lecture 31 - 3rd asessment - antidepressants
TRANSCRIPT
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PATHOGENESIS AND TREATMENT OF DEPRESSION
In every winters heart there is a
quivering spring, andbehind the veil of each night
there is a smiling dawn.
Khalil Gibran Definition and Classification of Depression
Monoamine and Hypercortisolemic Hypotheses
Pharmacodynamics and Toxicodynamics of
Antidepressants
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ENDOGENOUS DEPRESSION
Unipolar - Melancholy
Bipolar Overactivity / Deep Depression
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MONOAMINE HYPOTHESIS
Hypoadrenergic Disorder - MHPG
Hyposerotonergic Disorders 5HIAA
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EVIDENCE FAVORING MONOAMINE HYPOTHESIS
Monoamine Depletors - Depression
Monoamine Enhancer Ameliorate Depression
CSF Monoamine - Depression
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HYPERCORTISOLEMIC HYPOTHESIS
Overactivity of H-P-A Axis
Plasma Cortisol
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PHARMACOTHERAPY - DEPRESSION
Tricyclic Antidepressants (TCA)
Second Generation Antidepressants
MAO Inhibitors
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TRICYCLIC ANTIDEPRESSANTS
Imipramine (Tofranil)
Desipramine (Norpramin)
Amitriptyline (Elavil)
Protriptyline (Vivactil)
Doxepin (Singequan)
Nortriptyline (Aventyl)
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imipramine
CH2 NCH
3
CH3CH2CH
amitriptyline
N
(CH2)3 NCH3
Hdesipramine
N
(CH2)3 NCH3
CH3
clomipramine
N
(CH2)3 NCH3
CH3
Cl
CH2 NCH3
HCH2CH
nortriptyline
(CH2)3 NCH3
Hprotriptyline
CH2 NCH3
HCH2CH
doxepin
O
O
NCl
N N H
amoxapine
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NorepinephrineSerotoninDopamine
Response
A. Normal monoaminetransmission
NorepinephrineSerotoninDopamine
IncreasedResponse
B. Effect of tricyclicantidepressants
Tricyclicantidepressantdrugs block re-uptake
of neurotransmitter
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Inhibition of nerve terminal NE neuronal uptake system
Increase in synaptic concentrations of NE
Desensitization of nerve terminal 2-adrenoceptors
Increase of neuronal NE release during normal rates of
neuronal firing
Further increase in synaptic concentrations of NE
Desensitization of postsynaptic -adrenoceptors with
no change in postsynaptic 1-adrenoceptor sensitivity
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N
O
R1
R2 C
R1
C
R1R1: -(CH2)3N(CH3)2R2:H
Imipramine
R1: =CH(CH2)2N(CH3)2Amitriptyline
R1: =CH(CH2)2N(CH3)2Doxepin
R1: -(CH2)3NHCH3R2:H
Desipramine
R1: -(CH2)3N(CH3)2R
2
:-Cl
clomipramine
R1: -CH2CH(CH3)CH2N(CH3)2R2:H
Trimipramine
R1: =CH(CH2)2NHCH3Nortriptyline
R1: =(CH2)3NHCH3Protriptyline
R1
H
Structural relationships between various tricyclic antidepressants (TCAs)
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TCA ACUTE TOXICITY
Cardiac Arrhythmias - Propranolol
Convulsion - Diazepam
Anticholinergic symptoms - Physostigmine
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TCA DRUG INTERACTION
Alcohol CNS Depression
Guanethidine - Antihypertensive Action
MAO Hyperpyrexia, Convulsion
Sympathomimetics Hypertensive crisis
Antiepileptics - Efficacy
Oral Hypoglycemics - Efficacy
Phenylbutazone - Efficacy
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SECOND GENERATION ANTIDEPRESSANTS
Maprotiline (Ludiomil), Reboxetine
Amoxapine (Aserdin)
Fluoxetine (Prozac), Citalopram (Celexa)
Trazodone (Desyrel), Nefazodone (Serzone)
Bupropion (Wellbutrin)
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THIRD GENERATION ANTIDEPRESSANTS
Mitrazapine (Remeron)
Nefazodone (Serzone)
Fluvoxamine (Luvox)
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MAO
A. Normal monoamine
transmission
Synapticvesicle
Inactivemetabolites
NorepinephrineSerotoninDopamine
MAO inactivatesmono-amines(norepinephrine,serotonin, anddopamine)that leak from vesicle
Response
MAO
B. Effect of MAO
inhibitors
Synapticvesicle
Inactivemetabolites
NorepinephrineSerotoninDopamine
IncreasedResponse
MAO inhibitorsprevent inactivation of
monoamines withinneuron causing excessneurotransmitter todiffuse into synapticspace
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MAO INHIBITORS
Tranylcypromine (Parnate)
Isocarboxazid (Marplan)
Phenelzine (Nardil)
Moclobemide
Deprenyl (Selegiline)
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LithiumLithium
Valproic acidValproic acid
CarbamazepineCarbamazepine
BIPOLAR AFFECTIVE DISORDERBIPOLAR AFFECTIVE DISORDER TREATMENTTREATMENT
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Lithium
IP1IP1
Inositol
PI
PIP PIP2
PLC
IP2
IP3
Lithium
EFFECTS
DAGG
R
Outside
Receptor
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TremorsTremors propranolol, atenololpropranolol, atenolol
Choreoathetosis, motor hyperactivity, ataxiaChoreoathetosis, motor hyperactivity, ataxia
T
hyroid functionT
hyroid function Nephrogenic diabetes insipidusNephrogenic diabetes insipidus amelorideameloride
Chronic interstitial nephritisChronic interstitial nephritis
EdemaEdema
Sick sinusSick sinus -- contraindicationcontraindication
LITHIUMLITHIUM TOXIC EFFECTSTOXIC EFFECTS