PHARMACODYNAMICS OF ANTIDEPRESSANTS MOOD STABILIZING AGENTS ANXIOLYTICS SEDATIVE-HYPNOTICS Yogesh Dwivedi, Ph.D. Assistant Professor of Psychiatry and Pharmacology Psychiatric Institute Department of Psychiatry University of Illinois at Chicago Email: [email protected]Noradrenergic (NE) Synapse Presynaptic NE Receptors (Autoreceptors) α 2 Postsynaptic NE Receptors (Heteroreceptors) α 1 , α 2 , β 1 Tyr: Tyrosine TH: Tyrosine hydroxylase DOPA: L-Dihydroxyphenyl alanine L-AADC: L-Aromatic amino acid decarboxylase DBH: Dopamine β hydroxylase DA: Dopamine MAO: Monoamine oxidase VMAT: Vesicular amine transporter
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PHARMACODYNAMICS OF ANTIDEPRESSANTS
MOOD STABILIZING AGENTS ANXIOLYTICS
SEDATIVE-HYPNOTICS
Yogesh Dwivedi, Ph.D.Assistant Professor of Psychiatry and Pharmacology
•Pentamers•Inhibitory in action because the associated channels are permeable to negatively charged Cl- ions•Benzodiazepines are allosteric modulatorsto GABA neurotransmission
BenzodiazepineGABA
Serotonin and Noradrenergic Signaling Systems
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Monoamine Hypothesis of Depression
Monoamine Receptor Hypothesisof Depression
Normal functioning
Decrease in neurotransmitters Receptor upregulation due to lack of neurotransmitters
•All tricyclics block reuptake pumps for both 5HT and NEand they work negative allosteric modulators of neurotransmitter uptake process
•Some have more potency for inhibition of 5HT uptake pump(e.g. clomipramine, imipramine, amitryptyline)
•Others have more potency for inhibition of NE uptake pump(nortriptyline, desipramine)
•All tricyclics block α1 adrenergic, histaminergic, and M1 cholonergic receptors (causes side effects,e.g., weight gain, drowsiness, blurred vision)
•Tricyclics also block Na+ channels, thus may cause cardiac arrythmia
(Stahl, 2002)
Side Effects
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Side Effects
Selective Serotonin Reuptake Inhibitors (SSRI)•Selective and more potent inhibitors of serotonin uptake than tricyclics(fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram)
•No blockade of α1, histamine or M cholinergic receptors or Na+ pump
(Stahl, 2002)
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NE Selective Reuptake Inhibitors (NRIs)(reboxetine, 1555U88*, tomoxetine*)
•Selective to NE uptake
•May be more effective in noradrenaline deficiency syndrome (e.g., depression associated with fatigue, apathy, cognitive disturbances), or nonresponders to SSRIs
•Also act at presynaptic α2, postsynaptic α1, α2 and βadrenergic receptors (tremor, agitation, blood pressure)
•No blockade of histamine, M cholinergic receptors or Na+
pump as with tricyclics
*under clinical trial
NE/DA Reuptake Blockers (NDRIs)(Bupropion)
•Weak dopamine and weak NE reuptake blocker
•But is potent blocker of NE and dopamine neurotransmission
•Bupropion is metabolized into its hydroxylated activemetabolite, which is a potent NE reuptake blocker
•Effective for patients who can not tolerate side effects of SSRIs such as sexual dysfunction or nonresponders of SSRIs
•But without α1, M1 cholinergic or H receptor blocking properties
•Causes dual action on serotonin and adrenergic systems, thus amplifying these two systems synergistically
•Greater NE action at higher doses, thus greater efficacy at increased doses,as opposed to other antidepressantswhich have little difference in efficacy at higher doses
•Effective in patients who are responders but not remmiters to SSRIs Synergy
NE5HT
Monoamine Oxidase Inhibitors (MAOIs)-I
Two types of MAO
MAO-A --- metabolizes 5HT and NE selectively--- metabolizes certain amines, linked to
blood pressure
MAO-B --- protects neurons by metabolizing certain amines such as protoxins into toxins that may cause neuronal damage
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Monoamine Oxidase Inhibitors (MAOIs)-II
•Classic MAOIs--irreversible and nonselective(MAO-A and B enzyme activity can not be restored unless new enzyme is synthesized)
PhenelzineTanylcypromineIsocarboxazid
•Reversible and selective inhibitors of MAO-A (RIMAs)
Moclobemide (antidepressant action)
•Selective inhibitor of MAO-B
Deprenyl (neurodegenerative disorder)
5HT and NE Interaction
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Noradrenergic and specific SerotonergicAntidepressant (NaSSA)
(mirtazapine)
Stahl, 2002
• α2 receptor antagonist
•Increase NE and 5HT levels
•Blocks 5HT2A, 5HT3 and thus reduces side effects of anxiety, and sexual dysfunction
•But by blocking 5HT2C, and H1receptors cause sideeffects: sedation, and weight gain