Benzodiazepine and benzodiazepine-like drugs 9 8 1 2 3 5 7 4 6 1 Updates • www.pharmwiki.org – http://128.192.148.219/COPClasses/index.php/M ain_Page • Office Hours- Friday 5-6p or Facebook (Dr. Arthur Roberts) – Room 424 in Pharmacy South 2 Outline • • • • • • Structure of Benzodiazepine (BZD) Characteristics GABAA receptor and agonists BZD SAR BZD Metabolism Non-BZD – w site agonist 3 diazepine 9 1 8 benzene 7 5 2 4 3 6 benzo-di-azepine azepine 4 Benzodiazepines • GABA GABAA receptor • Properties – – – – – Sedation/hypnosis Decreased anxiety Anterograde amnesia (negative) Anticonvulsant Muscle relaxation g-aminobutyric acid 5 Benzodiazepines • Therapeutic and Efficacy half life • Anticonvulsants long half-lives – CNS and Status epilepticus alprazolam • Sleep short half-lives (Xanax) • Anti-anxiety long half-life, except aprazolam (Xanax) ~12 hours 6 Examples Anticonvulsant clonazepam (Klonopin) 18-50 hours Sleep triazolam (Halcion) 1.5-5.5 hours Anti-anxiety diazepam (Valium) 36-200 hours (active desmethyl metabolite) 7 B A g-aminobutyric acid (GABA) D (w site) Chloride Conductance C 8 KD’s of GABAA agonists Compound a1 Diazepam a2 a3 a5 16 nM 16 17 15 Clonazepam Triazolam Ro15-4513 1.3 1.8 2.6 1.7 1.2 2.6 2 3 1.3 1.2 0.24 Zolpidem 1.7 291 357 >15000 L-655-708 48 27 24 0.45 9 Rules • • • • a1-a3 and a5 non-selective a1-a3 anticonvulsant a1 sedation and hypnosis a2 and a5 anxiolytic 10 Benzodiazepines SAR 1 CH3 O N 7 X N 4 • 1,4 benzodiazepine • Electron withdrawing group (EWG) 7 position, – X= Cl < Br < F < CN < CF3 < NO2 – Stronger EWG give more potent compounds 11 Example clonazepam (Klonopin) equiv. dose = 0.5 mg oxazepam (Serax) equiv. dose = 20 mg 12 Benzodiazepines SAR (6-9) CH3 O N N CF3 6 CH3 F 8 CF3 N CH3 F O 9 N CF3 O N N F > > 13 Benzodiazepines SAR (5) CH3 O N CF3 #1 5 CH3 N N O #2 X O N N CF3 X CH3 N CF3 X #3 > ortho para X 14 Benzodiazepines SAR (5) CH3 N O N CF3 5 H • X aromatic ring antagonist 15 Flumazenil (Anexate) 5 • • • • • • GABAA receptor antagonist BZD overdoses hypersomnia X Patent Liver Carboxylic Acid Metabolite + Glucuronidation ADR: headache and insomnia 16 Benzodiazepines SAR (3-5) CH3 N CF3 O NH CF3 4,5 reduction CH3 O N N 3,4 shift 17 Benzodiazepines SAR (3) CH3 CH3 O N N potency O N 3 CF3 CH3 O CH3 CF3 O N 3 N half life OH 3 CF3 O CH2CH2CH3 N prodrug UGTs 18 Benzodiazepines SAR (3) (Prodrug) CH3 H CH H 3 O O N N H COOH COOH Cl3 CF CF Cl3 N N decarboxylase clorazepate desmethyldiazepam (active) (a.k.a. nordazepam (Nordaz)) 19 Benzodiazepines SAR (2) CH3 O N CF3 CH3 CH3 S N N CF3 N N N CF3 N 2-Thione > NHCH3 NH > N CF3 2-Imine 2-Methylamino > 20 Benzodiazepines SAR (1) CH2CH3 CH2CF3 O N CF3 H O O N N 1 CF3 N N 2 CF3 O N N 3 CF3 N 4 21 Benzodiazepines SAR (1,2imidazo ring) OH CH3 CH3 N CH2 N 10 N N N 9 2 1 N 3 N 4 N CF3 Triazole CF3 N CF3 8 N 7 6 5 Imidazole 22 Examples midazolam triazolam alprazolam (Xanax) 23 Metabolic Pathway of the Benzodiazepines and Their Half-lives Chlordiazepoxide (10h) desmethyl -chlordiazepoxide (6-20 h) demoxepam (72 h) Temazepam (13 h) 3-OH Diazepam Clorazepate (decarboxylated in stomach) Prazepam (1.3 h) Desmethyldiazepam (73 h) Nordiazepam Oxazepam (6.8 h) Desalkylflurazepam (74 h) 3-hydroxy desalkyl flurazepam (6-14 h) Halazepam (14 h) Flurazepam (2.5 h) Quazepam (Short,No data) 2-Oxoquazepam desulfuration (39 h) Lorazepam (14 h) Triazolam (2.9 h) a-Hydroxymethyl triazolam (<4 h) Alprazolam (12 h) a-Hydroxymethyl alprazolam rapid conjugation and excretion Midazolam (1.9 h or 68 min) a-Hydroxymethyl midazolam rapid conjugation and excretion GLUCURONIDATION Diazepam (43 h) METABOLISM 24 Metabolic Pathway of the Benzodiazepines and Their Half-lives desmethyl -chlordiazepoxide (6-20 h) Chlordiazepoxide (10h) demoxepam (72 h) Temazepam (13 h) 3-OH Diazepam Clorazepate (decarboxylated in stomach) Prazepam (1.3 h) Desmethyldiazepam (73 h) Nordiazepam Oxazepam (6.8 h) Desalkylflurazepam (74 h) 3-hydroxy desalkyl flurazepam (6-14 h) Halazepam (14 h) Flurazepam (2.5 h) Quazepam (Short,No data) 2-Oxoquazepam desulfuration (39 h) diazepam (Valium) Triazolam (2.9 h) clorazepate a-Hydroxymethyl triazolam (<4 h) Alprazolam (12 h) a-Hydroxymethyl alprazolam rapid conjugation and excretion Midazolam (1.9 h or 68 min) a-Hydroxymethyl midazolam rapid conjugation and excretion prazepam Lorazepam (14 h) halazepam GLUCURONIDATION Diazepam (43 h) 25 Metabolic Pathway of the Benzodiazepines and Their Half-lives Chlordiazepoxide (10h) desmethyl -chlordiazepoxide (6-20 h) demoxepam (72 h) Temazepam (13 h) 3-OH Diazepam Clorazepate (decarboxylated in stomach) Prazepam (1.3 h) Desmethyldiazepam (73 h) Nordiazepam Oxazepam (6.8 h) Desalkylflurazepam (74 h) 3-hydroxy desalkyl flurazepam (6-14 h) OH Halazepam (14 h) Flurazepam (2.5 h) Quazepam (Short,No data) 2-Oxoquazepam desulfuration (39 h) Lorazepam (14 h) Triazolam (2.9 h) a-Hydroxymethyl triazolam (<4 h) Alprazolam (12 h) a-Hydroxymethyl alprazolam rapid conjugation and excretion Midazolam (1.9 h or 68 min) a-Hydroxymethyl midazolam rapid conjugation and excretion midazolam a-hydroxymethyl midazolam GLUCURONIDATION Diazepam (43 h) 26 Non-benzodiazepines (NonBZD) • imidazopyridines • pyrazolopyrimidine • cyclopyrrolones 27 Non-BZD w site agonist N CH3 N H 3C CH2 O N CH3 H 3C • Zolpidem (Ambien) - Insomnia • Rapid absorption GI, but food delays 30 min • CYP3A4 inactivates – Duration 6-8 hours – half-life 2.5 hours (Liver disease) • 92% protein bound • ADR: amnesia 28 Non-BZD w site agonist NC N N N CH3 5 N O O CH3 • Zaleplon (Sonata) - Insomnia • 30% bioavailable. Onset 1hr food delays • Aldehyde oxidase inactive metabolite (X CYP450) – half-life 1 hour; duration 6-8 h • 60% protein bound • ADR Amnesia 29 Non-BZD w site agonist O O N N N N Cl N N H N O O N N Cl H O N CH3 O N N • • • • • • • CH3 Eszopiclone (Lunesta)- Insomnia S isomer of racemic zopiclone (EU denied patent) Rapid absorption peak in 1 hour, but food delays 50% protein binding Metabolized by CYP3A4 and CYP2E1 – active–desmethyl – inactive-N-oxide Half-life 6h ADR: headache, hallucinations anxiety, amnesia, Unpleasant taste (34%) 30 Huedo-Medina, T. B., Kirsch, I., Middlemass, J., Klonizakis, M., and Siriwardena, A. N. (2012) Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration, BMJ 345, e8343. 31 Alternative: Ramelteon (Rozerem) 1/10 M-II CH3 HN HN O O O H3CO N H Melatonin • Insomnia • Melatonin receptor (MT1 and MT2) agonist (No GABAA) – sleep-wake cycle and circadian rhythm • • • • • • Onset 30 mins Bioavailable is 1.8% Metabolized by CYP1A2, first pass converts to active metabolite M-II Food delays absorption 82% protein bound ADR: headache, depression, insomnia worsened 32 Outline • • • • • • Structure of Benzodiazepine (BZD) Characteristics GABAA receptor and agonists BZD SAR BZD Metabolism Non-BZD – w site agonist 33