Antidepressants Flashcards
Monoamine hypothesis?
Monoamine depletion leads to depression and monoamine preservation leads to mood elevation.
Reserpine was used to HTN but was shown to deplete dopamine, serotonin and NE leading to depression.
Iproniazid and Isoniazid used to treat TB were shown to inhibit MAO and lift depression in chronically ill pts.
Tricyclics block monamine reuptake and MOA inhibitors block degradation of monoamine NT – leading to lifted depression (elevation of mood)
One thing to watch out for is that it takes 2-4 weeks to take effect creating improvement but 6-8 weeks to achieve substantial benefit. – b/cit takes so long depression may be linekd to deficiency insignal transduction
MOAIs?
Isocarboxazid (hydrazine derivative, irriversible to MAO-A and B)
Phenelzine (hydrazine derivative, irriversible to MAO-A and B)
Tranylcypromine (non-hydrazine derivative, irriversible to MAO-A and B)
Selegiline (non-hydrazine derivative, MAO-B inhibitor approved for tx of early Parkinson’s but at high dosese may inhibit MAO-A eliciting an antidepressant effect)
Inhibition of MOA (mitochondrial enzyme) leading to the prevention of inactivation of excess NE, Dopamine and serotonin that may leak out of the synaptic vesicles when neuron is at rest. [MOA is a “safety valve” that inactivates NTs]
MOA-A -preferentially metabolizes NE and serotonin
MOA-A and MOA-B - metabolize dopamine and tyramine
**inhibition of MAO-A is what correlates to the antidepressant effect
Uses - rarely used due to food and drug interactions but may be prescribed for depression unresponsive to other antidepressants
AE - drowsiness, insomnia, nausea, orthostatic hypotension, weight gain, muscle pain, sexual dysfunction
- *serotonin syndrome
- *cheese reaction
Serotonin syndrome?
• 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.
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.
**to avoid this you can give the selegiline transdermal patch- does not cause cheese reaction b/c dose is not as high
Cheese reaction may be managed via phentolamine or prazosin as there is a massive increase in blood pressure during this episode.
Tricyclic antidepressants (TCAs)?
Amitriptyline Clomipramine Desipramine Imipramine Nortriptyline
TCAs block SERT and NET - reuptake inhibtors lead to increased MAO concentration in the cleft.
Clomipramine - more selective fo SERT
Disapramine and Nortriptyline - more selective for NET
[**variable affinity for the SERT and NET]
AE - a-adrenergic receptor block (orthostatic hypotension and reflex tachycardia), muscarinic receptor block (blurred vision, xerostomia, urinary retention, glaucoma aggravation), histamine receptor block (sedation and weight gain), cardiac fast sodium channel block (leading to arrhythmias), sexual effects esp with highly serotonergic agents such as clomipramine
- *narrow therapeutic index
- *overdose leads to lethal arrhythmias – which can be reversed with sodium bicarbonate
Selective serotonin reuptake inhibitors (SSRIs)?
Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline
**only block the SERT channel increasing serotonin in the synaptic cleft. There is minimal blocking activity on the M, A, and H1 receptors as seen in the TCAs.
DOC - initial tx of depression
Other uses…
- OCD
- panic disorder
- generalized anxiety disorder
- PTSD
- social anxiety disorder
- Premenstrual dysphoric disorder
- bulemia
- premature ejaculation
AE - increased serotongergic activity in the gut associated with nausea, GI upset and diarrhea, as well as in the spinal cord decreasing sexual function and interest, weight gain when taken SSRIs (esp paroxetine)
Fatal Overdose - very rare, but may induce seizures
Drug interactions associated with SSRIs?
• Fluoxetine and paroxetine inhibit CYP2D6:
high potential for drug interactions.
• Fluvoxamine inhibits CYP1A2, CYP2C19 and
CYP3A4: high potential for drug interactions.
• Citalopram, escitalopram and sertraline have
low potential for interactions.
*All SSRIs may cause a serotonin syndrome
when used in the presence of a MAO inhibitor or
another serotonergic drug.
SNRIs?
Venlafaxine
Duloxetine
*Serotonin and NE blockage but differ from TCAs in that they do not block H1, muscarinic and a1 receptors as well
**effective in treating depression in pts where SSRIs are ineffective
Venlafaxine?
SNRI
potent inhibitor of 5HT uptake and at high doses NE. There is also a weak blockage of dopamine reuptake.
Duloxetine?
SNRI
Inhibits serotonin and norepinephrine reuptake at all doses.
Buproprion?
Norepinephrine and dopamine reuptake inhibitor (NDRIs)
- inhibits NE and dopamine uptake
- increase NE and Dopamine release
- NOT associated with sexual dysfunction b/c it lacks the serotonergic component
*overdose associated with seizures
5HT2 antagonists/reuptake inhibitors (SARIs)?
Nefazodone and Trazodone
5HT reuptake is blocked by SSRIs. There are a lot of serotonin receptors and the one associated to treat depression is stimulation of 5HT1A receptors in the raphe nucleus. Stimulation of 5HT2 in forebrain leads to agitation or anxiety and sexual dysfunction in stimulation of spinal cord.
*weak inhibitors of SERT and NEt an dpotent antagonists at the 5-HT2 receptors
Nefazodone - associated wit hepatotoxicity
Trazodone - blocks a1 and h1 receptors, extreme sedation, good hypnotic, but there is a troublesome side-effect of priapism
Mirtazapine?
Noradrenergic and specific serotonergic antidepressant (NASSA)
Antagonist of central presynaptic a1 receptors that enhace the release of NE and 5-HT. Antagonist of 5-HT2 and 5-HT3 receptors as well as H1 antagonism leading to sedation and weight gain. Best use in insomnia or when agitation is prominent.
Discontinuation syndrome?
Abrupt discontinuation of antidepressants that lead to a wide array of symptoms such as - anxiety, irritability, tearfulness, lethargy, headache, insomnia, nausea, vomiting, electric-shock sensation.
This is much more common with drugs that have shorter half-life – paroxetine or venlafaxine more common, but fluoxetine has a long half life so this is less likely to lead to discontinuation syndrome.
What is the drug of choice for depression?
SSRI (for dpression and anziety disorders)
