Anxiolytics and Sedatives Flashcards
Buspirone mechanism
5HT1a Agonist (along with 6-hydroxybuspirone metabolite) Alpha-2 Antagonism (due to 1-PP metabolite)
Buspirone metabolism
Two routes, both by 3A4:
- 6-hydroxybuspirone: active as 5HT1a Agonist
- 1-PP: active as an Alpha-2 Antagonist
Chlordiazepoxide
Librium
1st Benzodiazepine; 1960
Diazepam brand name
Valium
Diazepam metabolism
Two routes:
- 3-hydroxydiazepam: active as Temazepam (Restoril)
- N-desmethyldiazepam: active as Nordazepam
Diazepam characteristics
More lipophilic than Chlordiazepoxide
- Faster onset
- 5-10x more potent
Chlordiazepoxide metabolism
Chlordiazepoxide, N-demethylation to... N-desmethylchlordiazepoxide, amino group to carbonyl.. Demoxepam, Nitro group reduced... Nordazepam, 3-position hydroxylation... Oxazepam. All of theses are active. Oxazepam will be glucuronidated.
Clorazepate brand name
Tranxene
Clorazepate metabolism
*Prodrug of Nordazepam* "-ate" for carboxylate group... Decarboxylation to Nordazepam (active) Then, 3-hydroxylation to Oxazepam (active) Then, Glucuronidation (inactive)
Lorazepam brand name
Ativan
Lorazepam metabolism
Direct Glucuronidation - NO active metabolites.
Lorazepam potency
More potent than Oxazepam due to 2-position Cl EWG.
Alprazolam brand name
Xanax
Alprazolam metabolism (similar to Triazolam)
Two routes, both by 3A4:
- 4-hydroxyalprazolam >
- alpha-hydroxyalprazolam
Both rapidly Glucuronidated; neither significantly contribute to action.
Clonazepam brand name
Klonopin
Clonazepam metabolism
Reduction of Nitro group to 7-aminoclonazepam (inactive)
Further N-acetylation.
Quazepam brand name
Doral
Quazepam metabolism
Benzene-Fluoro group to 2-oxoquazepam (active)
Quazepam indication
Insomnia
Midazolam brand name
Versed
Midazolam metabolism
3A4 Hydroxylation at alpha-“M”ethyl group (active)
Further Glucuronidation.
Midazolam indication
Preoperative sedation
Induction of anesthesia.
Triazolam brand name
Halcion
Triazolam metabolism (similar to Alprazolam)
Two routes, both by 3A4:
- 4-hydroxylation
- alpha-hydroxylation
Both rapidly Glucuronidated and excreted.
Flumazenil mechanism
Benzodiazepine Antagonist
Flumazenil brand name
Romazicon
Flumazenil structural alteration
Missing the 5-phenyl group altogether.
Flumazenil metabolism
Ester hydrolysis - short half life.
Flumazenil route of administration
IV
Most important characteristic of Barbituate SAR
5,5-disubstitution
Butabarbital sodium brand name
Butisol sodium
Butabarbital sodium C-5 carbons, t1/2, duration
6
45-60hrs
6-8hrs
Secobarbital brand name
Seconal
Secobarbital C-5 carbons, other modifications, and duration
8
Unsaturation in C-5 side chain
3-4hrs
Methohexital sodium C-5 carbons, and other modifications
9
Extra N-methyl
Extra unsaturation in C-5 side chains
Methohexital sodium characteristics
Added features increase lipophilicity, and increase activity.
Rapid onset and very short duration.
Methohexital sodium indication
Induction of anesthesia
Chloral hydrate
In water, small amounts go to Trichloroacetylaldehyde.
In presence of NADH, in vivo, goes to THE
- THE believed to be the sedative component.
Some migraine drugs contain Dichlorolphenazone
- Prodrug of Chloral hydrate
Meprobamate key point
Meprobamate is a 2C19 metabolite of Carisoprodol (soma), a muscle relaxant.
Zaleplon brand name
Sonata
Zaleplon metabolism
Major: Aldehyde Oxidase to 5-0xozaleplon (active)
Minor: 3A4 to N-deethylzaleplon (inactive?)
Zaleplon notable interaction
Cimetidine, an H2-antagonist, inhibits both Aldehyde Oxidase, and CYP-3A4.
Significantly increases t1/2 of Zaleplon.
Eszopiclone brand name
Lunesta
Eszopiclone metabolism
Two routes, both by 3A4:
- N-desmethylzopiclone (inactive)
- Eszopiclone N-oxide (inactive)
Ramelteon brand name
Rozerem
Ramelteon indication
Insomnia - for sleep onset.
Ramelteon metabolism
One route, by both CYP 1A2 and 2C19
- Hydroxyramelteon metabolites (inactive)
Ramelteon notable interaction
Fluvoxamine - 1A2/2C19 inhibition.
Ramelteon mechanism
MT1 and MT2 receptor agonist
Tasimelteon indication
24hr Sleep Wake disorder
- Usually for blind people (very expensive)
Tasimelteon metabolism
One route, by both CYP 1A2 and 3A4
- Hydroxy metabolite (inactive)
Dexmedetomidine brand name
Precedex
Dexmedetomidine indication
For sedation as an IV clinically.
Dexmedetomidine mechanism
Alpha-2 Agonist (autoreceptor)
Suvorexant brand name
Belsomra
Suvorexant mechanism
Orexin receptor, OX1 and OX2 antagonist
- Orexins promote wakefulness
Suvorexant metabolism
3A4 hydroxylation (inactive)
Gammahydroxybutyrate (GHB) also known as
Sodium oxybate (Xyrem)
Gammahydroxybutyrate (GHB) mechanism
GABA-B modulator.
Gammahydroxybutryate (GHB) key point
Restricted distribution program due to potential for abuse.
- Applies to chemicals that can be used in it’s synthesis as well: 1,4-butanediol, and Gammabutyrolactone.
- Both are GHB prodrugs.
What is Oxazepam?
Figure out.
Gammahydroxybutyrate (GHB) Indication
To treat excessive daytime sleepiness in narcolepsy patients, by helping them sleep.
Taken at bedtime, then 2.5-4hrs later.
Helps establish regular wake/sleep cycles.
Zolpidem tartrate brand name
Ambien
Zolpidem tartrate metabolism
3A4 aromatic ring methyl hydroxylation
- primary alcohol to carboxylate (inactive)
Zolpidem tartrate dosing consideration
Max of 5mg in women, slower clearance.
Z-Drug mechanism
Bind GABA receptors with an Alpha-1 subunit.
Eszopliclone good for
Sleep onset and maintenance.
Zolpidem tartrate good for
Sleep onset and maintenance.
Zaleplon good for
Sleep onset only.
Suvorexant good for
Sleep onset and maintenance.
Triazolam consideration
Not to be used in elderly.
If you had to use a BZD in an elderly patient…
Use Temazepam (Restoril)
