SSRI ANTI DEPPRESENT DRUGS- SEROTONIN SELECTIVE REUPTAKE INHIBITOR.pptx

SSRI

1. Selective Serotonin Reuptake Inhibitors (SSRI) 5.6.23

2. With introduction of Fluoxetine attitude ab ou t pharmacological treatement changed because of better tolerance than existing treatments and simplicity of dosing. Subsequently other SSRIs were introduced. SSRI YEAR Fluoxetine 1988 Sertraline 1992 Paroxetine 1993 Fluvoxamine 1994 Citalopram 1998 S- Citalopram 2002 HISTORY

3. Hormone found in - Pineal Gland Digestive Tract Platelets Brain - Acts as neurotransmitter Rolle in depression- regulates many functions of body and brain Mood Sleep Appetite Sexual Desire Cognition Serotonin

4. Serotonin deficiency can cause depressive symptoms Levels can be decreased due to ↓ production in brain cells ↓ no. of receptor sites Inability to bind properly with receptor sites Shortage of precursor chemical tryptophan.

5. SSRIs treat this deficiency of Serotonin - B locking the 5-HHT that allow serotonin reuptake from the synaptic cleft-> more serotonin accumulation.

6. These compounds are structurally unrelated . This may account for the differential response we see in some patients with one antidepressant vs another. Rationale for differential response may be related to different morphology of the serotonin transport protein (SERT /5-HTT) . Chemical structure

7. SSRIs are described as “ selective” because they affect primarily the reuptake pumps responsible for serotonin , as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well. Therefore , SSRI’s lack some of the side effects of the more general drugs . SSRI selectivity

8. SSRI selectivity SSRIs specifically inhibit serotonin reuptake, having 300-to-3000-fold greater selectivity for the serotonin transporter as compared to the norepinephrine transporter.

9. Absorption – Well absorbed orally and have peak effects in the range of 3-8 hrs . Absorption of Sertraline may be slightly increased by food. Distribution – Differences in plasma protein binding percentages ; with Sertraline, Fluoxetine & Paroxetine most highly bound; & Escitalopram least bound. Metabolism – All SSRIs are metabolized in the liver by CYP 450 enzymes. Wide Therapeutic Index- So their concentration not affected by other drugs. But potential for slowing/blocking the metabolism of many drugs. Pharmacokinetics

10. Elimination Drug Half- life 1. Fluoxetine 4-6 days Norfluoxetine (Active 7-9 days Metabolite) 2. Citalopram 35 hours 3. Escitalopram 27-32 hours 4. Sertraline 26 hours (Less active metabolite) 3-5 days 5. Paroxetine 21 hours 6. Fluvoxamine 15 hours

11. Dose-response curves Citalopram is linear Selectivity Citalopram and Escitalopram is the most selective Serotonergic reuptake blockade paroxetine is the most potent Dopamine reuptake blockade Sertraline is the most potent Anticholinergic effect paroxetine is the most potent Summary of pharmacokinetics differences

12. Licensed indication for SSRI treatment Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline tajor depressive disorder √ √ √ √ √ √ Generalized anxiety disorder √ √ √ Social anxiety disorders √ √ √ OCD √ √ √ √ √ PTSD √ √ Panic disorder ± Agoraphobia √ √ √ √ Premenstrual dysphoric disorder √ √ √ √ Bulimia nervosa √

13. Off labeled indication for SSRI treatment Bipolar depression Psychosomatic conditions Irritable bowel syndrome (IBS) Menopausal symptoms Premature ejaculation Migraine headache prophylaxis Chronic headache Musculo- skeletal pain Fibromyalgia

14. Escitalopram ( Cipralex ) Pros Low overall inhibition of P450s enzymes so fewer drug- drug interactions. Intermediate ½ life ( once daily dosing). More effective than Citalopram in acute response and remission . Cons Dose-dependent QT interval prolongation with doses of 10-30mg daily (doses of >30mg/day needs monitoring of QT interval). Nausea, headache.

15. Adverse Effects Of SSRIs MOST COMMON: Nausea (esp. Sertraline) Sexual Dysfunction in both genders (esp. paroxetine & Sertraline) Clinical rates approximate 50% of patients Headache (esp. Fluoxetine) Vomiting Dry mouth (esp. paroxetine) Abdominal pain

16. Adverse Effects Of SSRIs Weight changes: Weight gain (esp. paroxetine) Or Weight loss (esp. Fluoxetine) Increased risk of Bleeding Discontinuation syndrome (esp. paroxetine & Fluvoxamine) Increased potential for drug-drug interaction (esp. Fluvoxamine) Risks during pregnancy : Teratogenicity Persistent pulmonary hypertension Neonatal withdrawal syndrome

17. Adverse Effects Of SSRIs- More…. Mental and behavioral side effects Apathy and Emotional blunting Paradoxical anxiety (esp. Fluoxetine & Sertraline) Nervousness Irritability Akathisia / restlessness Suicidality (emergence of suicidal ideation) Hypomania or mania (manic switching) Abnormal dreaming

18. Adverse Effects Of SSRIs Central & Peripheral Nervous System side effects Sleep disturbance : Insomnia (esp. Fluoxetine) Somnolence (esp. paroxetine & Fluvoxamine) excessive dreaming Headache (esp. Fluoxetine) Dizziness Yawning Paraesthesia Tremor Extrapyramidal disorder

19. Adverse Effects Of SSRIs Gastro- Sntestinal System side effects ( esp. Sertraline and Fluvoxamine ) Nausea Vomiting Constipation Diarrhoea Anorexia Abdominal pain Dyspepsia Flatulence Dry mouth

20. Adverse Effects Of SSRIs Cardiovascular side effects QT- Prolongation and Torsade de Pointes ( esp. Citalopram & Escitalopram) Palpitation Autonomic side effects Increased sweating Flushing

21. Adverse Effects Of SSRIs Rare Adverse Effects Serotonin syndrome Hyponatraemia (probably more of an issue in the elderly) hyperprolactinemia Galactorrhea Mammary hypertrophy and gynaecomastia Extrapyramidal symptoms Seizure (esp. Fluoxetine ≥ 100mg/ day)

22. Fluoxetin e Citalopra m Escitalopr am Sertraline Paroxetin e Fluvoxam ine Most common side effects (Nausea) Headache Insomnia Nervousn ess Anxiety Drowsnes Anorexia Diarrhea Drymouth Drowsnes Insomnia Increased sweating Diarrhea Insomnia Diarrhea Headache Headache Insomnia Diarrhea Drymouth Ejaculatn failure, ↓ libido Drowsnes Dizziness Fatigue Drowsnes Headache Drymouth Dizziness Weakness Fatigue Sexual dysfunctn Sweating Diarrhea Insomnia Sexual Dysfuncti on,Gastro intestinal, Sedation Least common side effects Dizziness Weakness Drymouth Anxiety Agitation Tremor Sweating Sexual dysfuncti on Tremor Ejaculatn, ↓ libido, impotnce Fatigue Anxiety Agitation Anorexia Abnormal ejaculatn, ↓ libido, impotnce Drymouth Drowsnes Fatigue Sweating Dizziness Anxiety Anorexia Tremor Sweating Agitation Anorexia Nervousn ess Anxiety Tremor Constipat ion, ↓ appetite Anxiety Nervousn ess Tremors, Bruising, Rare bleeding Seizures

23. Serotonin Syndrome Administration of an SSRI in presen c e of another highly serotonergic drug ( MAOI, Lithium and L- Tryptophan) can lead to-> life- threatening " serotonin syndrome "

24. Manifestation NEURO : Myoclonus, Nystagmus, Headache, Tremors, Rigidity and Seizures. MENTAL STATE : Irritability, Confusions, Agitations, Hypomania and Coma. AUTONOMIC: Hyperpyrexia, sweating, diarrhea, cardiac arrythmia and death.

25. Management Discontinuation of all serotonergic agents Supportive care aimed at normalization of vital signs (oxygen and intravenous fluids, continuous cardiac monitoring, and correction of vital signs). Sedation with benzodiazepines Administration of serotonin antagonists (Cyproheptadine)

26. Abrupt withdrawal of SSRIs especially those with shorter half- life (Paroxetine/ Fluvoxamine ). Fluoxetine - lowest risk. Symptoms include headache, nausea, malaise, dizziness, weakness, agitation, irritability, flu- like symptoms, nervousness, poor concentration, rebound depression. Doesn’t appear until at least 6 weeks of treatment & usually resolves spontaneously in 3 weeks. SSRI discontinuation syndrome

27. Fluvoxamine > Fluoxetine > Paroxetine > Sertraline > Citalopram > Escitalopram Interacting effects may be dose dependent . SSRI levels tend not to be altered by other drugs but can potentially increase levels (inhibit metabolism) of certain drugs paroxetine > Y risperidone fluoxetine > Y buspirone fluvoxamine > Y olanzapine Drug- drug interactions

28. Fluoxetin e Citalopra m Escitalopr am Sertraline Paroxetin e Fluvoxam ine Pharmace rutical forms Tab- 10/20/40 mg Solution- 20mg/5m L Tab- 10/20/40 mg Tab- 5/10/20 mg Tab- 25/50/10 mg Tab- 10/20/30 /40 mg CR- 12.5/25/ 37.5 mg Tab- 25/50/10 mg Brand names Prodep, Flunil, Fludac, Flupar Celica,Cit adep Nexito, Recita, S- citadep, Feliz- S, Rexipra Serlift, Serta, Daxid Paxidep, Pari CR, Xet CR Uvox, Fluvoxin Half- life 4-6 days 35 hours 27- 32 hours 26 hours 21 hours 15 hours Time to Steady state 30- 60 days 7 days 7 days 7- 14 days 10- 14 days 5- 10 days Recomme nded doses 10- 80 mg/day 20- 40 mg/day 10- 20 mg/day 50- 100 mg/day 10- 50 mg/day 50- 300 mg/day