SSRIs(Antidepressants): A deep insight: By RxVichuZ!! ;)
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The document provides an overview of selective serotonin reuptake inhibitors (SSRIs), including their introduction, mechanism of action, pharmacokinetics, and potential adverse effects. It details the various SSRIs available, their uses in treating conditions such as depression and anxiety, and important cautions regarding drug interactions and dosing. The document reinforces SSRIs as the first-choice agents for several mental health disorders due to their wide efficacy and relative safety.
SSRIs(Antidepressants): A deep insight: By RxVichuZ!! ;)
- 1. PRESENTED TO:PSYCHIATRY DEPARTMENT PRESENTED BY: VISHNU.R.NAIR, PHARM.D INTERN, NATIONAL COLLEGE OF PHARMACY(NCP).
- 2. 1. GENERAL INTRODUCTION 2. CHEMISTRY 3. PHARMACOKINETIC PROFILE 4. MECHANISM OF ACTION 5. ADRs 6. DRUG INTERACTIONS(Summarized) 7. DOSES 8. IMPORTANT CATCHPOINTS REGARDING SSRIs
- 4. - Include a class of drugs, that mainly work by INHIBITION OF SERT(Serotonin transporter) - FLUOXETINE introduced in US in 1988 - Development of fluoxetine raised demands for search of drugs, that had : a. High affinity for monoamine receptors b. Little/no affinity for histaminergic, cholinergic & alpha-adrenoceptors - Currently there are 6 available SSRIs in clinical use. - General uses include: a. Major depression b. GAD(Generalized Anxiety Disorder) c. PTSD(Post-traumatic Stress Disorder) d. OCD(Obsessive-Compulsive Disorder) e. Panic disorder f. PMDD(Pre-menstrual dysphoric disorder)
- 5. g. Bulimia . Have high lipophilicity Popularly used, due to the following reasons: a. Easy to use b. Reduced safety issues in overdose c. Better tolerability d. No anticholinergic side-effects e. Cost-effective f. Broad spectrum of uses!!!
- 6. CHEMISTRY
- 7. - Similarity between FLUOXETINE, SERTRALINE & CITALOPRAM: a. Exist as isomers b. Formulated into (R) forms - PAROXETINE & FLUVOXAMINE not optically active! - ESCITALOPRAM (S) enantiomer of citalopram.
- 8. STRUCTURES OF FLUOXETINE & SERTRALINE
- 10. FLUOXETINE differs from other SSRIs: - Drug metabolized to an active metabolite (NORFLUOXETINE) - Norfluoxetine has higher plasma drug concentrations compared to that of fluoxetine - t1/2 of norfluoxetine 3 times higher than that of fluoxetine has the LONGEST HALF-LIFE of all SSRIs! - Above property warrants that fluoxetine should be DISCONTINUED 4 WEEKS/ LONGER, before initiating MAO-I therapy , to prevent risks of SEROTONIN SYNDROME!!! FLUOXETINE & PAROXETINE inhibit CYP2D6 high risk of drug- interactions!! FLUVOXAMINE inhibits CYP3A4 CITALOPRAM, ESCITALOPRAM & SERTRALINE very modest risk of drug interactions!
- 11. SSRI BA(in %) t1/2(in hrs) Active metabolite t1/2(hrs) Vd(in L/kg) PPB (%) Citalopram 80 33-38 ND* 15 80 Escitalopram 80 27-32 ND* 12-15 80 Fluoxetine 70 48-72 180 12-97 95 Fluvoxamine 90 14-18 14-16 25 80 Paroxetine 50 20-23 ND* 28-31 94 Sertraline 45 22-27 62-104 20 98 PHARMACOKINETIC PROFILES OF SSRIs: ND* : No data available from studies.
- 13. SERT(Serotonin Transporter): - Glycoprotein - 12 transmembrane regions are embedded in the axon terminal & cell-body membranes of serotonergic neurons - Extracellular serotonin binds to receptors on SERT conformational changes occur in SERT & 5-HT influx of sodium & chloride into cells binding of intracellular potassium leads to 2 consequences : a. Release of 5-HT inside cell b. Return of SERT to its original state - SSRIs bind SERT receptor at a site other than that of serotonin-binding site cause inhibition of SERT. - At therapeutic doses 80% of activity of SERT is inhibited (depending on functional polymorphism)
- 14. Possess modest effect on other neurotransmitters Little evidence, regarding effects on beta-adrenoceptors & NET Do not bind profoundly to histaminergic, muscarinic or other receptors.
- 15. ADRs
- 16. SSRIs INCREASE SEROTONERGIC TONE, not only in the BRAIN, but also throughout the BODY! GI ADRs: - Increased serotonergic activity in the gut leads to: 1. Nausea 2. GI upset 3. Diarrhea - GI ADRs develop in early course of treatment tend to improve after 1st week SEXUAL DYSFUNCTION: - Increased serotonergic activity at level of spinal cord reduces sexual function & interest - 30-40% of patients under SSRIs report the following: a. Loss of libido b. Delayed orgasm & arousal.
- 17. - Sexual ADRs persist as long as patient is on SSRI/ may diminish with time HEADACHES INSOMNIA/HYPERSOMNIA WEIGHT GAIN(Paroxetine) SUDDEN DISCONTINUATION of SSRIs with short half-life(Paroxetine, sertraline) can result in “DISCONTINUATION SYNDROME”, characterized by: a. Dizziness Begin 1-2 days after drug stoppage, continues for 1 week b. Paresthesias or more. TERATOGENICITY PROFILE: - Most antidepressants come under Category “C” agents , according to FDA teratogen classification system - PAROXETINE used in pregnancy increases risk of CARDIAC SPINAL DEFECTS(1st trimester) thus, comes under Category “D” - Post-birth complications(Pulmonary HTN) not clearly established in clinical
- 19. PAROXETINE & FLUOXETINE CYP2D6 inhibitors if used with 2D6 substrates(TCAs) results in TCA toxicity! FLUVOXAMINE CYP3A4 inhibitor causes increased plasma drug concentrations of 3A4 substrates (Diltiazem) results in bradycardia / hypotension!! SSRIs + MAO-I causes overstimulation of 5-HT receptors in central gray nuclei & medulla results in LIFE-THREATENING SEROTONIN SYNDROME, characterized by: a. Cognitive effects (Delirium, coma) b. Autonomic effects(HTN, tachycardia, diaphoresis) c. Somatic effects (Myoclonus, hyper-reflexia, tremor).
- 20. DOSES
- 21. SSRI MAXIMUM THERAPEUTIC DOSE(in mg/day) Citalopram 20-60 Escitalopram 10-30 Fluoxetine 20-60 Fluvoxamine 100-300 Paroxetine 20-60 Sertraline 50-200 DRUG-DOSING OF VARIOUS SSRIs.
- 23. Drugs inhibit reuptake of ONLY 5-HT Possess several advantages over TCAs: a. No anticholinergic ADRs b. No sedation/weight gain c. No propensity to cause seizures/ arrhythmias!!
- 24. ADRs of SSRIs: a. Most frequent complaint: NAUSEA b. Next common ADR: Anxiety c. Diarrhea d. Inhibition of ejaculation e. Co-administration of SSRIs with MAO-inhibitors results in LIFE- THREATENING SEROTONIN SYNDROME! f. Akathisia g. Since SSRIs affect PLATELET SEROTONIN LEVELS ABNORMAL BLEEDING can occur!
- 25. IMPORTANT CATCHPOINTS ABOUT INDIVIDUAL DRUGS
- 26. A. FLUOXETINE: - Longest-acting SSRI - Drug metabolized to NOR-FLUOXETINE retains anti-depressant activity B. FLUVOXAMINE: - Shortest-acting SSRI C. SERTRALINE & CITALOPRAM safe to be used along with WARFARIN! D. ESCITALOPRAM: Most-specific SSRI! E. PAROXETINE: Most TERATOGENIC SSRI!!
- 27. SSRIs are now 1st choice agents for: 1. Depression 2. OCD 3. PTSD 4. Bulimia nervosa 5. Premenstrual tension syndrome 6. Panic disorder.
- 28. THANK YOU!!!