NEW: Chemistry of Benzodiazepines, Non-BZD Anxiolytics, and Sedative/Hypnotics

What effects do all benzodiazepines cause?

- Anxiolytic

- Sedation

- Muscle relaxation

- Anticonvulsant

- Memory impairment

What are the key points of chlordiazepoxide?

- Very long half-life

- Extensively metabolized in vivo

- Metabolized via oxidative transamination

- Has multiple active metabolites

- First benzodiazepine on the market

What are the key points of diazepam?

- Metabolized via N-demethylation

- Very long half-life

- More pronounced muscle relaxation

In what dosage forms is diazepam available?

- Oral solution

- Oral tablet

- Rectal gel

- Nasal spray

- Solution for injection

What are the modifications of R3 on benzodiazepines?

- OH

- Maintains activity

- Decreases duration of action

What are the modifications of R7 on benzodiazepines?

- Increased activity with electron-withdrawing group

- Decreased activity with electron-donating group

Which positions should not be substituted on benzodiazepines?

- R6

- R8

What are the modifications of R2 on benzodiazepines?

- Proton-accepting group

- Interacts with histidine residue

What are the key points of quazepam metabolism?

- Metabolized by CYP3A4 and CYP2C9

- Has active metabolites

- Metabolites are glucuronidated for excretion

What happens if a benzodiazepine (weak base) is formulated in a very acidic solution?

Molecular destruction

What are the short-acting 1,2-heteroaryl fused benzodiazepines?

- Midazolam

- Triazolam

What are the intermediate-acting 1,2-heteroaryl fused benzodiazepines?

- Estazolam

- Alprazolam

What happens to a 1,2-heteroaryl fused benzodiazepine under acidic conditions?

B ring opens

What are the key points of midazolam?

- Very short-acting

- Strong sedation

- Causes anterograde amnesia

- Used for surgeries and anesthesia initiation

- Available as a nasal solution for seizures

How is midazolam metabolized?

- CYP3A4

- Omega-hydroxylation

- Has an active, equally potent metabolite

- Metabolite is glucuronidated for excretion

How is triazolam metabolized?

- CYP3A4

- Omega-hydroxylation

- Very short-lived intermediate metabolite

- Metabolite is glucuronidated for excretion

What are the key points of alprazolam?

- Metabolized by CYP3A4/5

- Major metabolite is inactive

- Minor metabolite is 1/2 as potent

- High-potency, high-affinity

- Immediate anxiolytic activity

- Intermediate-acting

What are the key points of estazolam?

- Intermediate-acting

- Immediate anxiolytic activity

- Hydroxylated, then glucuronidated

Which benzodiazepine has the most affinity?

Alprazolam

What are the key points of remimazolam metabolism?

- Ultra-short-acting

- Metabolized via ester hydrolysis

- Soft drug

What is the intermediate-acting metabolite of diazepam?

Oxazepam

What happens if R3 is a carboxylic acid?

- Increased absorption

- Increased dissolution

What are the key points of clorazepate dipotassium?

- Prodrug

- Decarboxylated in stomach acid

Which benzodiazepines are primarily used for seizure disorders (according to Dr. Beck)?

- Clonazepam

- Clobazam

What are the key points of flumazenil?

- Undergoes rapid hydrolysis

- Formulated in acidic solution

- Short duration of action (< 1 hour)

- Causes seizures

What are the key points of buspirone metabolism?

- CYP3A4

- 1-PP is the main metabolite

- Metabolite is slightly active (1/4 potency)

What are the key points of zolpidem metabolism?

- Non-benzodiazepine sedative/hypnotic

- Metabolized by CYP3A4, then ADH

What are the key points of zaleplon metabolism?

- Non-benzodiazepine sedative/hypnotic

- Metabolized by ALDH, then CYP3A4 or UGT

- Metabolites are excreted in the urine

- UGT metabolite is eszopiclone

What are the key points of eszopiclone metabolism?

- Metabolite of zaleplon

- Metabolized by esterases and CYP3A4

What are the key points of melatonin?

- Induces sleep

- Regulates circadian rhythm

- Amine has electrostatic interactions with Ser and Asn

- Ether has hydrogen bonding with His

What are the key points of ramelteon?

- MT1-selective agonist

- Single-enantiomer preparation

- Ring keeps ether in the right place

- Metabolized by CYP1A2

- Has an active metabolite

How does doxepin treat insomnia at low doses?

Central H1 receptor antagonist

Why do DORAs have a ring in the middle?

Restricts conformation

Where do benzodiazepines bind to elicit their action?

Between the alpha and gamma subunits of the GABA-A receptor

The benzodiazepine binding site on which alpha subunit is associated with sedation and hypnosis?

Alpha-1

Action by benzodiazepines...

Increases the activity of GABA by potentiating its binding

Chlordiazepoxide

DIazepam

Flurazepam

Temazepam

Quazepam

Midazolam

Short-acting

Triazolam

Short-acting

Estazolam

Intermediate-acting

Alprazolam

Intermediate-acting

Remimazolam

Lorazepam

Intermediate-acting

Oxazepam

Intermediate-acting

Clorazepate dipotassium

Clonazepam

Clobazam

Flumazenil

Buspirone

1-PP

Buspirone metabolite

Zolpidem

Zaleplon

Eszopiclone

Melatonin

Ramelteon

Tasimelteon

Doxepin

Suvorexant

Lemborexant

Daridorexant