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 ydwivedi psych uic edu Noradrenergic NE Synapse Presynaptic NE Receptors Autoreceptors 2 Postsynaptic NE Receptors Heteroreceptors 1 2 1 Tyr Tyrosine TH Tyrosine hydroxylase DOPA L Dihydroxyphenyl alanine L AADC L Aromatic amino acid decarboxylase DBH Dopamine hydroxylase DA Dopamine MAO Monoamine oxidase VMAT Vesicular amine transporter 1 Noradrenergic Pathway Frontal Cortex Cerebellum Frontal Cortex Locus Coeruleus Limbic Cortex 2 NE Deficiency Syndrome 3 Serotonergic 5HT Synapse Presynaptic 5HT Receptors Autoreceptors 5HT1A 5HTID Postsynaptic 5HT Receptors Heteroreceptors 5HT1A 5HT2A 5HT2C 5HT3 5HT4 6 7 Trp Tryptyophan TrypOHase Tryptophan hydroxylase 5HTP 5 Hydroxy tryptophan L AADC L AromaticAmino acid decarboxylase MAO Monoamine oxidase VMAT Vesicular amine transporter Serotonin Pathway Frontal Cortex Raphe Nucleus Basal ganglia Limbic Cortex Hypotalamus Brain stem 4 5 5HT Deficiency Syndrome 6 5HT NE Interaction 5HT and NE Interaction 7 Ionotropic aminobutyric acid GABA Receptors Benzodiazepine GABA subunit Channel pore Barbiturates Steroids Picrotoxin Pentamers Inhibitory in action because the associated channels are permeable to negatively charged Cl ions Benzodiazepines are allosteric modulators to GABA neurotransmission Serotonin and Noradrenergic Signaling Systems 8 Monoamine Hypothesis of Depression Monoamine Receptor Hypothesis of Depression Normal functioning Decrease in neurotransmitters Receptor upregulation due to lack of neurotransmitters 9 Gene Expression Hypothesis of Depression Brain derived neurotrophic factor BDNF 10 Pharmacodynamics of Antidepressants Classification of Antidepressants Tricyclics Selective Serotonin Reuptake Inhibitors SSRIs Norepinephrine Selective Reuptake Inhibitors NRIs Norepinephrine Dopamine Reuptake Inhibitors NDRIs Mixed Serotonin Norepinephrine Reuptake Inhibitors SNRIs Monoamine Oxidase Inhibitors MAOIs Noradrenergic and Specific Serotonergic Antidepressant NaSSA Serotonin2A Antagonist Serotonin Reuptake Inhibitors SARI 11 Tricyclics All tricyclics block reuptake pumps for both 5HT and NE and 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 1 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 12 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 1 histamine or M cholinergic receptors or Na pump 1 Stahl 2002 13 2 3 4 14 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 2 postsynaptic 1 2 and adrenergic 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 active metabolite 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 15 Mixed 5HT NE Reuptake Inhibitors SNRIs venlafaxine Combines the action of SSRI and NRI Selective 5HT and NE uptake blockers Weak DA uptake blocker as with TCA But without 1 M1 cholinergic or H receptor blocking properties Causes dual action on serotonin and adrenergic systems thus amplifying these two systems synergistically NE 5HT Greater NE action at higher doses thus greater efficacy at increased doses as opposed to other antidepressants which have little difference in efficacy at higher doses Effective in patients who are responders but not remmiters to SSRIs Synergy 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 16 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 Phenelzine Tanylcypromine Isocarboxazid Reversible and selective inhibitors of MAO A RIMAs Moclobemide antidepressant action Selective inhibitor of MAO B Deprenyl neurodegenerative disorder 5HT and NE Interaction 17 Noradrenergic and specific Serotonergic Antidepressant NaSSA mirtazapine postsynaptic 2 heteroreceptor 2 receptor antagonist Blocks 5HT2A 5HT3 and thus reduces side effects of anxiety and sexual dysfunction 5HT 1 heteroreceptor Increase NE and 5HT levels 5HT presynaptic 2 autoreceptor presynaptic 2 autoreceptor 5HT 5HT But by blocking 5HT2C and H1 receptors cause side effects sedation and weight gain Stahl 2002 Serotonin2A Antagonist Serotonin Reuptake Inhibitors SARI nefazodone trazodone Blocks 5HT uptake selectively but in a less potent manner than tricyclics This helps reduces depression However they are powerful 5HT2A antagonists 5HT2A antagonists are not potent antidepressants But blockade of 5HT2A receptors stimulate 5HT1A receptors which may help reduce depression 5HT2A antagonism also reduces the risk of anxiety sedation or sexual dysfunction which is normally associated with SSRIs 18 Postulated Neurotransmitter Receptor Hypothesis of Antidepressant Action Amount of NE Receptor Sensitivity Clinical Effect Antidepressants introduced Stahl 2002 Postulated Adaptive Mechanisms at Gene Exprerssion Nestler Hyman Malenka 19 Brain derived neurotrophic factor Pharmacodynamics of Mood Stabilizing Agents 20 Mood Stabilizing Agents Classic Mood Stabilizer Lithium Anticonvulsants Valproic acid Carbamazepine Lamotrigine Gabapentin Topiramate Lithium
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