This work deals with SSRIs, used clinically in the management of depression. Relevant pharmacology details, including special catchpoints regarding individual drugs has also been focused upon. My 76th powerpoint...

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

3. GENERAL INTRODUCTION

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

9. PHARMACOKINETIC
PROFILE

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.

12. MECHANISM OF ACTION

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

18. DRUG INTERACTIONS

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.

22. IMPORTANT CATCHPOINTS
REGARDING 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!!!