ANTIDEPRESSANT

PRESENTED TO---MR. ASHOK KUMAVAT

LECTURER
STCN

PRESENTED BY---VIKRAM SINGH

B.SC NURSING 3 RD YEAR
ST.THOMAS COLLEGE OF
NURSING

PHAGI, JAIPUR

ANTIDEPRESSANTS

Depression
common mental disorder that presents with depressed mood, loss of
interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or
appetite, low energy, and poor concentration (WHO def.)
Major Depressive Episode Criteria/Core symptoms
Five (or more) of the following symptoms have been present during the
same 2-week period and represent a change from previous functioning; at
least one of the symptoms is either (1) depressed mood or (2) loss of
interest or pleasure.

depressed mood most of the day

markedly diminished interest or pleasure
significant weight loss /gain
insomnia or hypersomnia
psychomotor agitation or retardation, fatigue or loss of energy
feelings of worthlessness or excessive or inappropriate guilt
diminished ability to think or concentrate
recurrent thoughts of death or suicidal ideation without a specific plan or a
suicide attempt (!)

Process of depression

NE System
Almost all NE pathways in the brain originate from the cell
bodies of neuronal cells in the midbrain, which send their
axons diffusely to the cortex, cerebellum and limbic areas
(hippocampus, hypothalamus, thalamus).
Mood: -- higher functions performed by the
cortex.
Cognitive function: -- function of cortex.
Drive and motivation: -- function of brainstem
Memory and emotion: -- function of the
hippocampus
Endocrine response: -- function of hypothalamus.

and receptors.

Serotonin System
As with the NE system, serotonin neurons located
in the pons and midbrain (in groups known as
raphe nuclei) send their projections diffusely to the
cortex, hippocampus, hypothalamus, thalamus,
etc. --same areas implicated in depression. This
system is also involve in:

Anxiety.
Sleep.
Sexual behavior.
Rhythms (Suprachiasmatic nucleus).
Temperature regulation.
CSF production.

Antidepressants

S S R Is

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Antidepressants
1. Tricyclic anti-depressants (TCAs).
Imipramine, desipramine, nortriptyline,
, amytriptiline, doxepin.
2. Monoamine oxidase inhibitors (MAOIs).
Isocarboxacid, phenelzine, .
3. Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine, paroxetine, trazodone.
4. Atypical anti-depressants (Others)
amoxapine, bupropion,
alprazolam,

Mechanism of Action
1. Inhibition of NE and 5-HT reuptake.
(TCAs, SSRIs).
2. Inhibition of MAO enzymes.
(MAOIs).
3. 5-HT2A and 5-HT2C antagonists.
( trazodone, mirtazapine)
4. Alteration of NE output .
(Bupropion)

Tricyclic Antidepressants (TCAs)

amytriptiline
imipramine
desipramine
nortriptyline
doxepin.

I. Tricyclic Antidepressants (TCAs)

Chemical structure with characteristic
three-ring nucleus lipophilic nature

Originally developed as antipsychotics

(1949), but were found to have no effect in
this indication.

imipramine

Mode of action
Block reuptake of NE,Serotonin and
Dopamine at nerve terminal,thus
increasing the NE,5HT or DA at the
extracellular and more of its action on at
receptor site.
Down regulation of Beta-adregernic
receptors

Pharmacological action
CNS-mood elevation in depress patient,can
cause ataxia,epilepsy,seizures and coma.
CVS-orthostatic hypotension
ANS-anticholinergic effects.Most potent
anticholinergic action

Pharmacokinetics
Administered orally rapid absorption, however extensive
first pass effect low and inconsistent BAV
Strong binding to plasma proteins (90-95% bound). They
are also bound in tissues + wide distribution (high
lipophilicity) = large distribution volumes (ineffectiveness of
dialysis in acute intoxications).

Biotransformation in the liver (CYP450, N-demethylation

and tricyclic ring hydroxylation) most of these metabolites
are active! CYP450 polymorphisms ! Glucuronidation inactive
metabolites excreted in the urine.

Elimination half-lives - generally LONG (T1/2 =10-80h).

Elderly patients even longer T1/2, risk of accumulation.

INDICATIONS

depression
Neuropathic pain
ADHD
Nocturnal Enuresis (Imipramine)
Panic disorder(Imipramine)
OCD(Clomipramine)
Others like eating
disorder,narcolepsy

Contraindication

Severe liver damage

Glaucoma
Prostatic hyperplasia
Epilepsy
lactation

Adverse Effects
Pharmacological Action

Adverse Effect

Muscarinic receptor Blockage/

Anticholinergic

Dry mouth, tachycardia, blurred

vision,
Constipation, Urinary retention,
Sexual dysfunction
Cognitive impairement

1 Adrenoceptor blockade

Drowsiness, orthostatic Hypotension,

Histamine H1 receptor Blockade

Drowsiness, Weight Gain

Membrane stabilizing properties

Cardiac arrythmia, Seizures

,tachycardia

Others

Rash, Oedema,

Toxic Effects

CVS: Conduction disturbances, Low BP, --- ecg

shows prolong PR and QT intervals, depressed
ST, flattened T waves. Heartblock occasionally
RS: Hypoxia, Aspiration pneumonia
CNS: Agitation, convulsions, hallucinations,
delerium, coma. dry mouth, dilated pupil,
blurred vision, urine retention, pyrexia

Management of toxicity

Supportive care
Cardiac monitoring---if arrythmia, ICU
Plasma level monitoring:
TCA has delayed gastric emptyin, do gastric
lavage if several hours after overdose
Activated Charcoal 1gm/kg PO/NG

2. MAO INHIBITORS

Isocarboxacid
Phenelzine

MAO INHIBITORS
Developed for the treatment of tuberculosis
(iproniazid derivatives) - 1951.
Are readily absorbed from GI tract and widely
distributed throughout the body.
May have active metabolites, inactivated by
acetylation.
Effects persist even after these drugs are no
longer detectable in plasma (1-3 weeks).

. MAO INHIBITORS
Mechanism of action (cont):

Acute administration causes:

NE and 5-HT in synaptic terminals in brain
but NE in PNS. NE synthesis.
Acute euphoria
Suppressed REM sleep.

Chronic administration causes:

Down regulation of receptors.
Down regulation of 5-HT2 receptors.

MAO INHIBITORS
Other side effects:
Hypotension
Sedation.

3. SSRIs
Fluoxetine
Sertraline
Paroxetine
Fluvoxamine
(Labeled for obsessive-compulsive disorder)

3. Selective Serotonin Re-uptake

Inhibitors (SSRI)
More modern (1st drug fluoxetine available in 1988) and safe
antidepressants
Principal mechanism of action:
selective inhibition of 5-HT (serotonin) reuptake more
extracellular seratonin More action on seratonin receptors
on post synaptic more stimulation
Other indications of SSRI - anxiety disorders: generalized
anxiety, panic disorder, social anxiety disorder, obsessivecompulsive disorder
+ bulimia nervosa, gambling

Pharmacokinetics
Good absorption after oral administration
Important biotransformation in the liver

CYP450 - 2D6 and 2C19 isoforms (polymorphism

interindividual variability in the clinical effect) and active
metabolites (e.g. fluoxetine)

Long half-lives of elimination(s)

fluoxetine (T1/2=50h) + active metabolite (T1/2 =240h)

Drug interaction: based on plasma protein binding and CYP

blockade

increased effect of co-administered TCA but also -blockers,

benzodiazepines etc.

Adverse effects
Relative improvement to other antidepressants (mostly mild)

Less Cardiotoxic compared to TCA

Generally, much safer in overdose
Lack anticholinergic effects and are not Sedating

GIT nausea, vomiting, diarrhea

Neuropsychiatry Headache, Irritability, Restless
(Akathisia). Agitation, Tremor, Insomnia and Seizures
Sexual dysfunctions Ejaculatory delay
Suicidal Behavior
Serotonin syndrome upon intoxication or drug interactions

SSRIs Pharmacokinetic comparison

Dose
mg/day

Drug
interaction

Half life

Steady
state
(Days)

Fluoxetine

5-20

high

2-4 days

30-60

Sertraline

50

low

26 Hrs

7-14

Paroxetime 20

high

20 Hrs

10-14

Citalopram

low

35 Hrs

20-40

SSRI discontinuation syndrome

not as significant as benzodiazepines
little to no abuse potential
Withdrawal symptoms: common
descriptions include dizziness, electric
shock-like sensations, sweating, nausea,
insomnia, tremor, confusion, and vertigo