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Sedative & Hypnotic Agents Part I
This document discusses sedative and hypnotic drugs, focusing on barbiturates and benzodiazepines, their pharmacodynamics, and implications for overdose and addiction. It highlights key differences in the mechanisms of action, metabolism, and effects of these drug classes, as well as their use in various medical contexts. Additionally, the document provides insight into age effects on drug pharmacokinetics and dynamics, along with considerations for use during pregnancy.
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Sedative & Hypnotic Agents Part I
- 1. Sedative & HypnoticDrugs I Brian J. Piper, Ph.D., M.S. January 22, 2013
- 2. Goals • Importance • Pharmacodynamics (GABA) • Barbiturates • Benzodiazepines
- 3. Structure • intentional overlap •Assessment – 80% drug (PD/PK) – 5% pathophysiology – 5% diagnostic criteria – 10% pioneers
- 4. Terminology • sedative: agentthat exerts a calming effect, anxiolytic • hypnotic: agent that increases likelihood of sleep onset & maintenance of sleep YES NO
- 5. Dose-Response Curve ForSedative- Hypnotics Trevor & Way (2012). Sedative-Hypnotic Drugs. In Katzung’s Basic & Clinical Pharmacology, p. 374.
- 6. Barbiturates • Examples: -barbital; phenobarbital, amobartibal, butabarbital • MOA: GABAA, increase duration of Cl- channel opening Loscher & Rogawski (2012). Epilepsia, 53(S8), 12-25.
- 7. Barbiturates • Example: phenobarbital • MOA: GABAA, increase duration of Cl- channel opening; AMPA antagonist • Effects: – anticonvulsant – sleep – memory impairment – tolerance/addiction Loscher & Rogawski (2012). Epilepsia, 53(S8), 12-25.
- 8. Overdose Potential 1942 - 1970 1926-1962
- 9. Other Uses • PhysicianAssisted Suicide (WA, OR, MT): – barbiturate + muscle relaxant + potassium chloride • Lethal Injection (34) brown: performs executions blue: does not perform executions green: no one executed 1976 - 2012
- 10. Benzodiazepines 1908 - 2005 http://www.howjsay.com/index.php?word=chlordiazepoxide&submit=Submit
- 11. Benzodiazepine Binding Siteon GABAA GABAA = α1 α2 α3 α4 α5 α6 β1 β2 β3 β4 γ1 γ2 γ3 δ ε π ρ Location: Binding α1β2 : GABA α1γ2 : benzodiazepines Trevor & Way (2012). Sedative-Hypnotic Drugs. In Katzung’s Basic & Clinical Pharmacology, p. 374.
- 12. Howland & Mycek(2006). Lippincott’s Illustrated Reviews, p. 107.
- 13. Is Flunitrazepam (Rohypnol)special? • In general, the pharmacodynamic differences between benzos are subtle while the pharmacokinetic differences are substantial. http://www.howjsay.com/index.php?word=flunitrazepam
- 14. Pharmacokinetic Comparison • Benzos also differ in whether their metabolites are biologically active Howland & Mycek (2006). Lippincott’s Illustrated Reviews, p. 106.
- 15. Age Effects onBenzodiazepine PK • Young (N=10, 23-39 y.o., mean = 28.8) and elderly (N=9, 67-83 y.o., mean = 72.0) received 1 mg loprazolam after an over- night fast • Young t1/2 = 11.2 h Elderly t1/2 = 19.8 h Swift et al. (1985). British Journal of Clinical Pharmacology, 20, 119-128.
- 16. Age Effects onBenzodiazepine PD • Young and elderly received 0.5 (left) or 1.0 mg (right) loprazolam (x 2) over 11 hours Swift et al. (1985). British Journal of Clinical Pharmacology, 20, 119-128.
- 17. Age Effects onBenzodiazepine PD • Young and elderly received 0.5 (left) or 1.0 mg (right) loprazolam (x 2) over 11 hours Swift et al. (1985). British Journal of Clinical Pharmacology, 20, 119-128.
- 18. Benzodiazepines & Reproduction •Pregnancy Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. • Cleft-palate? • Breast-feeding recommended
- 19. Flumazenil • History: FDA approval in 1991 • MOA: Benzodiazepine antagonist • Uses: reversal of BZD sedation http://www.howjsay.com/index.php?word=flumazenil&submit=Submit
- 20.
- 21. Benzodiazepine Addiction • gradual recognition • Withdrawal: rebound anxiety & insomnia Lader (2011). Addiction, 106, 2086-2109.
- 22. Barbiturates Benzodiazepines Most popular era 1950s 1960s - present PAM (low dose only) PAM (all doses) Mechanism of Cl– channel duration Cl– channel frequency Action AMPA/kainate antagonist Monotherapy yes unlikely Overdose Memory yes yes Impairment No! Loscher & Rogawski (2012). Epilepsia, 53(S8), 12-25.
- 23.
- 24. Self-Test #1 • Tor F Benzodiazepines and barbiturates bind to the same site on the GABAA receptor.
- 25. Self-Test #2 • T or F Diazepam (valium) was the best selling prescription drug in the U.S. in the 1960s. http://www.nytimes.com/2012/09/30/sunday-review/valium-and-the-new-normal.html?_r=0
- 26. Self-Test #3 • Whichof the following drugs has the highest risk of overdose? • A) Quazepam • B) Chlordiazepoxide • C) Alprazolam • D) Phenobarbital • E) Halazepam
Editor's Notes
- #6 anesthesia: condition of having sensation taken away.
- #7 GABAA is a pentemer with each subunit composed of 4 membrane spanning domains.Phenobarbital is currently used for acute seizure management, Amobarbital & butabarbital for insomnia.GAD: Glutamic Acid Decarboxylase; GABA-T: GABA Transaminase; SSA: succinic semialdehydeInteresting history is available here: http://en.wikipedia.org/wiki/Barbiturate
- #8 Phenobarbital is currently used for acute seizure management, Amobarbital & butabarbital for insomnia.GAD: Glutamic Acid Decarboxylase; GABA-T: GABA Transaminase; SSA: succinic semialdehyde; M1, M2, M3, M4: transmembrane domainsInteresting history is available here: http://en.wikipedia.org/wiki/Barbiturate
- #9 Norma JeaneMortenson had Nebutal in her system at autopsy.
- #10 Assisted suicide is explicitly prohibited in 34 states. Lethal injection is allowed in 34 states.The muscle relaxant used is a cousin of curare.
- #11 The organic chemist Sternbach developed chlordiazepoxide (Librium) in 1958 while working for the Swiss company Hoffman-La Roche.
- #13 Chloropromazine is a neuroleptic.
- #14 Pronouncedfloo nee traz a pam.
- #16 Groups weight was very similar. Half-life is 77% longer in the elderly!
- #17 1st dose given at night & second in morning. Behavioral testing completed after 2nd dose.
- #18 With 1.0 mg CRT was prolonged 2 h after ingestion by 55 ms and 112 ms (median values) in young and elderly groups (doubled). No significant effects were observed with the 0.5 mg dose.
- #19 Chlordiazepoxide (Librium).
- #20 (flu may zinul). Risk of seizures, especially with long-term BZD-induced sedation.
- #21 Similarly, an autoradiography study noted that “ The highest densities of benzodiazepine receptors in human brain were localized in cortical and hippocampal areas, nucleus accumbens, amygdala and mammillary bodies. Intermediate densities were found in the basal ganglia and thalamic and hypothalamic nuclei. [3H]Flunitrazepam binding was low in the brainstem nuclei and very low in white matter.
- #22 Z drugs = Zolpidem; Zaleplon.
- #23 Structure of barbituric acid (L) and benzo (R).
- #26 NY Times: “Valium was the best-selling prescription drug in America”
- #27 Alprazolam (Xanax).