Antidepressants PHARMACOLOGY REVISION NOTES

Antidepressants
TONY SCARIA 2010 KMC

Serotonergic pathway
found within the brainstem in the
midline raphe nuclei, which project to a wide portion of the
CNS including the hypothalamus, limbic system, neocortex,
cerebellum, and spinal cord

Serotonergic transmitters

NE pathway
The cell bodies of the norepinephrine-containing neurons are
located in the locus coeruleus and other medullary and pontine
nuclei . From the locus coeruleus, the axons of
the noradrenergic neurons descend into the spinal cord, enter
the cerebellum, and ascend to innervate the paraventricular,
supraoptic, and periventricular nuclei of the hypothalamus the
thalamus, the basal telencephalon, and the entire neocortex

Dopamine pathway
2 main dopaminergic pathways in brain
nigrostriatal system mesocortical system
projects from the midbrain
substantia nigra to the striatum in
the basal ganglia and is involved in
motor control
arises primarily in the ventral
tegmental area, which projects to
the nucleus accumbens and limbic
subcortical areas.
The mesocortical system is involved
in reward behavior and
addiction and in psychiatric
disorders such as schizophrenia

Dopamine recepetors
• Five dopamine receptors
• All are metabotropic GPCR
• two major categories:
• D1-like (D1 and D5) and D2-like (D2, D3, and D4)
D1-like D2-like
D1 and D5 D2, D3, and D4
Activation of D1-type receptors leads to
an increase in cAMP
activation of D2-like receptors reduces
cAMP levels

Classification
Typical (inhibits reuptake or metabolism of NA or 5HT) Atypical
MAO-A inhibitor TCA SSRI

TCA antidepressants
NA & 5HT reuptake inhibitor Predominantly NA reuptake inhibitor
• Imipramine
• Amitryptilline
• Doxepin
• Dothiepin
• Clomipramine
• Desimipramine
• Nortriptyline
• Amoxapine
• Reboxetine

TCA
TCA inhibit reuptake of 5HT & NE
increased concentration of of NE &
5HT

Initial effects causes
decrease in firing in
locus cerulus (NE)
and nucleus
raphe magnus (5-HT)
Inhibit reuptake of
NE/5-HT
Initial increase in 5HT & NE in synapse
stimulation of α2 & 5HT receptor
On long term causes
desensitization and increase
transmission of above
receptors.
Decreased NE & 5HT
Sedation
• Elevation of mood
• More
communicative
• REM sleep
suppressed & no
night awakening
LONG LAG TIME

PK
• Well absorbed; high first pass metabolism
• Highly protein bound
• Low safety margin low TI
• Metabolised by liver to active metabolites
• CYP2D6
• Imipramine  despramine
• Amitriptyline nortryptiline
• Hit & run drugs
• Long acting

• Amoxapine also blocks D-2 receptors (Antipychotic property)
• Metabolite of loxapine (antipsychotic)
• Mixed antidepressant + neuroleptic action
• Can produce EPS d/t D2 blockade
• Bupropion
• Inhibit DA uptake

Uses
• DOC-diabetic neuropathy
• Also in non diabetic neuropathic pain
• Imipramine – nocturnal enuresis
• Amitryptaline: Prophylaxis of migraine

MORE SEDATIVE TCA FOR AGITATED & ANXIETY
PATIENTS
LESS SEDATIVE FOR WITHDRAWN PATIENTS
Predominantly NA reuptake inhibitor are used
• AMITRYPTILLINE
• DOXEPINE
• IMIPRAMINE
• NORTRYPTILLINE

TCA block other receptors
α1 receptr Histamine Muscarinic Cardiac Na +
channel
• Postural
hypotension
• Sedation,
• Antipruritus
• Tachycardia,
• flushing,
• hyperthermia,
• paralytic
ileus/urinary
retention
• Dry mouth
• Arrhythmia,
• hypotension,
• heart block

S/E
• Seizures
• Sedation
• Postural hypotension , tachycardia
• Weight gain
• Fine tremors

• Clomipramine
• Maximum sexual dysfunction
• Offlabel use for premature ejaculation

Acute poisoning with TCA
• CF
• Delirium convulsion fever
• arrhythmia
• Anticholinergic symptoms as seen in atropine poisoning
• Respiratory depression
• Coma
• Acidosis
• Rx
• Supportive measure
• Physostigmine for anticholinergic features
• Na bicarbonate for acidosis
• Phenytoin / diazepam for seizures
• Lidocaine for arrhythmia

TCA
• Tolerance develops in 2-3 weeks for sedative & anticholinergic
• Drug is gradually withdrawn
• TCA potentiate sympathomimetics
• Displaced highly protein bound drugs (phenytoin aspirin
phenylbutazone)
• Along with MAO icheese reaction
• Along with SSRI  serotonin syndrome

Serotonin syndrome
• On combination of TCA+ SSRI or MAO +SSRI
• Central & peripheral serotonin (5-HT) receptors responsible for SS →
excess stimulation caused by excess serotonin precursors or agonists,
↑ serotonin release, ↓ serotonin reuptake, ↓ serotonin metabolism

serotonin syndrome

Selective serotonin reuptake inhibitor (SSRI)
SSRI
• Fluoxetine
• Fluvoxamine
• Paroxetine
• Sertraline
• Escitalopram
• Citalopram

MOA
• SSRI inhibit SERT
(involved in reuptake of
5HT) increased 5HT
 5HT1B over
stimulation over
period of time 5HT1B
desensitisation 
increased 5HT release

SSRI
• Block reuptake of serotonin only into serotonergic nerve ending
• No Muscarinic or α blockade
• No postural hypotension
• Low CVS S/E no arrhythmia
• Negligible anticholinergic S/E
• Less sedation
• No interference with cognitive / psychomotor function

SSRI
• No precipitation of seizure
• No weight gain
• lag time of 1 week
• safer in over dose  high TI

Clinical uses of SSRI
• Major depression
• OCD
• SSRI  DOC
• fluoxetine
• Panic attack
• BZD+SSRI
• Panic disorder
• SSRI
• Phobia
• Sertraline
• Post traumatic stress disorder
• Sertraline + paroxetine

Other uses
• Social anxiety disorder
• Fluvoxamine & venlafaxine
• Premenustral dysphoric disorder
• Fluoxetine & sertraline
• Bulimia nervosa
• Fluoxetine only
• Impulse control disorder
• Fluoxetine
• Premature ejaculation
• dapoxetine

PK
• CYP2D6

S/E
• Prominent GI S/E
• Nausea MC S/e
• Diarrhea
• Anxiety initially
• Sexual dysfunction
• Loss of libido
• Delayed orgasm
• Sleep disturbances
• To avoid that Fluoxetine is usually administered in the morning after break fast
• Weight gain  only with paroxetine
• Paroxetine teratogenic can cause cardiac septal defects

Drug interactions
• Serotonin syndrome
• SSRI + MAO
• With warfarin
• Citalopram & sertraline are safe

Individual SSRI
Fluoxetine Longest acting
Once weekly
Active metabolite + (nor fluoxetine )
Fluoxamine Shortest acting
Paroxetine Teratogenic  cardiac septal defects
Weight gain
Escitalopram Most specific SSRI

Atypical antidepressants
• Trazodone
• Nefazodone
• Mianserin
• Mirtazapine
• Bupropion
• Tianeptine
• Amineptine
• Atomoxetine

• Less S/E of sedation / anticholinergic S/E
• Safe in overdose
• Effective in patients not responding to TCA

Atypical antidepressant MOA S/E
trazodone α 1 anatgonist
Weak 5HT2 antagonist
• Sedation
• Priapism
• Postural hypotension
Mianserin Preseynaptic α 2 blockade • BM suppression
• Increases seizures
Mirtazapine (noradrenergic serotonergic
antagonist)NSSA
Preseynaptic α 2 blockade • Weight gain  used in Anorexia
nervosa
• Less interference with sexual
activity
Tianeptine Enhance serotonin reuptake
Amineptine Enhance serotonin reuptake
Nafazodone Inhibit serotonin reuptake
5HT2 blockade
• Short t1/2
• Hepatotoxicity
Atomoxetine Selective inhibit NE uptake • Used in ADHD
Duloxetin Inhibit NE & 5 HT reuptake • Used in Diabetic neuropathy
• Used in Fibromyalgia

Bupropion
• Dopamine & NE reuptake inhibitor
• Increase presynaptic release of NE & DA
• No action on 5 HT
• Used in Rx of
• Depression
• Prevention of seasonal depressive disorder
• Smoking cessation Rx
• ADHD  improve symptoms
• Off label uses for neuropathic pain & for
weight loss
Topirmate & felbamate
causes weight loss

5 HT & NE reuptake inhibitor (SNRI)
SNRI
• Duloxetine
• Milnacipran
• Levo milnacipran
• Venlafaxine
• Desvenlafaxine
SNRI are also Atypical antidepressants

SNRI
• SLIGHTLY FEWER S/E
• SLIGHTLY GREATER EFFICACY THAN SSRI
• MOA
• VERY SIMILAR TO SSRI BUT SPECIFIC
• S/E
• SIMILAR TO SSRI
• SUICIDAL TENDENCY

CLINICAL USES
• Depression  in patients whom SSRI are ineffective
• c/c joint & muscle pain  duloxetine
• Fibromyalgia  milnacipran ,duloxetine
• Urinary stress incontinence
• Post traumatic stress disorder  venlafaxine
• Hot flushes  desvenlafaxine

MAO
MAO – A MAO –B
• Metabolises 5HT NA DA Metabolises DA

MAO-A inhibitor
MAO –A inhibitor
IRREVERSIBLE REVERSIBLE (RIMA)
• Isocarboxazid
• Iproniazid
• Phenelzine
• Tranylcypromine
• Moclobemeide
• Clorgyline
No cheese reactionCheese reaction TONY SCARIA 2010 KMC

A/E of non selective MAO inhibitors
• Cheese reaction
• serotonin syndrome
• SSR given along with MAO
• MAO I with pethidine  seizures

MAO-b inhibitor  seligiline is also used for
depression
• In the form of transdermal patches

Cheese reaction
• Patients on irreversible MAO – I on intake Tyramine containing food
(Cheese /beer/pickle)
• Increased NA release  hypertensive crisis
• Not seen with RIMA
• Rx with phentolamine / prazosin / chlorpromazine

Newer drugs in major depressionn
Vilazodone Voritexetine
Inhibit serotonin reuptake
Partial 5HT1A agonism
Inhibit 5HT reuptake
5HT3 antagonism & 5HT1A agonism

Endogenous major depression
• 1st choice SSRI
• TCA used only in nonresponsive cases
• Mild & moderate cases  MAO-A inhibitor
• Maintenance by TCA (imipramine)
• Combined with Li in case of BPD

• Topical doxepin  used in pruritus

Li
Therapeutic level Prophylactic level Toxic level
0.8-1.2mEq/L 0.5-0.8mEq/L >2.0mEq/L

Mechanism of action of Li

Indications for Li
• Rx of a/c mania
• Prophylaxis of bipolar mood disorder

PK
• Rapidly absorbed from GIT
• Not metabolised in body almost completely excreted by kidney
• Reabsorption of LI depends on Na+ balance
• Reabsorbed in case of hyponatremia  Li toxicity
• Not protein bound
• Li is concentrated in
• Thyroid (3-5 times serum level)
• Saliva (2 times)
• Milk (0.3-1 time)
• CSF (0.4 times)

S/E of Li
Neurological • Tremors  MC
• Muscle weakness
• Increased DTR
• Drowsiness delirium
• Coma
Renal • Nephrogenic DI
 Inhibits action of ADH on distal tubule
• Tubular changes
• Nephrotic syndrome
Cardiovascular • T wave depression
Endocrine • Goitre
• Hypothyroidism
• Abnormal TFT
Dermatological • Acneiform eruptions
• Psoriasis
GIT • NVD
During pregnancy • Teratogenic  increased incidence of Ebsteins anomaly
• Secreted in breast milkTONY SCARIA 2010 KMC

C/I
• Presence of blood dyscrasia
• Leucocyte count is increased with Li therapy
• Presence of clear evidence of cardiac renal thyroid or neurological
dysfunction
• Concomitant administration of thiazide diuretics tetracyline or
anesthetics
• Stopped 2 days before Sx

Li
• treatment of
• a/c manic episode in patient of BPD
• MDP (manic depressive psychosis)bipolar depression.
• Prohylaxis of MDP 0.8 mEq
• Cyclothymia
• It has a low toxic : therapeutic ratio.
• therapeutic level of Lithium = 0.8 - 1.2 mEq/L.
• Lithium toxicity
• when serum lithium levels exceed 1.5 to 2 mEq/L. Hence frequent bood tests are
done to monitor the drug levels.

• S/E
• Teratogenic  EBSTEINS ANOMALY
• Tremors  postural  Rx propranolol
• Polyuria diabetes insipidus
• Renal failure
• Hypothyroidism
• Exacerbation of psoriasis

Lithium toxicity
• >1.5mEq
• Excreted changed through kidney
• R/F
• Low sodium diet / dehydration/renal impairement
• Symptoms
• GI symptoms
• Abdominal pain/vomiting
• Neurological
• Coarse tremors/ataxia /dysarthria

• Late signs of Li toxicity
• Impairement of consciousness
• Muscular fasciculations
• Increased deep tendon reflexes
• Convulsions
• Rx
• Stop Li
• Polyethyelene glycol
• Hemodialysis

Antidepressants PHARMACOLOGY REVISION NOTES

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Antidepressants PHARMACOLOGY REVISION NOTES