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SEROTONERGIC RECEPTORS 5-HYDROXY TRYPTAMINE Department of Pharmacology HSK College Of Pharmacy Bagalkot Presented by PARVINDER SINGH 1ST M.PHARMA

Contents : 

Contents Introduction Definition Chemistry of serotonin and synthesis Pharmacokinetics Receptors classification Mechanism of action Pharmacological actions Specific agonists and antagonists 2 DEPARTMENT OF PHARMACOLOGY


INTRODUCTION 5-HT is an amine autocoid. Now the question arises that what is Autocoid? The Autocoid is derived from a Greek word; where, autos means self and akos means healing or remedy or medicinal substance. These autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures & pharmacological activities. 3 DEPARTMENT OF PHARMACOLOGY

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They generally act on the tissues which produce them at the site of synthesis & are hence called as local hormones. Prostaglandins, histamines & serotonin belongs to the group of autocoids. Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted. It was chemically identified as 5- hydroxytryptamine. It was found in GIT and CNS, and was observed to be functioning as a neurotransmitter and as local hormone in peripheral vascular system. 4 DEPARTMENT OF PHARMACOLOGY

Definition : 

Definition Serotonin is an important neurotransmitter, a local hormone in the gut, a component of the platelet clotting process. About 90% of body’s content of 5-HT is localized in intestine. It is also present in the wasp and scorpion sting. And in plants like banana, pear, tomato etc. 5 DEPARTMENT OF PHARMACOLOGY

Chemistry and Synthesis : 

Chemistry and Synthesis Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of Indole ring. After synthesis, the free amines undergoes inactivation by the action of MAO(Mono Amine Oxidase). 6 DEPARTMENT OF PHARMACOLOGY

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Though 5-HT is present in diet, it gets metabolised before entering blood. It is synthesized from amino acid tryptophan. Tryptophan is converted into 5-Hydroxy tryptamine by the action of tryptophan hydroxylase. 5-hydroxy tryptamine is then decarboxylated to 5-HT by amino acid decarboxylase. 5-HT is mainly degraded through oxidative deamination catalyzed by monoamine oxidase followed by oxidation to 5-hydroxy indole acetic acid (5-HIAA) to a small extent by dehydrogenases. 5-HIAA is excreted in urine indicates the production of 5-HT in body and used in diagnosis of carcinoid syndrome. 8 DEPARTMENT OF PHARMACOLOGY

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4 Families of Receptors : 

4 Families of Receptors Channel linked (Ionotropic) G-protein coupled (Metabotropic) Kinase- linked (enzymatic) Intracellular (gene transcription)

Ionotropic receptors : 

Ionotropic receptors

G-Protein coupled receptors : 

G-Protein coupled receptors

The Major G Proteins : 

The Major G Proteins Gs Stimulatory- Activates Ca++ channels, activates adenylyl cyclase Gi Inhibitory- Activates K+ channels, inhibits adenylyl cyclase Gq – Activates phospholipase C Go - Inhibits Ca channels G12/13 – Diverse ion transporter interactions

Second Messengers- Adenylyl Cyclase : 

Second Messengers- Adenylyl Cyclase

Second Messenger- Phospholipase C : 

Second Messenger- Phospholipase C

1. 5-HT1 RECEPTOR : 

1. 5-HT1 RECEPTOR Occurs mainly in brain and its subtypes are 5-HT1 A, B, D,E,F . And are distinguished based on their distribution and pharmacological specificity. All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood and behavior, migraine and used to treat acute attacks. Moreover they activates potassium channels and inhibits calcium channels. 5-HT1D receptors inhibit noradrenaline. DEPARTMENT OF PHARMACOLOGY 19

2. 5-HT2 RECEPTOR : 

2. 5-HT2 RECEPTOR There are 3 subtypes A, B and C. These are linked to phospholipase C . It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors. 5-HT2C receptor present on endothelium produces vasodilation. DEPARTMENT OF PHARMACOLOGY 20

5HT2 subtypes : 

5HT2 subtypes

3. 5-HT3 RECEPTOR : 

3. 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system, mainly on autonomic and enteric neurons. These are of 2 types 5HT3A & 5HT3B These receptors have reflex effects on: Somatic and autonomic nerve endings; shows pain, itch and other visceral effects. Nerve endings in myenteric plexus; increase of peristalsis, emetic reflex. Region of medulla; nausea, vomiting. DEPARTMENT OF PHARMACOLOGY 22

4. 5-HT4 RECEPTOR : 

4. 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT, bladder and heart. In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex; Cisapride, Renzapride. 23 DEPARTMENT OF PHARMACOLOGY


PHARMACOLOGICAL ACTIONS Cardiovascular system: Arteries are constricted (by the action on smooth muscles) as well as dilated (through EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules. Smooth muscles: 5-HT is a potent stimulation of g.i.t., both by direct action as well as through enteric plexus. Peristalsis is increased and diarrhoea can occur. 24 DEPARTMENT OF PHARMACOLOGY


5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS: Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation. On smooth muscles it shows vasoconstriction and oxytocic effect. In migraine it is used only as a prophylactic agent. MOA It stimulates the receptors located in the brain. Adverse effects such as : Nausea, vertigo, drowsiness. G.I.irritation, bradycardia, insomnia.

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THERAPEUTIC USES: It is used as a prophylactic agent in migraine. Other antagonist drugs are: Pizofen It shows antihistaminic and antidepressant effect Causes drowsiness, urine retention and weight gain. Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-HT2C receptors.


2. 5-HT2A ANTAGONIST Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity. It produces antihypertensive activity. It acts on platelets and prevents its aggregation. It also causes bronchocostriction. Adverse effects are nausea, dryness of mouth, tiredness. Clinical use: as a prophylactic agent in Reynaud's disease. Cyproheptadine. It has anticholinergic and ca2+ channel blocking effect. It shows mild CNS depressant activity and causes sedation. It improves appetite by acting on hypothalamus. Used in curing Cushing’s syndrome and allergies.

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3. 5-HT3 ANTAGONISTS Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy. It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain. Adverse effects are headache, constipation, diarrhoea, abdomen pain etc. Used as prophylaxis and postoperative nausea and vomiting. Granisetron It is 15 times more potent than Ondansetron. It is similar to Ondansetron. Adverse effects fever, dizziness, anxiety etc.


OTHER DRUGS AFFECTING 5-HT SYSTEM P-Chlorophenylalanine: it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT. Tricyclic antidepressants: inhibit 5-HT uptake along with noradrenaline. Reserpine: blocks the uptake of 5-HT into storage granules. Ergot alkaloids: they exert their effect through 5-HT, adrenoreceptors or dopamine receptors. Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors. Adverse effects are muscle cramps, weakness, nausea, vomiting etc.

References : 

References Goodman Gilman’s: the basis of pharmacological therapeutics katzung’s : the basic principles of pharmacology. DEPARTMENT OF PHARMACOLOGY 30 THANK YOU

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