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Histamine, serotonin, & the ergot alkaloids


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  • 1. Histamine, Serotonin, & the Ergot Alkaloids By M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Sciences
  • 2. Histamine, Serotonin, & the Ergot Alkaloids Histamine  Serotonin  introduction  Introduction  Storage & Release  Carcinoid Syndrome  Receptor Subtypes  Organ System Effect  Functions  Cardiovascular system  Organ System Effects  GI Tract  Toxicity & Contraindications  CNS  Antagonists  Migraine  Vomiting  Ergot Alkaloids  Introduction  Clinical Uses  Drug Pictures
  • 3. Introduction  Biologically active amine  Synthesized from Histidine  Autacoid member (Local Hormone)  Has Physiologic & Pathologic Functions  Occurs in:  Plants  Animal tissues  Some venoms and stinging secretions.M.H.Farjoo
  • 4. Autacoids  Histamine  Serotonin  Prostaglandins  Leukotrienes  Thromboxanes  Endogenous peptides  CytokinesM.H.Farjoo
  • 5. Storage & Release Of Histamine  Stored in:  Mast cells / basophiles  Brain  Fundus of the stomach  Released by:  Immunologic reactions  Chemical and mechanical injuriesM.H.Farjoo
  • 6. Receptor Postreceptor Partially Selective Partially Selective DistributionSubtype Mechanism Agonists Antagonists Smooth muscle, Gq, IP3, DAG H1 endothelium, brain Histaprodifen Cetirizine Gastric mucosa, Cimetidine, ranitidine, Gs, cAMP H2 cardiac muscle, mast Amthamine tiotidine cells, brain Thioperamide, Presynaptic: brain, R-- iodophenpropit, Gi, cAMP H3 myenteric plexus, Methylhistamine, clobenpropit,1 other neurons imetit, immepip tiprolisant1 Not yet clinically important Eosinophils, Gi, cAMP Clobenpropit, H4 neutrophils, CD4 T imetit, clozapine Thioperamide cells
  • 7. Histamine Functions  Can be Physiologic and/or Pathologic.  Important mediator of immediate allergic and inflammatory reactions (triple response).  Has an important role in gastric acid secretion.  Functions as a neurotransmitter / neuromodulator.  Plays a role in chemotaxis of white blood cells.M.H.Farjoo
  • 8. Organ System Effects Of Histamine  Nervous System powerful stimulation of sensory  Cardiovascular System endings, especially those nerve mediating pain and itching. decrease in systolic and diastolic  Bronchiolar Smooth Muscle rate. Flushing,an increase in blood pressure and heart sense of bronchoconstriction warmth, headache  Gastrointestinal Tract contraction of intestinal smooth  Uterus muscle, large doses of histamine may cause diarrhea Abortion in pregnant women  Secretory Tissue anaphylaxis with stimulation of gastric acid, pepsin & intrinsic factor. Increases secretion in the small and large intestineM.H.Farjoo
  • 9. Toxicity & Contraindications of Histamine  Toxicity: (observed after the ingestion of spoiled fish)  Flushing  Hypotension  Tachycardia  Headache  Wheals  Bronchoconstriction  Gastrointestinal upset  Contraindications:  Asthmatics  Patients with active ulcer disease or GI bleedingM.H.Farjoo
  • 10. Histamine Antagonists  Physiologic Antagonists  Epinephrine (for anaphylaxis)  Release Inhibitors  Receptor Antagonists  H1 Receptor Antagonists  first-generation stronger sedative effects  second-generation more likely to block autonomic receptors. eg: action Longer duration of  H2 Receptor Antagonists Hydroxyzine once daily hence administration but more expensiveM.H.Farjoo
  • 11. Anticholinergic Drugs Comments ActivityFIRST-GENERATION ANTIHISTAMINESCarbinoxamine +++ Slight to moderate sedation Marked sedation; anti-motionDimenhydrinate +++ sickness activity Marked sedation; anti-motionDiphenhydramine +++ sickness activityHydroxyzine nd Marked sedation Slight sedation; anti-motionCyclizine – sickness activity Slight sedation; anti-motionMeclizine – sickness activity
  • 12. Anticholinergic Drugs Comments ActivityFIRST-GENERATION ANTIHISTAMINESBrompheniramine + Slight sedation Slight sedation; commonChlorpheniramine + component of OTC "cold" medication Promethazine Marked sedation; +++(Phenergan) antiemetic; block Moderate sedation; also hasCyproheptadine + antiserotonin activitySECOND-GENERATION ANTIHISTAMINESFexofenadine –Loratadine – Longer actionCetirizine –
  • 13. H1 Receptor Antagonists  Mechanism of action  Non histamine receptor blocking effects:  Sedation Diphenhydramine, Dimenhydrinate,  Antinausea and Antiemetic Actions Promethazine Diphenhydramine,  Antiparkinsonism Effects Dimenhydrinate, Promethazine  Anticholinoceptor Actions Diphenhydramine,  Adrenoceptor-Blocking Actions Dimenhydrinate, Promethazine. Can cause urinary retention, Promethazine. may  Local Anesthesia blurred vision cause orthostatic hypotension Diphenhydramine, Promethazine (more potent than procaine)M.H.Farjoo
  • 14. H1 Receptor Antagonists Cont,d  Clinical Uses  Allergic Reactions  Motion Sickness and Vestibular Disturbances  Nausea and Vomiting of Pregnancy  Toxicity Drug allergy!!!. Relatively  Drug Interactions after topical use of common H1 antagonists Lethal ventricular arrhythmias  Contraindications with terfenadine in combination Combined use with sedative or with ketoconazole, erythromycin or grapefruitblocking drugs autonomic juiceM.H.Farjoo
  • 15. H2 Receptor Antagonists  Will be discussed in the relevant sectionM.H.Farjoo
  • 16. Introduction  Serotonin is:  A Neurotransmitter in CNS  A local hormone in the gut  A component of the platelet clotting process  A potent stimulant of pain and itch nerves  A central (CNS) modulator of:  Migraine  Vomiting  Mood, sleep, appetite, temperature, blood pressureM.H.Farjoo
  • 17. Carcinoid Syndrome  Over 90% of the serotonin in the body is found in enterochromaffin cells in GI tract.  Carcinoid tumor secrets serotonin and is a neoplasm of enterochromaffin cells.  Carcinoid syndrome causes subendocardial fibroplasia and valvular or electrical malfunction.  In patients whose tumor is not operable, a serotonin antagonist is a useful treatment.M.H.Farjoo
  • 18. Carcinoid Syndrome  Cyproheptadine is a H1 and 5-HT2 blocker.  It also has antimuscarinic effects and causes sedation.  It is used in the treatment of the smooth muscle manifestations of carcinoid tumor and in cold-induced urticaria.M.H.Farjoo
  • 19. Carcinoid Syndrome  5-hydroxyindoleacetic acid (5-HIAA) is a metabolite of serotonin.  The excretion of 5-HIAA is a measure of serotonin synthesis.  The 24-hour excretion of 5-HIAA can be used as a diagnostic test for carcinoid tumor.  Banana contains large amounts of serotonin and must be prohibited during such tests.M.H.Farjoo
  • 20. Organ System Effect  Serotonin has no clinical applications as a drug but receptor selective agonists are of value.  For example buspirone, a 5-HT1A agonist, has anxiolytic effects.  Except 5-HT3 which is an ion channel, all serotonin receptors are G-protein coupled.M.H.Farjoo
  • 21. Receptor Distribution Agonists Antagonists5-HT1A Raphe nuclei, hippocampus Buspirone Substantia nigra, globus5-HT1B Sumatriptan pallidus, basal ganglia5-HT1D Brain Sumatriptan5-HT1E Cortex, putamen5-HT1F Cortex, hippocampus5-HT1P Enteric nervous system Platelets, smooth muscle,5-HT2A cerebral cortex5-HT2B Stomach fundus Choroid, hippocampus,5-HT2C substantia nigra Granisetron, Area postrema, sensory and5-HT3 Ondansetron, enteric nerves Tropisetron CNS and myenteric neurons, Cisapride,5-HT4 smooth muscle Metoclopramide5-HT5A,B Brain Clozapine5-HT6,7 Brain (5-HT7)
  • 22. Cardiovascular system  Serotonin is a powerful activator of chemosensitive endings located in the coronary vascular bed.  Activation of 5-HT3 receptors on these afferent vagal nerve endings causes chemoreceptor reflex (Bezold-Jarisch reflex).  The reflex response consists of marked bradycardia and hypotension.  Except in skeletal muscle and heart, serotonin contracts other vascular beds through 5-HT2 receptors.M.H.Farjoo
  • 23. Gastrointestinal tract  Serotonin stimulates peristalsis via:  This action is caused by the action on 5-HT2 receptors.  Agonists of 5-HT4 receptors in the ENS (Cisapride, Metoclopramide) increases acetylcholine and has a "prokinetic" effect.M.H.Farjoo
  • 24. Migraine  The mechanisms of action of drugs used in migraine are poorly understood.  Two hypotheses explain the actions of these drugs.  activating 5-HT1D/1B receptors on nerve endings inhibits the release of vasodilating peptides.  the vasoconstrictor actions of direct 5-HT agonists prevents vasodilation and stretching of the pain endings.  Triptans 5-HT1 agonists (eg: sumatriptan) are first- line therapy for severe migraine and are effective on cluster headache.M.H.Farjoo
  • 25. Migraine  Most adverse effects are mild but chest discomfort occurs in 1-5% of patients,  They are contraindicated in patients with coronary artery disease and in patients with angina.  their duration of effect is often shorter than the duration of the headache.  Several doses is required during a prolonged migraine but the adverse effects limit the maximum dose.M.H.Farjoo
  • 26. Migraine  Many other different drugs are also used in migraine.  Propranolol, amitriptyline, verapamil, valproic acid and topiramate are effective for the prophylaxis of migraine.  They are of no value in the treatment of acute migraine.  NSAIDs such as aspirin and ibuprofen are often helpful in controlling the pain of migraine.M.H.Farjoo
  • 27. Vomiting  5-HT3 receptors participate in the vomiting reflex.  They are particularly important in vomiting caused by anti cancer drugs.  Ondansetron is the prototypical 5-HT3 antagonist.  This drug is very important in the prevention of nausea and vomiting associated with surgery and cancer chemotherapy.M.H.Farjoo
  • 28. Introduction of Ergot Alkaloids Amine alkaloids Peptide alkaloids  Alkaloid’s Chemistry  Produced by a fungus that infects grain especially rye  Affect many kinds of receptors.  Ergot poisoning signs & symptoms (ergotism) :  Dementia with hallucinations Lysergic acid diethylamide (LSD)  Prolonged vasospasm, which may result in gangrene  Stimulation of uterine smooth muscle, which in pregnancy may result in abortionM.H.Farjoo
  • 29. Dopamine Serotonin Receptor UterineErgot Alkaloid Adrenoceptor Receptor (5-HT2) MuscleBromocriptine – +++ – 0Ergonovine ++ – (PA) +++Ergotamine – – (PA) 0 + (PA) +++ ––LSD 0 +++ + ++ in CNSMethysergide +/0 +/0 – – – (PA) +/0* PA means partial agonist (both agonist and antagonist effects can be detected)
  • 30. Introduction of Ergot Alkaloids (Cont,d)Amine alkaloids Peptide alkaloids
  • 31. Clinical Uses of Ergot Alkaloids  Migraine Ergotamine  Hyperprolactinemia Bromocriptine  Postpartum Hemorrhage (if Oxytocin fails) :  Uterus at term is very sensitive to ergot alkaloids  Induce powerful and prolonged contracture of uterus.  Should never be given before delivery.  Only for control of late uterine bleeding  Ergonovine maleate 0.2 mg is the agent of choice  It is usually effective within 1–5 minutesM.H.Farjoo
  • 32. Summary In English
  • 33. Thank you Any question?