slides collected from many eminent teachers nd few from sildeshare in view of ug/pg studnets not to miss any topic.

1. ANTIDEPRESSANTS
Dr,MAHI YERUVA
PG 1ST YEAR
PHARMACOLOGY
GMC ATP

2. DEPRESSION
• Definition:
• AFFECTIVE DISORDER
• A serious medical condition in which a
person feels very sad ,hopeless, and
unimportant and often is unable to live in a
normal way

3. CRITERIA FOR DEPRESSION
3
AT LEAST 5 OF THESE 9 SYMPTOMS ,
PRESENT NEARLY EVERY DAY:
1.DEPRESSED MOOD OR IRRITABLE MOST OF THE DAY
2.DECREASED INTEREST OR PLEASURE IN ACTIVITIES
3.SIGNIFICANT WEIGHT LOSS (5%) OR CHANGE IN
APPETITE
4.CHANGE IN SLEEP : INSOMNIA OR HYPERSOMNIA
5.CHANGE IN ACTIVITY : PSYCHOMOTOR AGITATION
OR RETARDATION
6.FATIGUE OR LOSS OF ENERGY
7.GUILT/WORTHLESSNESS
8.CONCENTRATION - DIMINISHED , INDECISIVENESS
9.SUICIDALITY: THOUGHTS OF DEATH OR SUICIDE, OR
HAS SUICIDE PLAN

4. TYPES OF DEPRESSION
¬ Depression are of Following types :
a.Uni-polar - Mind of subject swing in some direction
b.Bi-polar - Depression associated with mania some
times called as a manic depression
c.Endogenous – Depression due to shock or
stressful life events

7. TYPES OF DEPRESSION
• MAJOR DEPRESSION
• PERSISTENT DEPRESSIVE DISORDER-dysthymia
• SEASONAL AFFECTIVE DISORDER
• POSTPARTUM DEPRESSION
• PREMENSTRUAL DEPRESSION
• SITUATIONAL DEPRESSION
• POSTMENOPAUSAL DEPRESSION

8. 01/02/19

9. 9

10. 01/02/19
Amine hypothesis of mood
•Psychic depression: Decrease
concentration of noradrenaline &
serotonin in the brain.
•Elevated mood: Increase of
noradrenaline and serotonin in the
brain.
•Schizophrenia: increased
dopamine in the brain

11. 11

12. Neuro endocrine factors:
Abnormalities of the HPA axis: increased CORTISOL,
increased ACTH & CRH.
When dexa give no dec in cortisol levels.
Most depressed patients are Euthyroid, some have
subclinical hypothyroidism.
When TSH given no response to induce TRH.
Decreased GROWTH HORMONE.
Increased PROLACTIN levels.
12

13. 13

14. 14

15. 15

16. SITES OF ACTION OF
ANTIDEPRESSANTS
NORADRENERGIC NERVE
TERMINAL
SEROTONERGIC NERVE
TERMINAL
7

17. 17

18. ANTI-DEPRESSANT DRUGS
MONO-AMINE REUPTAKE INHIBITORS MONOAMINE OXIDASE INHIBITORS
NON SELECTIVE
(NORADRENALINE/SERATONIN)
REUPTAKE INHIBITORS
SSRIs
Fluoxetine
Fluoxamine
Paroxetine
Citalopram
Escitalopram
Sertraline
TCAs
SELECTIVE NA REUPTAKE
INHIBITORS
Reboxetine
Atomoxine
Maprotiline
OTHER SNRIs
Imipramine
Clomipramine
Amitryptaline
Doxepin
Venlaflaxine
Duloxetine
NON SELECTIVE SELECTIVE
Tranylcypromine Moclobemide
ATYPICAL ANTIDEPRESSANTS
Trazodone Mirtazapine Nefazodone
Bupropion Mianserin

19. 01/02/19

20.  St. John’s wort
(Active principle:Hyperforin)
ANTIDEPRESSANTS OF
NATURAL ORIGIN

21. 1.Drugs that block NE and 5HT reuptake:
• Examples: Imipramine, clomipramine,
Amitryptyline, Doxepin
• Chemically these are tri cyclic
antidepressants.
• These block reuptake of NA and 5HT
transporters.
• These permit more availability and longer stay of
NE and 5HT in synaptic cleft.
• In addition they bind to α-adrenergic ,histaminic,
and cholinergic receptors which account for side
effects.

22. 22

23. Tricyclic Anti depressants (TCA’s):• .
23

24. IMIPRAMINE - PHARMACOKINETICS
• Good oral absorption but undergo 1st pass
effect –variable bioavailablity.
• Highly bound to plasma protein and high Vd
• Metabolized in Liver: Active metabolites:
• Imipramine– desipramine and
• amitriptyline – nortriptyline
• Excreted via urine, t 1/2 – 16 to 24 Hrs.
One daily dose – because of active
metabolites
• Therapeutic window phenomenon: Optimal
effect at 50-200 ng/ml.
24

25. DRUG INTERACTIONS:
 TCA’s potentiate the effects of directly acting
sympathomimetics -- BP, Arrythmias.
Anticholinergics aggravates the toxicity of TCA
 T3, T4 Potentiate CNS stimulant effect of TCA’s.
MAO I’s with TCA’s show synergistic action.
 TCA’s block the uptake of Guanethidine along with NE.
 TCA’s reverse the antihypertensive action of clonidine.
25

26. DRAWBACKS:
• Low safety margin.
• Anticholinergic, CVS and neurological side
effects.
• Therapeutic lag (2-4 wks).
• The TCAs may exacerbate certain medical
conditions, such as unstable angina, benign
prostatic hyperplasia, epilepsy, and preexisting
arrhythmias 26

27. THERAPEUTIC USES:
• 2nd
or 3rd
line agents for MDD.
• OCD (Clomipramine)
• PANIC DISORDERS
• SCHOOL PHOBIA,PTSD.
• ADHD (ATOMOXETINE NERI)
• Nocturnal enuresis in children(Doc desmopressin)
• Neuropathic pain.
• Migraine.
• Low doses of TCAs, especially doxepin, can be
used to treat insomnia
27

28. Adverse effects:
• Blockade of muscarinic receptors leads
• Anti-cholinergic effects.
• life-threatening arrhythmias
• Block α-adrenergic receptors
• orthostatic hypotension, dizziness, and
reflex tachycardia .
Blockade of histamine H1 receptors
• Sedation.
28

29. 2.Selective Serotonin-Nor adrenaline
reuptake inhibitors(SNRIs):
• Examples :Duloxetine, Venlafaxine, Milnacipram
• SNRIs block the reuptake of NA and 5HT like TCAs
• They differ from TCAs and are more selective and
lack α1-adrenergic ,H1 and cholinergic receptor
blocking property.
• So fewer side effects than TCA.
• NOTE: VENlafaxiNE causEs cardiO TOxiciTy
• aT high dOsEs.

30. 3.Drugs which predominantly block NE reuptake
• TCAs: Despiramine , Nortryptaline,
protryptaline
• Newer: Amoxapine, Reboxetine,Maprotiline.
 These predominantly inhibit NA reuptake
resulting in increased concentration of NA in
synaptic cleft.
Note : Amoxapine blocks post synaptic
D2 receptors also and hence possess
antipyschotic action.

31. 4.Drugs which selectively inhibits
Seratonin (SSRIs)
• Examples : Sertraline,Fluoxetine,Fluvoxamine,
paroxetine, Citalopram, Escitalopram.
• SSRIs selectively blocks seratonin reuptake
and increases seratonin levels in the synaptic
cleft.
NOTE:
Most prescribed
Escitalopram is 100 times more potent than
Citalopram
Citalopram is prefered SSRI in Premenstrual
syndrome.

32. 5.Natural Anti-depressants
• St.John’s wort (Hyericum perforatam)
Hypericin
Hyperforin
• Mild MAO Inhibitors
• Stimulants at GABA receptors
Monoamine reuptake inhibitors

33. MaO (MONOaMiNE OxidasE ):
MAO is an mitochondrial enzyme involved in the oxidative
deamination of biogenic amines.
Two forms: MAO-A
MAO-B
MAO-A MAO-B
Deaminates 5HT, NA, DA Phenylethylamine,
DA
Distribution Adrenergic neurons,
intestine,liver,kidney
, placenta.
Dopamanergic
neurons,
brain,platelets,liver.
Inhibited by Clorgyline,
Moclobemide.
Seligiline.

34. Clorgyline Moclobemide
Phenelzine
Tranlcypromine
MAO i
MAO- A
Selective
Irreversible
inhibitors
Reversible
inhibitors
Non-
selective
MAO INHIBITORSMAO INHIBITORS

35. Mechanism of action:
• Inhibition of MAO-A decreases the deamination
of 5HT, NA in the nerve endings.
This causes local increase of 5HT,NA which is
associated with both antidepressant action and
hypertensive interactions .
EXAMPLE:
Meclobemide: Reversible inhibitor of MAO-A
Full MAO activity restored within 1-2 days

36. • Selective inhibition of MAO-B decreases
deamination of dopamine, is not associated with
antidepressant action and hypertensive reactions
• These are useful in the treatment of
parkinsonism.
Selegiline (Emsam) is the first and only once-
daily skin patch approved to treat major
depressive disorder (MDD)

37. Non selective MAO inhibitors:
•The active metabolites of non selective MAO
inhibitors inactivate the enzyme irreversibly.
•These are “hit and run” drugs ,takes 2-3
weeks and its effects last for 2-3 weeks.
•Return of MAO activity depends on synthesis of
fresh enzyme.

38. THERAPEUTIC USES:
Indicated for depressed patients who are unresponsive
or allergic to TCAs or who experience strong anxiety.
Treatment of phobic states.
Treatment of atypical depression (labile mood, rejection
sensitivity, and appetite disorders).
Parkinson's disease.
 School phobia, PTSD.
38

39. Adverse effects (MAOI’s):
 Hypertensive crises
 Hepatotoxicity
 Postural hypotension
 Increase in appetite
 Dizziness
 Sexual dysfunction.
 Less common- Headache, dry mouth,
blurred vision, constipation, etc.. 39

40. Drug interactions:
40

41. DRUG INTERACTIONS:
1.Cheese reaCtion:
Tyramine rich food articles like
Cheese
Beer
Red wine
Banana
yoghurt
Pickled meet

43. 2. Maoi + tCas:
shows synergistic effects
leads to hypertension, arrhythmia, seizures
3.Maoi inhibits Da DegraDation
more DA levels forms precursor for NE synthesis
and release
resulting in hypertensive crisis
4.Maoi inhibits liver MiCrosoMal enzyMes,
precipitating toxicity
>MAOI + Morphine: severe respiratory distress
>MAOI + Sulphonyl ureas: hypoglycemic coma
(tolbutamide)
>MAOI + Chloroquine : increased toxicity

44. Moclobomide : Advantages
• Reversible action (1-2 days after stoppage)
(restoration of normal MAO activity)
• Dietary restriction not required.
• Lack of anti cholinergic, sedative, cognitive
and CVS adverse effects.
• Used in elderly patients and with heart
diseases.
• Mild to moderate depression - alternative to
TCAs. 44

45. 45

46. ATYPICAL ANTIDEPRESSANTS
• TRAZODONE – inhibits 5HT reuptake
block 5 HT 2A receptor
desensitises presynaptic 5 HT
receptor
alpha 1blocking (side effect)
postural hypotension & priapism
sexual dysfunction
01/02/19

47. • Nafazodone more safe than trazodone.
(hepatotoxicity) but less alpha blocking side effects
• Mianserin blocks H1 & presynaptic alpha 2
• Mirtazapine- block presynaptic alpha 2 auto
receptors and 5 HT1 receptors not 5 HT 2 & 5HT 3
receptors. (No side effects of SSRI)
• Block H1 and 5 HT 2c receptors which lead to
sedation and increased appetite.
• Bupropion – weak inhibitor of reuptake of 5 HT ,NE
&DA
01/02/19

48. BUPROPION:
• Weak dopamine and norepinephrine reuptake inhibitor
• Bupropion also assists in decreasing the craving and
attenuating the withdrawal symptoms for nicotine in
tobacco users trying to quit smoking.
• Can help with cocaine withdrawal.
• Cause agitation, insomnia so avoid at bed time.
• Side effects
◦ Dry mouth
◦ Nervousness
◦ Tremor
◦ Increased risk for seizures at high doses. 48

49. MIRTAZAPINE:
• Enhances serotonin and norepinephrine
neurotransmission by blocking presynaptic α2
receptors and 5-HT1receptors.
• It is a sedative because of its potent
antihistaminic activity.
• No anti muscarinic side effects
• No interference with sexual functioning
• Sideeffects:
◦ Increased appetite and weight gain
◦ Marked sedation 49

50. Selective serotonin re-uptake
inhibitors (SSRIs)
 Fluoxetine-long acting/norfluoxetine
 Sertraline-no metabolism with cyp3A3
 Paroxetine-weight gain/teratogenic
 Citalopram-highly selective ssri
 Escitalopram-enantiomer of citalopram
 Fluvoxamine-short acting

51. 51

52. Pharmacokinetics: (ssri’s)
• All SSRI’s well absorbed after oral administration.
• Peak levels are seen in ~2-8 hours.
• Food has little effect on absorption.
◦ except with sertraline, food increases its absorption
• t1/2:-16-36 hours
◦ Fluoxetine t1/2 :-50 hours.
• It is available as a sustained-release preparation allowing
once-weekly dosing. 52

53. Pharmacological actions:
Behavioural effects:
Elevates the depressed mood.
Subject feels more energetic, less sleepy, and more
fresh
Tendency for suicide decreases.
CVS effects: no specific action on heart and
coronary arteries
Potentiation of action of sympathomimetic amines.

54. Therapeutic uses :
• Depression
• OCD
• Panic disorder
• GAD
• PTSD
• Social anxiety disorder
• Premenstrual dysphoric disorder
• Bulimia nervosa (only fluoxetine)
54

55. .• Overdose: Large intakes of SSRIs do not usually
cause cardiac arrhythmias (compared to the
arrhythmia risk for the TCAs).
• An exception is citalopram, it may cause QT
prolongation.
• Seizures can occur in over dose.
• All SSRIs have the potential to cause serotonin
syndrome when used in the presence of a MAOI or
other highly serotonergic drug.
• Serotonin syndrome include the symptoms of
hyperthermia, muscle rigidity, sweating,
myoclonus, and changes in mental status and vital
signs 55

58. Serotonin syndrome:
58

59. .
59

60. SSRI’s in children and teenagers:
• Should be used cautiously in children and teenagers.
• ~ 2% children report suicidal ideation with SSRI.
• Pediatric patients should be observed for worsening
depression and suicidal thinking with initiation or
dosage change of any antidepressant.
• Fluoxetine and escitalopram are approved for
childhood depression.
• Fluoxetine, sertraline, and fluvoxamine are approved
for OCD in children.
60

61. SSRI’s:
• Discontinuation syndrome:
 All of the SSRIs have the potential to cause a
discontinuation syndrome after abrupt withdrawal.
• Fluoxetine has the lowest risk of causing an SSRI
discontinuation
• Signs and symptoms of SSRI discontinuation
syndrome
◦ Headache, malaise, flu-like symptoms, agitation and
irritability, nervousness, and changes in sleep pattern
61

62. SSRIs
• ADVANTAGES
less sedation
less marked antimuscarinic action
safer than TCAs in elderly
They are more effective in moderate
depression.
They are well absorbed orally.

63. Adverse effects
 Cognitive behavioural symptoms-
agitation insomnia,anxiety(5HT2),hypomania,seizures
 Autonomic symptoms-
nausea(5HT3),salivation,diarrhoea(5HT4),
abdominal pain,flushed skin,and hyperthermia
 Neuromuscular symptoms-
hyper reflexia, shivering,twitchings and rigidity
 Serotonergic reaction-with
MAOI,pethidine,levodopa,amphetamine, buspirone,
bromocryptine, dextromethorphan

64. Management of overdosage
Treat in ICU.
1. Supportive Treatment
Gastric lavage with activated charcoal.
Dialysis ineffective
Endotracheal intubation & assistant ventilation may be
required.
2. Specific Treatment: Phenytoin, Lidocaine
Sod. Bicarbonate
Diazepam
Do not use physostigmine as it worsens arrhythmias

66. USES OF
ANTIDEPRESSANTS

67. Obsessive compulsive
neurosis
Nocturnal enuresis
Chronic fatigue syndrome
Bulimia
nervosa(fluoxetine)
Migraine
PANIC DISORDERS

68. ADHD
Deafferentiation pain
Non specific fibromyalgias
Pruritis (doxepin)
Erectile dysfunction
PTSD

69. Decreases suicidal tendencies

71. THANK YOU