SEROTONIN PHARMACOLOGY AND PHYSIOLOGY PP

The pharmacology of serotonin and it's receptors

1. 5- HYDROXYTRYPTAMINE AND 5-HYDROXYTRYPTAMINE RECEPTOR ANTAGONISTS DR. O. J. KEMELAYEFA DEPARTMENT OF PHARMACOLOGY & TOXICOLOGY

2. INTRODUCTION Like histamine, serotonin is widely distributed in nature, being found in plant and animal tissues, venoms, and stings. It is synthesized in biologic systems from the amino acid L-tryptophan by hydroxylation of the indole ring followed by decarboxylation of the amino acid. Hydroxylation at C5 by tryptophan hydroxylase-1 is the rate-limiting step and can be blocked by  p - chlorophenylalanine (PCPA; fenclonine) and by  p - chloroamphetamine . These agents have been used experimentally to reduce serotonin synthesis in carcinoid syndrome but are too toxic for general clinical use.

3. 5-hydroxytryptamine ( 5-HT) Serotonin- vasoconstrictor substance which appeared in the serum when blood clotted. Enteramine – smooth muscle contracting substance presence in the enterochromaffin cells of the gut mucosa. Sources- intestines (90%) , platelets, and brain, wasp, and scorpion sting, invertebrates and plants ( banana, pear, pineapple, tomato, stinging nettle, cowhage ).

4. Synthesis

5. 5-HYDROXYTRYPTAMINE is synthesized from the amino acid tryptophan and degraded primarily by MAO and a small extent by a dehydrogenase. The decarboxylase is non specific , acts on DOPA as well as 5 HTP to produce NA and 5HT

6. 5HT ( SEROTONIN) neurotransmission may be modified at the presynaptic level by inhibiting : Degradation Storage or Reuptake

7. 5HT RECEPTORS

8. Pharmacological actions CVS: larger arteries and veins are characteristically constrictive In the microcirculation 5-HT dilates arterioles and constricts venules, capillary pressure rises and fluid escapes. BP: triphasic response with iv injection of 5-HT in animals Early sharp fall in bp due to coronary chemoreflex Brief rise in bp due to vasoconstriction and increase cardiac output Prolonged fall in bp due to arteriolar dilatation and extravasation of fluid.

9. VISCERAL SMOOTH MUSCLE: 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

10. NERVE ENDING AND ADRENAL MEDULLA: Afferent nerve endings are activated causing tingling and pricking sensation, as well as pain. Depolarization of the visceral afferents elicits respiratory and cardiovascular reflexes, nausea, and vomiting RESPIRATORY: Brief stimulation of respiration and hyperventilation are the usual response

11. PLATELETS: Weak platelet aggregator CNS: Poor entry across blood brain barrier Direct injection in the brain produces sleepiness, changes in the body temperature, hunger, and variety of behavioral effects.

12. Pathophysiological role Neurotransmitter Precursor of melatonin Neuroendocrine function Nausea and vomiting Migraine Haemostasis raynaud’s phenomenon Variant angina

13. Hypertension Intestinal motility Carcinoid syndrome

14. DRUG AFFECTING 5-HT SYSTEM 5-HT PRECURSOR: Tryptophan increase brain 5-HT and produce behavioral effect SYNTHESIS INHIBITORS: P- Chlorophenylalanin selectively inhibit tryptophan hydroxylase and reduce 5-HT level in tissue

15. UPTAKE INHIBITORS: Tricyclic antidepressants inhibits 5-HT uptake along with NA. some like amitriptyline, clomipramine, desipramine, imipramine are selective serotonin reuptake inhibitors, and others uptake inhibitors Fluoxetine, Sertraline. STORAGE INHIBITORS Reserpine irreversibly binds to and inhibits the vesicular monoamine transporters (VMAT2), preventing the uptake of neurotransmitters like dopamine, norepinephrine, and serotonin into storage vesicles within presynaptic neurons. This leads to the depletion of these neurotransmitters in the brain and periphery, causing reduced sympathetic nerve activity, which results in its antihypertensive and tranquilizing effects. 

16. DEGRADATION INHIBITORS: Non- selective MAO inhibitors (tranylcypromine) and selective MAO-A ( clorgyline ) increases 5-HT content by preventing its degradation. NEURONAL DEGENERATION : 5,6-dihydroxytryptamine selectively destroys 5-HT neurons. The 5,6-Dihydroxytryptamine's (5,6-DHT) primary mechanism of action is its selective neurotoxicity to serotonergic neurons, caused by its high affinity for the SERT and its subsequent conversion into electrophilic autoxidation products that alkylate cellular components . At higher doses, it can also act as a dopaminergic and noradrenergic neurotoxin and cause widespread generalized toxicity by damaging cellular structures and promoting the formation of melanin polymers. 

17. 5-HT RECEPTOR AGONISTS D-LYSERGIC ACID DIETHYL AMIDE (LSD) Non-selective 5-HT agonist Activates subtypes of 5-HT receptors including 5-HT1A, 5-HT2A/2C, 5-HT5-7 Antagonize 5-HT2a receptors in ileum AZAPIRONES Buspirone, Gepirone acts as partial agonist of 5-HT 1a receptors in the brain Used as anxiolytic

18. 8 –HYDROXY-DIPROPYL-AMINO-TETRALINE Selective 5-HTA1 agonist Used as experimental tool. SUMATRIPTAN AND OTHER TRIPTAN ( RIZATRIPTAN, ELETRIPTAN,ALMOTRIPTAN,ZOLMITRIPTAN) Selective 5HT1B/1D agonists Most effective in treatment of acute migraine attack

19. CISAPRIDE Prokinetic drug Increase GIT motility Selective 5-HT4 agonist M- chlorophenylpiperazine Active metabolite of antidepressant drug Cisapride is  a gastroprokinetic agent, a drug that increases motility in the upper gastrointestinal tract . It acts directly as a serotonin 5-HT 4  receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system

20. TRAZODONE Found to be agonist of 5-HT 1B, 5-HT2A/2C receptor in the brain. Trazodone is  a medication used in the management and treatment of major depressive disorder . This drug is in the serotonin-antagonist-and-reuptake-inhibitor class of medications; it can be used as a component of combination therapy with other drugs or psychotherapies or as monotherapy for treating depression.

21. CLASSIFICATION OF 5HT RECEPTOR ANTAGONIST

22. 5-HT RECEPTOR ANTAGONISTS Cyproheptadine Methylsergide Ketanserin Clozapine Risperidone Ondansetron

23. CYPROHEPTADINE Block 5-HT2a receptor Utilized in controlling intestinal manifestations of carcinoid and post gastrectomy dumping syndrome. Used in motion sickness, increase appetite, Antagonize priapism caused by 5-HT uptake inhibitor like fluoxetine Side effects: drowsiness, dry mouth, ataxia and confusion

24. METHYSERGIDE Antagonize action of 5-HT on smooth muscle including that of blood vessels Potent 5HT2A/2C Antagonist and non selectively act on 5HT1 receptors Used for migraine prophylaxis by blocking the vasoconstrictor effect of serotonin. Side effect: stomach upset, drowsiness, and dry mouth

25. RISPERIDONE 5HT2A antagonist Ameliorates negative symptoms of schizophrenia Acts by balancing the level of dopamine and serotonin in the brain. Produce extrapyramidal side effects on slightly higher doses.

26. ONDANSETRON Selectively 5HT3 antagonist Remarkable efficacy in controlling nausea and vomiting following administration of highly emetic anticancer drugs and radiotherapy. Side effect: dry mouth, increased thirst, palpitation

27. KETANSERIN Selective 5HT2 receptor blocking property action on 5HT1, 5HT3, 5HT4 receptors. It has been used to reverse pulmonary hypertension caused by protamine. 5HT induced vasoconstriction, platelets aggregation and contraction of airway smooth muscles are antagonized but not contraction of guinea pig ileum or rat stomach. SE: drowsiness, fatigue, headache, sleep disturbances, dry mouth

28. CLOZAPINE 5HT2A/2C antagonist Inverse agonist activity at cerebral 5HT2A/2C receptors Efficacy in resistant cases of schizophrenia. SE: severe neutropenia