Antidepressants Flashcards
Depression is classified as
- Major depression
* Bipolar depression
• Depressive episodes are characterized by:
- Depressed or sad mood
- Pessimistic worry
- Diminished interest in normal activities
- Feelings of worthlessness
• Depressive symptoms also can be secondary to:
- Hypothyroidism
- Parkinson’s disease
- Inflammatory conditions.
THE MONOAMINE HYPOTHESIS
“Depression may be due to lowered monoamine neurotransmitter at brain
synapses. Treatment of depression may be achieved by restoring the monoamine levels or actions to normality
• The monoamine hypothesis was reinforced by the actions of antidepressants.
• Tricyclics block monoamine reuptake.
• MAO inhibitors block degradation of
monoamine neurotransmitters
WEAKNESSES OF THE
MONOAMINE HYPOTHESIS
• The pharmacological actions of both tricyclic and
MAO inhibitor classes of antidepressants are
immediate.
• But the clinical effects of the drugs take weeks.
• This discrepancy between biochemical and therapeutic effects suggests that the drugs trigger longer term changes.
• Depression may be linked to a deficiency in
signal transduction.
• Such a deficiency could lead to a deficient
response of target neurons to neurotransmission
and thus, depression.
ANTIDEPRESSANT DRUGS:
GENERAL FEATURES
• Antidepressants may take 2-4 weeks to produce
any improvement and 6-8 weeks to achieve
substantial benefit.
• All antidepressant drugs enhance monoamine
neurotransmission by one of several mechanisms.
• The most common mechanism is the inhibition
of the serotonin transporter (SERT), the norepinephrine transporter (NET), or both.
Types of antidepressant drugs?
Monoamine oxidase inhibitors Tricyclic antidepressants Serotonin selective reuptake inhibitors Dual serotonin & norepinephrine reuptake inhibitors 5-HT2 antagonists/reuptake inhibitors Norepinephrine & dopamine reuptake inhibitors Antagonists at alpha2, 5-HT2 & 5-HT3 receptors
List 4 MAOIs?
- Isocarboxazid
- Phenelzine
- Tranylcypromine
- Selegiline
• Monoamine oxidase inhibitors were the first
modern class of antidepressants.
• Introduced in the 1950s
MAOi moa?
• MAO is a mitochondrial enzyme that functions
as a “safety valve”.
• It inactivates excess norepinephrine, dopamine,
and serotonin that may leak out of synaptic
vesicles when the neuron is at rest.
• MAO inhibitors inactivate the enzyme:
neurotransmitter molecules escape degradation.
• This causes activation of norepinephrine and
serotonin receptors.
compare MAO-A and MAO-b?
• There are two isozymes of MAO: MAO-A and
MAO-B.
• MAO-A preferentially metabolizes norepinephrine
and serotonin.
• Both MAO-A and MAO-B metabolize dopamine
and tyramine.
• The antidepressant effect of MAOIs correlates
with inhibition of MAO-A.
MAOIs currently available for treatment of depression are:
• The hydrazine derivatives: phenelzine and isocarboxazid
• The non-hydrazines: tranylcypromine and
selegiline.
• Phenelzine, isocarboxazid, and tranylcypromine bind irreversibly and nonselectively to MAO-A and MAO-B.
Selegiline moa?
• The MAO-B inhibitor selegiline is approved for
treatment of early Parkinson’s disease.
• Selegiline has antidepressant effects at high doses that also inhibit MAO-A.
• Selegiline is the first antidepressant available in
a transdermal delivery system
example: SELEGILINE PATCH
MAOIs: USES?
• MAO inhibitors are now rarely used in clinical
practice due to toxicity and food and drug
interactions.
• Used in treatment of depression unresponsive to other antidepressants.
MAOi AE?
- Drowsiness
- Insomnia
- Nausea
- Orthostatic hypotension
- Weight gain
- Muscle pain
- Sexual dysfunction
MAO inhibitors are associated with two classes
of serious drug interactions:
- SEROTONIN SYNDROME
* CHEESE REACTION
describe SEROTONIN SYNDROME?
• The combination of a MAOI with a serotonergic
agent may result in serotonin syndrome.
• Life-threatening.
• The syndrome includes hyperthermia, muscle
rigidity and myoclonus.
• Serotonin syndrome is the result of overstimulation of 5-HT1A and 5-HT2 receptors.
• An irreversible MAOI with a serotonergic agent is the most toxic combination.
• But any drug or combination that increases
serotonin can cause serotonin syndrome.
SEROTONIN SYNDROME: MANAGEMENT?
• Discontinuation of all serotonergic agents.
• Supportive care.
• Sedation with benzodiazepines.
• Administration of the serotonin antagonist
cyproheptadine.
Describe the cheese reaction?
What other types of drugs and example can precipitate a cheese reaction?
• Tyramine is contained in certain foods, such as
aged cheeses, chicken liver, soy products, pickled
fish and red wines.
• Tyramine is normally inactivated by MAO in the gut.
• Patients on an MAOI cannot degrade tyramine.
• Tyramine then causes release of catecholamines
resulting in tachycardia, hypertension, arrhythmias,
seizures, and possibly, stroke.
• Sympathomimetic drugs may also cause significant hypertension when combined with an MAO inhibitor.
• OTC cold preparations that contain pseudoephedrine and phenylpropanolamine
are contraindicated in patients taking MAOIs.
THE CHEESE REACTION: MANAGEMENT
• Phentolamine or prazosin are helpful in the
management of tyramine-induced hypertension.
• The selegiline transdermal patch is better
tolerated and safer.
• It is unlikely to cause tyramine-induced
hypertensive crisis.
List 5 TCAs?
- Amitriptyline
- Clomipramine
- Desipramine
- Imipramine
- Nortriptyline
moa of tca? Differences in moa between TCAs?
• TCAs block SERT and NET.
• This leads to increased monoamine concentration in the cleft.
• There is variability in affinity for SERT vs NET.
• For example, clomipramine is more selective for
SERT.
• Desipramine and nortriptyline are more selective for NET
