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5-Hydroxytrptamine & it's Antagonist

5-hydroxytryptamine (serotonin) receptor antagonists are drugs that help control nausea and vomiting related to chemotherapy and surgery by blocking serotonin from activating the vomiting reflex. The document details the history, synthesis, and function of serotonin in the body, as well as the pharmacological action of different serotonin receptor subtypes. It discusses the mechanisms through which these antagonists operate, specifically focusing on 5-HT3 receptor antagonists like ondansetron, highlighting their importance in treating chemotherapy-induced nausea and vomiting.

Education◦
Department of Pharmacology Subject :- Pharmacology - 1 Topic :- 5-Hydroxytryptamine & it’s Antagonist
5-Hydroxytrptamine Receptor Antagonists {5HT3RAs} Introduction :- They are a group of drugs which are used to control, prevention, treatment of nausea & vomiting partially that caused by Chemotherapy, radiation therapy or postoperatively. They get their name through their ability to block 5-HT (also known as Serotonin) from activating nerves that bring about the vomiting reflux.
History Overview of important finding in the History of Serotonin before & around the period in which Serotonin was identified as Neurotransmitter, associated with the central Nuclei of the Autonomic Nervous System. 5-Hydroxytryptamine or Serotonin Blockers, were originally discovered in the 1990s & are one of the newest types of anti-vomiting drugs on market. Identification of Serotonin’s vascular properties (publication year : 1912) as an ‘adrenaline mimicking substance’ without attempt to isolate it) by O'Connor preceded the discovery of Serotonin in the gastrointestinal tract by Erspamer (1937) & in Blood by Rapport (1948,1949), Who identified it’s structure as 5-HT [1949].
History of Serotonin 1932 - Bayliss, Ogden “Vasotonins”- Can be removed by interposing lungs 1946-1949 - Joint work of Page, Green, Rapport. 1951 - Hamlin, Fischer (Synthesis of Serotonin) 1953 - Twarog, Page (Serotonin in Human brain) 1956 - Bogdanski, Pletcher, Brodie, Udenfriend First identification of Serotonin in the brain by fluorescence. 1957 - Serotonin as chemical mediator. 1979 - Peroutka, Snider Radioligand binding technology 5HT1, 5HT2 binding sites.
Serotonin Acts As :- • Neurotransmitter • Local Hormone • Component of platelet clotting process • Role in migraine (Headache) • Mediator of Signs & Symptoms of Carcinoid syndrome (carcinoid Tumor) (Serotonin antagonists as TREATMENT)
5-HYDROXYTRYPTAMINE (5HT, Serotonin) Synonyms :- 5-HT, 5-Hydroxytryptamine, Enteramine, Thrombocytin, 3-(β-Aminoethyl)-5- hydroxyindole, Thrombotonin Chemical Formula :- C10H12N2O Approximately 90% of Human body’s total serotonin is located in the enterochromaffin cells in the GI tract, where it is used to regulated intestinal movements.
1.) Serotonin was the name given to the vasoconstrictor substance which appeared in serum when blood clotted & Enteramine to the Smooth muscle. 2.) In the early 1950’s both were shown to be 5-hydroxytryptamine (5HT). 3.) About 90% of body’s Content of 5-HT localized in the intestines; most of the rest is in platelets & brain. 4.) It is also found in wasp (Flying insect) & Scorpion sting & widely distributed in invertebrates & plants (banana, pear, pineapple, tomato, stinging nettle, cowage).
Synthesis & Destruction
1.) 5-Hydroxytryptamine β-aminoethyl-5- hydroxyindole. 2.) It is Synthesized from the amino acid tryptophan & degraded primarily by MAO & to a small extent by a dehydrogenises. 3.) The decarboxylase is non-specific, acts on DOPA as well as 5-HTP to produce NA and 5- HT respectively.
How Do Serotonin Blocking Drugs Works :-
- Cells lining the gastrointestinal tract release serotonin when damaged by Chemotherapy and Radiation therapy. This Serotonin binds to Serotonin receptors on nerves that transmit impulses to turn stimulates other nerves involved in the vomit reflex. 5-HT3 receptor antagonists prevents serotonin from binding to 5-HT3 receptors in the small intestine thereby reducing the likelihood of nausea & vomiting. The way 5-HT3 receptor antagonists work to prevent postoperative nausea &vomiting is less well understood. - Vomiting & nausea are brought about by a complex pathway that involves several steps. Ultimately this pathway involves activation of an area within the brain known as the “vomiting centre”. This centre is responsible for co- ordinating signals from the body, processing them, & activating the vomiting reflex. The vomiting centre receives signals from different parts of the brain, including the balance centre, in addition to the stomach & throat.
SEROTONERGIC (5-HT) RECEPTORS :-
1.) Gaddum & Picarelli (1957) Classified 5-HT receptors into musculatropic (D type) Neurotropic (M type). 2.) Four Families of 5-HT receptors (5-HT1, 5-HT2, 5-HT3, 5-HT4-7). 3.) All 5-HT receptors (except 5-HT3) are G protein Couples receptors which function through decreasing (5-HT1) or increasing (5-HT4, 5-HT6, 5-HT7). - Based on biochemical & pharmacological Criteria, Serotonin receptors are classified into seven main receptor subtypes 5-HT1-7. - Major pharmacotherapeutic importance are those designated 5-HT1, 5-HT2, 5-HT4 & 5-HT5-7. All which are G-protein-Coupled where as the 5-HT3 subtypes represents a ligandgated ion channel.
Drug acting on Serotonergic Neurotransmission :- - The Figure above depicts how Serotonin neurotransmission may be modified at the presynaptic level by inhibiting degradation storage or reuptake.
5-HT1 Receptors 1.) Five Subtypes (5-HT1A,B,D,E,F) have been identified. 2.) The 5-HT1C receptor is now designated 5-HT2C. 3.) All Subtypes of 5-HT1 receptor inhibits adenylcyclase. 4.) The Most important location of 5-HT1A receptor are Raphe Nuclei of brain stem & hippocampus. 5-HT1 Receptors Agonists The 5-HT1 receptors agonists are a subfamily of the 5- HT Serotonin receptors that binds to the endogenous neurotransmitter Serotonin.
- Mediate inhibitory neurotransmission, including 5- HT1A, 5-HT1B, 5-HT1D, 5-HT1E & 5-HT1F. - There is no 5-HT1C receptors, as it was reclassified as the, 5-HT2C receptor. 5-HT1AAgonists :- Busirone is a partial 5-HT1A agonist used clinically for the treatment of anxiety & depression. 5-HT1B & 5-HT1D Agonists :- The ‘Triptans’ are as drug class useful as abortive medication for the treatment of acute migraine headaches. They are very effective medication that bind to 5-HT1B & 5-HT1D receptors in cranial vessels which leads to vasoconstriction & decreased releases of nuropeptides involved in ‘Sterile Inflammation’.
5-HT2 Receptors 1.) There are 3 Subtypes of 5-HT2 receptors; all are coupled to phospholipids C. 2.) 5-HT2A receptor also inhibits K+ Channels resulting is slow depolarization of neurons. 5-HT2C Agonist Trazodone was previously believed to be a 5-HT2C receptor antagonist. However, recent publications report that trazodone would behave as a 5-HT2C agonist. This drug is used generally as Somnorific.
5-HT2 Antagonists
5-HT3 Receptor The 5- Hydroxytryptamin e3 (5-HT3) receptor is a member of the cys-loop family of legend gated ion channels, of which the nicotinic acetylcholine receptor is the prototype. Fig.1 :- Representative traces of inward currents evoked by 25mM 5-HT in mouse 5-HT3A & 5-HT3A/B receptors.
1.) This is the neuronal 5-HT receptor which rapidly depolarize nerve ending by opening the cation channel located within it. 2.) Somatic & autonomic nerve endings pain, itch, coronary chemo reflux, Fall in BP due to withdrawal of sympathetic tone. 3.) Nerve endings in myentaic plexus augmentation of peristalsis, emetic reflux. 4.) Area postrema & nucleus tracts solitaries in brain stem nausea, vomiting. 5-HT3 Antagonists :- This class included drugs such as Ondansetron, palonosetron & others. There agents are particularly useful in the treatment of chemotherapy induced nausea & vomiting(CINV).
5-HT4-7 Receptors 5-HT4 Agonist :- Cisapride is a Serotonin and cholinergic agonist used as a prokinetic drug. Its was withdrawn from the U.S. market because of cardiovascular toxicity. 1.) The 5-HT4 receptor has been demonstrated in the mucosa, plexuses & smooth muscle of Gut probably involved in augmenting intestinal secretion & peristalsis. 2.) It is also located in brain.
Reference :- • https://www.myvmc.com/treatments/5-ht3-receptor-antagonists-serotonin- blockers/ • (Date :- 08/11/2017 Time :- 5.23pm) • http://pharmacologycorner.com/serotonin-5ht-receptors-agonists-antagonist/ • (Date :- 08/11/2017 Time :- 9.30pm) • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103470/ • (Date :- 09/11/2017 Time :- 7.30am) • Essential of Medical Pharmacology By K.D. Tripathi 5th edition, 2003 Reprint – 2004 Page no. : 145 to 155