Transcript MAO Inhibitors

Chapter 12:
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
• For a diagnosis of major depressive disorder to be
made, symptoms must be present for at least 2
weeks and must not be precipitated or influenced
by a medical illness or medication
• Depression, in general, is classified as major
depression (i.e., unipolar depression) or bipolar
depression (i.e., manic depressive illness)
3
Introduction
• Individuals must possess at least five symptoms,
one of which is either depressed mood OR
diminished interest or pleasure in activities
a) Change in appetite
b) Change in sleep
c) Low energy and decreased libido
d) Poor concentration (or difficulty making
decisions)
e) Feelings of worthlessness or inappropriate
guilt
f) Psychomotor agitation or retardation
g) Recurrent thoughts of suicide
4
Pathophysiology of Major Depression
I.
The neurotrophic hypothesis
II. The monoamine hypothesis
5
Neurotrophic Hypothesis
• Depression appears to be associated with a drop
in brain-derived neurotrophic factor (BDNF) levels
in the cerebrospinal fluid and serum as well as
with a decrease in tyrosine kinase receptor B
activity
• BDNF is thought to exert its influence on neuronal
survival and growth effects by activating the
tyrosine kinase receptor B in both neurons and
glia
6
Neurotrophic Hypothesis
• Animal and human studies indicate that stress
and pain are associated with a drop in BDNF
levels and that this loss of neurotrophic support
contributes to atrophic structural changes in the
hippocampus and perhaps other areas such as
the medial frontal cortex and anterior cingulate
• Studies suggest that major depression is
associated with substantial loss of volume in the
hippocampus, anterior cingulate and medial
orbital frontal cortex
7
Monoamine hypothesis of depression
• The monoamine hypothesis grew originally out of
associations between the clinical effects of
various drugs that cause or alleviate symptoms of
depression and their known neurochemical effects
on monoaminergic transmission in the brain
• The monoamine hypothesis of depression
suggests that depression is related to a deficiency
in the amount or function of cortical and limbic
serotonin (5-HT), norepinephrine (NE), and
dopamine (DA)
8
Monoamine hypothesis of depression
• The chronic activation of monoamine receptors by
antidepressants appears to increase in BDNF
transcription
• One of the weaknesses of the monoamine
hypothesis is the fact that amine levels increase
immediately with antidepressant use, but
maximum beneficial effects of antidepressants are
not seen for many weeks
• The time required to synthesize neurotrophic
factors has been proposed as an explanation for
this delay of antidepressant effects
9
Antidpressents
• Most antidepressants exert important actions on
the metabolism of monoamine neurotransmitters
and their receptors, particularly norepinephrine
and serotonin
• The pharmacologic effects of any of the
antidepressant drugs on neurotransmission occur
immediately, whereas the time course for a
therapeutic response occurs over several weeks
• It takes at least 2 weeks to produce significant
improvement in mood "therapeutic lag", and
maximum benefit may require up to 12 weeks or
more
10
Antidpressents
• In monoamine systems, reuptake of the
transmitter is the main mechanism by which
neurotransmission is terminated; thus, inhibition of
reuptake can enhance neuro-transmission,
presumably by slowing clearance of the
transmitter from the synapse and prolonging the
dwell-time of the transmitter in the synapse
• Monoamine oxidase inhibitors (MAOIs) enhances
monoaminergic neurotransmission by inhibiting
monoamine metabolism and thereby enhancing
neurotransmitter storage in secretory granules
11
Drug Selection: General Considerations
•
Various types of antidepressants are available:
1. Selective Serotonin Reuptake Inhibitors
(SSRIs)
2. Serotonin norepinephrine reuptake inhibitors
(SNRIs)
3. Monoamine oxidase inhibitors (MAOIs)
4. 5-HT2 Antagonists
5. Bupropion
12
Selective Serotonin Reuptake Inhibitors
(SSRIs)
• They are the most commonly prescribed group of
antidepressants
• They specifically inhibit serotonin reuptake,
having 300- to 3000-fold greater selectivity for the
serotonin transporter as compared to the
norepinephrine transporter
• Agents:
Fluoxetine
(Prozac®),
paroxetine,
sertraline,
fluvoxamine,
Citalopram,
&
Escitalopram (s-citalopram)
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)
• Stimulation of 5-HT2C receptors may contribute to
the agitation or restlessness sometimes induced
by serotonin reuptake inhibitors
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
1) GIT: nausea, GIT upset, diarrhea.
2) Sexual dysfunction: loss of libido, delayed
3)
4)
5)
6)
orgasm, or diminished arousal.
CNS: Sleep disturbances. For this reason,
fluoxetine is usually administered in the morning
after breakfast
Weight gain particularly paroxetine
SSRIs have also been associated with
extrapyramidal side effects, especially those with
Parkinson’s disease
There is an association of paroxetine with cardiac
septal defects in first trimester exposures
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
•
Citalopram and escitalopram have the least
effect on the cytochrome P450 system & have
the most favorable profile regarding D–D
interactions
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
* Fluoxetine is metabolized to an active product, norfluoxetine. The elimination half-life of norfluoxetine is
22
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:
a) Selective serotonin-norepinephrine reuptake
inhibitors (SNRIs)
b) Tricyclic antidepressants (TCAs)
23
a) Selective Serotonin-Norepinephrine Reuptake
Inhibitors
• Agents:
venlafaxine,
desvenlafaxine,
duloxetine & milnacipran*
and
• All SNRIs bind the serotonin (SERT) and
norepinephrine (NET) transporters
• At dosages <150 mg/day, venlafaxine is a potent
inhibitor of serotonin reuptake and, at medium to
higher doses, is an inhibitor of norepinephrine reuptake
• Duloxetine inhibits serotonin and norepinephrine
reuptake at all doses
*Milnacipran is not used to treat depression. It is approved for the treatment of fibromyalgia
24
a) Selective Serotonin-Norepinephrine Reuptake
Inhibitors
• Unlike the TCAs, the SNRIs have little activity at
adrenergic, muscarinic, or histamine receptors
and, thus, have fewer of these receptor-mediated
adverse effects than the TCA
26
SNRIs- Clinical uses
1. Depression:
in
patients
in
whom
SSRIs
are
ineffective
2. chronic joint and muscle pain: duloxetine
3. Fibromyalgia: milnacipran
4. Urinary stress incontinence (duloxetine
in
Europe)
• Off-label uses include autism, binge eating disorders, hot
flashes (desvenlafaxine), pain syndromes, premenstrual
dysphoric disorders, and post-traumatic stress disorders
(venlafaxine)
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
interactions than the SSRIs
fewer
CYP450
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
• Within the TCAs, there is considerable variability
in affinity for SERT versus NET:
o Clomipramine has relatively very little affinity for
NET but potently binds SERT
o Desipramine
(Imipramine’s
metabolite)
and
nortriptyline, are relatively more selective for NET
o Imipramine has more serotonin effects initially
30
II.Tricyclic Antidepressants (TCA)
• TCAs also block serotonergic, α-adrenergic,
histaminic, and muscarinic receptors
• Actions at these receptors are probably
responsible for many of the untoward effects of
the TCAs
• TCAs such as doxepin are sometimes prescribed
as hypnotics and used in treatments for pruritus
because of their antihistamine properties
• Amoxapine also blocks the D2 receptor
31
II. TCA- Clinical uses
1. Depression: that is unresponsive to more
commonly used antidepressants )SSRIs or
SNRIs)
2. Panic disorder
3. Control bed-wetting in children (older than 6
years) by causing contraction of the internal
sphincter of the bladder (Imipramine)1
4. Treatment of migraine headache and chronic
pain syndromes for which the cause of the pain is
unclear (Amitriptyline)
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
• Compared with TCAs and MAOIs, the other
antidepressants are generally much safer in
overdose
35
TCA overdose
• A 1500 mg dose of imipramine or amitriptyline
is enough to be lethal in many patients
• Symptoms: ventricular tachycardia, fibrillation
and seizures are sometimes seen
• Management: cardiac monitoring, airway
support, and gastric lavage. Sodium
bicarbonate is often administered to uncouple
the TCA from cardiac sodium channels
36
TCA overdose
• If a patient is severely depressed, potentially
suicidal, impulsive, or has a history of
substance abuse, prescribing a relatively safe
antidepressant agent with close clinical followup is appropriate
37
MAO inhibitors
• Agents:
selegline,
tranylcypromine
phenelzine,
and
• 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
• The MAO inhibitors inactivate the enzyme,
permitting neurotransmitter molecules to
escape degradation and, therefore, to both
accumulate within the presynaptic neuron
and leak into the synaptic space
• Selective MAO-A inhibitors are more
effective in treating major depression than
type B inhibitors
39
MAO inhibitors
• MAOIs are classified by their specificity for MAOA or -B and whether their effects are reversible or
irreversible
• Phenelzine and tranylcypromine are examples of
irreversible, nonselective MAOIs
• Moclobemide is a
inhibitor of MAO-A
reversible
and
selective
• 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 drugfood 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
• Fluoxetine, because of its long half-life, should be
discontinued for 4–5 weeks before an MAOI is
initiated
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)
• MAOIs prevent the breakdown of tyramine in the
gut resulting in high serum levels that enhance
peripheral noradrenergic effects, including raising
BP dramatically (Hypertensive crisis)
• Can be minimized with a low-tyramine diet that
begins several days before starting the MAOI &
continues for 3-4 weeks after stopping the MAOI
48
Youdim et al. Nature Reviews Neuroscience 7, 295–309 (April 2006) | doi:10.1038/nrn1883
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
5-HT2 antagonists
• Agents: Nefazodone, Trazodone, mirtazapine and
mianserin (not marketed in the U.S.)
• Inhibition of 5-HT2A receptors in both animal and
human studies is associated with substantial
antianxiety, antipsychotic, and antidepressant
effects
• Nefazodone is a weak inhibitor of both SERT and
NET, whereas trazodone is also a weak but
selective inhibitor of SERT
51
5-HT2 antagonists
• Trazodone’s primary metabolite, m-cpp, is a
potent 5-HT2A antagonist, and much of
trazodone's benefits as an antidepressant might
be attributed to this effect
• Trazodone
also
has
weak-to-moderate
presynaptic α-adrenergic–blocking properties and
is a modest antagonist of the H1 receptor
52
5-HT2 antagonists
• 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
5-HT2 antagonists- Clinical uses
• Depression: Mirtazapine can be advantagous
in patients with depression having sleep
difficulties
• Low doses of trazodone (50-100 mg) have
been used widely both alone and concurrently
with SSRIs or SNRIs to treat insomnia
54
I.5-HT2 antagonists- ADRs
1) Sedation (trazodone & mirtazapine): probably
because of their potent H1-blocking activity.
Sedation necessitates dosing at bedtime
2) Dose-related GIT SEs
3) Priapism: uncommon but serious side effect
requiring surgical intervention in one-third of the
cases reported
4) weight gain (mirtazapine)
5) Nefazodone
has
been
associated
with
hepatotoxicity, including rare fatalities and cases
of hepatic failure requiring transplantation
55
II. Bupropion
• It acts as a weak dopamine and norepinephrine
reuptake inhibitor to alleviate the symptoms of
depression
• Bupropion has virtually no direct effects on the
serotonin system
• Unlike the SSRIs, bupropion does not cause
sexual side effects
• It does not block muscarinic, histaminergic, or
adrenergic receptors
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
• Bupropion is occasionally associated with
CNS stimulations (agitation, insomnia, and
anorexia)
58
Bupropion- D/D interactions
• Bupropion is metabolized primarily by
CYP2B6, and its metabolism may be altered
by drugs such as cyclophosphamide
59