DEPRESSION
3 December 2004
ANTIDEPRESSANT DRUGS
Mood disturbance
Abnormal conditions
Primary
Secondary
INTRODUCTION
Norepinephrine (NE) and serotonin (5-HT) are neurotransmitters in pathways that function in the expression of mood.
Sajeda Sabt
Pharmacology
Problem# 2
DEPRESSION
3 December 2004
Anti-Depressant drugs
TRICYCLICS
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
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
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
5-HT + NE
Dopamine, phenethylamines
Sajeda Sabt
Pharmacology
Problem# 2
DEPRESSION
3 December 2004
REVERSIBLE
IRREVERSIBLE
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
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
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
Sajeda Sabt
Pharmacology