Post on 24-May-2018
1
PHARMACODYNAMICS OF ANTIDEPRESSANTS
MOOD STABILIZING AGENTS ANXIOLYTICS
SEDATIVE-HYPNOTICS
Yogesh Dwivedi, Ph.D.Assistant Professor of Psychiatry and Pharmacology
Psychiatric InstituteDepartment of Psychiatry
University of Illinois at ChicagoEmail: ydwivedi@psych.uic.edu
Noradrenergic (NE) SynapsePresynaptic NE Receptors(Autoreceptors)
α2
Postsynaptic NE Receptors(Heteroreceptors)
α1, α2, β1
Tyr: TyrosineTH: Tyrosine hydroxylaseDOPA: L-Dihydroxyphenyl alanineL-AADC: L-Aromatic amino acid decarboxylaseDBH: Dopamine β hydroxylaseDA: DopamineMAO: Monoamine oxidaseVMAT: Vesicular amine transporter
2
Noradrenergic Pathway
Locus Coeruleus
Frontal Cortex
Frontal Cortex
Limbic Cortex
Cerebellum
3
NE Deficiency Syndrome
4
Serotonergic (5HT) Synapse
Presynaptic 5HT Receptors(Autoreceptors)
5HT1A, 5HTID
Postsynaptic 5HT Receptors(Heteroreceptors)
5HT1A, 5HT2A, 5HT2C, 5HT3,5HT4,6,7
Trp: TryptyophanTrypOHase: Tryptophan hydroxylase5HTP: 5-Hydroxy tryptophanL-AADC: L-AromaticAmino acid decarboxylaseMAO: Monoamine oxidaseVMAT: Vesicular amine transporter
Serotonin Pathway
Frontal Cortex
Basal ganglia
Limbic CortexHypotalamus
Brain stem
Raphe Nucleus
5
6
5HT Deficiency Syndrome
7
5HT-NE Interaction
5HT and NE Interaction
8
Ionotropic γ-aminobutyric acid (GABA) Receptors
α subunit
Channel pore
Barbiturates
Steroids
Picrotoxin
•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
9
Monoamine Hypothesis of Depression
Monoamine Receptor Hypothesisof Depression
Normal functioning
Decrease in neurotransmitters Receptor upregulation due to lack of neurotransmitters
10
Gene Expression Hypothesis of Depression
Brain-derived neurotrophic factor(BDNF)
11
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)
12
Tricyclics
•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
13
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)
1
14
2
3
4
15
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
16
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 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
17
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
18
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
α1 heteroreceptor
presynapticα2 autoreceptor
postsynapticα2 heteroreceptor
presynapticα2 autoreceptor
5HT5HT
5HT5HT
Serotonin2A Antagonist/ 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 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
19
Receptor Sensitivity
Antidepressants introduced
Clinical Effect
Amount of NE
Postulated Neurotransmitter Receptor Hypothesis of Antidepressant Action
(Stahl, 2002)
Postulated Adaptive Mechanisms at Gene Exprerssion
(Nestler, Hyman, Malenka)
20
Brain-derived neurotrophic factor
Pharmacodynamics of Mood Stabilizing Agents
21
Mood Stabilizing Agents
Classic Mood Stabilizer:
Lithium
Anticonvulsants:
Valproic acidCarbamazepine
LamotrigineGabapentinTopiramate
MARCKS (PKC, PKA)
Li
LiLi
Li
Li
e.g. Bcl-2 Li
Neuroprotection (?)
Lithium Action-I
(Squire)
22
Ca2+
5HT2A, 5HT2C, α2AR
Lithium Action-II
Inositol
IP3 DAG
Brain Development
•GSK3-β phosphorylates and thus degrades β-catenin
•Li blocks this degradation
Lithium Action-III
(Nestler, Hyman, Malenka)
23
Reduces neuronal activity by:-Reducing flux of ions through voltage-gated ion channels, such as Na+, K+, Ca2+
-Enhancing inhibitory neurotransmission with GABA, by increasing its synthesis,release, or inhibiting its breakdown
-Reducing excitatory neurotransmission with glutamate by reducing its release
Anticonvulsants
Stahl, 2002
CAI: Carbonic anhydraseinhibitor
GRI: GABA reuptake inhibitor
•Inhibit PKC (carbamazepine)
•Inhibit adenylyl cyclase activity (carbamazepine)
•Decreases inositol monophospahte activity (carbamazepine)
•Increase neurogenesis (valproic acid)
•Increase expression of Bcl-2, thus cause neuroprotection(valproic acid)
Other Mechanisms of Action ofAnticonvulsants