1. Drugs Used in Depression (Old Group)
DR: Asmaa Fady.
MD., MSC, M.B, B.Ch
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10/1/2019

2. Learning objectives: By the end of the lecture, the student should:
Realize neurotransmitter defect in different types of depression.
Mechanism of Action of antidepressants (biogenic amine theory)
Classify the existing antidepressant drugs.
Explain the Pharmacodynamics potentials, Pharmacokinetics differences Side effects and uses of TCA drugs.
Explain the Pharmacodynamics potentials, Pharmacokinetics differences Side effects and uses of MAOI drugs.
Understand Drug interaction of old type antidepressants.
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10/1/2019

3. Definition:
Depression is a common mood disorder characterized by inability to experience pleasure, changes in sleep patterns and appetite, loss of energy and suicidal thoughts.
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4. Classification of Depressive Disorders
Type
Cause
Treatment lines
1- Reactive “Secondary” Depression.
60%
Adverse life events, death or diseases
Spontaneous Recovery
2- Major “Endogenous” unipolar Depression.
25%
-Spontaneous..
- Biochemical causes
Antidepressants.
Electro-Convulsive Therapy (ECT).
3- Bipolar Affective “Manic-Depressive” Disorder
15%
Spontaneous.
-Genetically determined. - Biochemical error.
Lithium. +
Antidepressant. + antipsychotic
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5. Mechanism of Action of antidepressants (biogenic amine theory)
the biogenic amine theory proposes that depression is due to a deficiency of monoamines, such as norepinephrine and serotonin, at certain key sites in the brain.
Conversely, the theory proposes that mania is caused by an overproduction of these neurotransmitters.
Monoamine depletion causes the post synaptic receptors upregulations leads to depression.
Abnormally functioning gene causing depression.
However, the biogenic amine theory of depression and mania is overly simplistic.
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10/1/2019

6. NE & 5HT systems:
NE & 5HT pathways are originated in the mid brain, which send their axons to the cortex, cerebellum and limbic areas.
NE function is related to mood, cognition, motivation, memory and emotional responses.
5HT is involved in anxiety, sexual behavior, temperature regulation, CSF production.
Antidepressants potentiate, either directly
or indirectly, the actions of
norepinephrine and/or serotonin (5-HT)
in the brain.
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10/1/2019

7. Classification Of Anti-Depressants
Old group
TCAs
MAOIs
New group
SSRIs
SNRIs
Atypical AD
(1st generation)
2nd generation
3rd generation
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8. Classification Of Anti-Depressants
1)First generation antidepressants :
a. Tricyclic Antidepressants (TCAs), the most widely used were:
Amitriptyline
Doxepin
b. Monoamine Oxidase Inhibitors (MAOIs), the two most widely used were:
Moclobemide
Phenelzine
Unpleasant side effects: constipation, sweating, shaking or trembling, and difficulty sleeping.
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9. Classification Of Anti-Depressants
2) Second generation antidepressants : (SSRIs )
known as Selective Serotonin Reuptake Inhibitors (SRRIs),
They were introduced at the beginning of the 1980s.
Commonly used agents were:
Fluoxetine (Prozac)
Citalopram
Paroxetine
Sertraline
SSRIs quickly became widely used instead of TCAs and MAOIs as they were considered to cause far less troublesome side effects.
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10. Classification Of Anti-Depressants
3) Third generation antidepressants : (SNRIs )
known as Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
were introduced during the 1990s
Examples of SNRIs include:
Venlafaxine.
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11. Tricyclic Antidepressants (TCA)
* Members:
1- Imipramine
2- Desipramine
3- Clomipramine
4- Amitriptyline
5- Nortriptyline
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12. TCAs: Pharmacokinetics
1- Absorption:
orally extensive hepatic first pass metabolism.
2_ Distribution:
Highly bound to plasma & tissue proteins.
Highly lipid soluble Pass easily BBB & Placental barriers.
3- Hepatic Metabolism:
a- Change of Tertiary amines Active Secondary amines:
- Imipramine (Active) Active Desipramine.
- Amitriptyline (Active) Active Nortriptyline.
b- Glucuronic acid conjugation Inactive metabolites.
4- Excretion in urine mainly in conjugated form.
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13. Cocaine like action Alpha 2- 5HT presynaptic inhibitory receptors
Alpha and beta adrenergic receptors
5HT receptors
10/1/2019
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14. TCAs Pharmacodynamics: (Mechanism of Action)
Inhibit Neuronal Uptake1 of Noradrenaline & Serotonin
NA, 5HT Inter-Synaptically.
Actions of Tricyclic Antidepressants:
1- Antidepressant Effect:
 Weeks  Weeks 
The antidepressant effect appears after 2-3 WEEKS and lasts for 2-3 WEEKS after stop of TCA.
2- SEDATION: Especially at beginning of treatment & in Normal individuals.
Amitriptyline > Imipramine > Desipramine.
3- Lower Seizure Threshold.
4- Anti-Cholinergic (Anti-Muscarinic = Atropine-Like).
Amitriptyline > Imipramine > Desipramine.
5- Anti-Histaminic (H1-Block).: sedation.
6- Alpha 1 blocking effect (VD hypotension reflex tachycardia
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15. Therapeutic Uses of TCA:
1- Psychic depression (Main Use). 2- Panic & Phobic states. 3- Obsessive Compulsive disorders (Clomipramine or Better SSRI as Fluoxetine). 4- Chronic neuropathic pain 5- Nocturnal enuresis in children (Imipramine). But ADH is better alternative
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16. Adverse Effects & Toxicity OF TCA
1- Delayed onset of action (2-3 weeks). 2- C.N.S.: SEDATION, Seizures, Tremors, Confusion & Delirium. 3- C.V.S.: a- Postural hypotension (alpha1-block). b- Tachycardia (Atropine-like). c- CARDIOTOXICITY : FATAL ventricular TACHYARRHYTHMIAS (prolonged QRS complex) 4- ATROPINE-like effects (Blurring of vision, dry mouth, tachycardia, constipation & urinary retention) Take care: Contraindicated in: Glaucoma & Enlarged Prostate. Alpha 1 blovking effect.
10/1/2019

17. Adverse Effects & Toxicity OF TCA
5- Weight gain.
6-Allergic Obstructive jaundice & Agranulocytosis.
7- Low therapeutic index
8- Acute Toxicity: Common & FATAL.
a- Manifestations: Excitement, Seizures, Arrhythmia & Atropine Like effect.
b- Treatment: - ICU - Stomach wash + Activated Charcoal.
+ Diazepam to Treats excitement & Seizures.
+ Phenytoin to Treats Seizures & Ventricular arrhythmias.
+ NAHCO3 to Treats Ventricular arrhythmias.
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18. Drug Interactions of TCA
1- Potentiate:
a- Sedatives e.g. Alcohol.
b-Anticholinergics e.g. Major tranquillizers & Anti- Parkinsonians.
c-Direct Catecholamines e.g. Adrenaline by # their Neuronal Uptake.
2- Antagonize:
Antihypertensive effect of Clonidine & alpha Methyl-Dopa due to Down- regulation of Presynaptic alpha 2-receptors.
3- TCA + MAO-I :
Severe Atropine-like Toxicity (Hypertension & Convulsions)
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19. Monoamine Oxidase Inhibitors (MAOIs):
Monoamine oxidase (MAO) is an enzyme responsible for degradation of neurotransmitters (NE, dopamine, 5-HT)
Mechanism of action:
MAOIs, such as phenelzine, form stable complexes with the enzyme, causing irreversible inactivation.
This results in increased stores of norepinephrine, serotonin, and dopamine within the neuron.
Antimuscarinic action.
Alpha 1 blocker effect.
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20. The least used AD due to its side effects and multiple drug & food interaction
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21. Classification of MAO-I
Non selective MAO inhibitors: → Antidepressants.
i.e Phenelzine.
2) Selective MAO-A inhibitors: (substrate is NA & 5-HT.)
i.e Moclobemide- Clorgyline.
3) Selective MAO-B inhibitors: (substrate is only dopamine)
Anti-Parkinsonian.
i.e Selegiline
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22. Therapeutic uses of MAO-I
MAOIs are indicated for depressed patients who are unresponsive or allergic to TCAs and SSRIs or who have strong anxiety.
A special subcategory of depression, called atypical depression, may respond better to MAOIs.
The antidepressant effect appears after 2-3 WEEKS and lasts for 2-3 WEEKS after stop of MAOI.
 Weeks  Weeks .
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23. Adverse Effects & Toxicity of MAO-I
1- C. N. S.: Excitation → Insomnia, hyperhidrosis, hallucination & Seizures.
2- C. V. S.: Hypotension & Postural hypotension (alpha 1 blockers)
3- Some has Atropine-like effect.
4- Weight gain.
5- hepatotoxicity.
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24. Drug- food Interactions of MAO-I
1- Cheese Reaction:
Eating or drinking foods that contain TYRAMINE or DOPA such as Aged cheese, Broad beans or Yogurt → MAOI inhibits degradation of tyramine obtained from the diet.
Tyramine causes the release of large amounts of stored catecholamines from nerve terminals, Severe Hypertension (Pheochromocytoma-like reaction).
Treatment by IV Phentolamine or Nitroprusside + B Blocker.
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25. Drug- drug Interactions of MAO-I
2- L-DOPA (Anti-Parkinsonian) → Agitation & Hypertension.
3- SSRI (Fluoxetine), Melatonin & Meperidine → Serotonin Syndrome → Excitation, Hyperthermia, Cardiac arrhythmia, Hypotension, Tremors & Coma. May be FATAL.
4- MAOI + TCA → Toxicity.
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26. اسم ورقم المقرر – Course Name and No.
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