Lecture 31 - 3rd Asessment - Antidepressants

PATHOGENESIS AND TREATMENT OF DEPRESSION In every winter’s heart there is a quivering spring, and behind 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

ENDOGENOUS DEPRESSION • Unipolar - Melancholy

• Bipolar – Overactivity / Deep Depression

MONOAMINE HYPOTHESIS

• Hypoadrenergic Disorder - MHPG

• Hyposerotonergic Disorders – 5HIAA

EVIDENCE FAVORING MONOAMINE HYPOTHESIS

• Monoamine Depletors - Depression

• Monoamine Enhancer – Ameliorate Depression

•  CSF Monoamine - Depression

HYPERCORTISOLEMIC HYPOTHESIS

• Overactivity of H-P-A Axis • Plasma Cortisol

PHARMACOTHERAPY - DEPRESSION

• Tricyclic Antidepressants (TCA) • Second Generation Antidepressants

• MAO Inhibitors

TRICYCLIC ANTIDEPRESSANTS • Imipramine (Tofranil) • Desipramine (Norpramin) • Amitriptyline (Elavil) • Nortriptyline (Aventyl) • Protriptyline (Vivactil) • Doxepin (Singequan)

N (CH2)3 imipramine

N (CH2)3 clomipramine

N

CH3

CH CH2 CH2 N

CH3

amitriptyline

Cl CH3 N CH3

CH3 CH3

CH CH2 CH2 N H nortriptyline N N

doxepin

(CH2)3

CH3 H

O amoxapine

N

N

desipramine

CH3 (CH2)3

O

CH CH2 CH2 N

N

N

protriptyline H Cl

CH3 H

CH3 H

A. Normal monoamine transmission

B. Effect of tricyclic antidepressants

Norepinephrine Serotonin Dopamine

Response

Norepinephrine Serotonin Dopamine

Tricyclic antidepressant drugs block re-uptake of neurotransmitter

Increased Response

Inhibition of nerve terminal NE neuronal uptake system Increase in synaptic concentrations of NE Desensitization of nerve terminal α2-adrenoceptors Increase of neuronal NE release during normal rates of neuronal firing Further increase in synaptic concentrations of NE Desensitization of postsynaptic β-adrenoceptors with no change in postsynaptic α1-adrenoceptor sensitivity

O

N

R2

C

C

R1

R1

R1 R1: -(CH2)3N(CH3)2 R2:H Imipramine

R1: =CH(CH2)2N(CH3)2 Amitriptyline

R1: -(CH2)3NHCH3 R2:H Desipramine

R1: =CH(CH2)2NHCH3 Nortriptyline

R1: -(CH2)3N(CH3)2 R2:-Cl clomipramine R1: -CH2CH(CH3)CH2N(CH3)2 R2:H Trimipramine

R1: =CH(CH2)2N(CH3)2 Doxepin

R1

H

R1: =(CH2)3NHCH3 Protriptyline

Structural relationships between various tricyclic antidepressants (TCAs)

PHARMACODYNAMICS and TOXICODYNAMICS of TCA • Sedation – Amitriptyline, Desipramine, Protriptyline • Anticholinergic Activity – Amitriptyline, Nortriptyline, Desipramine • Arrhythmias and Hypotension – Amitriptyline, Doxepin, Nortriptyline • Impotence • Motor Overstimulation – Tremor, Hyperreflexia, Convulsion

TCA ACUTE TOXICITY • Cardiac Arrhythmias - Propranolol • Convulsion - Diazepam

• Anticholinergic symptoms - Physostigmine

TCA DRUG INTERACTION • Alcohol – CNS Depression • Guanethidine -  Antihypertensive Action • Phenylbutazone -  Efficacy • MAO – Hyperpyrexia, Convulsion • Sympathomimetics – Hypertensive crisis • Antiepileptics -  Efficacy • Oral Hypoglycemics -  Efficacy

SECOND GENERATION ANTIDEPRESSANTS • Maprotiline (Ludiomil), Reboxetine • Amoxapine (Aserdin) • Fluoxetine (Prozac), Citalopram (Celexa) • Trazodone (Desyrel), Nefazodone (Serzone) • Bupropion (Wellbutrin)

THIRD GENERATION ANTIDEPRESSANTS • Mitrazapine (Remeron) • Nefazodone (Serzone) • Fluvoxamine (Luvox)

A. Normal monoamine transmission Synaptic vesicle

MAO inactivates mono-amines (norepinephrine, serotonin, and dopamine) that leak from vesicle

MAO Inactive metabolites Norepinephrine Serotonin Dopamine

Response

B. Effect of MAO inhibitors Synaptic vesicle

MAO inhibitors prevent inactivation of monoamines within neuron causing excess neurotransmitter to diffuse into synaptic space

MAO Inactive metabolites Norepinephrine Serotonin Dopamine

Increased Response

MAO INHIBITORS • Tranylcypromine (Parnate) • Isocarboxazid (Marplan) • Phenelzine (Nardil) • Moclobemide • Deprenyl (Selegiline)

BIPOLAR AFFECTIVE DISORDER– TREATMENT



Lithium



Valproic acid



Carbamazepine

Outside Receptor PIP

PIP2

R

PI

PLC

Inositol

G

DAG

IP3 IP1 IP1

IP2

Lithium

Lithium

EFFECTS

LITHIUM – TOXIC EFFECTS 

Tremors – propranolol, atenolol



Choreoathetosis, motor hyperactivity, ataxia



↓ Thyroid function



Nephrogenic diabetes insipidus – ameloride



Chronic interstitial nephritis



Edema



Sick sinus - contraindication