Professional Documents
Culture Documents
Antidepressants
1
Introduction
• Worldwide, depression is a major cause of
disability and premature death
• Depression is the most common of the affective
disorders (defined as disorders of mood rather
than disturbances of thought or cognition)
• In addition to the significant suicide risk,
depressed individuals are more likely to die from
other causes, such as heart disease or cancer
2
Introduction
• Depressive symptoms also can occur secondary
to other illnesses such as hypothyroidism,
Parkinson's disease, and inflammatory conditions
5
Neurotrophic Hypothesis
6
Neurotrophic Hypothesis
7
Monoamine hypothesis of depression
8
Monoamine hypothesis of depression
11
Drug Selection: General Considerations
12
Selective Serotonin Reuptake Inhibitors
(SSRIs)
• They are the most commonly prescribed group of
antidepressants
13
Selective Serotonin Reuptake Inhibitors
(SSRIs)
• As a class, these medications have little or no
affinity for cholinergic, β-adrenergic or histamine
receptors and do not interfere with cardiac
conduction
• They are well tolerated by patients who are
especially sensitive to the anticholinergic and
orthostatic effects of the TCAs and MAOIs
• SSRI have largely replaced TCAs and MAOIs as
the drugs of choice in treating depression
14
SSRIs- Mechanism of action
• SSRIs allosterically inhibit the serotonin transporter
(SERT) by binding the receptor at a site other than
active binding site for serotonin
• In the serotonin system, 5-HT1A and 5-HT7
autoreceptors on cell bodies in the raphe nucleus and
of 5-HT1D autoreceptors on serotonergic terminals
suppress neuronal release of serotonin and result in a
decrease in neuronal firing
• Repeated treatment leads to gradual down-regulation
and desensitization of autoreceptor mechanisms over
several weeks, with a return or increase of presynaptic
activity, production, and release of serotonin
15
SSRIs
• Stimulation of 5-HT3 receptors is suspected to
contribute to common ADRs, including GIT (NV)
and sexual effects (delayed or impaired orgasm)
17
SSRIs- Clinical uses
1. Major Depression: the primary indication
Obsessive-compulsive disorder (OCD)
(fluvoxamine, clomipramine)
2. Panic disorder
3. Generalized anxiety disorder
4. Posttraumatic stress disorder (Sertraline and
paroxetine)
5. Social anxiety disorder (SAD): fluvoxamine,
venlafaxine
6. Premenstrual dysphoric disorder (fluxetine &
sertraline)
7. Bulimia nervosa (only fluoxetine)
8. Premature ejaculation
18
SSRIs- ADEs
19
SSRIs- D/D interactions
A. Pharmacokinetic interactions:
• The SSRIs are potent inhibitors of the CYP450
• The potential for drug-drug interactions differs
significantly across the SSRIs
• Paroxetine and fluoxetine are potent CYP2D6
inhibitors responsible for the elimination of TCA
drugs, neuroleptic drugs, and some
antiarrhythmic and β-adrenergic antagonist drugs
20
SSRIs- D/D interactions
A. Pharmacokinetic interactions:
• Fluvoxamine, a CYP3A4 inhibitor, may elevate
the levels of concurrently administered
substrates for this enzyme such as diltiazem and
induce bradycardia or hypotension
21
SSRIs- D/D interactions
B. Pharmacodynamic interactions:
• The most serious interaction with the SSRIs are
with MAOIs that produce a serotonin syndrome
• Fluoxetine* has to be discontinued 4 to 6 weeks
before an MAOI can be administered to mitigate
the risk of serotonin syndrome
22 of norfluoxetine is
* Fluoxetine is metabolized to an active product, norfluoxetine. The elimination half-life
about three times longer than fluoxetine and contributes to the longest half-life of all the SSRIs
Serotonin-Norepinephrine Reuptake
Inhibitors
• Two classes of antidepressants act as combined
serotonin and norepinephrine reuptake inhibitors:
23
a) Selective Serotonin-Norepinephrine Reuptake
Inhibitors
26
SNRIs- Clinical uses
27
I. SNRIs- ADRs
• SNRIs have many of the serotonergic adverse
effects associated with SSRIs
• In addition, SNRIs may also have noradrenergic
effects, including increased blood pressure and
heart rate, and CNS activation, such as insomnia,
anxiety, and agitation
• All the SNRIs have been associated with a
discontinuation syndrome resembling that seen
with SSRI discontinuation
• The SNRIs have relatively fewer CYP450
interactions than the SSRIs
28
II.Tricyclic Antidepressants (TCA)
• The TCAs were the dominant class of
antidepressants until the introduction of SSRIs in
the 1980s and 1990s
• Agents: imipramine (the prototype drug),
amitriptyline, clomipramine, doxepin ,
trimipramine, desipramine, nortriptyline, and
protriptyline
• Maprotiline & amoxapine are not members of the
tricyclic family. However, their pharmacology is so
similar to that of the TCAs and are commonly
included in the general class of TCAs
29
II.Tricyclic Antidepressants (TCA)
• The TCAs activity is thought to relate primarily to
their inhibition of 5-HT and NE reuptake
30
II.Tricyclic Antidepressants (TCA)
• TCAs also block serotonergic, α-adrenergic,
histaminic, and muscarinic receptors
33
II.TCA- ADRs
1. Antimuscarinic SEs: dry mouth ,constipation,
urinary retention, blurred vision, and confusion
2. Life-threatening arrhythmias: The TCAs are
class 1A antiarrhythmic agents
3. Sedation (H1 antagonism)
4. weight gain
5. Sexual dysfunction
6. At therapeutic doses, the TCA drugs lower the
seizure threshold and at toxic doses can cause
life-threatening seizures (especially Maprotiline)
7. Amoxapine has dopamine receptor antagonist
properties and can induce EPS, gynecomastia,
lactation, and neuroleptic malignant syndrome
34
TCAs overdoses
• Acute poisoning with tricyclic antidepressants
or MAO inhibitors is potentially life-threatening
35
TCA overdose
36
TCA overdose
37
MAO inhibitors
• Agents: selegline, phenelzine, and
tranylcypromine
• MAO exists in the human body in two
molecular forms, known as type A and type B
• Norepinephrine and serotonin are
preferentially metabolized by MAO-A. MAO-B
is more likely to be involved in the catabolism
of human brain dopamine
38
MAO inhibitors
39
MAO inhibitors
• MAOIs are classified by their specificity for MAO-A
or -B and whether their effects are reversible or
irreversible
• Phenelzine and tranylcypromine are examples of
irreversible, nonselective MAOIs
• Moclobemide is a reversible and selective inhibitor
of MAO-A
• Selegiline is an irreversible MAO-B–specific agent
at low doses, but at higher doses it becomes a
nonselective MAOI similar to other agents
41
MAO inhibitors
• Despite their efficacy in treating depression,
because of their risk for drug-drug and drug-
food interactions, the MAO inhibitors are
considered to be last-line agents in many
treatment venues
42
MAO Inhibitors-Clinical use
• Depression:
– Reserved for treatment of depressions that
resist therapeutic trials of the newer, safer
antidepressants
– Selegiline is the first antidepressant available
in a transdermal delivery system
43
MAO Inhibitors-ADRs
• Orthostatic hypotension, weight gain, edema, and
sexual dysfunction are common during MAOI
therapy
• Sexual SEs: highest rates are associated with the
irreversible nonselective MAOIs (phenelzine and
tranylcypromine)
• Phenelzine tends to be more sedating than either
selegiline or tranylcypromine
• Hepatotoxicity is likely to occur with isocarboxazid
or phenelzine
44
MAO Inhibitors-D-D interactions
1) Pharmacodynamic interaction
• These combinations of an MAOI with a
serotonergic agent (SSRIs, SNRIs, and most
TCAs) may result in a life-threatening serotonin
syndrome
• Most case reports of serotonin syndrome (and
most fatalities) have occurred with a combination
of an MAOI and an SSRI
• It is caused by overstimulation of 5-HT receptors
in the central gray nuclei and the medulla
45
MAO Inhibitors-D-D interactions
1) Pharmacodynamic interaction
• Serotonin syndrome consists of a constellation of
psychiatric, neurological, and CV symptoms
• Symptoms range from mild to lethal and include
a triad of cognitive (delirium, coma), autonomic
(hypertension, tachycardia, diaphoreses) and
somatic (myoclonus, hyperreflexia, tremor)
effects
46
MAO Inhibitors-D-D interactions
• Most serotonergic antidepressants should be
discontinued at least 2 weeks before starting a
MAOI
47
MAO Inhibitors-D-D interactions
• Serious interaction with MAOIs occurs when an
MAOI is combined with tyramine in the diet (e.g.
smoked, aged, or pickled meat or fish, aged
cheeses, etc)
49 49
MAO Inhibitors-D-D interactions
• Serious hypertension can occur with concomitant
administration of OTC cough and cold
medications containing sympathomimetic amines
(pseudoephedrine and phenylpropanolamine)-
CONTRAINDICATIONS
50
HT2 antagonists- 5
51
HT2 antagonists- 5
52
HT2 antagonists- 5
• Mirtazapine has a complex pharmacology:
1) It is an antagonist of 5-HT2 and 5-HT3
receptors
2) By blocking presynaptic α2-adrenoceptors and
enhances the release of both norepinephrine
and 5-HT
• Mirtazapine is a potent H1 antagonist, which is
associated with the drug's sedative effects
53
HT2 antagonists- Clinical uses- 5
54
I.5-HT2 antagonists- ADRs
56
Bupropion- Clinical uses
1) Depression
2) Bupropion is approved as a treatment for
smoking cessation
• The mechanism by which bupropion is helpful in
this application is unknown, but the drug may
mimic nicotine's effects on dopamine and
norepinephrine and may antagonize nicotinic
receptors
57
Bupropion & Mirtazapine- SEs
58
Bupropion- D/D interactions
59