Benzodiazepine and benzodiazepine-like drugs

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Updates

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ain_Page

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Outline

• Structure of Benzodiazepine (BZD)• Characteristics• GABAA receptor and agonists

• BZD SAR• BZD Metabolism• Non-BZD – site agonist

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diazepine

azepine

benzo-di-azepine

benzene8

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Benzodiazepines

• GABA GABAA receptor

• Properties – Sedation/hypnosis– Decreased anxiety– Anterograde amnesia (negative)– Anticonvulsant– Muscle relaxation

-aminobutyric acid

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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

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alprazolam(Xanax)

Examples

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clonazepam (Klonopin)18-50 hours

Anticonvulsant Sleep

triazolam (Halcion)1.5-5.5 hours

Anti-anxiety

diazepam (Valium)36-200 hours

(active desmethyl metabolite)

(site)

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Chl

orid

e C

ondu

ctan

ceA B

C

-aminobutyric acid (GABA)

D

KD’s of GABAA agonists

Compound 1 2 3 5

Diazepam 16 nM 16 17 15

Clonazepam 1.3 1.7 2 -

Triazolam 1.8 1.2 3 1.2

Ro15-4513 2.6 2.6 1.3 0.24

Zolpidem 1.7 291 357 >15000

L-655-708 48 27 24 0.45

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Rules

• and 5 non-selective

• 1-3 anticonvulsant

• 1 sedation and hypnosis

• 2 and 5 anxiolytic

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• 1,4 benzodiazepine• Electron withdrawing group (EWG) 7 position,

– X= Cl < Br < F < CN < CF3 < NO2

– Stronger EWG give more potent compounds

Benzodiazepines SAR1

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Example

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clonazepam (Klonopin)equiv. dose = 0.5 mg

oxazepam (Serax)equiv. dose = 20 mg

Benzodiazepines SAR (6-9)

> >

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Benzodiazepines SAR (5)

>

ortho para

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• X aromatic ring antagonist

Benzodiazepines SAR (5)

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Flumazenil (Anexate)

• GABAA receptor antagonist

• BZD overdoses• hypersomnia• X Patent• Liver Carboxylic Acid Metabolite + Glucuronidation• ADR: headache and insomnia

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Benzodiazepines SAR (3-5)

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Benzodiazepines SAR (3)

potency half life

UGTs

prodrug

3 3 3

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Benzodiazepines SAR (3) (Prodrug)

H

decarboxylase

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H H

clorazepate desmethyldiazepam (active)(a.k.a. nordazepam (Nordaz))

Cl Cl

Benzodiazepines SAR (2)

> > >

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Benzodiazepines SAR (1)

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Benzodiazepines SAR (1,2-imidazo ring)

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3

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5678

910

Examples

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midazolam triazolam alprazolam (Xanax)

MeTabolism

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diazepam (Valium) clorazepate prazepam halazepam

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OH

midazolam hydroxymethyl midazolam

Non-benzodiazepines (Non-BZD)

• imidazopyridines

• pyrazolopyrimidine

• cyclopyrrolones

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• 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

Non-BZD site agonist

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• 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

Non-BZD site agonist

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O

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• 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%)

Non-BZD site agonist

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H

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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.

• 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

Melatonin

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Alternative: Ramelteon (Rozerem)

1/10 M-II

Outline

• Structure of Benzodiazepine (BZD)• Characteristics• GABAA receptor and agonists

• BZD SAR• BZD Metabolism• Non-BZD – site agonist

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