Serotonin

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Serotonin

  1. 1. Serotonin5-Hydroxytryptamine (5-HT) By: Dr. Vahid Nikoui Email: nikoui@razi.tums.ac.ir
  2. 2. (Rate limiting) OH COOH COOH Tryptophan C NH2 hydroxylase C NH2 N N In diet. Active Tryptophan CNS transport 5-Hydroxytryptophan 5-OH Tryptophan decarboxylase C COOH OH H N C NH25-Hydroxy Indole N Acetic Acid 5-OH Indole Acetaldehyde 5-Hydroxytryptamine
  3. 3. Distribution (PNS) Majority released from gut  Responsible for smooth muscle contractions  Release stimulated by food intake  Inhibits release of gastric acid  Softens stool Cardiovascular system – vasoconstrictor/vasodilator of vessels Bronchioconstriction Uterine contractions
  4. 4. Serotonin roles Peripheral  Peristalsis  Vomiting  Platelet aggregation and haemostasis  Inflammatory mediator  Sensitisation of nociceptors  Microvascular controlHunter Area ToxicologyService
  5. 5. Serotonin roles Central  Control of appetite  Sleep  Mood  Hallucinations  Stereotyped behaviour  Pain perception  VomitingHunter Area ToxicologyService
  6. 6. 5-HT ReceptorsReceptor 5-HT 1 5-HT 2 5-HT 3 5-HT 4 5-HT 5 5-HT 6 5-HT 7 5-HT1A 5-HT 2A 5-HT 3A 5–HT5A 5-HT 1B 5-HT 2B 5-HT 3B 5–HT5BSubtype 5-HT 1D 5-HT 2C 5-HT 1E 5-HT 1F Major ionsignaling cAMP↓ IP3 cAMP cAMP ↓ cAMP cAMP  channelpathway
  7. 7. Serotonin receptors 5–HT1  7 trans–membrane domains  G protein linked  cAMP dependant  Anxiolytic and antidepressant  Subtypes  5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1FHunter Area ToxicologyService
  8. 8. 5-HT1A Receptor CNSforum.com
  9. 9. 5-HT1A Partial Agonist Mechanism
  10. 10. 5-HT1A Antagonist mechanism
  11. 11. 5–HT1 5–HT1A  Limbic system  Regulation of emotions  Neocortex  Hypothalamus  Substantia gelatinosa  Proprioception 5–HT1BHunter Area ToxicologyService
  12. 12. 5–HT1 5–HT1D  Autoreceptors  Inhibitory feedback  Heteroreceptors  Modulate release  Acetylcholine  Glutamate  Anti–migraine effect of SumatriptanHunter Area ToxicologyService
  13. 13. Serotonin in Migraine Neurogenic vs. Vascular theories1. Cyproheptadine, Methysergide – prophylaxis2. Sumatriptan, Ergotamine – acute attacks3. MAO inhibitors and TCAs – both
  14. 14. 5–HT1 5–HT1E  ? functional role 5–HT1F  ? functional role  Distribution includes CNS, uterus, mesentery  Inhibit cAMP  High affinity for  Sumatriptan, MethysergideHunter Area ToxicologyService
  15. 15. Serotonin receptors 5–HT2  7 trans–membrane domains  G protein linked  Phospholipase C dependant  Subtypes  5–HT2A, 5–HT2B, 5–HT2CHunter Area ToxicologyService
  16. 16. 5-HT2 Receptor Mechanism
  17. 17. 5-HT2 Antagonist Mechanism
  18. 18. 5–HT2 5–HT2A  Periphery  Contraction of vascular/non–vascular smooth muscle  Platelet aggregation  Increased capillary permeability  Modulation of the release of other neurotransmitters and hormones  ACh, Adrenaline, Dopamine, Excitatory amino acids, VasopressinHunter Area ToxicologyService
  19. 19. 5–HT2 5–HT2A  CNS  Motor behaviour  Head twitch  Sleep regulation  Nociception  NeuroexcitationHunter Area ToxicologyService
  20. 20. 5–HT2  5–HT2B  Stomach fundus  5–HT2C  CSF production  Locomotion  Eating disorders  Anxiety  MigraineHunter Area ToxicologyService
  21. 21. Serotonin receptors  5–HT3  Ligand gated cation channels  5-HT4  Coupled to adenylyl cyclase  5-HT5  Coupled to adenylyl cyclase  Subtypes  5–HT5A, 5–HT5BHunter Area ToxicologyService
  22. 22. 5–HT3 Peripheral  Located exclusively on neurons and mediate neurotransmitter release - parasympathetic, sympathetic, sensory and enteric  Cardiac inhibition/activation, pain, initiation of the vomiting reflex Central  Facilitate dopamine and 5–HT release, inhibit ACh and noradrenaline release  Anxiety, depression, memory, tolerance and dependenceHunter Area ToxicologyService
  23. 23. Serotonin receptors 5-HT6  Coupled to adenylyl cyclase  Significance unknown 5-HT7  Coupled to adenylyl cyclase  Significance unknownHunter Area ToxicologyService
  24. 24. Serotinergic Drugs 5-HT1A : Buspirone, Ipsapirone, Tandospirone Treat anxiety, depression (partial agonist) 5-HT 1D/1B : Sumatriptan, Naratriptan, Zolmitriptan Treat migraine (partial agonist) 5-HT 2A/2C : Methysergide, Trazodone, Risperidone, Ketanserin, Ritanserin, Mianserin Treat migraine, depression, schizophrenia (antagonist)
  25. 25. Serotinergic Drugs 5-HT 3 : Ondansetron, Granisetron, Tropisetron, Memantine, Mirtazapine Treat chemotherapy-induced emesis (antagonist) 5-HT 4 : Cisapride, Metoclopramide, Mosapride, Dazopride, Tegaserod Treat GI disorders (agonist)
  26. 26. Serotinergic drugs Serotonin precursors  S–adenyl–L–methionine  L–tryptophan  5–hydroxytryptophan  DopamineHunter Area ToxicologyService
  27. 27. Serotinergic drugs Serotonin re–uptake inhibitors  Citalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Venlafaxine  Clomipramine, Imipramine  Nefazodone, Trazodone  Chlorpheniramine  Cocaine, Dextromethorphan, Pentazocine, PethidineHunter Area ToxicologyService
  28. 28. Serotinergic drugs Serotonin agonists  Fenfluramine, P–chloramphetamine  Bromocriptine, Dihydroergotamine, Gepirone  Eltoprazin, QuipazineHunter Area ToxicologyService
  29. 29. Serotinergic drugs Irreversible Monoamine oxidase inhibitors (MAOIs)  Clorgyline, Isocarboxazid, Nialamide, Pargyline, Phenelzine, Tranylcypromine  Selegiline  Furazolidone  ProcarbazineHunter Area ToxicologyService
  30. 30. Serotinergic drugs Reversible inhibitors of MAO (RIMAs)  Brofaramine  Befloxatone, Toloxatone  MoclobemideHunter Area ToxicologyService
  31. 31. Serotinergic drugs Miscellaneous/mixed  Lithium  Lysergic acid diethylamide (LSD)  3,4–methylenedioxymethamphetamine (MDMA, ecstasy), methylenedioxyethamphetamine (eve)  Propranolol, PindololHunter Area ToxicologyService
  32. 32. Serotonin Syndrome Toxic, potentially fatal effects Require a combination of serotonergic agents, such as an SSRI with an MAOI. Other agents is including TCAs, Dextromethorphan, Meperidine and MDMA.
  33. 33. Sternbach criteria Mental status changes (confusion, hypomania) Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhoea Incoordination Diarrhoea FeverHunter Area Toxicology Service
  34. 34. Treatment Suspected agents should be discontinued. OTC drugs containing ingredients known to increase serotonin levels, such as Dextromethorphan, Pseudoephedrine or Phenylpropanolamine, also should be discontinued. Benzodiazepines for mild to moderate cases Cyproheptadine, Methysergide, and Propranolol for severe cases
  35. 35. Drugs used to treat serotonin syndrome Non–specific blocking agents  Methysergide  Cyproheptadine –blockers  Propranolol  PindololHunter Area ToxicologyService
  36. 36. Drugs used to treat serotonin syndrome  Benzodiazepines  Lorazepam  Diazepam  Clonazepam  Neuroleptics  Chlorprothixene  Chlorpromazine  HaloperidolHunter Area ToxicologyService
  37. 37. Drugs used to treat serotonin syndrome  Miscellaneous  Chlormethiazole  Nitroglycerine  Drugs used for neuroleptic malignant syndrome  Dantrolene  BromocriptineHunter Area ToxicologyService
  38. 38. Antagonist potencies Ki values (5–HT2)  Chlorprothixene (0.43 nM) > Chlorpromazine > Cyproheptadine > Haloperidol (36 nM)  limited experience suggests haloperidol ineffective Ki values (5–HT1)  Chlorprothixene (230 nM) > Haloperidol > Chlorpromazine > Cyproheptadine (3200 nM)Hunter Area ToxicologyService
  39. 39. Receptor Overview
  40. 40. 5-HT2 Subtypes
  41. 41. Thanks for Your Attention

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