Benzodiazepine and benzodiazepine-like drugs PHRM 4060 Spring 2010 Benzodiazepine and benzodiazepine-like drugs 1 2 3 4 5 6 7 9 8 http://en.wikipedia.org/wiki/Tizanidine  Used as an alternative to benzodiazapines.

Updates www.pharmwiki.org http://128.192.148.219/COPClasses/index.php/Main_Page Office Hours- Friday 5-6p or Facebook (Dr. Arthur Roberts) Room 424 in Pharmacy South

Outline Structure of Benzodiazepine (BZD) Characteristics GABAA receptor and agonists BZD SAR BZD Metabolism Non-BZD – w site agonist

1 2 3 4 5 6 7 diazepine 9 8 benzene benzo-di-azepine azepine

Benzodiazepines GABA GABAA receptor Properties Sedation/hypnosis PHRM 4060 Spring 2010 Benzodiazepines GABA GABAA receptor Properties Sedation/hypnosis Decreased anxiety Anterograde amnesia (negative) Anticonvulsant Muscle relaxation g-aminobutyric acid http://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid http://en.wikipedia.org/wiki/Anterograde_amnesia http://en.wikipedia.org/wiki/Gabapentin (GABA analog) http://en.wikipedia.org/wiki/Pregabalin Lyrica (GABA analog)

Benzodiazepines Therapeutic and Efficacy half life PHRM 4060 Spring 2010 Benzodiazepines Therapeutic and Efficacy half life Anticonvulsants  long half-lives CNS and Status epilepticus Sleep  short half-lives Anti-anxiety  long half-life, except aprazolam (Xanax) ~12 hours alprazolam (Xanax) http://en.wikipedia.org/wiki/Status_epilepticus http://www.rxlist.com/ambien-drug/clinical-pharmacology.htm

Examples Anticonvulsant Sleep Anti-anxiety clonazepam (Klonopin) PHRM 4060 Spring 2010 Examples Anticonvulsant Sleep Anti-anxiety Elimination half life is Italics http://en.wikipedia.org/wiki/Clonazepam http://en.wikipedia.org/wiki/Triazolam http://www.rxlist.com/halcion-drug/clinical-pharmacology.htm/ http://www.rxlist.com/valium-drug/clinical-pharmacology.htm http://en.wikipedia.org/wiki/Diazepam clonazepam (Klonopin) 18-50 hours triazolam (Halcion) 1.5-5.5 hours diazepam (Valium) 36-200 hours (active desmethyl metabolite)

A B (w site) D C g-aminobutyric acid (GABA) PHRM 4060 Spring 2010 http://en.wikipedia.org/wiki/GABAA_receptor http://en.wikipedia.org/wiki/Inverse_agonist 2 GABA need to bindhttp://pubs.niaaa.nih.gov/publications/arh314/310-339.htm http://pharmacologycorner.com/inverse-agonists/ Chloride Conductance

KD’s of GABAA agonists Compound Diazepam 16 nM 16 17 15 Clonazepam 1.3 PHRM 4060 Spring 2010 KD’s of GABAA agonists Compound a1 a2 a3 a5 Diazepam 16 nM 16 17 15 Clonazepam 1.3 1.7 2 - Triazolam 1.8 1.2 3 Ro15-4513 2.6 0.24 Zolpidem 291 357 >15000 L-655-708 48 27 24 0.45 http://www.sciencedirect.com/science/article/pii/S0165614797011188?via=ihub# http://molpharm.aspetjournals.org/content/67/4/1005.full http://en.wikipedia.org/wiki/Ro15-4513 -weak partial inverse agonist http://en.wikipedia.org/wiki/L-655,708 –a5 inverse agonist

Rules a1-a3 and a5 non-selective a1-a3 anticonvulsant a1 sedation and hypnosis a2 and a5 anxiolytic

Benzodiazepines SAR 1,4 benzodiazepine PHRM 4060 Spring 2010 Benzodiazepines SAR 1 7 4 1,4 benzodiazepine Electron withdrawing group (EWG)  7 position, X= Cl < Br < F < CN < CF3 < NO2 Stronger EWG give more potent compounds http://en.wikipedia.org/wiki/List_of_benzodiazepines

Example clonazepam (Klonopin) oxazepam (Serax) equiv. dose = 0.5 mg PHRM 4060 Spring 2010 Example http://en.wikipedia.org/wiki/Clonazepam http://www.vhpharmsci.com/vhformulary/tools/benzodiazepines-comparison.htm http://en.wikipedia.org/wiki/Oxazepam http://en.wikipedia.org/wiki/List_of_benzodiazepines clonazepam (Klonopin) equiv. dose = 0.5 mg oxazepam (Serax) equiv. dose = 20 mg

Benzodiazepines SAR (6-9) > >

Benzodiazepines SAR (5) > ortho para

Benzodiazepines SAR (5) X aromatic ring  antagonist

Flumazenil (Anexate) GABAA receptor antagonist BZD overdoses PHRM 4060 Spring 2010 Flumazenil (Anexate) 5 GABAA receptor antagonist BZD overdoses hypersomnia X Patent Liver  Carboxylic Acid Metabolite + Glucuronidation ADR: headache and insomnia BZ=Benzodiazapine http://en.wikipedia.org/wiki/Flumazenil http://www.old.health.gov.il/units/pharmacy/trufot/alonim/Anexate_dr.pdf If you have liver disease Flumazenil is the only GABAA receptor antagonist on the market The patent has expired for it.

Benzodiazepines SAR (3-5) PHRM 4060 Spring 2010 Benzodiazepines SAR (3-5) decreased potency; change in conformation of the diazepine ring

Benzodiazepines SAR (3) potency half life prodrug UGTs

Benzodiazepines SAR (3) (Prodrug) PHRM 4060 Spring 2010 Benzodiazepines SAR (3) (Prodrug) H H H Cl Cl decarboxylase http://en.wikipedia.org/wiki/Clorazepate http://en.wikipedia.org/wiki/Nordazepam clorazepate desmethyldiazepam (active) (a.k.a. nordazepam (Nordaz))

Benzodiazepines SAR (2) >

Benzodiazepines SAR (1) PHRM 4060 Spring 2010 Benzodiazepines SAR (1) N1 substitution should be small, H, Methyl, Ethyl as in 1-3 Benzyl is more bulky and would be less active as is but would be converted to 3 on metabolism

Benzodiazepines SAR (1,2-imidazo ring) PHRM 4060 Spring 2010 Benzodiazepines SAR (1,2-imidazo ring) 2 1 10 3 9 4 8 5 7 6 short half-lives; oxidation of methyl to alcohol and glucuorination http://pharmrev.aspetjournals.org/content/63/1/243/F3.expansion.html

Examples triazolam midazolam alprazolam (Xanax) PHRM 4060 Spring 2010 http://en.wikipedia.org/wiki/Midazolam – lethal injection - open ring form under acidic conditions http://en.wikipedia.org/wiki/Triazolam - used to treat insomnia and jet lag; President George W. Bush used it. http://en.wikipedia.org/wiki/Alprazolam - anti-anxiety triazolam midazolam alprazolam (Xanax)

MeTabolism

halazepam diazepam (Valium) prazepam clorazepate PHRM 4060 Spring 2010 http://en.wikipedia.org/wiki/Demoxepam http://en.wikipedia.org/wiki/Chlordiazepoxide http://en.wikipedia.org/wiki/Diazepam http://en.wikipedia.org/wiki/Clorazepate http://en.wikipedia.org/wiki/Halazepam http://en.wikipedia.org/wiki/Prazepam http://www.rxlist.com/valium-drug/clinical-pharmacology.htm

PHRM 4060 Spring 2010 OH http://en.wikipedia.org/wiki/N-Desalkylflurazepam http://en.wikipedia.org/wiki/Flurazepam http://en.wikipedia.org/wiki/Midazolam http://en.wikipedia.org/wiki/Triazolam http://en.wikipedia.org/wiki/Alprazolam http://en.wikipedia.org/wiki/Lorazepam midazolam a-hydroxymethyl midazolam

Non-benzodiazepines (Non-BZD) imidazopyridines pyrazolopyrimidine cyclopyrrolones

Non-BZD site agonist PHRM 4060 Spring 2010 Non-BZD site agonist 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 http://scialert.net/fulltext/?doi=jpt.2008.93.101&org=10 http://en.wikipedia.org/wiki/Zolpidem http://www.ncbi.nlm.nih.gov/pubmed/2158421 Used as a “Date Rape Drug”

Non-BZD site agonist PHRM 4060 Spring 2010 Non-BZD site agonist O 5 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 http://en.wikipedia.org/wiki/Zaleplon

Non-BZD site agonist PHRM 4060 Spring 2010 Non-BZD site agonist H 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%) http://en.wikipedia.org/wiki/Zopiclone http://en.wikipedia.org/wiki/Eszopiclone EU denied patent because it was too similar to Zopliclone http://www.who.int/medicines/areas/quality_safety/4.6ZopicloneCritReview.pdf

Huedo-Medina, T. B. , Kirsch, I. , Middlemass, J. , Klonizakis, M 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.

Alternative: Ramelteon (Rozerem) PHRM 4060 Spring 2010 Alternative: Ramelteon (Rozerem) 1/10 M-II 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 http://en.wikipedia.org/wiki/Ramelteon http://www.ncbi.nlm.nih.gov/pubmed/20478852 http://dmd.aspetjournals.org/content/38/8/1381.long http://link.springer.com/chapter/10.1007%2F0-387-27682-3_8 http://www.landesbioscience.com/curie/chapter/1971/ The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17 – 25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20 – 100 fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699659/ http://www.nejm.org/doi/full/10.1056/NEJMp0907708  Ramelteon not effective.

Outline Structure of Benzodiazepine (BZD) Characteristics GABAA receptor and agonists BZD SAR BZD Metabolism Non-BZD – w site agonist