Drugs Affecting 5HT System

DRUGS AFFECTING 5HT SYSTEM

1. 5HT Precursor

Tryptophan increases brain 5HT and produces behavioural effects because tryptophan hydroxylase in brain is not saturated by the amount of tryptophan available physiologically.

2. Synthesis Inhibitor

p-Chlorophenylalanine (PCPA) selectively inhibits tryptophan hydroxylase (rate limiting step) and reduces 5HT level in tissues. It is not used clinically due to high toxicity.

3. Uptake Inhibitor

Tricyclic antidepressants inhibit 5HT uptake along with that of NA. Some like fluoxetine, sertraline are selective serotonin reuptake inhibitors (SSRI).

4. Storage Inhibitor

Reserpine blocks 5HT (as well as NA) uptake into storage granules and causes depletion of all monoamines. Fenfluramine selectively releases 5HT and has anorectic property.

5. Degradation Inhibitor

Nonselective MAO inhibitor (tranylcypromine) and selective MAOA inhibitor (chlorgyline) increase 5HT content by preventing its degradation.

6. Neuronal Degeneration

5, 6 dihydroxytryptamine selectively destroys 5HT neurones.

7. 5HT Receptor Agonists

A diverse range of compounds producing a variety of actions have been found to activate one or more subtypes of 5HT receptors. Notable among these are:

a.      D-Lysergic acid diethyl amide (LSD)—Synthesized as an ergot derivative LSD was found to be an extremely potent hallucinogen. It is a nonselective 5HT agonist— activates many subtypes of 5HT receptors including 5HT_1A on raphe cell bodies, 5HT_2A/2C (probably responsible for the hallucinogenic effect) and 5HT₅₇ in specific brain areas. However, it antagonizes 5HT_2A receptors in the ileum. A number of other hallucinogens also interact with brain 5HT receptors.

b.     Azapirones like buspirone, gepirone and ipsapirone are a new class of antianxiety drugs which do not produce sedation. They act as partial agonists of 5HT_1A receptors in the brain.

c.      8-Hydroxydipropylamino tetraline (8OH DPAT) is a highly selective 5HT_1A agonist which is used only as an experimental tool.

d.     Sumatriptan and other triptans are selective 5HT_1B/1D agonists, constrict cerebral blood vessels and have emerged as the most effective treatment of acute migraine attacks.

e.      Cisapride This prokinetic drug which increases gastrointestinal motility is a selective 5HT₄ agonist. Renzapride is still more selective for 5HT₄ receptors.

f.       m-chlorophenyl piperazine (mCPP) It is an active metabolite of the antidepressant drug trazodone; found to be an agonist of 5HT_1B as well as 5HT_2A/2C receptors in the brain. In human volunteers it induces anxiety and enhances release of prolactin, ACTH, and growth hormone.

8. 5HT Receptor Antagonists

A variety of drugs block serotonergic receptors; many are nonselective, but some newer ones are highly subtype selective.