30 Antidepressant Agents

ANTIDEPRESSANTS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
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ANTIDEPRESSANTS
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ANTIDEPRESSANTS
MAJOR DEPRESSIVE DISORDER

 Depressed mood most of the time for at least 2
weeks and or
 Loss of interest or pleasure in most activities
 Other characteristics
1. Disturbances in sleep and appetite
2. Deficits in cognition and energy
3. Thoughts of guilt, worthlessness, and suicide
are common
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ANTIDEPRESSANTS
Monoamine hypothesis
Neurotrophic hypothesis
Neuroendocrine Factors
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ANTIDEPRESSANTS
AMINE HYPOTHESIS OF
MOOD
Norepinephrine (NE) and
serotonin (5-HT)
 NTAs that function in
the expression of mood
Functional decrease in the
activity
 Depression
Functional increase in the
activity
 Mood elevation
5
ANTIDEPRESSANTS
Brain derived
neurotrophic factor
(BDNF)
 Regulation of neural
plasticity, resilience, and
neurogenesis
 Exert its influence on
neuronal survival and
growth effects by activating
the tyrosine kinase receptor
B in both neurons and glia
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ANTIDEPRESSANTS
Brain derived
neurotrophic factor
(BDNF)
 Affects
1. Hippocampus
2. Anterior cingulate
gyrus
3. Medial frontal cortex
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ANTIDEPRESSANTS
Adrenocorticotropic hormone
 Nonsuppression of adrenocorticotropic hormone

(ACTH) release in the dexamethasone suppression
test
 Dysregulation of the stress hormone axis
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ANTIDEPRESSANTS
Thyroid hormone
 Thyroid dysregulation has also been reported in

depressed patients
 Blunting of response of thyrotropin to

thyrotropin-releasing hormone, and elevations in
circulating thyroxine during depressed states
9
ANTIDEPRESSANTS
Sex steroids
 Estrogen deficiency states, which occur in the

postpartum and postmenopausal periods, are
thought to play a role in the etiology of depression
in some women
 severe testosterone deficiency in men is sometimes

associated with depressive symptoms
10
ANTIDEPRESSANTS
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRIs)
 Primary action: inhibition of the serotonin
transporter (SERT)
 Six major approved SSRIs
 Fluoxetine (prototype)
 Sertraline and citalopram- isomers and
formulated in racemic forms
 Paroxetine and fluvoxamine- not optically active
 Escitalopram- S enantiomer of citalopram
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ANTIDEPRESSANTS
SELECTIVE SEROTONIN
REUPTAKE INHIBITORS
(SSRIs)
MOA: Inhibits serotonin
transporter (SERT)
 Glycoprotein with 12
transmembrane regions
embedded in the axon terminal
and cell body membranes of
serotonergic neurons
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ANTIDEPRESSANTS
INHIBITORS (SSRIs)
Other indications
1. Generalized Anxiety Disorder (GAD)
2. Post-traumatic stress disorder (PTSD)
3. Obsessive Compulsive Disorder (OCD)
4. Panic Disorder
5. Premenstrual Dysphoric Disorder (PMDD)
and Bulimia
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ANTIDEPRESSANTS

INHIBITORS (SSRIs)
 Require hepatic metabolism
 All are lipophilic
 Half-lives of 18-24 hours
 Fluoxetine
 Norfluoxetine- active metabolite
 Half-life of several days
 Once weekly formulation
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ANTIDEPRESSANTS

INHIBITORS (SSRIs)
 Fluoxetine and paroxetine are potent
inhibitor of the CYP2D6 isoenzyme
 Fluvoxamine is an inhibitor of CYP3A4
 Citalopram, escitalopram and sertraline
have more modest CYP interactions
15
ANTIDEPRESSANTS
INHIBITORS (SSRIs)
TOXICITY
 Nausea
 Headache
 Anxiety
 Agitation
 Insomnia
 Sexual dysfunction
16
ANTIDEPRESSANTS
INHIBITORS (SSRIs)
 TOXICITY
 Jitteriness
 Alleviated by starting at low doses
 Adjunctive use of benzodiazepines
 Extrapyramidal effects
 Akathisia- restlessness, constant motion
 Dyskinesia- involuntary muscle movement
 Dystonia- sustained muscle contraction-
twisting or abnormal posture
 Can cause seizures
17
ANTIDEPRESSANTS

INHIBITORS (SSRIs)
TOXICITY
 Withdrawal syndrome
 Nausea
 Dizziness
 Anxiety
 Tremor
 Palpitations
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ANTIDEPRESSANTS
INHIBITORS (SSRIs)
DRUG INTERACTIONS
 Serotonin syndrome
 Interaction between fluoxetine and
a MAOI
 Life-threatening
 Fluoxetine has to be discontinued 4 weeks
or longer before an MAOI can be
administered
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ANTIDEPRESSANTS

INHIBITORS (SSRIs)
DRUG INTERACTIONS
 Severe muscle rigidity
 Myoclonus
 Hyperthermia
 Cardiovascular instability
 CNS stimulatory effects-seizures
20
ANTIDEPRESSANTS
INHIBITORS (SSRIs)
DRUG INTERACTIONS
 Drugs include
 MAOIs
 TCAs
 Meperidine
 MDMA methyldeoxyMA (“ecstasy”)
-
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ANTIDEPRESSANTS

INHIBITORS (SSRIs)
DRUG INTERACTIONS
 Management
 Anti- seizure drugs
 Muscle relaxants
 Blockers of 5-HT receptors
 Cyproheptadine
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ANTIDEPRESSANTS
SELECTIVE SEROTONIN-NOREPINEPHRINE
REUPTAKE INHIBITORS (SNRIs)
A. Venlafaxine and Duloxetine
B. Tricyclic Antidepressants
C. 5HT2A Antagonists
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ANTIDEPRESSANTS
VENLAFAXINE
 Metabolized in the liver to desvenlafaxine
 Lowest protein binding amongst all anti-
depressant (27-30%)
 Similar half lives of 11 hours (once daily dosing)
 45% desvenlafaxine are excreted unchanged in the
urine
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ANTIDEPRESSANTS
DULOXETINE
 Well absorbed
 Half life 12 hours
 Tightly bound to protein
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ANTIDEPRESSANTS
SELECTIVE SEROTONIN-
NOREPINEPHRINE REUPTAKE
INHIBITORS (SNRIs)
MOA: inhibits NE transporter
(NET)
 Structurally very similar to the 5-
HT transporter
 12-transmembrane domain complex
that binds norepinephrine
 Moderate affinity for dopamine
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ANTIDEPRESSANTS
 Venlafaxine is a weak inhibitor of NET
 Desvenlafaxine, duloxetine, and milnacipran are
more balanced inhibitors of both SERT and NET
 The affinity of most SNRIs tends to be much
greater for SERT than for NET
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ANTIDEPRESSANTS
 The SNRIs differ from the TCAs in that they lack the
potent antihistamine, -adrenergic blocking, and
anticholinergic effects of the TCAs
 Favored over the TCAs in the treatment of MDD and

pain syndromes because of their better tolerability
28
ANTIDEPRESSANTS
B. TRICYCLIC ANTIDEPRESSANTS (TCAs)

 Imipramine, amitriptyline
 Structurally related to the phenothiazine
antipsychotics
 Well absorbed orally
 May undergo first-pass metabolism
 High volume of distribution
 Not readily dialyzable
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ANTIDEPRESSANTS
 Extensive hepatic metabolism is required before
elimination
 Half-lives of 8-36 hours
 Once-daily dosing
 Wide therapeutic window
 Serum levels are reliable in predicting
response and toxicity
 Nortriptyline, desipramine
 Active metabolites
 Secondary amines
30
ANTIDEPRESSANTS
 MOA
 Inhibit the reuptake mechanisms
(transporters) responsible for the termination
of the synaptic actions of both NE and 5-HT
 Potentiation of NTA actions at
postsynaptic receptors
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ANTIDEPRESSANTS
 PHARMACOLOGIC EFFECTS
 Inhibits the reuptake of NE at nerve endings in
the ANS
 Peripheral autonomic sympathomimetic
effects
 Sedation is common
 Antagonism of muscarinic receptors
 Marked with amitriptyline
32
ANTIDEPRESSANTS
 Cardiovascular effects
 Hypotension from alpha adrenoceptor
blockade
 Arrhythmias
 Convulsions
 Overdosage
33
ANTIDEPRESSANTS
 CLINICAL USES
 Major depressive disorders
 Alternative agent
 Psychomotor retardation
 Sleep disturbances
 Poor appetite
 Weight loss
34
ANTIDEPRESSANTS
 OTHER CLINICAL USES
 Bipolar affective disorders
 Acute panic attacks
 Phobic disorders
 Enuresis
 Attention deficit hyperkinetic disorder
 Chronic pain states
35
ANTIDEPRESSANTS
 TOXICITY
1. Based on pharmacodynamic actions
 Excessive sedation
 Lassitude
 Fatigue
 Occasional confusion
36
ANTIDEPRESSANTS
 TOXICITY
2. Sympathomimetic effects
 Tachycardia
 Agitation
 Sweating
 Insomnia
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ANTIDEPRESSANTS
 TOXICITY
3. Atropine-like effects
4. Orthostatic hypotension, ECG
abnormalities, and cardiomyopathies
5. Tremor and paresthesias
6. Weight gain
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ANTIDEPRESSANTS
 TOXICITY
 OVERDOSAGE
 Extremely hazardous
 Ingestion of as little as a 2-week supply is lethal
 Manifestations
 Agitation Respiratory depression
 Delirium Circulatory collapse
 Neuromuscular irritability
 Convulsions
 Coma
 Hyperpyrexia
 Cardiac conduction defects 39
ANTIDEPRESSANTS
 DRUG INTERACTIONS
 Additive depression of the CNS with other
central depressants
 Ethanol
 Barbiturates
 Opioids
 Benzodiazepines
40
ANTIDEPRESSANTS
 Reversal of antihypertensive action of
guanethidine
 Blocking its transport into sympathetic
nerve endings
41
ANTIDEPRESSANTS
5-HT2 ANTAGONISTS
Trazodone and nefazodone
 Rapidly absorbed and undergo extensive hepatic
metabolism
 Short half lives- split dosing
 Trazodone prescribed as single dose at night as a
hypnotic in lower doses
 Both drugs have active metabolites that also
exhibits 5HT2 antagonism
 Nefazodone- potent inhibitor of CYP3A4
ANTIDEPRESSANTS
5-HT2 ANTAGONISTS
 MOA: blocks 5HT2A
 5HT2A is GPCR
 Nefazodone
 Weak inhibitor of both SERT and NET
 Potent antagonist of the postsynaptic 5-HT2A
receptor, as are its metabolites
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ANTIDEPRESSANTS
5-HT2 ANTAGONISTS
 Trazodone
 Weak but selective inhibitor of SERT with little
effect on NET
 M-CPP, primary metabolite is a potent 5-HT2
antagonist, and has antidepressant effect
 Weak-to-moderate presynaptic -adrenergic
blocking properties
 Modest antagonist of the H1 receptor
44
ANTIDEPRESSANTS
TETRACYCLIC AND UNICYCLIC

ANTIDEPRESSANTS
Drugs that don’t fit into the other categories
 Bupropion
 Mirtazapine
 Amoxapine
 Maprotiline
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ANTIDEPRESSANTS

ANTIDEPRESSANTS
Bupropion
 Unicyclic aminoketone structure
 Different side-effect profile than most
antidepressants
 Resembles amphetamine in chemical structure
 CNS activating properties
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ANTIDEPRESSANTS

ANTIDEPRESSANTS
Bupropion
 Rapidly absorbed with mean protein binding of
85%
 Three active metabolites one of which is
hydroxybupropion- being developed as an anti-
depressant
 Biphasic elimination 1st phase: 1 hour; 2nd phase:
14 hours
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ANTIDEPRESSANTS
ANTIDEPRESSANTS
Mirtazapine
Not commonly associated with sexual side effects
Tetracyclic chemical structure and belongs to the
piperazino-azepine group of compound
Demethylated followed by hydroxylation and
glucuronide conjugation
Half-life 20–40 hours, dosed once in the evening
because of its sedating effects
48
ANTIDEPRESSANTS

ANTIDEPRESSANTS
Mirtazapine
 MOA: complex pharmacology
 Antagonist of the presynaptic 2 autoreceptor and
enhances the release of both NE and 5-HT
 Antagonist of 5-HT2 and 5-HT3 receptors
 Potent H1 antagonist- sedative effects
49
ANTIDEPRESSANTS
ANTIDEPRESSANTS
Amoxapine
 N-methylated metabolite of loxapine, an older
antipsychotic drug
 Structural similarities with maprotiline
 Rapidly absorbed with protein binding of about 85%
 Half-life is variable, given in divided doses
 7-hydroxyamoxapine, is a potent D2 blocker and is
associated with antipsychotic effects
50
ANTIDEPRESSANTS
ANTIDEPRESSANTS
Amoxapine and Maprotiline
 MOA: potent NET inhibitors and less potent
SERT inhibitors
 Both possess anticholinergic properties
 Amoxapine is a moderate inhibitor of the
postsynaptic D2 receptor
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ANTIDEPRESSANTS
MONOMAMINE OXIDASE INHIBITORS (MAOIs)

 Hydrazides
 C-N-N moiety
 Phenelzine, isocarboxazid
 No longer marketed
 Combine irreversibly with MAO
 Nonhydrazides
 Lack the C-N-N moiety
 Tranylcypromine
 Combine reversibly with MAO
52
ANTIDEPRESSANTS

 Structurally related to amphetamines
 Orally active
 Nonselective inhibitors
53
ANTIDEPRESSANTS

 Nonselective inhibitors
 Inhibit MAO-A
 Metabolizes NE, 5-HT and tyramine
 Inhibit MAO-B
 Metabolizes dopamine
54
ANTIDEPRESSANTS

Selective inhibitor
 Selegiline
 Used in Parkinson’s disease
 Selectively inhibits MAO-B at low doses
 Less selective at higher doses
55
ANTIDEPRESSANTS
MONOMAMINE OXIDASE INHIBITORS

(MAOIs)
 Tranylcypromine
 Fastest onset of effect
 Shorter duration of action (about 1 week)
than other MAOIs (2-3 weeks)
 Given daily
 Inhibition of MAO persists even after these
drugs are no longer detectable
in plasma
56
ANTIDEPRESSANTS

 MOA
 Increase brain amine levels by interfering
with their metabolism in the nerve endings
 Increase vesicular stores of NE and 5-HT
57
ANTIDEPRESSANTS

(MAOIs)
 MOA
 When neuronal activity discharges the vesicles
 Increased amounts of the amines are
released
 Enhances the action of the NTAs
58
ANTIDEPRESSANTS

 Increase NE in sympathetic nerve terminals
 Peripheral sympathomimetic effects
 Long-term use can decrease BP
 CNS stimulating effects
 Seizures may occur with overdosage
59
ANTIDEPRESSANTS

 CLINICAL USES
 Major depressive disorders
 Anxiety
 Phobic features
 Hypochondriasis
60
ANTIDEPRESSANTS

 TOXICITY
 Hyperthermia
 CNS stimulation, agitation and convulsions
 Shock
61
ANTIDEPRESSANTS
(MAOIs)
 Inhibitors of hepatic drug-metabolizing
enzymes
 Hypertensive crisis
 Occur in patients who consume food
with high concentration of indirect
sympathomimetic tyramine
 Administration with SSRIs- serotonin
syndrome
62
ANTIDEPRESSANTS
63

30 Antidepressant Agents

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30 Antidepressant Agents

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ANTIDEPRESSANTS

MAJOR DEPRESSIVE DISORDER

 Nonsuppression of adrenocorticotropic hormone

 Dysregulation of the stress hormone axis

 Thyroid dysregulation has also been reported in

 Blunting of response of thyrotropin to

 Estrogen deficiency states, which occur in the

 severe testosterone deficiency in men is sometimes

SELECTIVE SEROTONIN REUPTAKE

SELECTIVE SEROTONIN REUPTAKE

SELECTIVE SEROTONIN REUPTAKE

SELECTIVE SEROTONIN REUPTAKE

SELECTIVE SEROTONIN REUPTAKE

A. Venlafaxine and Duloxetine

 Favored over the TCAs in the treatment of MDD and

B. TRICYCLIC ANTIDEPRESSANTS (TCAs)

TETRACYCLIC AND UNICYCLIC

TETRACYCLIC AND UNICYCLIC

TETRACYCLIC AND UNICYCLIC

TETRACYCLIC AND UNICYCLIC

MONOMAMINE OXIDASE INHIBITORS (MAOIs)

MONOMAMINE OXIDASE INHIBITORS (MAOIs)

MONOMAMINE OXIDASE INHIBITORS (MAOIs)

MONOMAMINE OXIDASE INHIBITORS (MAOIs)

MONOMAMINE OXIDASE INHIBITORS

MONOMAMINE OXIDASE INHIBITORS (MAOIs)

MONOMAMINE OXIDASE INHIBITORS

MONOMAMINE OXIDASE INHIBITORS (MAOIs)

MONOMAMINE OXIDASE INHIBITORS (MAOIs)

MONOMAMINE OXIDASE INHIBITORS (MAOIs)

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