BenzodiazepinesBenzodiazepines

Chris HarveyChris Harvey

Medicinal ChemistryMedicinal Chemistry

April 26, 2007April 26, 2007

OverviewOverview

• HistoryHistory

• Clinical ApplicationsClinical Applications

• Mechanism of ActionMechanism of Action

• StructureStructure– GeneralGeneral– Sub-classesSub-classes– Individual examplesIndividual examples

• Future ResearchFuture Research

HistoryHistory

The first benzodiazepine (benzo) was The first benzodiazepine (benzo) was synthesized by an Austrian scientist named Dr. synthesized by an Austrian scientist named Dr. Leo Sternbach in the mid 1950’s while working Leo Sternbach in the mid 1950’s while working at Hoffman-La Roche. The new compound’s at Hoffman-La Roche. The new compound’s potential as a pharmaceutical was not potential as a pharmaceutical was not initially recognized, however, Dr. Sternbach’s initially recognized, however, Dr. Sternbach’s persistent research eventually uncovered it’s persistent research eventually uncovered it’s efficacy as a tranquilizer. In 1959, efficacy as a tranquilizer. In 1959, chlordiazepoxide (Librium) was introduced as chlordiazepoxide (Librium) was introduced as the first of many benzos to come. Just four the first of many benzos to come. Just four years later, in 1963, diazepam (Valium) came years later, in 1963, diazepam (Valium) came on the market. Clinicians quickly recognized on the market. Clinicians quickly recognized the potential of benzos as a safer alternative the potential of benzos as a safer alternative to the barbiturate class of anxiolytics. to the barbiturate class of anxiolytics.

Clinical ApplicationsClinical Applications

• AnxiolyticAnxiolytic– GAD, PTSD, OCD, etc.GAD, PTSD, OCD, etc.– Panic DisorderPanic Disorder– Specific PhobiasSpecific Phobias

• AnticonvulsantAnticonvulsant– Status epilepticusStatus epilepticus– Myoclonic epilepsyMyoclonic epilepsy

• Muscle relaxantMuscle relaxant• Sleep aidSleep aid• Pre-operative anesthesiaPre-operative anesthesia• Alcohol withdrawalAlcohol withdrawal

Mechanism of ActionMechanism of Action

Benzodiazepines Benzodiazepines act as GABA (act as GABA (γγ--aminobutyric acid) aminobutyric acid) potentiators. They potentiators. They bind to BZ receptors on bind to BZ receptors on the GABA-BZ receptor the GABA-BZ receptor complex, which allows complex, which allows them to allosterically them to allosterically modulate and enhance modulate and enhance the activity of GABA. the activity of GABA. This results in This results in increased increased hyperpolarization at hyperpolarization at target neurons, making target neurons, making them less responsive to them less responsive to excitatory stimuli. excitatory stimuli.

StructureStructure• 2-Keto Benzos2-Keto Benzos

– Some administered as prodrugSome administered as prodrug– All have active metabolites All have active metabolites

(commonly desmethyldiazepam)(commonly desmethyldiazepam)– Long half-lives (most in Long half-lives (most in

excess of 60 hours) excess of 60 hours)

• 3-hydroxy Benzos3-hydroxy Benzos– No active metabolitesNo active metabolites– Not metabolized in the liverNot metabolized in the liver– Intermediate half-lives (most Intermediate half-lives (most

~ 8-20 hours)~ 8-20 hours)

• Triazolo BenzosTriazolo Benzos– Additional heterocyclic ring Additional heterocyclic ring

attached at the 1 and 2 attached at the 1 and 2 positionspositions

– Some active metabolitesSome active metabolites– Short to intermediate half-Short to intermediate half-

lives (anywhere from 3-14 lives (anywhere from 3-14 hours)hours)

1 2

3

Diazepam

2-Keto Benzos2-Keto Benzos

• First isolated benzo First isolated benzo

• Oxidized to Oxidized to desmethyldiazepam in desmethyldiazepam in the liverthe liver

• Indicated for treatment Indicated for treatment of anxiety and insomniaof anxiety and insomnia

• Most prolific and Most prolific and versatile benzoversatile benzo

• Indicated for treatment Indicated for treatment of anxiety, seizure, of anxiety, seizure, muslce tension, insomnia, muslce tension, insomnia, and alcohol withdrawaland alcohol withdrawal

Chlordiazepoxide (Librium) Diazepam (Valium)

2-Keto Benzos2-Keto Benzos

• Longest half-life of any Longest half-life of any benzo (~ 40-250 hours)benzo (~ 40-250 hours)

• Indicated primarily for Indicated primarily for treatment of insomnia, may treatment of insomnia, may also serve as an also serve as an anxiolyticanxiolytic

• High potentcy (~ 20 times High potentcy (~ 20 times stronger per miliigram stronger per miliigram than diazepam)than diazepam)

• Causes moderate Causes moderate anterograde amnesiaanterograde amnesia

• Indicated for treatment Indicated for treatment of anxiety, also a highly of anxiety, also a highly effective anticonvulsant effective anticonvulsant

Flurazepam (Dalmane) Clonazepam (Klonopin)

2-Keto Benzos2-Keto Benzos

• The original date-rape The original date-rape drug, and the origin of drug, and the origin of the term “roofie”the term “roofie”

• Pharmacologically very Pharmacologically very similar to clonazepam, similar to clonazepam, but possesses much but possesses much stronger amnesic stronger amnesic properties.properties.

• One of only two drugs in One of only two drugs in the U.S. for which a the U.S. for which a first possession charge first possession charge is a mandatory felony. is a mandatory felony. The other of the two is The other of the two is crack cocaine.crack cocaine.

Flunitrazepam (Rohypnol)

3-hydroxy Benzos3-hydroxy Benzos

• Indicated for treatment Indicated for treatment of anxiety, seizure, of anxiety, seizure, insomnia, panic insomnia, panic disorder, and alcohol disorder, and alcohol withdrawal.withdrawal.

• Unique among benzos in Unique among benzos in it’s use as an it’s use as an adjunctive anti-emeticadjunctive anti-emetic

• Indicated for treatment Indicated for treatment of anxiety, insomnia, of anxiety, insomnia, and alcohol withdrawal.and alcohol withdrawal.

• Common metabolite of Common metabolite of many 2-keto benzos many 2-keto benzos following their following their oxidation to oxidation to desmethyldiazepamdesmethyldiazepam

Lorazepam (Ativan) Oxazepam (Serax)

Triazolo BenzosTriazolo Benzos

• First benzo approved by First benzo approved by FDA for treatment of FDA for treatment of panic disorder.panic disorder.

• Also used as an Also used as an adjunctive treatment adjunctive treatment for depression while for depression while adjusting to SSRIs.adjusting to SSRIs.

• Very rapid onsetVery rapid onset

• Very short half-lifeVery short half-life

• Possesses amnesic Possesses amnesic properties similar to properties similar to clonazepamclonazepam

• Used almost Used almost exclusively as a pre-exclusively as a pre-op anesthetic op anesthetic

Alprazolam (Xanax) Triazolam (Halcion)

Future ResearchFuture Research

• Research is moving away from benzodiazepines Research is moving away from benzodiazepines as they are being displaced by newer drugs, as they are being displaced by newer drugs, which generally have fewer side-effects and lower which generally have fewer side-effects and lower addiction potentials.addiction potentials.– Newer anxiolyticsNewer anxiolytics

• SSRIs (Prozac, Zoloft, Lexapro, etc.)SSRIs (Prozac, Zoloft, Lexapro, etc.)

• Atypical anxiolytic/antidepressant drugsAtypical anxiolytic/antidepressant drugs– Buspirone (BuSpar)Buspirone (BuSpar)– Venlafaxine (Effexor)Venlafaxine (Effexor)– Duloxetine (Cymbalta)Duloxetine (Cymbalta)

– Newer sleeping medicationsNewer sleeping medications• Zolpidem (Ambien)Zolpidem (Ambien)

• Zaleplon (Sonata)Zaleplon (Sonata)

• Eszopiclone (Lunesta) Eszopiclone (Lunesta)

ReferencesReferences

• Schatzberg M.D., A. F., Cole M.D., J. O., Schatzberg M.D., A. F., Cole M.D., J. O., DeBattista M.D., C. (2005) DeBattista M.D., C. (2005) Manual of Clinical Manual of Clinical PsychopharmacologyPsychopharmacology. 5. 5thth edition. Washington DC: edition. Washington DC: American Psychiatric Publishing Inc.American Psychiatric Publishing Inc.

• Schatzberg M.D., A. F., Nemeroff M.D., C. B. Schatzberg M.D., A. F., Nemeroff M.D., C. B. (2006) (2006) Essentials of Clinical PsychopharmacologyEssentials of Clinical Psychopharmacology. . 22ndnd edition. Washington DC: American Psychiatric edition. Washington DC: American Psychiatric Publishing Inc.Publishing Inc.

• Katzung M.D., B. G. (2001) Katzung M.D., B. G. (2001) Basic and Clinical Basic and Clinical PharmacologyPharmacology. 8. 8thth edition. McGraw-Hill. edition. McGraw-Hill.

• www.wikipedia.comwww.wikipedia.com