Serotonin (5-Hydroxytryptamine) PDF

Serotonin (5-Hydroxytryptamine) By Dr. Ali H.Saud BSc (Pharm) MSc PhD Department of pharmacology College of Medicine Basra university November 26,2024  Objectives 1.Describe serotonin agonists and antagonists 2.Describe...

Serotonin (5-Hydroxytryptamine) By Dr. Ali H.Saud BSc (Pharm) MSc PhD Department of pharmacology College of Medicine Basra university November 26,2024  Objectives 1.Describe serotonin agonists and antagonists 2.Describe uses of serotonin agonists and antagonists 3.List adverse effects of serotonin agonists and antagonists  Autacoids These are heterogeneous group of chemical substances with wide spectrum of biological effects , synthesized by different tissues and exerting local effect with no or very minute serum level, and these included: ✔ histamine ✔ serotonin ✔ Prostaglandins ✔ Kinins ✔ leukotriens  Introduction Serotonin is one of most important neurotransmitter has many physiological roles and serotonin agonists and antagonists have many clinical applications. Distribution of serotonin In human , about 90% of total body serotonin present in enterochromaffin cells , 8% in platelets and 2% in CNS. Biosynthesis of serotonin  Fate of serotonin Serotonin under go metabolism by monoamine oxidase enzyme (MAO) into 5-hydroxy indol acetic acid(5-HIAA), this compound is water soluble. Excessive excretion of (5-HIAA) can seen in the following conditions and considered as diagnostic test for tumors:- 1. Carcinoid syndrome 2. Ingestion of bananas  Physiological roles of serotonin in the body 1. Regulation of temperature. 2. Control of appetite. 3. Perception of pain. 4. In pathogenesis of carcinoid syndrome. 5. In pathogenesis of migraine headache. 6. In pathogenesis of depression. 7. In pathogenesis of anxiety. 8. Involved in intestinal motility. 9. It acts as a neurotransmitter in the brain. 0. Control of vomiting. 1. Involved in sleep 2. Involved in thinking and cognition  Mode of action of 5-HT Serotonin exerts its action by binding to 7 subtypes of receptor six of them are G-protein coupled and only one of them 5-HT3 is ionic channels coupled. 5-TH1 5-HT5 5-HT2 5-HT6 5-HT3 5-HT7 5-HT4  Pharmacological action of 5-HT 1.Effect on Cardiovascular system serotonin produces triphasic response which includes: A. Bradycardia, decrease cardiac out put and decrease blood pressure due to chemoreceptor reflex. B. Vasoconstriction which cause increase in blood pressure. C. Then, again a decrease in blood pressure attributed to vasodilation in vessels supplying skeletal muscle.  Pharmacological action of 5-HT(cont.) 2.Effect on Respiratory system In normal person, serotonin has a small direct stimulant effect on bronchiolar smooth muscle due to release of Ach from bronchial nerve ending, while in patient with carcinoid tumor bronchospasm is noticed. Serotonin may also cause hyperventilation as a result of the chemoreceptor reflex or stimulation of bronchial sensory nerve endings..  Pharmacological action of 5-HT(cont.) 3.Effect on gastrointestinal tract Serotonin has a powerful stimulant effect on gastrointestinal smooth muscle, increasing tone and facilitating peristalsis movement, this is probably due to its action on the 5-HT4 receptor that found in the smooth muscle of the bowel, furthermore activation of 5-HT4 receptor that found in the ENS may cause release of Ach which in turn enhance GI motility, cisapride(withdrawal from US market in 2000) is a potent 5-HT4 agonist was used for treatment of GERD  Pharmacological action of 5-HT(cont.) 4.Effect on nervous system Serotonin act as neurotransmitter in the CNS, furthermore , serotonin is a potent stimulant of pain and itch sensory nerve endings and is responsible for some of the symptoms caused by insect and plant stings  Pharmacological action of 5-HT(cont.) 5.Effect on secretion of glands Serotonin has inhibitory effects on exocrine glands secretions. 6.Effect on the uterus Serotonin in high dose may cause fetal distress due to impaired placental blood flow  Serotonin receptor agonists 1. Buspirone : has agonist activity on 5HT-1A receptor, used for anxiety and dose not produce addiction and its preferred in elderly patients 2. Almotriptan,Eletriptan,Frovatriptan,Naratriptan ,Rizatriptan,Sumatriptan and Zolmitriptan have agonist activity on 5-HT 1D/1B receptors used almost exclusively for migraine headache.  Serotonin receptor agonists(cont.) S/E of triptans 1. Tingling 2. Chest pain Disadvantage of triptans 1.Short duration of action 2. Very expensive  C/I of triptans 1.All are contraindicated in IHD 2. Frovatriptan is contraindicated in patients with peripheral vascular disease. 3. Naratriptan is contraindicated in patients with severe hepatic or renal impairment 4. Zolmitriptan is contraindicated in patients with Wolff-Parkinson-White syndrome.  Serotonin receptor agonists(cont.) 3. Cisapride: has agonist activity on 5-HT4 receptor that found in the gastrointestinal tract and in the heart, so its used in treatment of GERD. Cisapride was withdrawal from market in 2000. Why? 4. Tegaserod: has partial agonistic activity on 5-HT 4, and used for irritable bowel syndrome (IBS) with constipation, with drawl from market in 2007. 5. Dexfenfluramine: was widely used as an appetite suppressant due to its stimulant effect on 5-HT receptor. 6. fluoxetine: it will further discus with antidepressant drugs  Serotonin receptor agonists(cont.) 7. Lorcaserin: 5-Ht2C receptor appetite suppressant for obesity 8. Ergot alkaloids: 5-HT1/2 and other receptors Ergots act on the following receptors: 1- Serotonin receptor. 2- α adrenoceptor. 3- Dopamine receptor. Ergots act as agonist , partial agonist or antagonist  Serotonin syndrome Serotonin syndrome occurs when overdose with a single drug, or concurrent use of several drugs, results in excess serotonergic activity in the central nervous system. characterized by muscle rigidity, hyperthermia ,arrhythmia, hypertension and headache.Should be treat immediately by 5-HT blockers and sedative agents like diazepam  Serotonin receptor antagonists 1.Cyproheptadine: has potent 5-HT2 receptor blocking as well as H1 blocking actions. It cause sedation due to its antimuscarinic effect. Therapeutic uses: 1.Cold urticaria 2. Appetite stimulant 3. Prophylaxis of migraine 4. Carcinoid syndrome. 5. Allergic rhinitis Serotonin receptor antagonists(cont.) 2. Ketanserin: exert its action by block 5-HT2A as well as α1 adrenoceptors, also it inhibit platelet aggregation. It was used in the treatment of hypertension. 3. Ondansetron: is the prototypical 5-HT 3 antagonist. This drug is very important in the prevention of nausea and vomiting associated with surgery and cancer chemotherapy.  THE ERGOT ALKALOIDS Clinical uses 1. Bromocriptine: Used in acromegaly and hyperprolactinaemia 2. Ergometrine: Used in post-partum hemorrhage (PPH) 3. Lysergic acid diethylamide (LSD) :It is a hallucinogenic agent 4. Methysergide: Used in migraine prophylaxis 5. Dihydroergotoxin : Used in cerebral insufficiency and Alzheimer’s dementia.  HOME WORK Q1.Name some 5-HT receptor antagonist? Q2.Where is serotonin distributed in the body ? Q3. What is the role of 5-HT agonist in migraine?