1PHARMACODYNAMICS OF ANTIDEPRESSANTS MOOD STABILIZING AGENTS ANXIOLYTICSSEDATIVE-HYPNOTICSYogesh Dwivedi, Ph.D.Assistant Professor of Psychiatry and PharmacologyPsychiatric InstituteDepartment of PsychiatryUniversity of Illinois at ChicagoEmail: [email protected] (NE) SynapsePresynaptic NE Receptors(Autoreceptors)α2Postsynaptic NE Receptors(Heteroreceptors)α1, α2, β1Tyr: TyrosineTH: Tyrosine hydroxylaseDOPA: L-Dihydroxyphenyl alanineL-AADC: L-Aromatic amino acid decarboxylaseDBH: Dopamine βhydroxylaseDA: DopamineMAO: Monoamine oxidaseVMAT: Vesicular amine transporter2Noradrenergic PathwayLocus CoeruleusFrontal CortexFrontal CortexLimbic CortexCerebellum3NE Deficiency Syndrome4Serotonergic (5HT) SynapsePresynaptic 5HT Receptors(Autoreceptors)5HT1A, 5HTIDPostsynaptic 5HT Receptors(Heteroreceptors)5HT1A, 5HT2A, 5HT2C, 5HT3,5HT4,6,7Trp: TryptyophanTrypOHase: Tryptophan hydroxylase5HTP: 5-Hydroxy tryptophanL-AADC: L-AromaticAmino acid decarboxylaseMAO: Monoamine oxidaseVMAT: Vesicular amine transporterSerotonin PathwayFrontal CortexBasal gangliaLimbic CortexHypotalamusBrain stemRaphe Nucleus565HT Deficiency Syndrome75HT-NE Interaction5HT and NE Interaction8Ionotropic γ-aminobutyric acid (GABA) Receptorsα subunitChannel poreBarbituratesSteroidsPicrotoxin•Pentamers•Inhibitory in action because the associated channels are permeable to negatively charged Cl-ions•Benzodiazepines are allosteric modulatorsto GABA neurotransmissionBenzodiazepineGABASerotonin and Noradrenergic Signaling Systems9Monoamine Hypothesis of DepressionMonoamine Receptor Hypothesisof DepressionNormal functioningDecrease in neurotransmitters Receptor upregulation due to lack of neurotransmitters10Gene Expression Hypothesis of DepressionBrain-derived neurotrophic factor(BDNF)11Pharmacodynamics of AntidepressantsClassification 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)•Serotonin2AAntagonist/Serotonin Reuptake Inhibitors (SARI)12Tricyclics•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 α1adrenergic, 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 Effects13Side EffectsSelective 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)11423415NE 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, α2and βadrenergic receptors (tremor, agitation, blood pressure)•No blockade of histamine, M cholinergic receptors or Na+pump as with tricyclics*under clinical trialNE/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 SSRIs16Mixed 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 α1, M1cholinergic 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 SSRIsSynergyNE5HTMonoamine Oxidase Inhibitors (MAOIs)-ITwo types of MAOMAO-A --- metabolizes 5HT and NE selectively--- metabolizes certain amines, linked to blood pressureMAO-B --- protects neurons by metabolizing certain amines such as protoxins into toxins that may cause neuronal damage17Monoamine 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-BDeprenyl (neurodegenerative disorder)5HT and NE Interaction18Noradrenergic and specific SerotonergicAntidepressant (NaSSA)(mirtazapine)Stahl, 2002• α2receptor 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 gainα1heteroreceptorpresynapticα2 autoreceptorpostsynapticα2 heteroreceptorpresynapticα2 autoreceptor5HT5HT5HT5HTSerotonin2AAntagonist/ Serotonin ReuptakeInhibitors (SARI)(nefazodone, trazodone)•Blocks 5HT uptake selectively but in a less potent manner than tricyclics•This helps reduces depression•However, they are powerful 5HT2Aantagonists•5HT2Aantagonists are not potent antidepressants•But blockade of 5HT2Areceptors stimulate 5HT1Areceptors, which may help reduce depression•5HT2Aantagonism also reduces the risk of anxiety, sedation or sexual dysfunction which is normally associated with SSRIs19Receptor SensitivityAntidepressants introducedClinical EffectAmount of NEPostulated Neurotransmitter Receptor Hypothesis of Antidepressant Action(Stahl, 2002)Postulated Adaptive Mechanisms at Gene Exprerssion(Nestler, Hyman, Malenka)20Brain-derived neurotrophic factorPharmacodynamics of Mood Stabilizing Agents21Mood
View Full Document
Unlocking...