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Integrated Drug Structure, Action, and Therapeutics > Anxiolytic and Sedative Drugs (Proteau) > Flashcards

Anxiolytic and Sedative Drugs (Proteau) Flashcards

1
Q

Buspirone

  • Type
  • Structure
  • Metabolism
A
  • 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)
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2
Q

What type of agonist is buspirone?

A

5HT1a agonist

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3
Q

What is the t1/2 of buspirone and its metabolites?

A

t1/2 = 2-4 hours
t1/2 of apha2 antagonist = 6 hours
t1/2 of other 5HT1a agonist is 6 & 1/2 hours

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4
Q

What is the SAR of benzodiazepines?

A

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

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5
Q

Chlordiazepoxide

  • Type
  • Structure
  • Metabolism
A
  • BDZ (anti-anxiety)
  • Cl EWG at 7.
  • 1st BDZ anxiolytic
  • Can go through N-demethylation to form at least 4 active compounds
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6
Q

Diazepam

  • Type
  • Structure
  • Metabolism
A
  • 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)
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7
Q

What is the half-life of diazepam and it’s metabolites?

A

t1/2 of diazepam = 35 hours
t1/2 of N-desmethyldiazepam = 100hr
t1/2 of temazepam = 12 hours
t1/2 of oxazepam = 7 hours

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8
Q

Metabolism of diazepam. What is the ratio of metabolites formed?

A

4:1 ratio of temazepam to nordazepam

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9
Q

Compare chlordiazepoxide to diazepam. Why would you use one over the other?

A

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)

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10
Q

Clorazepate

  • type
  • structure
  • metabolism
A
  • 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.
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11
Q

What is the half-life of clorazepate?

A

t 1/2 = 2 hours

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12
Q

Lorazepam

  • type
  • structure
  • metabolism
A
  • BDZ (anti-anxiety)
  • extra Cl EWG at 2’ position, so more potent than oxazepam
  • inactivated through direct glucuronidation, so no active metabolites
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13
Q

Alprazolam

  • Type
  • Structure
  • Metabolism
A
  • 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.
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14
Q

What is the t 1/2 of alprazolam?

A

12 hours

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15
Q

Clonazepam

  • type
  • structure
  • metabolism
A
  • 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
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16
Q

What is the t 1/2 of clonazepam?

A

34 hours

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17
Q

How can you detect clonazepam after 1 month?

A

Look for nitro groups in hair follicles

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18
Q

Quazepam

  • Type
  • Structure
  • Metabolism
A
  • BZD used as sedative/hypnotic to treat insomnia
  • 2-thio group, Cl @ 7, F @ 2’ (F is more EWing than Cl)
  • 2-oxoquazepam (active)
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19
Q

What is the half-life of quazepam and it’s metabolite?

A

t1/2 = 33 hours, t1/2 of oxoquazepam = 40 hours

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20
Q

Midazolam

  • Type
  • Structure
  • Metabolism
A
  • 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
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21
Q

What is the half-life of midazolam and it’s metabolite?

A

t 1/2 = 2 hours, alpha-hydroxylation metabolite t 1/2 = 60-80 minutes

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22
Q

Triazolam

  • Type
  • Structure
  • Metabolism
A
  • BZD used as sedative/hypnotic
  • triazole, Cl @ 7, Cl @ 2’
  • 3A4 to 4-hydroxylation or alpha-hydroxylation. Both products are rapidly glucuronidated and excreted.
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23
Q

What is triazolam structurally similar to? What is the difference?

A

Alprazolam. It is called 2’-chloroalprazolam.

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24
Q

Flumazenil

  • Type
  • Strcuture
  • Metabolism
A
  • BZD antagonist

- imidazole, BZD core, ethyl ester, EWG = F @ 7.

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25
Q

What structural feature makes flumazenil an antagonist?

A

It lacks the 5-phenyl group of the agonists

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26
Q

What is the half-life of flumazenil? What is the length of the half-life due to?

A

t1/2 = 1 hour. Used IV. Short half-life due to ester hydrolysis.

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27
Q

Is the lipophilic form of a barbiturate protonated at the nitrogens?

A

Yes. The charged form is more hydrophilic.

28
Q

Is the salt form or the protonated form of a barbiturate more active?

A

The neutral form is the active form over the charged form.

29
Q

What part of the structure of barbituric acid makes it unable to cross the BBB?

A

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.

30
Q

For sedative action, what must a barbiturate have?

A

It must have 5,5-disubstitution.

31
Q

What increases the potency of a barbiturate?

A

The total number of combined carbons at the R5 and R5’ up to 7-9 carbons.

32
Q

What happens to duration of a barbiturate as the number of carbons at C5 increases?

A

Duration decreases because of distribution into fatty tissues and muscles.

33
Q

What happens in a barbiturate as you increase branching at C5? Unsaturation at C5?

A

Both of these increase activity, decrease duration, and decrease toxicity.

34
Q

What happens in a barbiturate if you add a phenyl group at C5?

A

A phenyl group increases duration of action (10-16 hours) and leads to greater anticonvulsant activity (such as phenobarbital)

35
Q

What occurs in a barbiturate if you substitute S for O?

A

The lipid solubility increases, which decreases duration but provides a quicker onset.

36
Q

Are there any barbiturates with thio-substitution in the US?

A

Not currently. Thiopental sodium is no longer available in the US.

37
Q

Is barbituric acid a sedative?

A

No, it does not have di-substitution at the C5.

38
Q

Butabarbital sodium

  • type
  • structure
  • # of C-5 carbons
  • duration of action
A
  • Barbiturate
  • butane chain
  • 6 C-5 carbons
  • 6-8 hours (intermediate duration of action)
39
Q

What is the half-life of butabarbital?

A

t 1/2 = 45-60 hours

40
Q

Secobarbital

  • type
  • structure
  • # of C-5 carbons
  • duration of action
A
  • 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)
41
Q

Methohexital sodium

  • type
  • structure
  • # of C-5 carbons
  • duration of action
A
  • 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
42
Q

Chloral hydrate

  • type
  • structure
  • metabolism
A
  • 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.
43
Q

What do some migraine medications contain?

A

They contain trichloralphenazone, which is a prodrug of chloral hydrate.

44
Q

Meprobamate

  • type
  • structure
  • metabolism
A
  • misc. sedative/hypnotic
  • structurally similar to felbamate, which had liver toxicity due to active intermediate
  • No active metabolites, therefore no liver toxicity
45
Q

What drug is metabolized to meprobamate? What enzyme is used?

A

Carisprodol, a muscle relaxant uses 2C19 to form meprobamate.

46
Q

What is the half-life of meprobamate?

A

8 hours

47
Q

zolpidem tartrate

  • type
  • target
  • structure
  • metabolism
A
  • 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.
48
Q

What is the half-life of zolpidem tartrate?

A

t1/2 = 2 & 1/2 hours

49
Q

What is unique about the drug clearance?

A

It is slower for women than men

50
Q

Zaleplon

  • type
  • target
  • structure
  • metabolism (major and minor)
A
  • 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
51
Q

What does cimetidine do to zaleplon?

A

It inhibits both aldehyde dehydrogenase and 3A4, which significantly increases the half-life of zaleplon.

52
Q

What is the half-life of zaleplon?

A

1 hour

53
Q

Eszopiclone

  • type
  • target
  • structure
  • metabolism
A
  • 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
54
Q

What is the half-life of eszopiclone?

A

5 hours

55
Q

Melatonin

  • type
  • structure
A
  • melatonin receptor agonist
  • indole, acetamide, ether
  • tryptophan derivative
  • endogenous agonist
56
Q

Ramelteon

  • type
  • structure
  • metabolism
A
  • MT1, MT2 receptor agonist
  • to treat insomnia
  • indole mimic, ether, and propyl amide.
  • 1A2, 2C19 to form hydroxyramelteon inactive metabolites
57
Q

What is the half-life of ramelteon?

A

1 - 2 &1/2 hours

58
Q

What interactions would ramelteon have?

A

With a drug that inhibits or induces 1A2 or 2C19

59
Q

Tasimelteon

  • type
  • structure
  • metabolism
A
  • melatonin receptor agonist
  • indole mimic, propyl amide
  • 1A2, 3A4 to form inactive hydroxy metabolites
60
Q

What does tasimelteon treat?

A

It treats non-24 hours sleep-wake disorder, which is mainly an issue for blind people

61
Q

What is the half-life of tasimelteon?

A

1-2 hours

62
Q

Gamma hydroxybutyrate (GHB)

  • structure
  • type
  • metabolism
A
  • 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
63
Q

Why is there a restriction on GHB? How is it supposed to work?

A

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.

64
Q

What are 1,4-butanediol and gamma butyrolactone prodrugs of?

A

GHB

65
Q

Dexmedetomidine

  • structure
  • type
  • used for
A
  • alpha2 agonist
  • phenyethylamine core, S-enantiomer
  • structurally related to clonidine and the imidazoline alpha -2 agonists
  • Used clinically for sedative purposes
66
Q

Suvorexant

  • type
  • structure
  • metabolism
A
  • orexin receptor antagonist
  • single R enantiomer
  • big molecule, indole mimic
  • main route of metabolism is 3A4 hydroxylation to inactive products
67
Q

What is the half-life of suvorexant?

A

12 hours

Integrated Drug Structure, Action, and Therapeutics (20 decks)

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