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Seretonin (5HT) and Its Antagonists Pharmacology

This document discusses serotonin (5-hydroxytryptamine or 5-HT), its sources, physiological effects, and pharmacological actions. It highlights the importance of serotonin in various bodily functions, pathophysiological roles, and its interaction with various drugs including agonists and antagonists. Additionally, it covers the impact of serotonin on conditions such as migraine, nausea, and hypertension.

Health & Medicine◦
DR. CHAVAN P. R. PHARM D Seretonin and Its Antagonists
Introduction 5-hydroxytryptamine (5-HT)  Seretonin - vasoconstrictor substance which appeared in the serum when blood clotted  Enteramine - smooth muscle contracting substance present in enterochromaffin cells of gut mucosa Sources – intestines (90%), platelets and brain, wasp and scorpion sting, invertebrates and plants (banana, pear, pineapple, tomato, stinging nettle, cowhage).
Receptors
Pharmacological actions CVS  Larger arteries and veins are characteristically constricted,  In the microcirculation 5-HT dilates arterioles and constricts venules, capillary pressure rises and fluid escapes.  BP: Triphasic response with i.v. injection of 5-HT in animals. • Early sharp fall in BP—due to coronary chemoreflex. • Brief rise in BP—due to vasoconstriction and increased cardiac output. •Prolonged fall in BP—due to arteriolar dilatation and extravasation of fluid.
Visceral smooth muscles  Potent stimulation of G.i.t. and constriction of bronchi Glands  Inhibits gastric secretion (both acid and pepsin), but increases mucus production and has ulcer protective property
Nerve endings and adrenal medulla  Afferent nerve endings are activated causing tingling and pricking sensation, as well as pain.  Depolarization of visceral afferents elicits respiratory and cardiovascular reflexes, nausea and vomiting Respiration  Brief stimulation of respiration and hyperventilation are the usual response
Platelets  Weak Platelets aggregator CNS  Poor entry across blood brain barrier  Direct injection in the brain produces sleepiness, changes in body temperature, hunger and a variety of behavioural effects.
Pathophysiologic role 1. Neurotransmitter 2. Precursor of melatonin 3. Neuroendocrine function 4. Nausea and vomiting 5. Migraine 6. Haemostasis 7. Raynaud’s phenomenon 8. Variant angina 9. Hypertension 10. Intestinal motility 11. Carcinoid syndrome
DRUGS AFFECTING 5-HT SYSTEM 5-HT PRECURSORS  Tryptophan increase brain 5-HT & produce behavioral effects. SYNTHESIS INHIBITORS  p-Chlorophenylalanin selectively inhibit tryptophan hydroxylase & reduce 5-HT level in tissue. UPTAKE INHIBITORS  Tricyclic antidepressants inhibit 5-HT uptake along with NA .Some like fluoxetine ,sertraline are selective serotonin reuptake inhibitors.
STORAGE INHIBITORS  Reserpine block 5-HT uptake into storage granules & cause depletion of all cell monoamines . DEGRADATION INHIBITORAS  Non-selective MAO inhibitors (tranylcypromine) & selective MAO –A inhibitors (chlorgyline) increase 5-HT content by preventing its degradation. NEURONAL DEGENRATION  5,6 Dihydroxytryptamine selectively destroys 5-HT neurons .
5-HT RECEPTOR AGONISTS D-Lysergic acid diethyl amide(LSD)  Non selective 5-HT agonist  Activates subtypes of 5-HT receptors including 5-HT1A, 5HT2A/2C ,5HT5-7  Antagonize 5HT2A receptor in ileum AZAPIRONES  Like buspirons ,gepirone act as partial agonist of 5HT1A Receptor in brain. 8 HYDROXYDIPROPYLAMINO TETRALINE  Selective 5HT1A agonist  Used as experimental tool
SUMATRIPTAN AND OTHER TRIPTAN  Selective 5HT1B/1D agonists  Most effective in treatment of acute migraine attack CISAPRIDE  Prokinetic drug  increase g.i.t motility  Selective 5HT4 agonist  M-Cholorophenylpiperazine  Active metabolite of antidepressant drug TRAZODONE  found to be agonist of 5HT1B 5HT2A/2C Receptor in brain.
5-HT RECEPTOR ANTAGONISTS  Cyproheptadine  Methysergide  Ketanserin  Clozapine  Risperidone  Ondansetron
CYPROHEPTADINE  Block 5HT2A receptor  Utilized in controlling intestinal manifestations of carcinoid & postgastrectomy dumping syndrome  Antagonize priapism caused by 5HT uptake inhibitor like fluoxetine  Side effects: Drowsiness, Dry Mouth , Ataxia Confusion.
METHYSERGIDE  Antagonize action of 5HT on smooth muscles including that of blood vessels  Potent 5HT2A/2C ANTAGONIST & Non selectively act on 5HT1 receptors  Used for migraine prophylaxis
RISPERIDONE  5HT2A antagonist  Ameliorates negative symptoms of schipherenia  Produce extrapyramidal side effects on slightly higher doses
ONDANSETRON  Selectively 5HT3 Antagonist  Remarkable efficacy in controlling nausea & vomiting following administration of highly emetic anticancer drugs & radiotherapy .
KETANSERIN  Selective 5HT2 receptor blocking property with action on 5HT1,5HT3 & 5HT4 receptors .  5HT induced vasoconstriction ,platelets aggregation & contraction of airway smooth muscles are antagonized but not contraction of guinea pig ileum or rat stomach .
CLOZAPINE  5HT2A/2C blocker  Inverse agonist activity at cerebral 5HT2A/2C Receptors  Efficacy in resistant cases of schizophrenia
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