Benzodiazepines Overview

Benzodiazepines

• Benzodiazepines enhance GABA binding to the GABA_A receptor.
• This interaction causes various pharmacological effects, including sedation/hypnosis, decreased anxiety, anterograde amnesia, anticonvulsant effects, and muscle relaxation.
• The therapeutic use of benzodiazepines depends on their half-life.
• Anticonvulsants typically have long half-lives and rapid CNS entry.
• Sleep-promoting benzodiazepines ideally have short half-lives.
• Anti-anxiety compounds generally have longer half-lives.
• Different GABA_A receptor subtypes affect the efficiency of benzodiazepines.
• Various alpha subunits (α₁, α₂, α₃, α₅) within the GABA_A receptor influence benzodiazepine function.
• Subtypes containing α₁ are linked to sedation/hypnosis.
• Subtypes containing α₂ and α₃ are linked to anxiolytic activity.
• Subtypes containing α₁ , α₂ , and α₃ may be linked to anticonvulsant activity.

Benzodiazepine Receptor Structure and Function

• The GABA_A receptor is a ligand-gated ion channel that allows chloride flux into the neuron.
• Benzodiazepines increase GABA binding efficiency at the receptor.
• This leads to an amplified effect.

Structure-Activity Relationships (SAR)

• Electron-withdrawing groups at the 7-position of the benzodiazepine ring increase potency.
• Examples include Cl, Br, F, CN, CF₃, and NO₂
• Substitutions at positions 6, 8, and 9 decrease activity.
• The aromatic ring at position 5 is necessary for activity.
• Electron-withdrawing groups at the ortho (1) and di-ortho (2) positions increase potency; para substitutions greatly decrease potency
• Compounds lacking an aromatic ring at the 5-position display antagonist activity
• Reduction of the 4,5 or shift to 3,4 double bond decreases potency
• Alkyl substitution at the 3-position decreases potency.
• Hydroxyl substitution at the 3-position has minimal effect on potency but does shorten half-life. Esters at 3 position are readily hydrolyzed to compounds in position 2
• 3-carboxylic acids are pro-drugs. They undergo decarboxylation in the stomach to 3-H compounds.
• The 2-carbonyl group optimizes activity. 2-thione, 2-imine, and 2-methylamino groups are less potent.
• N¹ substitution should be small (e.g., H, methyl, ethyl) in the 1-3 position. Benzyl is bulky and less active, but metabolizes into a molecule in the 3 position.

Fused Triazole and Imidazole Compounds

• Triazole and imidazole compounds show selectivity for hypnosis or anxiolytic activity (e.g., midazolam, triazolam, alprazolam).
• These compounds generally have short half-lives. Metabolism involves CH3 oxidation, forming an alcohol, followed by glucuronide formation.
• Some have rapid absorption, onset within 30min-1hr.

Metabolic Patterns

• The metabolism pathways and half-lives for various benzodiazepines are varied.
• Several benzodiazepines break down to oxazepam as a final product.
• Compounds close to glucuronidation steps have short half-lives, meaning they are less likely to accumulate in the body with multiple dosing.
• Triazole and imidazole compounds also have fairly short half-lives and do not accumulate.
• Chlordiazepoxide has prolonged half-life (10 hrs)
• Diazepam has several metabolites with very long half-lives (e.g. demoxepam 72 hrs).

Non-benzodiazepines

• Zolpidem (Ambien), Zaleplon (Sonata), Eszopiclone (Lunesta) are related to sleep-inducing drugs.
• Ramelteon (Rozerem) is a melatonin receptor agonist.
• Different compounds have differing half-lives, rates of absorption, and metabolization
• Zolpidem: Rapid absorption, onset 30 min after administration, half-life 2.5 hrs (increased in liver disease), duration 6-8 hrs, metabolized by 3A4 to inactive metabolite, 92% protein bound, ADR: amnesia.
• Zaleplon: 30% bioavailable; onset 1 hour with food delays; metabolized by aldehyde oxidase to inactive metabolite, CP450 involvement; half-life 1 hr; duration 6-8 hrs; 60% protein bound; ADR: amnesia
• Eszopiclone: S isomer of zopiclone, rapid absorption peak in 1 hour with food delays, 50% protein binding, metabolized by 3A4 and 2E1 to one active (desmethyl) and one inactive (N-oxide) metabolite, half-life 6 hrs; ADR: headache, hallucinations, anxiety, amnesia, unpleasant taste.
• Ramelteon: Agonist at melatonin receptors, onset 30 mins, 1.8% bioavailable, metabolized by 1A2 to active metabolite, food delays absorption, 82% protein bound; ADR: headache, depression, insomnia worsened.