Selective Serotonin Reuptake Inhibitors (SSRIs)

Mechanism of Action
300-3000 fold selectivity to block 5-HT >NE reuptake.
Receptors: M, α & H (little blockade)

Uses:
Depression (1st line of treatment of MDD )
Anxiety disorders (GAD, OCD, Panic, …..)
Eating Disorders e.g. Bulimia nervosa, Anorexia Nervosa

1. Selective Serotonin Reuptake Inhibitors ( SSRIs) Prof. Sawsan Aboul-Fotouh Department of pharmacology, faculty of Medicine, Ain-Shams University SSRI

2. Selective Serotonin Reuptake Inhibitors ( SSRIs)

3. SSRIs Mechanism of Action 300-3000 fold selectivity to block 5-HT >NE reuptake. Receptors: M, α & H (little blockade) Uses: Depression ( 1 st line of treatment of MDD ) Anxiety disorders (GAD, OCD, Panic, …..) Eating Disorders e.g. Bulimia nervosa, Anorexia Nervosa ( Fluoxetine , Paroxetine , Citalopram, Escitalopram , Sertraline , Fluvoxamine ) SSRI

4. Eating Disorders Anorexia Nervosa D istorted body image

5. 5 . Vasomotor menopausal symptoms: “ Brisdelle “paroxetine” 7.5 mg tab .” 1 st Non-Hormonal Treatment (FDA 2013). Other SSRIs & SNRIs also used off-label 4. Post-traumatic stress disorder and impulse control disorder as Trichotillomania (esp. Prozac), gambling ….. 6. Premenstrual dysphoric disorder (PMDD). FDA approved fluoxetine ,  sertraline , and  paroxetine for  PMDD 7. Premature ejaculation: ALL SSRIs esp. F luoxetine, Citalopram

6. Less Obesity Less Cardiotoxicity ?! (Citalopram→↑QT) Less Risk of overdose NO or Less Less Autonomic Blockade

7. Q: Sleep disturbance Paroxetine is sedating useful in pts with difficulty in sleeping. Fluoxetine is activating useful in pts with fatigue or excessive somnolence Adverse effects: ↑ Risk of Suicide In children and teenagers

8. Fluoxetine and paroxetine potent inhibitors for CYP 2D6 → Drug interactions with: TCAs , Antipsychotic drugs, Antiarrhythmic& β-Blocker . TCAs, Antipsychotics, Antiarrhythmic β-Blocker .

9. Paroxetine not recommended to be given with tamoxifen (estrogen receptor blocker). It inhibits CYP2D6, that converts the prodrug tamoxifen to active metabolites ( endoxifen ↓ 58%) →↓ tamoxifen effectiveness in hormone positive cancer breast. Also, Paroxetine was found to have an estrogenic effect “weak agonist”  → promote the development and growth of breast tumors in women. Bupropion active metabolites Venlafaxine has No interaction with Tamoxifen Prodrug

10. Venlafaxine has No Drug interaction with CYP

11. US Pharm.  2015;40(11):HS34-HS40. (>450 ms in males, >470 ms in females) TCAs & Citalopram

12. FDA issued a warning for citalopram and the risk of QT prolongation at doses higher than 40 mg/day

13. Q: Managing SSRI-induced sexual dysfunction?? delayed ejaculation in ♂ & ↓ sexual desire in ♀ Reduce the dose of the drug if possible. In erectile dysfunction sildenafil ( Viagra ) may improve sexual function. Replace it with other having fewer sexual side effects: ( Mirtazapine, Bupropion, Vortioxetine, Agomelatine )

14. With All SSRIs when used with MAOI. → Washout (2 Wks ) period before administration of each other Q: SSRIs Overdoses? Hyperthermia Confusion

15. Akathisia and other EPS also can complicate the use of SSRIs e.g. Fluoxetine, Paroxetine. SSRIs inhibit tyrosine kinase in S. Nigra → ↓ Dopamine (DA) in BG A lso ↑ 5-HT level and 5-HT 2A activation →↓ DA in BG. SSRIs inhibit CYP2D6 → ↑ risk of EPS with antipsychotics metabolized with CYP2D6 e.g. Aripiprazole, Risperidone, Fluphenazine …. Akathisia Dystonia SSRIs-induced Extrapyramidal Symptoms (EPS)