Lezione del 29/04/2005 Anno accademico 2004/05

Serotonina e farmaci del sistema serotoninergico

Goodman&Gilman’s

Sintesi e metabolismo della serotonina 5-HT N-acetilase o-metil- transferasi melatonina

Il terminale serotoninergico

Recettori e meccanismi di trasduzione intracellulare Esistono almeno 7 tipi di recettori serotoninergici, suddivisi in alcuni sottotipi. I recettori sono per lo più associati a proteine G (7 domini transmembrana). Il recettore di tipo 3 (5-HT3) è un recettore canale che trasporta cationi (Na+, K+ con una simile permeabilità, ma può trasportare anche Ca2+)

Recettori serotoninergici

Comparison of the percentage amino acid identity between the different human 5-HT receptor subtypes

Principali recettori 5-HT Nome Effettore Distribuzione Patologia Funzione 5-HT1A Gi/cAMP↓ Go/Ca2+↑ Ippocampo, setto Ansia, ipertensione Autorecettore 5-HT1B Striato, Ippocampo vasi, TSSA Ansia Depressione Comp.aggres 5-HT1D (***) Trigemino Muscolatura vasale Emicrania, depressione Vasculopatia Vasocostrizione 5-HT1E Caudato, putamen, amigdala ____ _____ 5-HT1F (****) Emicrania

Principali recettori 5-HT Nome Effettore Distribuzione Patologia Funzione 5-HT2A Gq/G11 PLC,Ca2+↑ (*****) m. vasale e gastrointestinale, piastrine ipertensione, alterazione mot G.I. Aggregazionecontrazione 5-HT2B m. ileale, stomaco, utero, vasi, endotelio _____ Contrazione 5-HT2C (*******) plessi coroidei, ipotalamo, endotelio Emicrania, 5-HT3 Canale ionico Striato, corteccia, Sostanza Nigra., gangli simp. neuroni sens. vomito _____

Principali recettori 5-HT Nome Effettore Distribuzione Patologia Funzione 5-HT4 Gs/cAMP↑ (*******) plesso mienterico, m. G.I. Disordini G.I. Propulsione Intestinale 5-HT5A Gs/cAMP↑ Ippocampo, cort,cervelletto, midollo spinale ____ _____ 5-HT5B _______ Ippocampo, cort,cervelletto, midollo spinale 5-HT6 Gs/cAMP↑ (********) ippocampo, accumbens Psicosi (?) _____ 5-HT7 Gs/cAMP↑ (*********) ippocampo, m. vasale ipertensione _____

Legenda tabelle (*) solo molecole di interesse terapeutico; (**)patologia; (***5-HT1D)Striato, Accumbens, Rafe, nuclei base, ganglio trigemino, m. vasale; (****5-HT1F) Corteccia, talamo, bulbo olfattorio, midollo spinale, utero, mesenteri; (*****5-HT2A) Corteccia, ippocampo, bulbo olfattorio, midollo spinale, s. gastrointestinale, m. vasale e bronchiale, endotelio, piastrine; (******5-HT2C) Plessi coroidei, ponte, striato, ippocampo, ipotalamo, endotelio, m. spinale; (*******5-HT4) Striato, talamo, ippocampo, bulbo olfattorio, plesso mienterico, m. esofagea e vasale; (********5-HT6)Caudato, putamen, accumbens, corteccia, ippocampo, ganglio cervicale superiore; (*********5-HT7) Ippocampo, ipotalamo, talamo, collicolo sup., rafe, gangli simpatici, m. vasale e intestinale S.N= S. Nigra, TSSA= terminali nervosi s. autonomo, Aggres =aggresssività, dep=depressione, almG.I. =alterata motilità gastrointestinale, neuroni sens.= neuroni sensitivi

Potential therapeutic areas Class and examples Site Action Potential therapeutic areas 5HT1p agonists  Buspirone  Sumitriptam Inhibitory gastric motor neurones Fundal relaxation Functional dyspepsia 5HT3 antagonists Ondansetron Granisetron      Alosetron Cilansetron Vagal afferents Enteric interneurones   & secreto-motor neurones Mesenteric afferents Inhibit nausea due to   5HT release; Inhibit opiate induced nausea; Inhibit sprial evoked responses to intestinal distension Chemotherapy induced nausea Post operative nausea Visceral hypersensitivity   in IBS 5HT4 agonists  Prucalopride Cholinergic colonic   motor nerves (enhances   acetylcholine release) Stimulates peristalsis Accelerates colonic transit Constipation 5HT4 partial agonist  Tegaserod Primary afferent enteric neurones Enterocytes Extrinsic mesenteric afferents Stimulates peristalsis Stimulates chloride secretion Inhibits afferent firing in response to    distension Constipated IBS Combined 5HT4 agonist and 5HT3 antagonist     Cisapride Motor neurones Increase oesphageal peristalsis; lower oesphageal sphineter pressure Accelerating gastric emptying and small bowel transit Impaired oesphageal peristalsis Gastroparesis Chronic intestinal pseudo-

Spiller R - British Journal of Clinical Pharmacology  54 (1), 11-20, 2002

Spiller R- British Journal of Clinical Pharmacology  54 (1), 11-20, 2002

Serotonergic modulating drugs for functional gastrointestinal diseases Schematic illustration of selected neuronal and cellular sites where 5HT receptor modulators can act as discussed in the text. 5HT acting via 5HT1p receptors on the gastric inhibitory neurone causes the release of NO which relaxes the gastric fundus. 5HT3 antagonists inhibit splanchnic afferent nerve response to painful distension and inhibit vagal responses to chemotherapy induced 5HT release. They also inhibit discharge of secreto-motor nerves, which act via VIP, and NO. 5HT4 agonists induce peristaltic contractions by stimulating IPAN. These activate ascending excitatory pathways, mediated via acetylcholine and substance P, together with descending inhibitory pathways, mediated via NO and VIP release. Abbreviations: IPAN=intrinsic primary afferent neurone, VIP=Vasoactive intestinal peptide, SP=substance P, NO=nitric oxide.

Cellule enterocromaffini (EC) della mucosa rettale Microvilli Granuli secretori Membrana basolaterale Spiller, Robin - British Journal of Clinical Pharmacology  54 (1), 11-20, 2002

Regolazione della secrezione di 5-HT nelle ECs Spiller R - British Journal of Clinical Pharmacology  54 (1), 11-20, 2002

Goodman&Gilman’s

Farmaci e sistema serotoninergico: Recettori 5-HT3: antagonisti come l’ondansetron, il tropisetron, il dolasetron ed il granisetron sono usati come antiemetici nella nausea ed il vomito indotto da farmaci antiblastici Questi farmaci verranno trattati successivamente

Alosetron 2,3,4,5-tetraidro-5-metil-2-[(5-metil-1-H-imidazol-4-yl)metil]-1-H-pirido(4,3-b)indol-1-one, idrocloruro

A Randomized Controlled Clinical Trial of the Serotonin Type 3 Receptor Antagonist Alosetron in Women With Diarrhea-Predominant Irritable Bowel Syndrome IRRITABLE BOWEL syndrome (IBS) is one of the most common functional gastrointestinal disorders seen in primary care and gastroenterology practices. Irritable bowel syndrome primarily affects women, with prevalence estimates of 14% to 24% of women in the United States and Great Britain. It negatively affects patients' daily activities and quality of life and contributes to significant increases in health care resource utilization … The serotonin type 3 (5-HT3) receptor antagonists represent valuable therapeutic compounds for the treatment of IBS. The 5-HT3 receptors have been identified on sensory neurons of the gut and mediate reflexes that control gastrointestinal motility and secretion, bowel function, and perception of pain. In patients with IBS, 5-HT3 receptor antagonists increase colonic compliance, slow colonic transit, and improve stool consistency Camilleri et al., Arch Intern Med 161 (2001), pp. 1733–1740.

Tegaserod 3-(5-methossi-1H-indol-3-ilmetilene)-N-pentilcarbazimidamide maleato

Tegaserod In the past, treatment decisions were often based on the patient's individual symptoms because there was no single drug that was effective in relieving abdominal pain, bloating and constipation associated with irritable bowel syndrome. However, there is growing evidence that serotonin (5-HT), via its subtype 4 (5-HT4) receptors, plays a pivotal role in the maintenance of overall gastrointestinal motor function. The advent of innovative 5-HT4 receptor agonists has demonstrated that 5-HT4 receptor stimulation can trigger the peristaltic reflex in both animal and human gastrointestinal tract.

Effect of tegaserod versus placebo in patients with irritable bowel syndrome. Müller-Lissner et al., Aliment Pharmacol Ther 15 (2001), pp. 1655–1666

Serotonina e controllo dell’appetito Meguid MM et al., Nutrition 16:843-57, 2000