La presentazione è in caricamento. Aspetta per favore

La presentazione è in caricamento. Aspetta per favore

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

Presentazioni simili


Presentazione sul tema: "Lezione del 29/04/2005 Anno accademico 2004/05."— Transcript della presentazione:

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

2

3

4 Goodman&Gilmans

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

6 Il terminale serotoninergico

7 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-HT 3 ) è un recettore canale che trasporta cationi (Na +, K + con una simile permeabilità, ma può trasportare anche Ca 2+ )

8 Recettori serotoninergici

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

10 Principali recettori 5-HT NomeEffettoreDistribuzionePatologiaFunzione 5-HT 1A G i/cAMP G o / Ca 2+ Ippocampo, settoAnsia, ipertensione Autorecettore 5-HT 1B G i/cAMP G o / Ca 2+ Striato, Ippocampo vasi, TSSA Ansia Depressione Comp.aggres Autorecettore 5-HT 1D G i/cAMP G o / Ca 2+ (***) Trigemino Muscolatura vasale Emicrania, depressione Vasculopatia Vasocostrizione 5-HT 1E G i/cAMP Caudato, putamen, amigdala ____ _____ 5-HT 1F G i/cAMP (****) Emicrania_____

11 Principali recettori 5-HT NomeEffettoreDistribuzionePatologiaFunzione 5-HT 2A G q /G 11 PLC,Ca 2+ (*****) m. vasale e gastrointestinale, piastrine ipertensione, alterazione mot G.I. Aggregazione contrazione 5-HT 2B G q /G 11 PLC,Ca 2+ m. ileale, stomaco, utero, vasi, endotelio _____ Contrazione 5-HT 2C G q /G 11 PLC,Ca 2+ (*******) plessi coroidei, ipotalamo, endotelio Emicrania, _____ 5-HT 3 Canale ionico Striato, corteccia, Sostanza Nigra., gangli simp. neuroni sens. vomito _____

12 Principali recettori 5-HT NomeEffettoreDistribuzionePatologiaFunzione 5-HT 4 G s /cAMP (*******) plesso mienterico, m. G.I. Disordini G.I.Propulsione Intestinale 5-HT 7 G s /cAMP (*********) ippocampo, m. vasale ipertensione _____ 5-HT 6 G s /cAMP (********) ippocampo, accumbens Psicosi (?) _____ 5-HT 5A G s /cAMP Ippocampo, cort,cervelletto, midollo spinale _________ 5-HT 5B _______ Ippocampo, cort,cervelletto, midollo spinale _______

13 Legenda tabelle (*) solo molecole di interesse terapeutico; (**)patologia; (***5-HT 1D )Striato, Accumbens, Rafe, nuclei base, ganglio trigemino, m. vasale; (****5- HT 1F ) Corteccia, talamo, bulbo olfattorio, midollo spinale, utero, mesenteri; (*****5-HT 2A ) Corteccia, ippocampo, bulbo olfattorio, midollo spinale, s. gastrointestinale, m. vasale e bronchiale, endotelio, piastrine; (******5-HT 2C ) Plessi coroidei, ponte, striato, ippocampo, ipotalamo, endotelio, m. spinale; (*******5-HT 4 ) Striato, talamo, ippocampo, bulbo olfattorio, plesso mienterico, m. esofagea e vasale; (********5- HT 6 )Caudato, putamen, accumbens, corteccia, ippocampo, ganglio cervicale superiore; (*********5-HT 7 ) 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

14 Class and examples SiteAction Potential therapeutic areas 5HT 1p agonists Buspirone Sumitriptam Inhibitory gastric motor neurones Fundal relaxationFunctional dyspepsia 5HT 3 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 5HT 4 agonists Prucalopride Cholinergic colonic motor nerves (enhances acetylcholine release) Stimulates peristalsis Accelerates colonic transitConstipation 5HT 4 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 5HT 4 agonist and 5HT 3 antagonist Cisapride Motor neuronesIncrease oesphageal peristalsis; lower oesphageal sphineter pressure Accelerating gastric emptying and small bowel transit Impaired oesphageal peristalsis Gastroparesis Chronic intestinal pseudo-

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

16

17 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 5HT 1p receptors on the gastric inhibitory neurone causes the release of NO which relaxes the gastric fundus. 5HT 3 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. 5HT 4 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.

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

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

20 Goodman&Gilmans

21 Farmaci e sistema serotoninergico: Recettori 5-HT 3 : antagonisti come londansetron, 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

22 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

23 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-HT 3 ) receptor antagonists represent valuable therapeutic compounds for the treatment of IBS. The 5-HT 3 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-HT 3 receptor antagonists increase colonic compliance, slow colonic transit, and improve stool consistency Camilleri et al., Arch Intern Med 161 (2001), pp. 1733–1740.

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

25 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-HT 4 ) receptors, plays a pivotal role in the maintenance of overall gastrointestinal motor function. The advent of innovative 5-HT 4 receptor agonists has demonstrated that 5-HT 4 receptor stimulation can trigger the peristaltic reflex in both animal and human gastrointestinal tract.

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

27

28 Meguid MM et al., Nutrition 16:843-57, 2000 Serotonina e controllo dellappetito


Scaricare ppt "Lezione del 29/04/2005 Anno accademico 2004/05."

Presentazioni simili


Annunci Google