Serotonin (5-HT) Receptors PDF

Serotonin (5-Hydroxytreptamine 5-HT ) ‫االستاذ الدكتور قاسم صالح النعیمی‬ It is widely distributed in plants and animals. Highest concentration in mammals is found in the pineal gland, acting as a precursor for melatonin. It is synthesized from the amino acid try...

Serotonin (5-Hydroxytreptamine 5-HT ) ‫االستاذ الدكتور قاسم صالح النعیمی‬ It is widely distributed in plants and animals. Highest concentration in mammals is found in the pineal gland, acting as a precursor for melatonin. It is synthesized from the amino acid tryptophan by decarboxylase. hydroxylase decarboxylase Tryptophan (aminoacid)--------------Hydroxytryptophan ------------------5 – Hydroxytreptamine (5-HT) Enzyme Enzyme serotonin is stored in entrochromaffin cells of GIT90%, and 10% is stored in platelets and inside vesicles in nerve endings, and acts on several types of receptors, mainly located in CNS. Pharmacokinetics: Not effective orally, metabolized primarily by MAO enzymes to 5- hydroxyindole acetic acid , and to a small extent by a dehydrogenase. Receptors : Four families of 5-HT receptors (5-HT1, 5- HT2, 5-HT3, 5-HT4-7) comprising of 14 receptor subtypes have so far been recognized. - 5-HT1 Receptors : Five subtypes (5-HT1 A, B,C, D, E, ) have been identified, and all are present in CNS, and its function to regulate sleep, apetite , temperature , thinking, and cognitive functions. Also these receptors mediate vasoconstriction mainly 5-HT1B. - 5-HT2 Receptors : Present in smooth muscles, platelets and CNS. There are 3 subtypes of 5-HT2 receptor.A,B,C. 5HT2A mainly in platelet and increase platelet aggregation , while in CNS responsible for depression and hallucination. - 5-HT3 Receptor : Present in the CNS. And mediate vomiting through stimulation of vomiting center in CTZ chemoreceptor trigger zone. 1  - The 5-HT4 receptor has been demonstrated in the mucosa, plexuses and smooth muscle of the gut → probably involved in augmenting intestinal secretion and peristalsis, - The recently cloned 5-HT5, 5-HT6 and 5-HT7 receptors are closely related to the 5-HT4 receptor.These are mainly located in specific brain areas, but their functional role is not known. An interesting finding is that clozapine (atypical antipsychotic) has high affinity for 5-HT6 and 5-HT7 receptors. Serotonin Agonists: Buspirone, is serotonin partial agonist on 5HT1A receptors, is a useful effective anxiolytic agent, mainly in elderly.with no addiction property Sumatriptan Sumatriptan is a selective agonist of 5-HT1 receptors and is highly effective in treating acute attacks of migraine, but is not useful in the prevention. It relieves the nausea and vomiting, but the headache may recur, necessitating repeated administrations. It is administered orally or by the subcutaneous route. The bioavailability of oral dose is only 14%; thus, the oral dose is several times larger than the subcutaneous dose. Adverse effects include flushing and heat at the injection site, neck pain, dizziness, and tingling of the hands. The drug is contraindicated with symptomatic ischemic heart diseases, angina, and hypertension as it may cause coronary vasoconstriction. -Selective Serotonine Reuptake inhibitor SSRIs. The selective serotonin reuptake inhibitors (SSRI) like fluoxetine, sertraline, etc. inhibit only serotonine reuptake and have anti depressant and antianxiety property. -Reserpine blocks serotonine (as well as NA) uptake into storage vesicles by inhibiting VMAT-2, and causes depletion of all monoamines. -Tegaserod: it is 5HT4 partial agonist in GIT used in IBS with constipation. 2 -Cisapride, This prokinetic drug is a selective 5-HT4 agonist which increases gastrointestinal motility is used in reflux esophagitis Renzapride is still more selective for 5-HT4 receptors. Serotonin Antagonists: a. Cyproheptadine: is a potent antagonist of 5-HT and to a smaller extent of histamine and acetylcholine. (It primarily blocks 5-HT2A receptors and has additional H1 antihistaminic, anticholinergic and sedative properties). It stimulates appetite probably by acting directly on the hypothalamus. It can block the release of hydrocortisone, and the production of aldosterone. It is mainly used to relieve the itching associated with skin disorders such as allergic dermatitis. The common adverse reaction are drowsiness, dry mouth, confusion,ataxia, weight gain b. Methysergide: blocks the actions of 5-HT on a variety of smooth muscles. It also has a weak direct vasoconstrictor effect. It is an effective prophylactic agent for migrainous headaches. But has no effect in treating acute attacks, even may worsen the condition. Adverse reactions include gastrointestinal irritation, drowsiness, vertigo, and psychic disturbances. Prolong use can cause retroperitoneal, pleural and endocardial fibrosis. c. Ondansetron: is specific 5-HT3 receptor antagonist. Given orally or intravenously, it is useful in the management of nausea and vomiting associated with cytotoxic drugs and radiotherapy. Adverse reactions include headache, constipation, and allergic reactions. Granisetron and Tropisetron are the other selective 5-HT3 antagonists. d. Prochlorperazine and haloperidol have anti-5-HT activity and are sometimes used for resistant acute attacks of schizophrenia. e. Ketanserin: It has selective 5-HT2 receptor blocking property with negligible action on 5-HT1, 5-HT3 and 5-HT4 receptors. f. Clozapine : atypical antipsychotic is a 5-HT6 AND HT7 blocker. Clozapine is efficative in resistant cases of schizophrenia. 3 Receptor Side and function Drugs 5HT1: 1.CNS:Sleep,apetite , temperature, cognition: 1.Busbiron act as an agonist on 5HT1A, and A,B, C 2.blood vessels: Vasoconstriction,mainly anxiolytic.mainly in elderly , with no addiction property. D, E cerebreal vessles (5HT1B) 2.Triptans (sumtriptans ) At 5HT1B and mediate VC, so used treatment of migraine. 5HT2 5HT2 present in PLT Ketanserin block 5HT2A receptor in PLT and decrease PLT A, And promotes platelets aggregation , while in aggregation.. B, CNS implicated in depression and hallucination olanzapine and risperidone ( atypical antipsychosis ) C block 5HT2A/ 2C in CNS. 5HT3 CNS,, stimulate vomiting center Ondansetron.bloc 5HT3 in vomiting center, mainly caused And in GIT, regulate motility by cancer therapy 5HT4 GIT increase motility. This receptor is found to Tegaserod in 2002 be disfunction in IBS and in constipation. Agonist of 5HT4, used to treat IBS and constipation. And present in cardiac muscle withdrawn from the market in 2007. Why? 5HT5 CNS NO drugs 5HT6 -7 CNS Clozapine is effective in resistant cases of schizophrenia Serotonin syndrome: Acute serotonin syndrome presented with tremor ,muscle rigidity , convulsion and hyperthermia, arrhythmia and hypertension due to increased serotonin activity at 5HT1A, 5HT2A in the CNS due to administration of 2 serotonergic agents at the same time or sometimes toxic dose of a single drug. Carcinoid syndrome: The carcinoid tumours produce massive quantities of 5-HT characterized by bowel hypermotility and bronchoconstriction Chronic serotonin toxicity: 5HT stimulate fibrogenesis leading to thickening of cardiac valves with longterm treatment with serotonergic drugs e.g ergotamine, sumatriptan. 4