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Problem# 2

DEPRESSION

3 December 2004

ANTIDEPRESSANT DRUGS
Mood disturbance

Abnormal conditions

Normal emotion that affect us in response to negative or positive event

Primary

Secondary

Unipolar (Depressive disorder), 1 episode or more

Bipolar Both directions Depression + mania)

Other psycho. Illness (Schizophrenia or dementia)

Physical illness (Endocrine or cancer)

INTRODUCTION
Norepinephrine (NE) and serotonin (5-HT) are neurotransmitters in pathways that function in the expression of mood.

What is the theory of mood disorders?


Biogenic amine theory (Amine hypothesis of mood) depression due to a deficiency of monoamines (NE, 5, HT) at synapses at certain key sites in the brain ( esp. the LIMBIC SYSTEM ) Mania is caused by an overproduction of these neurotransmitters. DRUG TREATMENT OF AFFECTIVE DISORDERS

Antidepressants Drugs (Mood Elevating Drugs)

Mood Stabilizing Drugs (Anti-Maniac Drugs)

Sajeda Sabt

Pharmacology

Problem# 2

DEPRESSION

3 December 2004

Anti-Depressant drugs

TRICYCLICS

MONOAMINE OXIDASE INHIBITORS

ATYPICAL ANTIDEPRESSANTS

SSRI

NOTE
THEY generate these classes of drugs based on the removal mechanism of monoamines in the synaptic cleft, which are 1. Reuptake mechanism I 2. destruction of the monoamines by monoamine oxidase inhibitors 3. they go to the circulation and destroyed in the tissues by the enzyme COMT

TRICYCLICS
EXAMPLES

Also called norepinephrine reuptake inhibitors May inhibit serotonin reuptake also Called tricyclics because their structure contains 3 rings.

TERTIARY AMINE TRICYCLICS Amitriptyline inhibit NE, 5HT Imipramine inhibit NE, 5-HT

SECONDARY AMINE TRICYCLICS Desipramine inhibits NE Nortriptyline NE Protriptyline NE

GENERAL MECHANISM OF ACTION Inhibit the neuronal neurotransmitter re-uptake of NE and Serotonin in the presynaptic nerve terminals concentration of monoamines in the synaptic cleft anti-depressant effect

Sajeda Sabt

Pharmacology

Problem# 2

DEPRESSION

3 December 2004

OTHER ACTIONS Block these receptors: Serotogenic ( block Ach receptors) adrenergic Muscarinic Therefore they produce there side effects, which are: Antimuscarinic effects) Blurred vision, dry mouth, constipation .etc Arrythmias due to increase NE activity Block adrenergic cause postural hypotension Sedation due to serotonergic receptors blockers

NOTE Do not block dopamine transport Indirectly can enhance forebrain dopamine activity Have low therapeutic index. Long time to produce the effect, starts to begin after 2 weeks and the full effect will appear after 4-6 weeks Long term use down regulation of receptors

MONOAMINE OXIDASE INHIBITORS (MOA-I)

WHAT IS MONOAMINE OXIDASE? It is a mitochondrial enzyme found in neuronal and other tissues, such as the gut and the liver and the platelets. This enzyme inactivates the cytoplasmic neurotransmitters esp. in the neurons and decreases its action on the postsynaptic membrane.

MODE OF ACTION Irreversibly or reversibly inactivates the enzyme MAO, permitting neurotransmitter molecules (NE AND 5-HT) to accumulate in the presynaptic neuron and to leak into the synaptic space

MAO - A Types of MAO MAO -B

5-HT + NE

Dopamine, phenethylamines

Sajeda Sabt

Pharmacology

Problem# 2

DEPRESSION

3 December 2004

SELECTIVE Types of MAO - I NONSELECTIVE

REVERSIBLE

MAO -A Eg:moclobemide MAO -B SELEGLINE

IRREVERSIBLE

E.G: phenelzine, tranylcypromine

Notes
Non- selective MAO has risky effects produce cheese reaction Pt suddenly develops sudden hypertensive crisis and leads to stroke death When taken with sympathomimitic drugs severe effects Therefore the use of MAO inhibitors is now limited because of the complicated dietary restrictions ( tyramine containing food like cheese, chicken liver, beer and red wine) required of patients taking MAO. Tyramine: is destroyed by MAO enzyme primarily, increased in level when giving MAO-I cause increase of catecholamines increase the Bp Should not be administered with SSRI due to risk of life threating ( Serotonin syndrome) Long use of MAO I cause hypotension

SELECTIVE SEROTONIN- REUPTAKE INHIBITORS


NEW DRUGS Unique only drugs that inhibit the serotonin re-uptake ONLY EXAMPLES: Fluoxetine Paroxetime Fluvoxamine Sertraline MODE OF ACTION: SELECTIVE inhibitors for 5-HT receptors Down- regulation of 5-HT receptors Adverse Effects: nausea,, vomiting,insomnia, anxiety, sexual dysfunction, weight loss, tremors

Sajeda Sabt

Pharmacology

Problem# 2

DEPRESSION

3 December 2004

ATYPICAL ANTIDEPRESSANTS

EXAMPLES: nefazodone, Trazodone, mitrazapine Mechanism: mixed effects on reuptake mechanism Some affect dopamine reuptake (Bupropion) Inhibit 5-HT, NE and H1 blocking action ( trazodone) Therefore SEDATION is the most side effect

LITHIUM SALTS

USED FOR BIPOLAR DISORDERS

INORGANIC ION TAKEN ORALLY AS LITHIUM CARBONATE Not known mechanism of action, it may: Interfere with IP3 formation Interfere with CAMP formation. Used prophylactically in treating manic-depressive pts and in treating Narrow therapeutic effect o Monitor of plasma concentration o Many unwanted effect: Nausea, thirst and polyuria (Nephrogenic diabetes insipidus), hypothyroidism CNS toxicity: ataxia, tremor, convulsion Overdose: confusion, cardiac dysrhythmias Alternative mood stabilizing drugs : Carbamazepine ( anti-epileptic drug), Valproate

References: 1. Appointment 2. Lippincott's 3. Katzung

Sajeda Sabt

Pharmacology

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