Serotonin or 5HT

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serotonin or 5HT

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PHARMACOLOGY OF SEROTONIN RECEPTOR :

PHARMACOLOGY OF SEROTONIN RECEPTOR Prepared by: Sonu M.Pharm ( I st Sem.) RBIP, Mohali , Punjab

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content INTRODUCTION SYNTHESIS AND DEGRADATION PATHWAY OF SEROTONIN SEROTONIN RECEPTOR SITE OF ACTION PATHOPYSIOLOGICAL ROLES SEROTONIN AGONISTS SEROTONIN ANTAGONISTS ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Before the identification of 5-hydroxytryptamine, it was known that when blood is allowed to clot, a vesoconstrictor substance is released from the clot into the serum; this substance is called as serotonin 5-HT is β -aminoethyl-5-hydroxyindole. It is synthesized from the amino acid tryptophan and degraded primarily by MAO and to small extend by a dehydrogenase ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

Serotonin Pathways in Brain:

Serotonin Pathways in Brain ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Gaddum and Picarelli in 1957 classified 5 HT receptor into musculotropic (D type) and neurotropic (M type) on the basis of pharmacological criteria. The present system of c lassifcation of 5HT receptor is based on molecular characterization and cloning of the receptor cDNA ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Seven families of 5 hydroxytryptamine receptor comprising of 14 receptor subtypes have so far being recoganised . All the serotonin receptor (except 5-HT 3 ) are G protein coupled receptor where as 5-HT 3 receptor is a ligand gated cation channel. G protein couple function through decreasing or increasing cAMP production or by generating IP 3 /DAG as second messangers and ligand gated channel act on activation elicits fast depolarization ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

5- HT RECEPTORS:

5- HT RECEPTORS 5-HT 1 Receptors . All 5 members of the 5-HT 1 -receptor subfamily inhibit adenylyl cyclase. At least one 5-HT 1 -receptor subtype, the 5-HT 1A receptor, also activates a receptor-operated K + channel and inhibits a voltage-gated Ca 2+ channel, a common property of receptors coupled to the pertussis toxin-sensitive G i /G o family of G proteins. The 5-HT 1A receptor is found in the raphe nuclei of the brainstem, where it functions as an inhibitory, somatodendritic auto receptor on cell bodies of serotonergic neurons. Another subtype, the 5-HT 1D receptor, functions as an auto receptor on axon terminals, inhibiting 5-HT release . 5-HT 1D receptors, abundantly expressed in the substantia nigra and basal ganglia , may regulate the firing rate of dopamine-containing cells and the release of dopamine at axonal terminals. ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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ASBASJSMCOLLEGE OF PHARMACY, BELA(ROPAR)

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ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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5-HT 2 Receptors . The 3 subtypes of 5-HT 2 receptors are linked to phospholipase C with the generation of two second messengers, diacylglycerol (a cofactor in the activation of protein kinase C) and inositol trisphosphate (which mobilizes intracellular stores of Ca 2+ ). 5-HT 2A receptors are broadly distributed in the CNS, primarily in serotonergic terminal areas. High densities of 5-HT 2A receptors are found in prefrontal , parietal , and somatosensory cortex , claustrum , and in platelets . 5-HT 2A receptors in the GI tract are thought to correspond to the D subtype of 5-HT receptor originally described by Gaddum and Picarelli . 5-HT 2B receptors originally were described in stomach fundus . The expression of 5-HT 2B receptor mRNA is highly restricted in the CNS. 5-HT 2C receptors have a very high density in the choroid plexus , an epithelial tissue that is the primary site of cerebrospinal fluid production. The 5-HT 2C receptor has been implicated in feeding behavior and susceptibility to seizure efficiencies. . ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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5-HT 3 Receptors. The 5-HT 3 receptor is unique, being the only monoamine neurotransmitter receptor that is known to function as a ligand -operated ion channel . The 5-HT 3 receptor corresponds to Gaddum and Picarelli's M receptor. Activation of 5-HT 3 receptors elicits a rapidly desensitizing depolarization, mediated by the gating of cations . These receptors are located on parasympathetic terminals in the GI tract , including vagal and splanchnic afferents. In the CNS, a high density of 5-HT 3 receptors is found in the solitary tract nucleus and in the area postrema . 5-HT 3 receptors in both the gastrointestinal tract and the CNS participate in the emetic response, providing an anatomical basis for the antiemetic property of 5-HT 3 -receptor antagonists. ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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5-HT 4 Receptors . 5-HT 4 receptors are widely distributed throughout the body. In the CNS, the receptors are found on neurons of the superior and inferior colliculi and in the hippocampus . In the GI tract, 5-HT 4 receptors are located on neurons of the myenteric plexus and on smooth muscle and secretory cells . The 5-HT 4 receptor is thought to evoke secretion in the alimentary tract and to facilitate the peristaltic reflex. 5-HT 4 receptors couple to G s to activate adenylyl cyclase, leading to a rise in intracellular levels of cyclic AMP ( cAMP ). ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Additional Cloned 5-HT Receptors . Two other cloned receptors, 5-HT 6 and 5-HT 7 , are linked to activation of adenylyl cyclase. Circumstantial evidence suggests that 5-HT 7 receptors play a role in smooth-muscle relaxation in the GI tract and the vasculature. The atypical antipsychotic drug clozapine has a high affinity for 5-HT 6 and 5-HT 7 receptors; whether this property is related to the broader effectiveness of clozapine compared to conventional antipsychotic drugs is not known. Clozapine appears to be effective in many patients who do not respond to conventional antipsychotic drugs . Two subtypes of the 5-HT 5 receptor have been cloned; although the 5-HT 5A receptor has been shown to inhibit adenylyl cyclase, functional coupling of the cloned 5-HT 5B receptor has not yet been described. ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

Sites of 5HT action:

Sites of 5HT action Enterochromaffin cells- Enterochromaffin cells, are located in the GI mucosa, with the highest density found in the duodenum. These cells synthesize 5-HT from tryptophan and store 5-HT. Basal release of enteric 5-HT is augmented by mechanical stretching, such as that caused by food or the administration of hypertonic saline, and also by efferent vagal stimulation. 5-HT probably has an additional role in stimulating motility via the myenteric network of neurons, located between the layers of smooth muscle. The greatly enhanced secretion of 5-HT and other autacoids in malignant carcinoid leads to a multitude of cardiovascular, gastrointestinal, and CNS abnormalities. In addition, the synthesis of large amounts of 5-HT by carcinoid tumors may result in tryptophan and niacin deficiencies (pellagra). ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Cardiac system- 5HT act as a vasodialator . Arteries are constricted (by action on smooth muscle) as well as dialates (through EDRF release) by direct action of 5-HT. Large arteries and veins are characterstically constricted. In microcirculation,5HT dialates arterioles and constricts venules In animals , bradykardia is mostaly seen due to activation of coronary reflex ( bezold jarisch reflex). On I V injection, triphasic response is classically seen. Early sharp fall in BP-due to coronary reflexes. Rise in BP- due to vasoconstrictionandincreased cardic Output. Prolonged fall in BP- due to arteriolar dialation .

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Platelets. Platelets differ from other formed elements of blood in expressing mechanisms for uptake, storage, and endocytotic release of 5-HT. 5-HT is not synthesized in platelets, but is taken up from the circulation and stored in secretory granules by active transport, similar to the uptake and storage of norepinephrine by sympathetic nerve terminals . Na + -dependent transport across the surface membrane of platelets is followed by uptake into dense core granules via an electrochemical gradient generated by an H + - translocating ATPase .. Measuring the rate of Na + -dependent 5-HT uptake by platelets provides a sensitive assay for 5-HT-uptake inhibitors. Main functions of platelets include adhesion, aggregation, and thrombus formation to plug holes in the endothelium; conversely, the functional integrity of the endothelium is critical for platelet action. A complex local interplay of multiple factors, including 5-HT, regulates thrombosis and hemostasis . When platelets make contact with injured endothelium, they release substances that promote platelet aggregation, and secondarily, they release 5-HT. ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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5-HT binds to platelet 5-HT 2A receptors and elicits a weak aggregation response that is markedly augmented by the presence of collagen. If the damaged blood vessel is injured to a depth where vascular smooth muscle is exposed, 5-HT exerts a direct vasoconstrictor effect, there by contributing to hemostasis , which is enhanced by locally released autocoids ( thromboxane A 2 , kinins , and vasoactive peptides). Conversely, 5-HT may stimulate production of nitric oxide and antagonize its own vasoconstrictor action, as well as the vasoconstriction produced by other locally released agents. ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Gastrointestinal tract- Enterochromaffin cells in the mucosa appear to be the location of the synthesis and most of the storage of 5-HT The stimulatory response occurs at nerve endings on longitudinal and circular enteric muscle (5-HT 4 ), at postsynaptic cells of the enteric ganglia (5-HT 3 and 5-HT 1P ), and by direct effects of 5-HT on the smooth-muscle cells (5-HT 2A in intestine and 5-HT 2B in stomach fundus ). In esophagus , 5-HT acting at 5-HT 4 receptors causes either relaxation or contraction, depending on the species Enteric 5-HT is released in response to acetylcholine, sympathetic nerve stimulation, increases in intraluminal pressure, and lowered pH , triggering peristaltic contraction. 5-HT 1 – slow depolarization of enteric plexus neurones 5-HT 2A – intestinal smooth muscles- contraction 5-HT 3 –fast depolarization of enteric plexus neurons, release of 5-HT 5-HT 4 –Lower esophageal sphincter-contraction, Enteric plexus- ach release- peristalsis, Intestinal mucosa-secretion ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Central nervous system - A multitude of brain functions are influenced by 5-HT, including sleep, cognition, sensory perception, motor activity, temperature regulation, nociception , mood, appetite, sexual behaviour, and hormone secretion. Serotonin act as neurotransmitter. it occurs at many sites of brain. serotonin is a precursor of melotonin in the penial gland. It acts on area postrema which causes the vomiting reflexes caused by chemical triggers such as chemotherapy drugs. On I V injections of serotonin it doesnot cross blood brain barrier. direct injection in brain it produces behavirals effects like sleepiness, change in body temprature (hypothermia),hunger etc. ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Smooth muscle : It is a potent sitmulator of git . Peristalsis is increased and diarrhoea occurs due to increased secretion. It also constrict bronchi & uterus. Glands: It inhibts the gastric secretions(acid & pepsin) but increase the mucus secretion. So prefer as ulcer protective. Respiration system: A brief stimulation of respiration and hyperventilation are the usual response, but large doses can cause transient aponea through coronary chemoreflex . ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

PATHOPHYSIOLOGICAL ROLES:

PATHOPHYSIOLOGICAL ROLES Neurotransmitter Precursor of melatonin Nausea and vomiting Migrane Haemosatasis Raynauds phenomenon Variant angina Hypertension Intestinal motility Caricinoid syndrome ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

Serotonin recEPTOR agonist :

Serotonin rec EPTOR agonist 5-HT 1A Receptor agonist Azapirones , buspirone , gepirone , tandosiprone 5 -HT 1B Receptor agonist Triptans - , sumatriptan , rizatriptan , naratriptan , zolmitriptan , almotriptan , frovatriptan , eletriptan . 5-HT 1D Receptor agonist Triptans - sumatriptan , rizatriptan , naratriptan zolmitriptan , almotriptan , frovatriptan , eletriptan . 5-HT 1F Receptor agonist LY-334,370   5-HT 1P Receptor agonist 5-hydroxyindalpine ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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5-HT 2A  receptor agonist LSD , mescaline, pislocin 5-HT 2C  receptor agonist lorcaserin 5-HT 3  receptor agonist 2-methyl-5-HT 5-HT 4  receptor agonist Cisapride , mosapride 5-HT 7  receptor agonist AS-19 ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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BUSPIRONE It is 5HT 1A receptor agonist, used as antianixety. it stimulates pre synaptic 5HT 1A auto receptors It reduces the activity of dorsal raphe serotonergic neurons. Dose 5-15mg ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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SUMATRIPTANS Selective agonist of 5HT 1D and 1B receptors. These receptor are found in cerebral and meningeal vessels and mediate vasoconstriction . These drugs are effective in treatment of acute migraine headache. It mediate the contraction of dilated cranial extracerebral blood vessel, especially the arterio venous shunt in carotid artery . Since the dilation of shunt diverts the blood from brain parenchyma. It also reduces 5HT and inflammatory neuropeptides released around the affected vessels as well as the extravasation of plasma protein across Dural vessel. Dose 10 mg repeated once after 2 hrs if required ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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DESFENFLURAMINE Reduce the food see kind behavior enhancing serotonergic transmission in hypothalamus. However tolerance to this action appears in about 2-3 months. They have tranquillizing rather then stimulant property. These drugs are banded due ecocardiograghic abnormalities, valvular defects, pulmonary hypertension and sudden death. ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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CISAPRIDE It is a prokinetic drug and antiemetic property it act through 5HT 4 agonist which promotes Ach release from the myenteric neurons, aided by weak 5 HT 3 antagonism which suppresses inhibitory transmission of myenteric plexus. Enteric neuronal activation via 5HT 4 receptor also promotes cAMP-dependent cl secretion in the colon, increase the water content of the stool. It is used in gastro esophageal refluxes disease, nonulcer dyspepsia , impaired gastric empting and chronic constipation. Dose is 10-20mg tds ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

Serotonin receptor antagonist :

Serotonin receptor antagonist Cyproheptadine Methysergide Ketanserin Clozapine Risperiodone Ondansetron, granisetron, tropisetron Ergot alkaloids ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Cyproheptadine It is 5HT 2A receptor blocker and have additional H1 antihistamine, anti cholinergic and sedative property. It increases the appetite and has been recommended in children and poor eaters to promote weight gain It is also used in controlling the intestinal manifestations of carcinoid and post gasotrectomy dumping syndromes. It have side effects like drowsiness, dry mouth, confusion ,ataxia , weight gain . ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Clozapine and Risperidone These are 2 antipsychotic drugs which produce there response through the serotonin receptor blockage. ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Ketanserine Blockes 5HT 1c and 5HT 2 receptor and has little or no antagonistic activity on other 5HT receptor. It blockes the 5HT 2 receptor on platelets and anatagonizes platelet aggregation promoted by serotonin. This drug do have potently blocks vascular α adrenoreceptors which produce the hypotensive action. Used in hypertension and in chronic vasospastic condition ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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Ondansetrone It is prototype of the new 5HT 3 receptor antagonist has antiemetic activity developed to control the cancer chemotherapy induced vomiting and postoperative nausea and vomiting It blocks the depolarizing action of 5HT through 5HT 3 receptor on the vagal afferents in the git , as well as in NTS and CTZ It block both emetogenic impluse from both at the peripheral origin and the central relay ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

Thank you :

Thank you

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ASBASJSMCOLLEGE OF PHARMACY, BELA(ROPAR)

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CENTRAL NERVOUS SYSTEM . A multitude of brain functions are influenced by 5-HT, including sleep, cognition, sensory perception, motor activity, temperature regulation, nociception, mood, appetite, sexual behaviour, and hormone secretion. All of the cloned 5-HT receptors are expressed in the brain, often in overlapping domains. The principal cell bodies of 5-HT neurons are located in raphe nuclei of the brainstem and project throughout the brain and spinal cord. In addition to being released at discrete synapses, release of serotonin also seems to occur at sites of axonal swelling, termed varicosities , which do not form distinct synaptic contacts. 5-HT released at nonsynaptic varicosities is thought to diffuse to outlying targets, rather than acting on discrete synaptic target Serotonergic nerve terminals contain all of the proteins needed to synthesize 5-HT from L-tryptophan . Newly formed 5-HT is rapidly accumulated in synaptic vesicles, where it is protected from MAO. 5-HT released by nerve-impulse flow is reaccumulated into the pre-synaptic terminal by an Na + -dependent carrier, the 5-HT transporter. Pre-synaptic re-uptake is a highly efficient mechanism for terminating the action of 5-HT released by nerve-impulse flow. MAO localized in postsynaptic elements and surrounding cells rapidly inactivates 5-HT that escapes neuronal re-uptake and storage. ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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GASTEROINTESTINAL TRACT . Enterochromaffin cells in the mucosa appear to be the location of the synthesis and most of the storage of 5-HT in the body and are the source of circulating 5-HT. 5-HT released from these cells enters the portal vein and is subsequently metabolized by MAO-A in the liver vagal stimulation also acts locally to regulate . 5-HT released by mechanical or GI function. Motility of gastric and intestinal smooth muscle may be either enhanced or inhibited via at least 6 subtypes of 5-HT receptors . The stimulatory response occurs at nerve endings on longitudinal and circular enteric muscle (5-HT 4 ), at postsynaptic cells of the enteric ganglia (5-HT 3 and 5-HT 1P ), and by direct effects of 5-HT on the smooth-muscle cells (5-HT 2A in intestine and 5-HT 2B in stomach fundus ). In esophagus , 5-HT acting at 5-HT 4 receptors causes either relaxation or contraction, depending on the species. Abundant 5-HT 3 receptors on vagal and other afferent neurons and on enterochromaffin cells play a pivotal role in emesis. Serotonergic terminals have been described in the myenteric plexus. Enteric 5-HT is released in response to acetylcholine, sympathetic nerve stimulation, increases in intraluminal pressure, and lowered pH , triggering peristaltic contraction. ASBASJSM COLLEGE OF PHARMACY, BELA(ROPAR)

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