Anxiolytic and Sedative Drugs (Proteau) Flashcards
Buspirone
- Type
- Structure
- Metabolism
- Non-BDZ anxiolytic
- Azaspirodecandione (azapirone): has spiro, azo, and dione components
- 3A4 to produce alpha2 antagonist (6 hr t1/2) and 5HT1a agonist (6&1/2 hr t1/2)
What type of agonist is buspirone?
5HT1a agonist
What is the t1/2 of buspirone and its metabolites?
t1/2 = 2-4 hours
t1/2 of apha2 antagonist = 6 hours
t1/2 of other 5HT1a agonist is 6 & 1/2 hours
What is the SAR of benzodiazepines?
1) Essential 7-membered ring
2) EWG at position 7. The more electron-withdrawing, the more potent the compound. Additional EWG at 2’ will increase potency.
3) Substitutions are allowed at 1, 3, and 2’
4) Substitutions at 4’, 6, 8, and 9 either reduce or abolish anxiolytic activity
Chlordiazepoxide
- Type
- Structure
- Metabolism
- BDZ (anti-anxiety)
- Cl EWG at 7.
- 1st BDZ anxiolytic
- Can go through N-demethylation to form at least 4 active compounds
Diazepam
- Type
- Structure
- Metabolism
- BDZ (anti-anxiety)
- z- carbonyl
- Can be hydroxylated to temazepam at 3 position or de-methylated at 1 position to nordazepam. Both are active and can be oxidized to oxazepam (also active)
What is the half-life of diazepam and it’s metabolites?
t1/2 of diazepam = 35 hours
t1/2 of N-desmethyldiazepam = 100hr
t1/2 of temazepam = 12 hours
t1/2 of oxazepam = 7 hours
Metabolism of diazepam. What is the ratio of metabolites formed?
4:1 ratio of temazepam to nordazepam
Compare chlordiazepoxide to diazepam. Why would you use one over the other?
Diazepam is more lipophilic than chlordiazepoxide, so it has a fast onset. It is also 5-10x more potent.
It is dosed more frequently (2-4X daily)
Clorazepate
- type
- structure
- metabolism
- BDZ (anti-anxiety)
- Prodrug. carboxylate at 3 position, Cl at 7 position.
- Goes through decarboxylation to form Nordazepam as the active drug, which undergoes 3 hydroxylation to form oxazepam, which is inactivated through glucuronidation.
What is the half-life of clorazepate?
t 1/2 = 2 hours
Lorazepam
- type
- structure
- metabolism
- BDZ (anti-anxiety)
- extra Cl EWG at 2’ position, so more potent than oxazepam
- inactivated through direct glucuronidation, so no active metabolites
Alprazolam
- Type
- Structure
- Metabolism
- BDZ (anti-anxiety)
- triazole instead of carbonyl, with alpha methyl group
- 3A4 is used to form 4-hydroxy alprazolam or alpha-hydroxy alprazolam. Both are quickly glucuronidated, and neither is thought to contribute significantly to overall anxiolytic effect.
What is the t 1/2 of alprazolam?
12 hours
Clonazepam
- type
- structure
- metabolism
- BDZ (anti-convulsant used to treat panic disorders)
- nitro EWG at 7 and 2’ Cl EWG
- Reduction of nitro group yields 7-aminoclonazepam (inactive) that can be further N-acetylated
What is the t 1/2 of clonazepam?
34 hours
How can you detect clonazepam after 1 month?
Look for nitro groups in hair follicles
Quazepam
- Type
- Structure
- Metabolism
- BZD used as sedative/hypnotic to treat insomnia
- 2-thio group, Cl @ 7, F @ 2’ (F is more EWing than Cl)
- 2-oxoquazepam (active)
What is the half-life of quazepam and it’s metabolite?
t1/2 = 33 hours, t1/2 of oxoquazepam = 40 hours
Midazolam
- Type
- Structure
- Metabolism
- BDZ used to as sedative/hypnotic. Used as preoperative sedation or for induction of anesthesia
- imidazole, Cl @ 7, F @ 2’
- 3A4 –> alpha-hydroxylation (active) –> glucuronidation
What is the half-life of midazolam and it’s metabolite?
t 1/2 = 2 hours, alpha-hydroxylation metabolite t 1/2 = 60-80 minutes
Triazolam
- Type
- Structure
- Metabolism
- BZD used as sedative/hypnotic
- triazole, Cl @ 7, Cl @ 2’
- 3A4 to 4-hydroxylation or alpha-hydroxylation. Both products are rapidly glucuronidated and excreted.
What is triazolam structurally similar to? What is the difference?
Alprazolam. It is called 2’-chloroalprazolam.
Flumazenil
- Type
- Strcuture
- Metabolism
- BZD antagonist
- imidazole, BZD core, ethyl ester, EWG = F @ 7.
What structural feature makes flumazenil an antagonist?
It lacks the 5-phenyl group of the agonists
What is the half-life of flumazenil? What is the length of the half-life due to?
t1/2 = 1 hour. Used IV. Short half-life due to ester hydrolysis.
Is the lipophilic form of a barbiturate protonated at the nitrogens?
Yes. The charged form is more hydrophilic.
Is the salt form or the protonated form of a barbiturate more active?
The neutral form is the active form over the charged form.
What part of the structure of barbituric acid makes it unable to cross the BBB?
The methylene (2 protons) at C5 is very acidic, and cannot cross the BBB because it it exists in its ionized form at physiological pH.
For sedative action, what must a barbiturate have?
It must have 5,5-disubstitution.
What increases the potency of a barbiturate?
The total number of combined carbons at the R5 and R5’ up to 7-9 carbons.
What happens to duration of a barbiturate as the number of carbons at C5 increases?
Duration decreases because of distribution into fatty tissues and muscles.
What happens in a barbiturate as you increase branching at C5? Unsaturation at C5?
Both of these increase activity, decrease duration, and decrease toxicity.
What happens in a barbiturate if you add a phenyl group at C5?
A phenyl group increases duration of action (10-16 hours) and leads to greater anticonvulsant activity (such as phenobarbital)
What occurs in a barbiturate if you substitute S for O?
The lipid solubility increases, which decreases duration but provides a quicker onset.
Are there any barbiturates with thio-substitution in the US?
Not currently. Thiopental sodium is no longer available in the US.
Is barbituric acid a sedative?
No, it does not have di-substitution at the C5.
Butabarbital sodium
- type
- structure
- # of C-5 carbons
- duration of action
- Barbiturate
- butane chain
- 6 C-5 carbons
- 6-8 hours (intermediate duration of action)
What is the half-life of butabarbital?
t 1/2 = 45-60 hours
Secobarbital
- type
- structure
- # of C-5 carbons
- duration of action
- barbiturate
- unsaturation in the C-5 side chain
- 8 C-5 carbons (increased potency from 6)
- 3-4 hours (short duration due to unsaturation at C-5 carbon)
Methohexital sodium
- type
- structure
- # of C-5 carbons
- duration of action
- Barbiturate
- Extra N-methyl group (increases potency), extra saturation
- 9 C-5 carbons (increased potency)
- Short duration (used to induce anesthesia): structurally short duration due to increased # of carbons and unsaturation
- Also rapid onset, but not sure why
Chloral hydrate
- type
- structure
- metabolism
- Misc. sedative/hypnotic
- If you add water to a trichloroacetaldehyde you get the chloral hydrate (which is an aldehyde hydrate). If you take water out of chloral hydrate, you get trichloroacetaldehyde.
- NADH reduces trichloroacetaldehyde to trichloroethanol (TCE), which is believed to be the active sedative.
What do some migraine medications contain?
They contain trichloralphenazone, which is a prodrug of chloral hydrate.
Meprobamate
- type
- structure
- metabolism
- misc. sedative/hypnotic
- structurally similar to felbamate, which had liver toxicity due to active intermediate
- No active metabolites, therefore no liver toxicity
What drug is metabolized to meprobamate? What enzyme is used?
Carisprodol, a muscle relaxant uses 2C19 to form meprobamate.
What is the half-life of meprobamate?
8 hours
zolpidem tartrate
- type
- target
- structure
- metabolism
- Z drug; misc sedative/hypnotic
- binds to GABAa receptors with alpha-1 subunit
- 6,5 aromatic ring system with nitrogens (common to Z drugs)
- 2 para methyl groups
- 3A4 is used for aromatic ring methyl group oxidation, which forms a primary alcohol and then a carboxylate. Inactive products.
What is the half-life of zolpidem tartrate?
t1/2 = 2 & 1/2 hours
What is unique about the drug clearance?
It is slower for women than men
Zaleplon
- type
- target
- structure
- metabolism (major and minor)
- Z drug
- targets GABAa receptors on the alpha1 subunit
- 6,5 aromatic ring system with N’s in different places than zolpidem
- major uses aldehyde dehydrogenase to get 5-oxozaleplon
- minor uses 3A4 to form N-deethylzaleplon
- inactive products
What does cimetidine do to zaleplon?
It inhibits both aldehyde dehydrogenase and 3A4, which significantly increases the half-life of zaleplon.
What is the half-life of zaleplon?
1 hour
Eszopiclone
- type
- target
- structure
- metabolism
- Z drug
- targets GABAa receptor on alpha1 subunit
- single S enantiomer
- 6,5 aromatic ring system with nitrogen
- 3A4 used to form N-desmethylzopiclone and eszopiclone N-oxide, which are both inactive
What is the half-life of eszopiclone?
5 hours
Melatonin
- type
- structure
- melatonin receptor agonist
- indole, acetamide, ether
- tryptophan derivative
- endogenous agonist
Ramelteon
- type
- structure
- metabolism
- MT1, MT2 receptor agonist
- to treat insomnia
- indole mimic, ether, and propyl amide.
- 1A2, 2C19 to form hydroxyramelteon inactive metabolites
What is the half-life of ramelteon?
1 - 2 &1/2 hours
What interactions would ramelteon have?
With a drug that inhibits or induces 1A2 or 2C19
Tasimelteon
- type
- structure
- metabolism
- melatonin receptor agonist
- indole mimic, propyl amide
- 1A2, 3A4 to form inactive hydroxy metabolites
What does tasimelteon treat?
It treats non-24 hours sleep-wake disorder, which is mainly an issue for blind people
What is the half-life of tasimelteon?
1-2 hours
Gamma hydroxybutyrate (GHB)
- structure
- type
- metabolism
- misc. sedative
- Similar structure to GABA (and acts at GABA-B receptors)
- endogenous: small levels in system
- metabolized to sodium oxybate, which treats excessive daytime sleepiness in narcolepsy patients
Why is there a restriction on GHB? How is it supposed to work?
Because it is the date-rape drug. It is dosed at bedtime and 2 &1/2 to 4 hours later to help people establish better sleep/wake cycles. It is generally for narcolepsy patients to combat daytime sleepiness.
What are 1,4-butanediol and gamma butyrolactone prodrugs of?
GHB
Dexmedetomidine
- structure
- type
- used for
- alpha2 agonist
- phenyethylamine core, S-enantiomer
- structurally related to clonidine and the imidazoline alpha -2 agonists
- Used clinically for sedative purposes
Suvorexant
- type
- structure
- metabolism
- orexin receptor antagonist
- single R enantiomer
- big molecule, indole mimic
- main route of metabolism is 3A4 hydroxylation to inactive products
What is the half-life of suvorexant?
12 hours
