnestic effects of benzodiazepine hypnotic agents. J Clin Psychiatry 49:134–137

    Google Scholar 

  23. Laurijssens BE, Greenblatt DJ (1996) Pharmacokinetic-pharmacodynamic relationships for benzodiazepines. Clin Pharmacokinet 30:52–76

    Article  CAS  PubMed  Google Scholar 

  24. Ballenger JC, Burrows GD, DuPont RL Jr et al (1988) Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. Arch Gen Psychiatry 45:413–422

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  26. Dupont RI, Swinson RP, Ballenger JC et al (1992) Discontinuation of alprazolam after long-term treatment of panic-related disorders. J Clin Psychiatry 12:352–354

    CAS  Google Scholar 

  27. Tesar GE, Rosenbaum JF, Pollack MH et al (1991) Double-blind, placebo-controlled comparison of clonazepam and alprazolam for panic disorder. J Clin Psychiatry 52:69–76

    CAS  PubMed  Google Scholar 

  28. Scavone JM, Greenblatt DJ, Shader RI (1987) Alprazolam kinetics following sublingual and oral administration. J Clin Psychopharmacol 7:332–334

    Article  CAS  PubMed  Google Scholar 

  29. Greenblatt DJ, Wright CE (1993) Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet 24:453–471

    Article  CAS  PubMed  Google Scholar 

  30. Fyer AJ, Liebowitz MR, Gorman JM, Campeas R et al (1987) Discontinuation of alprazolam treatment in panic patients. Am J Psychiatry 144:303–308

    Article  CAS  PubMed  Google Scholar 

  31. DeVane CL, Ware MR, Lydiard RB (1991) Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam. Psychopharmacol Bull 27:463–473

    CAS  PubMed  Google Scholar 

  32. Rickels K, Feighner JP, Smith WT (1985) Alprazolam, amitriptyline, doxepin, and placebo in the treatment of depression. JAMA Psychiatry 42:134–141

    CAS  Google Scholar 

  33. McKeon A, Frye MA, Delanty N (2008) The alcohol withdrawal syndrome. J Neurol Neurosurg Psychiatry 79:854–862

    Article  CAS  PubMed  Google Scholar 

  34. Greenblatt DJ, Shader RI, MacLeod SM, Sellers EM, Franke K, Giles HG (1978) Absorption of oral and intramuscular chlordiazepoxide. Eur J Clin Pharmacol 13:267–274

    Article  CAS  PubMed  Google Scholar 

  35. Wilkinson GR (1978) The effects of liver disease and aging on the disposition of diazepam, chlordiazepoxide, oxazepam and lorazepam in man. Acta Psychiatr Scand 58(Suppl274):56–74

    Article  Google Scholar 

  36. Conry JA, Ng YT, Paolicchi JM et al (2009) Clobazam in the treatment of Lennox-Gastaut syndrome. Epilepsia 50:1158–1166

    Article  CAS  PubMed  Google Scholar 

  37. Wildin JD, Pleuvry BJ, Mawer GE, Onon T, Millington L (1990) Respiratory and sedative effects of clobazam and clonazepam in volunteers. Br J Clin Pharmacol 29:169–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. McKernan RM, Rosahl TW, Reynolds DS et al (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA-A receptor alpha1 subtype. Nat Neurosci 3(6):587–592

    Article  CAS  PubMed  Google Scholar 

  39. Vajda FJ, Lewis SJ, Harris QL, Jarsrott B, Young NA (1987) Tolerance to the anticonvulsant effects of clonazepam and clobazam in the amygdaloid kindled rat. Clin Exp Neurol 23:155–164

    CAS  PubMed  Google Scholar 

  40. Crestani F, Low K, Keist R, Mandelli MJ et al (2001) Molecular targets for the myorelaxant action of diazepam. Mol Pharmacol 59:442–445

    CAS  PubMed  Google Scholar 

  41. Jick H, Miettinen OS, Shapiro S, Lewis GP et al (1970) Comprehensive drug surveillance. JAMA 213:1455–1460

    Article  CAS  PubMed  Google Scholar 

  42. Greenblatt DJ, Shader RI (1974) Benzodiazepines. N Engl J Med 291:1011–1015

    Article  CAS  PubMed  Google Scholar 

  43. Reves JG, Fragen RJ, Vinik HR, Greenblatt DG (1985) Midazolam: pharmacology and uses. Anesthesiology 62:310–324

    Article  CAS  PubMed  Google Scholar 

  44. Spina SP, Ensom MH (2007) Clinical pharmacokinetic monitoring of midazolam in critically ill patients. Pharmacotherapy 27:389–398

    Article  CAS  PubMed  Google Scholar 

  45. Salzman C, Shader RI, Greenblatt DJ, Harmatz JS (1983) Long v short half-life benzodiazepines in the elderly: kinetics and clinical effects of diazepam and oxazepam. Arch Gen Psychiatry 40:294–297

    Article  Google Scholar 

  46. Jann MW (1988) Buspirone: an update on a unique anxiolytic agent. Pharamacotherapy 8:100–116

    Article  CAS  Google Scholar 

  47. Allen MD, Greenblatt DJ, Arnold JD (1979) Single and multiple dose kinetics of estazolam, a triazolo benzodiazepine. Psychopharmacology 66:267–274

    Article  CAS  PubMed  Google Scholar 

  48. Roehrs T, Zorick F, Lord N et al (1983) Dose related effects of estazolam on sleep of patients with insomnia. J Clin Psychopharmacol 3:152–156

    CAS  PubMed  Google Scholar 

  49. DeVane CL (1981) Temazepam evaluation. Pharmacotherapy 1:12

    Google Scholar 

  50. Fuccella LM (1979) Bioavailability of temazepam in soft gelatin capsules. Br J Clin Pharmacol 8:31S–35S

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bixler EO, Kales A, Soldatos CR, SAcharf MB et al (1978) Effectiveness of temazepam with short-intermediate, and long-term use sleep laboratory evaluation. J Clin Pharmacol 18:110–118

    Article  CAS  PubMed  Google Scholar 

  52. Kales A, Scharf MB, Kales JD, Soldatos CR (1979) Rebound insomnia. A potential hazard following withdrawal of certain benzodiazepines. JAMA 241:1692–1695

    Article  CAS  PubMed  Google Scholar 

  53. Griffiths RR, Johnson MW (2005) Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J Clin Psychiatry 66(Suppl 9):31–41

    CAS  PubMed  Google Scholar 

  54. Varhe A, Olkkola KT, Neuvoven PJ (1994) Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 56:601–607

    Article  CAS  PubMed  Google Scholar 

  55. Kales A, Sharf M, Bixler EO et al (1981) Dose response studies with quazepam. Clin Pharmacol Ther 30:194–200

    Article  CAS  PubMed  Google Scholar 

  56. Chung M, Hilbertt JM, Gural RP, Radwanski E et al (1984) Multi-dose quazepam kinetics. Clin Pharmacol Ther 35:520–524

    Article  CAS  PubMed  Google Scholar 

  57. Roth TG, Roehrs TA, Koshorek GL, Greenblatt DJ, Rosenthal LD (1997) Hypnotic effects of low doses of quazepam in older insomniacs. J Clin Psychopharmacol 17:401–406

    Article  CAS  PubMed  Google Scholar 

  58. Mamelak M, Csima A, Price V (1984) A comparative 25 night sleep laboratory study on the effects of quazepam and triazolam on chronic insomniacs. J Clin Pharmacol 24:65–75

    Article  CAS  PubMed  Google Scholar 

  59. Yasui-Furukori N, Takahata T, Kondo T et al (2004) Time effects of food intake on the pharmacokinetics and pharmacodynamics of quazepam. Br J Clin Pharmacol 55:382–388

    Article  Google Scholar 

  60. Najib J (2006) Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia. Clin Ther 28:491–516

    Article  CAS  PubMed  Google Scholar 

  61. Dopp JM, Phillips BG et al (2014) Sleep disorders. In: DiPiro JT, Talbert RL, Yee GC (eds) Pharmacotherapy: a pathophysiologic approach, 9th edn. McGraw Hill, New York, pp 1115–1126

    Google Scholar 

  62. De Bodinat C, Guardiola-Lemaitre B, Mocaer E, Renard P et al (2010) Agomelatine, the first melatonergic antidepressant discovery, characterization and development. Nat Rev Drug Discov 9:628–642

    Article  PubMed  Google Scholar 

  63. Rajaratnam SMW, Cohen DA, Rogers NL (2009) Melatonin and melatonin analogues. Sleep Med Clin 4:179–193

    Article  Google Scholar 

  64. Karim A, Tolbert D, Cao C (2006) Disposition kinetics and tolerance of escalating single doses of ramelton, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for insomnia. J Clin Pharmacol 46:140–148

    Article  CAS  PubMed  Google Scholar 

  65. Greenblatt DJ, Harmatz JS, Karim A (2007) Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelton, a hypnotic agent acting via melatonin receptors MT1 and MT2. J Clin Pharmacol 47:485–496

    Article  CAS  PubMed  Google Scholar 

  66. Uemura N, McCrea J, Sun H et al (2015) Effects of orexin receptor antagonist suvorexant on respiration during sleep in healthy subjects. J Clin Pharmacol 55:1093–1100

    Article  CAS  PubMed  Google Scholar 

  67. Patel KV, Aspesi AV, Evoy KE (2015) Suvorexant: a dual orexin receptor antagonist for the treatment of sleep onset and sleep maintenance insomnia. Ann Pharmacother 49:477–483

    Article  CAS  PubMed  Google Scholar 

  68. Bonacci JM, Venci JV, Gandhi MA (2015) Tasimelteon (Hetlioz™): a new melatonin receptor agonist for the treatment of non-24-hour sleep wake disorder. J Pharm Pract 28:473–478

    Article  PubMed  Google Scholar 

  69. Torres R, Kramer WG, Baroldi P (2015) Pharmacokinetics of the dual melatonin receptor agonist tasimelteon in subjects with hepatic or renal impairment. J Clin Pharmacol 55:525–533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Drover DR (2004) Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives – zaleplon, zolpidem, and zopiclone. Clin Pharmacokinet 43:227–238

    Article  CAS  PubMed  Google Scholar 

  71. Von Moltke LL, Greenblatt DJ, Granda BW et al (1999) Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations. Br J Clin Pharmacol 48:89–97

    Article  Google Scholar 

  72. Greenblatt DJ, Harmatz JS, Singh NN et al (2013) Gender differences in pharmacokinetics and pharmacodynamics of zolpidem following sublingual administration. J Clin Pharmacol 54:282–290

    Article  PubMed  Google Scholar 

  73. Wolf B, Griffiths RR (1991) Physicial dependence on benzodiazepines: differences within the class. Drug Alcohol Depend 29:153–156

    Article  CAS  PubMed  Google Scholar 

  74. Holford NHG, Sheiner LB (1982) Kinetics of pharmacologic response. Pharmacol Ther 16:143–166

    Article  CAS  PubMed  Google Scholar 

  75. Ellinwood EH, Nikaido A, Heatherly D (1984) Diazepam: prediction of pharmacodynamics from pharmacokinetics. Psychopharmacology 83:297–298

    Article  CAS  PubMed  Google Scholar 

  76. Ellinwwod EH, Heatherly DGH, Nikaido AM et al (1985) Comparative pharmacokinetics and pharmacodynamics of lorazepam, alprazolam, and diazepam. Psychopharmacology 86:392–399

    Article  Google Scholar 

  77. Wright CE, Sisson TL, Fleishaker JG, Antal EJ (1997) Pharmacokinetics and psychomotor performance of alprazolam: concentration-effect relationship. J Clin Pharmacol 37:321–329

    Article  CAS  PubMed  Google Scholar 

  78. Gupta SK, Ellinwood EH, Nikaido AM, Heatherly DG (1990) Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines. I Lorazepam. J Pharmacokinet Biopharm 18:89–102

    Article  CAS  PubMed  Google Scholar 

  79. Gupta SK, Ellinwood EH, Nikaido AM, Heatherly DG (1990) Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines. II Triazolam. Pharm Res 7:570–576

    Article  CAS  PubMed  Google Scholar 

  80. Dos Santos FM, Goncalves JC, Caminta R et al (2009) Pharmacokinetic/pharmacodynamics modeling of psychomotor impairment induced by oral clonazepam in healthy volunteers. Ther Drug Monit 31:566–574

    Article  PubMed  Google Scholar 

  81. Pomara N, Lee SH, Bruno D et al (2015) Adverse performance effects of acute lorazepam administration in elderly long-term users: pharmacokinetic and clinical predictors. Prog Neuropsychopharmacol Biol Psychiatry 56:129–135

    Article  CAS  PubMed  Google Scholar 

  82. Greenblatt DJ, Harmatz JS, von Moltke LL et al (1998) Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo. Clin Pharmacol Ther 64:553–561

    Article  CAS  PubMed  Google Scholar 

  83. Greenblatt DJ, Harmatz JS, Singh NN et al (2014) Pharmacokinetics of zolpidem from sublingual zolpidem tartrate tablets in healthy elderly versus non-elderly subjects. Drugs Aging 31:731–736

    Article  CAS  PubMed  Google Scholar 

  84. Hampton LM, Daubresse M, Chang H-Y, Alexander GC, Budnitz DS (2015) Surveillance of advertise psychiatric medication events. JAMA Psychiatry 313:1256–1257

    Google Scholar 

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  1. Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA

    C. Lindsay DeVane PharmD

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Correspondence to C. Lindsay DeVane PharmD .

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Editors and Affiliations

  1. Univ. North Texas Sys, Col Pharmacy, Department of Pharmacotherapy, FORT WORTH, Texas, USA

    Michael W. Jann

  2. Department of Pharmacotherapy, Univ. North Texas Sys, Col Pharm, FORT WORTH, Texas, USA

    Scott R. Penzak

  3. Department of Pharmacotherapy, Univ. North Texas Sys, Col Pharm., FORT WORTH, Texas, USA

    Lawrence J. Cohen

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DeVane, C.L. (2016). Clinical Pharmacokinetics and Pharmacodynamics of Anxiolytics and Sedative/Hypnotics. In: Jann, M., Penzak, S., Cohen, L. (eds) Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents. Adis, Cham. https://doi.org/10.1007/978-3-319-27883-4_10

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