Download Antidepressant Drugs

Antidepressant Drugs
*Symptoms of depression:
Intense feelings of sadness, hopelessness as well as changes in
sleep patterns and appetite, loss of energy and suicidal thoughts.
*Most clinically useful antidepressant drugs potentiate either
directly or indirectly, the action of norepinephrine(NE) and ⁄ or
serotonin(5-HT) in the brain.
*Types of depression:(1) "reactive" or "secondary" depression(most common),
occurring in response to real stimuli such as grief, illness, etc
(2) "endogenous" depression, a genetically determined
biochemical disorder manifested by inability to experience
ordinary pleasure or to cope with ordinary life events
*The amine hypothesis of mood:
-Brain amines particularly NE and 5HT are neurotransmitter in
pathway that function in the expression of mood.
-Functional decrease in activity of such amines result in
depression while functional increase in activity result in mood
elevation.
*Difficulties with amines hypothesis include:
1-Although antidepressants may cause changes in brain level
of NE and 5-HT within hrs, weeks may required for clinical
effects.
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2-Most antidepressants ultimately cause down-regulation of
amines receptors necessitating increasing the dose of the
antidepressant drug.
Tricyclic Antidepressants (TCAs)
-Imipramine, Clomipramine, Amitriptyline and Nortryptilin
are the prototypical drugs of the class as mixed norepinephrine
and serotonin uptake inhibitors .
*Mechanism of action:The TCAs have affinity for both receptors and transporters
of monoamine transmitters and behave as antagonists
in both respects.
Thus, the neuronal reuptake of norepinephrine and
serotonin is inhibited, with a resultant increase in activity.
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*TCAs action:-Elevate mood, improve mental alertness, increase physical
activity.
-The onset of mood elevation is slow, requiring 2 wks or longer.
*Therapeutic uses of TCAs:- depression.
-Enuresis –bed wetting in children-(imipramine)
-Chronic pain (neuropathic pain) (amitriptyline).
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*Adverse effects:-Blockade of Ach receptors lead to blurred vision, urinary
retention, constipation, and aggravation of glaucoma .
-Increased catecholamine activity results in cardiac over
stimulation.
-Blockade of -adrenoceptors, causing orthostatic
hypotension and reflex tachycardia.
-Imipramine is the most likely and nortriptyline is the least
likely to cause orthostatic hypotension.
-Blockade of histamine 1 receptors lead to sedation.
-Sexual dysfunction in minority of patients.
*Drugs interaction with TCAs:1-Pronounced sedation with drugs which have sedative effects
e.g. opioid analgesics, antihistamines, anxiolytics and alcohol
3-Potentiate the effect of catecholamines and other direct acting
sympathomemetics
*Selective serotonin re-uptake inhibitors(SSRIs)
-300-3000 fold greater selective for serotonin transporter than
for norepinephrine transporter(in contrast to TCAs that nonselectively inhibit uptake of norepinephrine and serotonin).
-SSRIs have little blocking activity at muscarinic, adrenoceptors, and histaminic 1 receptors (much less adverse
effects than TCAs)
-SSRIs include fluxetine(prototype), citalopram, escitalopram,
fluvoxamine, paroxetine, and sertraline
-Take 2wks to start improvement in mood(12 wks for full
effect)
*Pharmacokinetics of SSRIs:-The majority of SSRIs have half-life (16-36 hrs)
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-Fluxetine differs in 2 respects:
A-it has longer half-life (50 hrs)
B-it has active metabolite (S-norfluxetine) with 10 days h½
-Fluxetine and paroxetine are potent enzyme inhibitors (TCAs,
ß-adrenergic antagonists)
-Excretion of SSRIs is through kidneys (in paroxetine and
sertraline there is also fecal excretion)
*Therapeutic uses:-Depression(as effective as TCAs)
-Pre-menstrual dysphoric disorder.
-SSRIs are generally free of sedative effects and remarkably safe
in overdose. Combined with the ease of once-a-day dosing,
these qualities may explain why they have become the most
widely prescribed antidepressants.
*Adverse effects of SSRIs;
-Generally side effects are less than in TCAs and MAO
inhibitors.
-Paroxetine is sedating, fluxetine is not.
-Sexual dysfunction (which is less in bupropion, mitrazepine)
-Used cautiously in children and teenagers because of
increased risk of suicide
-Over dose not causing arrhythmia, but fluxetine over dose
may cause epilepsy (therapeutic dose is 20mg-day)
-weight gain
*Drugs interaction with SSRIs:1-Serotonin syndrome(hyperthermia, muscular rigidity, and
changes in mental status and vital signs) if MAO inhibitors is
co-administered .
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2-CNS toxicity if given with dopaminergic drugs e.g. selegiline
(anti Parkinson drug).
*Monoamine oxidase inhibitors (MAOIs)
-They includes:
A-Non-selective inhibitors of MAO:
Phenelzine and isocarboxazide (no longer marketing), they
bound irreversibly to MAO (A and B) with prolonged duration
of action .
Tranylcypromine which bound reversibly to MAO(A and B)
with long duration of action.
B-Selective inhibitors of MAO:
-Selegiline is selective for MAO-B at low doses, but at high
doses it is less selective, used in Parkinson's disease and has
been approved in major depression.
-Moclobemide is selective for MAO-A
*Pharmacokinetic of MAOIs
-Readily absorbed from GIT
-Duration of action is about 7 days in tranylcypromine, and 2-3
wks in Phenelzine and selegiline after drug discontinuance.
*Mechanism of action of MAOIs
-Increase the availability of amines (serotonin) by preventing
their destruction by MAO enzyme in pre-synaptic terminal
-Increased synaptic dopamine is also relevant to the efficacy of
MAOIs
*Adverse effects of MAOIs:-
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-Severe and unpredictable side effects limit the use of MAOIs
e.g .food containing tyramine- reaction
Tyramine contained in some foods e.g. aged cheeses,
chicken liver and beer normally inactivated by MAO-B in the
gut. Individuals receiving MAOIs are unable to degrade
tyramine which will cause release of large amount of stored
catecholamines from nerve terminal resulting in headache,
tachycardia, hypertension, cardiac arrhythmias and stroke.
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Treatment of mania and bipolar disorders
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*Lithium
*Possible mechanism of action of lithium:
lithium Inhibit synthesis of phosphatidylinositol
biphosphate(PIP2) (chemical mediator responsible for mania)
leading to its relative depletion in neuronal membrane of the
CNS
*Pharmacokinetic of lithium:-Absorbed rapidally and completely from gut
-Distributed throughout the body
-Excreted through kidneys
-lithium is very toxic with very low therapeutic index.
*Clinical uses:-Lithium carbonate continue to be the standared treatment of
bipolar disorders.
*Toxicity of lithium:-Ataxia, tremor, confusion and convulsion.
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-Dry mouth, polyurea.
-Decreased thyroid function.
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