Chemistry of Benzodiazepines and Sedatives

name

chlordiazepoxide

function

1st benzodiazepine on market

• characteristic benzo activities (antianxiety, sedation, muscle relaxation, seizure protection, memory impairment)

• super long half life (5-30h); extensively metabolized in vivo (several active metabolites)

name

diazepam

function

benzodiazepine

• more pronounced muscle relaxation than chlordiazepoxide

• available as oral tab, soln, soln for inj, rectal gel, nasal spray

• long-acting (30-60h); (has long-acting active metabolite, same desmethyldiazepam as with chlordiazepoxide)

• pka ~3.3, can’t be formulated as solution for injection bc it would be super acidic, which would destroy the molecule

name

GABA

• binds between the alpha and beta subunits of the GABAa receptor

where do benzodiazepines bind?

between the alpha and gamma subunits of the GABAa receptor

name

flurazepam

• long-acting benzo for insomnia

name

quazepam

• long-acting benzo for insomnia

• 2 major active metabolites via CYP3A4 and 2C9

are benzodiazepines acids or bases?

weak organic bases

name

midazolam

• short-acting 1,2-heteroaryl fused benzodiazepine (very short half-life 1-5h)

• available as short-acting sedative parenteral and nasal spray for seizure protection

• strong hypnotic, anxiolytic, and memory-impairing effects (anterograde amnesia)

• used during minor procedures for anesthetic induction

• only one that can be formulated as a HCl salt

• acidic solution for injection (inactive in solution and repaired back to active form in vivo)

• has active equipotent metabolite that is quickly inactivated

name

triazolam

• short-acting 1,2-heteroaryl fused benzodiazepine

• oral, not parenteral

• defined as hazing no active metabolite (has metab that is glucuronidated too quickly)

name

estazolam

• intermediate-acting 1,2-heteroaryl fused benzo

• same main route of metab as alprazolam

name

alprazolam

• intermediate-acting 1,2-heteroaryl fused benzo

• available as oral tab and ODT

• very attractive benzo for rapid onset, high potency, intermediate action

• slowly metabolized to inactive metabolite via CYP3A4;also has active metab but not main route

name

remimazolam

• ultra-short acting benzo

• prepared as besylate salt for soln for inj

• soft drug! (super quick onset and quick recovery, half life = 45min)

• used as sedative in ICU and procedural sedation

• organ-independent metabolism; inactive acid metabolite

name

oxazepam

• intermediate-acting benzo (11-20h half-life)

name

lorazepam

• intermediate-acting benzo

• available as oral tab, XR cap, soln for inj, oral soln,

name

clorazepate dipotassium

• long-acting benzo used for seizures

• prodrug of desmethyldiazepam

• R3 carboxylic acid helps absorption by increasing H2O solubility and dissociation

• increased stomach pH decreases conversion to active metabolite

name

clonazepam

• long-acting benzo used primarily in tx of seizure disorders

name

clobazam

• used primarily in tx of seizure disorders