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Serotonin receptors agonists & antagonists

5HT IN DETAIL

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Serotonin receptors agonists & antagonists

  1. 1. Dr Ankita Jire JR Dept of pharmacology GMC Nagpur 12/24/2016 1Serotonin receptors: Agonists & antagonists
  2. 2.  Introduction  Sources & Chemistry  Synthesis  Serotonin receptors  Pharmacological actions of serotonin  Pathophysiological roles  Serotonin receptors:Agonists  Serotonin receptors:Antagonists  Summary 12/24/2016 2Serotonin receptors: Agonists & antagonists
  3. 3. Serotonin or 5-Hydroxytryptamine (5-HT)  Biogenic monoamine  Identified as neurotransmitter in central nervous system (CNS) & also have prominent peripheral actions  Serotonin is found in GIT Platelets CNS 12/24/2016 3Serotonin receptors: Agonists & antagonists
  4. 4.  Present in vertebrates, tunicates, molluscs, arthropods, coelenterates, fruits & nuts  Component of venoms of common stinging nettle, wasps & scorpions. 12/24/2016 4Serotonin receptors: Agonists & antagonists
  5. 5.  5-HT [3-(β-aminoethyl)-5-hydroxyindole] 12/24/2016 5Serotonin receptors: Agonists & antagonists
  6. 6. 12/24/2016 6Serotonin receptors: Agonists & antagonists
  7. 7.  Hydroxylation at C5 by tryptophan hydroxylase-1 is rate-limiting step  5-Hydroxyindole Acetic Acid(5-HIAA) formation accounts for nearly 100% of metabolism of 5-HT in brain  5-Hydroxyindole Acetic Acid (5-HIAA) from brain & peripheral sites of 5-HT storage & metabolism is excreted in urine  Larger amounts are excreted by patients with malignant carcinoid 12/24/2016 7Serotonin receptors: Agonists & antagonists
  8. 8.  In 1957, Gaddum and Picarelli  M receptors -located on parasympathetic nerve endings, controlling release of acetylcholine  D receptors -located on smooth muscle 5-HT receptor M receptors D receptos 12/24/2016 8Serotonin receptors: Agonists & antagonists
  9. 9.  The current classification scheme (Hoyer et al., 1994) includes seven subfamilies of 5-HT receptors 5HT receptors 5-HT1 5-HT1A 5-HT1B 5-HT1D 5-HT2 5-HT2A 5-HT2B 5-HT2C5-HT3 5-HT4 5-HT5 5-HT6 5-HT712/24/2016 9Serotonin receptors: Agonists & antagonists
  10. 10. 12/24/2016 10Serotonin receptors: Agonists & antagonists
  11. 11.  Five members  Preferentially couple to G protein & inhibit adenylyl cyclase  5-HT1A, 5-HT1B & 5-HT1D receptor subtypes activate K+ & inhibit Ca2+ channels 12/24/2016 11Serotonin receptors: Agonists & antagonists
  12. 12. 12/24/2016 12Serotonin receptors: Agonists & antagonists
  13. 13. Receptor 5-HT1A 5-HT1D/1B Location Raphe nuclei of the brainstem Substantia nigra & basal ganglia Function Neuronal inhibition Behavioural effects: sleep, feeding, thermo- regulation, anxiety Contraction CSF production Neuronal excitation 12/24/2016 13Serotonin receptors: Agonists & antagonists
  14. 14.  3 subtypes  Couple to G protein→activate phospholipase C function through Inositol triphosphate / Diacylglycerol  5-HT2A inhibits K+ channels 12/24/2016 14Serotonin receptors: Agonists & antagonists
  15. 15. Receptor 5HT2A 5HT2B 5HT2C Location Vascular & visceral smooth muscles, platelets,prefrontal cortex Gastric fundus Choroid plexus, hypothalamus Function Neuronal excitation, Smooth muscle contraction, Platelet aggregation, Vasoconstriction Contraction CSF production, feeding behaviour & mood 12/24/2016 15Serotonin receptors: Agonists & antagonists
  16. 16.  Ionotropic receptor, belonging to nicotinic- acetylcholine superfamily of receptors Location -Parasympathetic terminals in GI tract, including vagal & splanchnic afferents -CNS Solitary tract nucleus & in area postrema Function Emesis Neuronal excitation Behavioural effects: anxiety 12/24/2016 16Serotonin receptors: Agonists & antagonists
  17. 17.  Couple to G proteins activate adenylyl cyclase increase in intracellular cyclic AMP Location -GIT neurons of myenteric plexus & on smooth muscle & secretory cells -CNS superior & inferior colliculi Hippocampus Function Evoke intestinal secretion & peristaltic reflex 12/24/2016 17Serotonin receptors: Agonists & antagonists
  18. 18.  Closely related to 5-HT4 receptor  Mainly located in specific brain areas but their functional role is not known 12/24/2016 18Serotonin receptors: Agonists & antagonists
  19. 19. 12/24/2016 19Serotonin receptors: Agonists & antagonists
  20. 20. 1.CARDIOVASCULAR SYSTEM A) Blood Pressure i.Early sharp fall-due to coronary chemoreflex (Bezold Jarisch Reflex) ii.Brief rise - due to vasoconstriction & increased cardiac output iii. Prolonged Fall-due to dilatation of blood vessels 12/24/2016 20Serotonin receptors: Agonists & antagonists
  21. 21. FALL FALL RISE 12/24/2016 21Serotonin receptors: Agonists & antagonists
  22. 22. B) Effects on Blood vessels and Hemostasis 12/24/2016 22Serotonin receptors: Agonists & antagonists
  23. 23. C) Heart: +ve Inotropic, +ve Chronotropic 2. Visceral smooth muscle GIT- ↑ peristalsis &↑ secretion Bronchi- Bronchoconstriction 12/24/2016 23Serotonin receptors: Agonists & antagonists
  24. 24. 3. Glands Inhibits gastric secretion (acid & pepsin) but ↑ mucus production ulcer protective property 4.Nerve endings Activation of afferent nerve endings- tingling & pricking sensation, pain 12/24/2016 24Serotonin receptors: Agonists & antagonists
  25. 25. 5.Respiration Brief stimulation of respiration & hyperventilation Large doses can cause transient apnea (coronary chemoreflex) 6.Platelets (5-HT 2A receptor) Causes changes in shape of platelets & is a weak aggregator 7.CNS Direct injection in brain causes sleepiness, change in body temperature, hunger & behavioural effects 12/24/2016 25Serotonin receptors: Agonists & antagonists
  26. 26.  Neurotransmitter Involved in sleep, temperature regulation, thought, cognitive function, behaviour, mood, appetite, vomiting & pain perception  Precursor of melatonin in pineal gland Regulates biological clock & maintain circadian rhythm  Neuro-endocrine function Regulate hypothalamic neurons that control release of anterior pituitary hormones 12/24/2016 26Serotonin receptors: Agonists & antagonists
  27. 27.  Nausea & vomiting Evoked by cytotoxic drugs/radiotherapy is mediated by release of 5-HT  Migraine Initiates vasoconstrictor phase of migraine & participates in neurogenic inflammation of cranial blood vessels  Haemostasis Causes platelet aggregation & clot formation at site of injury to blood vessel & also promotes retraction of injured vessel  Raynaud’s phenomenon 5-HT release from platelets may trigger acute vasospastic episodes of larger arteries 12/24/2016 27Serotonin receptors: Agonists & antagonists
  28. 28.  Hypertension ↑ responsiveness to 5-HT & ↓ uptake & clearance by platelets seen in hypertensives  Intestinal motility Enterochromaffin cells & 5-HT containing neurons regulate peristalsis & local reflexes in gut (activated by intestinal distension)  Carcinoid tumours Produce massive amounts of 5-HT leading to bowel hypermotility & bronchoconstriction -Pellagra due to diversion of tryptophan for synthesizing 5-HT 12/24/2016 28Serotonin receptors: Agonists & antagonists
  29. 29. 12/24/2016 29Serotonin receptors: Agonists & antagonists
  30. 30. 1.Triptans  Indole derivatives  Selective 5-HT1D/1B agonists Ex.Sumatriptan, Eletriptan, Frovatriptan ,Naratriptan, Zolmitriptan, Rizatriptan, Almotriptan  Mechanism of action -5-HT1D/1B receptor mediated constriction of dilated cranial blood vessels, especially arterio-venous shunts in carotid artery -Dilatation of these shunt vessels during migraine attack is believed to divert blood flow away from brain parenchyma 12/24/2016 30Serotonin receptors: Agonists & antagonists
  31. 31.  Indication Treatment of acute attacks of moderate to severe migraine not responding to analgesics Sumatript an Frovatript an Rizatripta n Naratripta n Zolmitript an Oral bioavail- Ability(%) 15 25 45 70 40 T max(Hours) 1.5-2 2-4 1-1.5 2-3 1.5-2 T ½(Hours) 2 26 2-3 6 2-3 Oral dose(mg) 50-100 2.5 5-10 2.5 2.5 Max dose (mg/day) 200 7.5 30 5 10 Comparative features of triptans 12/24/2016 31Serotonin receptors: Agonists & antagonists
  32. 32. Side effects  Tightness in head & chest, paresthesias in limbs, dizziness, weakness  Bradycardia, coronary vasospasm & risk of myocardial infarction Contraindications Ischaemic heart disease, hypertension, epilepsy Sumatriptan & Ergotamine should not be administered within 24 hours of each other12/24/2016 32Serotonin receptors: Agonists & antagonists
  33. 33.  Donitriptan Fewer side effects than sumatriptan but same cardiovascular side effects Trexima (oral tablet) • Combination of sumatriptan succinate & naproxen sodium • FDA approval-T/t of acute migrain • Designed to provide faster relief & lesser relapse rate 12/24/2016 33Serotonin receptors: Agonists & antagonists
  34. 34. 2. selective 5-HT4 agonist  Prokinetic drugs- increases gastrointestinal motility Ex.Metoclopramide,Cisapride,Mosapride,Renzapride, Prucalopride 5-HT4 receptor activation on primary afferent neurones (PAN) of ENS via excitatory interneurones Enhance ACh release from myenteric motor neurones  Indication -Gastroesophageal reflux disease -Gastroparesis -Refractory severe chronic constipation Side effect Blocks delayed rectifying K+ channels in heart—prolongs Q- Tc interval & predisposes to torsades de pointes/ventricular fibrillation 12/24/2016 34Serotonin receptors: Agonists & antagonists
  35. 35. 3. Azapirones  Selective partial agonists of 5-HT1A receptors in brain Ex.Buspirone, gepirone & ipsapirone  Reduces activity of dorsal raphe serotonergic neurons  Mimics antianxiety properties of benzodiazepines but does not interact with GABAA receptors  Indication Anxiety disorders Side effects -Dizziness, nausea,headache, light-headedness -Rise in BP in patients on MAO inhibitors 12/24/2016 35Serotonin receptors: Agonists & antagonists
  36. 36. 4. Lysergic acid diethyl amide (LSD) 5. 8-Hydroxy(2 N,N- Dipropylamino)- Tetraline (8-OH-DPAT) 6. Lorcaserin Receptors Nonselective 5-HT agonist 5-HT1A, 5-HT2A/2C, 5-HT5-7 5-HT1A selective receptor agonist Selective 5- HT2C agonist Action Potent hallucinogen Anti-depressant, anti-anxiety Anti-Obesity 12/24/2016 36Serotonin receptors: Agonists & antagonists
  37. 37. 12/24/2016 37Serotonin receptors: Agonists & antagonists
  38. 38. 1. Selective 5-HT3 antagonists  Ex-Ondansetron, Granisetron, Ramosetron & Palonosetron,Alosetron  Blocks depolarizing action of 5-HT exerted through 5-HT3 receptors on vagal afferents in g.i.t. as well as in Nucleus Tractus Solitarius & Chemoreceptor Trigger Zone  Indication -Nausea & vomiting following administration of highly emetic anticancer drugs & radiotherapy -Postoperative nausea -Hyperemesis of pregnancy -Irritable bowel syndrome 12/24/2016 38Serotonin receptors: Agonists & antagonists
  39. 39. Drug Chemical nature Receptor interactions T1/2 (hour) Dose (iv) Ondansetron Carbazole derivative 5-HT3 antagonist 3.9 0.15 mg/kg Granisetron Indazole 5-HT3 antagonist 9-11.6 10 μg/kg Dolasetron Indole moiety 5-HT3 antagonist 7-9 1.8 mg/kg Palonosetron Isoquinoline 5-HT3 antagonist: highest affinity 40 0.25 mg Side effects -Constipation or diarrhea, headache & lightheadedness -Hypotension, bradycardia, chest pain, allergic reactions 12/24/2016 39Serotonin receptors: Agonists & antagonists
  40. 40. 2. 5-HT2 receptor antagonists Ex. Trazodone & nefazodone  Primary metabolite m-chlorphenylpiperazine (m-cpp) is potent 5-HT2 antagonist -α Adrenergic antagonist  Indication Major depression, Anxiety  Side effects Hepatotoxicity,sedation,postural hypotension,priapism 12/24/2016 40Serotonin receptors: Agonists & antagonists
  41. 41. 3.Cyproheptadine  Primarily blocks 5-HT2A receptors  Additional H1 antihistaminic, anticholinergic & sedative properties  Indication -Intestinal manifestations of carcinoid & postgastrectomy dumping syndromes -migraine prophylaxis Side effects Drowsiness, dry mouth, confusion, ataxia, weight gain 12/24/2016 41Serotonin receptors: Agonists & antagonists
  42. 42. 4. Methysergide  Congener of methylergonovine  Potent 5-HT2A/2C antagonist  Acts on 5-HT1 receptors also  Indication Migraine prophylaxis, carcinoid & postgastrectomy dumping syndrome Side effects Abdominal, pulmonary & endocardial fibrosis 12/24/2016 42Serotonin receptors: Agonists & antagonists
  43. 43. 5.Ketanserin  Selective 5-HT2 receptor antagonist (5HT2A>5HT2C) Ritanserin (more 5HT2A agonist)  Additional weak α1, H1 & dopaminergic blocking activities  Antagonize 5-HT induced vasoconstriction, platelet aggregation & contraction of airway smooth muscle  Indication Raynaud’s disease 12/24/2016 43Serotonin receptors: Agonists & antagonists
  44. 44. 6. Clozapine  Inverse agonist at cerebral 5-HT2A/2C receptors  Indication Resistant cases of schizophrenia 7. Risperidone,Olanzapine & Quetiapine  Combined 5-HT2A + dopamine D2 antagonist  Indication Schizophrenia 12/24/2016 44Serotonin receptors: Agonists & antagonists
  45. 45. 1.Synthesis inhibitor P-Chlorophenylalanine (PCPA) selectively inhibits tryptophan hydroxylase & reduces 5-HT level in tissues 2. Uptake inhibitor a)Selective serotonin reuptake inhibitors (SSRI) b) Serotonin and noradrenaline reuptake inhibitors (SNRIs) c)Tricyclic antidepressants Inhibit monoamine reuptake & interact with muscarinic, α adrenergic, H1, 5-HT1, 5-HT2 receptors12/24/2016 45Serotonin receptors: Agonists & antagonists
  46. 46. 12/24/2016 46Serotonin receptors: Agonists & antagonists
  47. 47. Drug Bioavail ability (%) Plasma T1/2 (Hours) Active metabolite T1/2 (Hours) Vd (L/Kg) Protein binding(%) Citalopram 80 33-38 - 15 80 Escitalopram 80 27-32 - 12-15 80 Fluoxetin 70 48-72 180 12-97 95 Fluvoxamine 90 14-18 14-16 25 80 Paroxetin 50 20-23 - 28-31 94 Sertraline 45 22-27 62-104 20 98 12/24/2016 47Serotonin receptors: Agonists & antagonists
  48. 48.  Indication Depression, Obsessive- compulsive disorders, panic disorder, premenstrual dysphoric disorder , posttaumatic stress disorder, Generalized anxiety disorder,  Side Effects Insomnia, increased anxiety, irritability & decreased libido,diarrhoea 12/24/2016 48Serotonin receptors: Agonists & antagonists
  49. 49.  Monoamine Oxidase Inhibitors(MAOI) enhance effects of SSRIs due to inhibition of serotonin metabolism  Synergistic ↑in extracellular brain serotonin serotonin syndrome  Symptoms Hyperthermia, muscle rigidity, myoclonus, tremors, autonomic instability, confusion & irritability coma & death  Treatment Stop all serotonergic drugs Nonselective serotonin antagonists12/24/2016 49Serotonin receptors: Agonists & antagonists
  50. 50.  Inhibits uptake of both NA & 5-HT  Ex. Venlafaxine, Duloxetine  Indication Depression, anxiety  Side effects Nausea, sweating, anxiety, dizziness, impotence 12/24/2016 50Serotonin receptors: Agonists & antagonists
  51. 51. 3.Storage inhibitor  Reserpine Blocks 5-HT & NA uptake into storage vesicles by inhibiting VMAT-2 depletion of all monoamines  Indication Hypertension Side effects Sedation, mental depression,suicidal tendency, extrapyramidal symptoms 12/24/2016 51Serotonin receptors: Agonists & antagonists
  52. 52. 4.Degradation inhibitor Nonselective Monoamine Oxidase Inhibitors (tranylcypromine) & Selective MAO-A inhibitor (chlorgyline) ↑5-HT content by preventing its degradation 5. Neuronal degeneration 5, 6 dihydroxytryptamine selectively destroys 5-HT neurones 12/24/2016 52Serotonin receptors: Agonists & antagonists
  53. 53. 6. Noradrenergic & specific serotonergic antidepressant (NaSSA) Mirtazapine  Blocks α2 auto-receptors (on NA neurones) & hetero-receptors (on 5-HT neurones) enhancing both NA & 5-HT release  Augmented NA further increases firing of serotonergic raphe neurones via α1 receptors  Selective enhancement of antidepressive 5-HT1 receptor action is achieved by concurrent blockade of 5-HT2 & 5-HT3 receptors which are responsible for some adverse effects of high serotonergic tone  Indication Mild & severe depression with insomniaSide effects Increased appetite & weight gain 12/24/2016 53Serotonin receptors: Agonists & antagonists
  54. 54. 12/24/2016 54Serotonin receptors: Agonists & antagonists
  55. 55. Recept or Location Main function Signalling system Significant drugs Agonists Antagonists 5-HT1A CNS(Raphe nuclei of brain stem) Neuronal inhibition Behavioural effects: sleep, feeding, thermo- regulation, anxiety G protein (Gi/Go) ↓ cAMP (may modulate Ca2+ channels) Buspirone (partial agonist) Ergotamine 5-HT1B CNS (Subiculum) vascular smooth muscle Presynaptic inhibition Behavioural effects Pulmonary vasoconstriction Triptans 5-HT1D CNS(Cranial blood vessels) Cerebral vasoconstriction Triptans Ergotamine (PA) 12/24/2016 55Serotonin receptors: Agonists & antagonists
  56. 56. Receptor Location Main function Signalling system Significant drugs Agonists Antagonists 5-HT2A CNS, PNS, smooth muscle, platelets Neuronal excitation Behavioural effects Smooth muscle contraction (gut, bronchi, etc.) Platelet aggregation, Vasoconstriction/va sodilatation G protein (Gq/G11) ↑ IP3, Ca2+ LSD,α methyl 5HT Ketanserin Ritanserin Cyproheptadine Methysergide 5-HT2B Gastric fundus Contraction LSD,α methyl 5HT 5-HT2C CNS (Choroid plexus,hypo thalamus) CSF production Neuronal excitation LSD,α methyl 5HT Methysergide 12/24/2016 56Serotonin receptors: Agonists & antagonists
  57. 57. Receptor Location Main function Signalling system Significant drugs Agonists Antagonists 5-HT3 PNS, CNS Neuronal excitation Emesis Behavioural effects: anxiety Ligand- gated cation channel 2-methyl 5HT Dolesatron Granisetron Ondansetron Palonosetron Tropisetron 5-HT4 (GI tract), CNS Neuronal excitation GI motility G protein ↑cAMP Metoclo- Pramide, cisapride GR-113808 5-HT5 CNS Modulation of exploratory behaviour As above - - 5-HT6 CNS, leukocytes Learning & memory? As above - - 5-HT7 CNS, GI tract, blood vessels Thermoregulation? Circadian rhythm? As above - - 12/24/2016 57Serotonin receptors: Agonists & antagonists
  58. 58.  The pharmacological basis of therapeutics - Goodman and gilman (12th edition)  Basic And Clinical Pharmacology(Katzung)12th edition  General pharmacology-Basic concepts(HL Sharma & KK Sharma)2nd edition  Subtypes of receptors for serotonin:Annual review of pharmacology & toxicology 1990  Neurotransmitters 12/24/2016 58Serotonin receptors: Agonists & antagonists
  59. 59. 12/24/2016 59Serotonin receptors: Agonists & antagonists

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5HT IN DETAIL

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