Antidepressants Overview Quiz
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Questions and Answers

What is the structure of Nefazodone?

Nefazodone

How is Nefazodone metabolized?

  • Oxidative deamination (correct)
  • Hydrolysis
  • Glucuronidation
  • None of the above

What is the structure and half-life of Venlafaxine?

Venlafaxine (Effexor) - NSRI. Half-life of approximately 11 hours.

What is the dose-dependent blocking of Venlafaxine?

<p>At low doses, Venlafaxine acts as an SSRI, while at high doses, it inhibits NET. (A)</p> Signup and view all the answers

What is the structure, half-life, and origin of Fluoxetine?

<p>Fluoxetine (Prozac) - SSRI. Half-life of approximately 50 hours. Derived from Benadryl (ABA).</p> Signup and view all the answers

What is Norfluoxetine?

<p>Norfluoxetine is the demethylated metabolite of Fluoxetine. It is not a substrate for P-gp.</p> Signup and view all the answers

What are the important SAR features and metabolism of Fluoxetine?

<p>SAR features:</p> <ul> <li>Trifluoromethyl should be para to ether.</li> <li>4 atoms between substituted aromatic &amp; basic feature. Metabolism:</li> <li>Oxidative dealkylation.</li> </ul> Signup and view all the answers

What is the effect of substituting on the 4C or 2C of Fluoxetine?

<p>Substitution on 4C increases 5-HT reuptake inhibition, while substitution on 2C increases NE reuptake inhibition. (A)</p> Signup and view all the answers

What is the MPO of Fluoxetine and does it cross the BBB?

<p>MPO = 2.55 and it does cross the BBB. (B)</p> Signup and view all the answers

What is the structure of Sertaline and what is important about it's structure?

<p>Sertaline (Zoloft). It is conformationally constrained and has a unique structure with an aromatic ring and a hexane ring.</p> Signup and view all the answers

What is the structure of Paroxetine?

<p>Paroxetine (Paxil) - SSRI. It has an aromatic ring with an oxygen ring attached and a fluorine atom on the other ring.</p> Signup and view all the answers

What is the structure and key features of Citalopram?

<p>Citalopram (Celexa) - SSRI. It contains a tertiary amine, a triple bond nitrogen, and a quaternary carbon with an attached oxygen. It has the highest selectivity for SERT over NET.</p> Signup and view all the answers

What is the structure and key features of Duloxetine?

<p>Duloxetine (Cymbalta) - SNRI. It contains a napthalene ring and an aryl bioisostere.</p> Signup and view all the answers

Flashcards

Nefazodone Structure

Nefazodone is a tricyclic antidepressant with a similar structure to trazodone. It contains a central seven-membered ring fused to two six-membered rings. One of the six-membered rings contains a nitrogen atom, while the other has a carbon atom linked to a phenyl ring.

Nefazodone Properties

Nefazodone is less sedating than trazodone, but shares a similar metabolism. It's a CYP3A4 inhibitor, which can lead to drug interactions. Additionally, it can cause idiosyncratic hepatotoxicity, making liver monitoring crucial.

Nefazodone Metabolism

Nefazodone is primarily metabolized by oxidative deamination, a similar process to trazodone. This involves the removal of an amino group from the molecule, leading to the formation of various metabolites.

Venlafaxine Structure

Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) with a phenethylamine core structure. It has a single hydroxyl group and a half-life of approximately 11 hours.

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Venlafaxine Dose-Dependent Blocking

Venlafaxine acts as a selective serotonin reuptake inhibitor (SSRI) at low doses. However, at higher doses, it also inhibits norepinephrine reuptake, making it an SNRI. This dose-dependent effect allows for flexibility in treatment.

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Desvenlafaxine Structure

Desvenlafaxine is the primary metabolite of venlafaxine. It's also an SNRI, but with two hydroxyl groups instead of one. Desvenlafaxine is a demethylated analog of venlafaxine and has a similar half-life of approximately 11 hours.

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Fluoxetine Structure

Fluoxetine is a serotonin reuptake inhibitor (SSRI) derived from benadryl with both active enantiomers. It has a unique structure with a trifluoromethyl group and a basic nitrogen atom. Its half-life is significantly long, around 50 hours, leading to steady state in 4-5 weeks.

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Norfluoxetine

Norfluoxetine is the demethylated metabolite of fluoxetine. Unlike fluoxetine, it's not a substrate for the P-glycoprotein transporter. This means it has a very low residence time in the body.

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Fluoxetine SAR & Metabolism

Fluoxetine's pharmacophore is based on its trifluoromethyl and basic nitrogen atom. For optimal activity, the trifluoromethyl group should be para to the ether. There needs to be 4 atoms separating the substituted aromatic ring from the basic feature. Fluoxetine is primarily metabolized through oxidative dealkylation.

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Fluoxetine SAR: Substitution Effects

Substitutions on the 4th carbon atom of fluoxetine's structure are associated with serotonin reuptake inhibition. Conversely, substitutions on the 2nd carbon atom are linked to norepinephrine reuptake inhibition. Smaller Ki values indicate higher selectivity for serotonin, while larger Ki values suggest greater selectivity for norepinephrine.

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Fluoxetine MPO & BBB Permeability

Fluoxetine has an MPO (molecular permeability) of 2.55, which is below the typical threshold of 4 for crossing the blood-brain barrier. However, it still manages to cross the BBB efficiently. This suggests that MPO alone may not be a fully reliable predictor of drug permeability.

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Sertaline Structure

Sertaline is an SSRI with a unique structure. It has a conformationally constrained molecule with an aromatic ring containing two chlorine atoms attached to a simple hexane ring.

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Paroxetine Structure

Paroxetine is an SSRI with a distinct structure. It contains an aromatic ring with an oxygen ring attached and a fluorine atom on the other ring.

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Study Notes

Nefazodone

  • Nefazodone is less sedating than trazodone, with similar metabolism.
  • It's a CYP3A4 inhibitor and has idiosyncratic hepatotoxicity.
  • Its metabolism involves oxidative deamination, similar to trazodone.

Venlafaxine (Effexor)

  • Venlafaxine (Effexor) is a norepinephrine-serotonin reuptake inhibitor (NSRI).
  • It contains a phenethylamine moiety.
  • Its half-life (t1/2) is approximately 11 hours.
  • At low doses, it acts as a selective serotonin reuptake inhibitor (SSRI).
  • At higher doses, it inhibits norepinephrine reuptake (NET) as well.

Desvenlafaxine (Pristiq)

  • Desvenlafaxine is the primary metabolite of venlafaxine.
  • It has two hydroxyl groups (a demethylated analog of venlafaxine).
  • Its half-life (t1/2) is approximately 11 hours.

Fluoxetine (Prozac)

  • Fluoxetine is an SSRI derived from Benadryl (ABA).
  • Both enantiomers are active.
  • Its half-life (t1/2) is approximately 50 hours, reaching steady-state in 4-5 weeks.

Norfluoxetine

  • Norfluoxetine is the demethylated substrate of fluoxetine.
  • It's not a P-gp substrate.
  • It's the primary metabolite of fluoxetine.

Fluoxetine SAR and Metabolism

  • Fluoxetine's structure, specifically its aromatic substitution, plays a crucial role in its activity and metabolism.
  • A substituted aromatic ring with specific substituent positions leads to differing degrees of 5-HT reuptake inhibition or norepinephrine reuptake inhibition.
  • Specific atoms and bond distances contribute to high selectivity towards 5-HT.
  • Metabolism primarily involves oxidative dealkylation.

Fluoxetine Substitution SAR

  • Substituting the 4 carbon position of the Fluoxetine structure increases 5-HT reuptake inhibition.
  • Substituting the 2 carbon position of the Fluoxetine structure increases norepinephrine reuptake inhibition.

Fluoxetine BBB Penetration

  • Fluoxetine's apparent blood-brain barrier penetration is relatively low, measured by an MPO, or metabolism potential.
  • However, it still crosses the blood-brain barrier.
  • The MPO (2.55) is less than the 4 required for efficient cross-barrier penetration, however it still crosses.

Sertraline (Zoloft)

  • Sertraline has a conformationally constrained structure.
  • Its structure features an aromatic ring with two chlorine atoms attached and a simple hexane ring.

Paroxetine (Paxil)

  • Paroxetine's structure includes an aromatic ring with an attached oxygen ring, and a fluorine substituent on another ring.

Citalopram (Celexa)

  • Citalopram is an SSRI administered as a racemic mixture.
  • It's the only tertiary amine antidepressant with a triple-bonded nitrogen moiety.
  • It displays high selectivity for serotonin reuptake (SERT) over norepinephrine reuptake (NET).
  • A quaternary carbon with an oxygen group is present in its structure

Duloxetine (Cymbalta)

  • Duloxetine is an SNRI administered as R-Duloxetine.
  • Its structure includes a naphthalene ring and an aryl bioisostere.

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Description

Test your knowledge on various antidepressants including Nefazodone, Venlafaxine, Desvenlafaxine, and Fluoxetine. This quiz covers their mechanisms, pharmacokinetics, and unique properties. Perfect for students and professionals in pharmacology or psychiatry.

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