Università di Camerino Scuola del farmaco e dei prodotti della salute Farmaci antiulcera Prof. Carlo Polidori Università di Camerino Scuola del farmaco e dei prodotti della salute

Tipi di cellule secretorie nel lume gastrico

Recettori presenti nelle cellule parietali Definizione di ulcera: Ferita che non evolve a guarigione spontanea. L’ulcera gastrica è una lesione profonda della mucosa gastrica di almeno 3 mm o più di diametro.

Inibitori di Pompa protonica

Meccanismo di azione dei PPI Chimicamente tutti gli inibitori di pompa protonica sono costituiti da un anello benzimidazolico e un anello piridinico e variano tra di loro in base alle sostituzioni presenti in queste due strutture. Sono piridine facilmente protonabili. Una volta che hanno raggiunto la mucosa gastrica dopo assorbimento sistemico si accumulano selettivamente nei canalicoli secretori gli spazi altamente acidi della cellula parietale. All-interno di questo spazio gli inibitori di pompa protonica subiscono una conversione catalitica verso specie altamente reattive le sulfenamidi tiofiliche che sono dei cationi permanenti. Queste specie reattive interagiscono in superficie con una H+, K+-ATPase sul lume dello spazio secretorio della cellula parietale formando un legame disulfidico attraverso due cisteine localizzate nell’unità alfa dell’enzima. Questo è il residuo che è coinvolto nel trasporto dello ione idrogeno. Questo legame covalente con l’enzima da parte della sulfenamide tiofilica risulta in un impedimento della secrezione gastrica specifica e di lunga durata.

La comparsa di malformazioni gravi nel gruppo trattato con omeprazolo non era significativamente diverso da quelle presenti nel gruppo di controllo e il controllo con GERD. Anche gli altri PPI non hanno mostrato gravi malformazioni durante la somministrazione in donne gravide. In ogni caso l’omeprazolo rimane il farmaco di elezione nel trattamento della GERD in donne in gravidanza. Vol 52: july 2006• Canadian Family Physician

Crescita batterica da PPI Sebbene i PPI causano un cambiamento della flora intestinale nell’intestino tenue fino ad ora non c’è evidenza che questo fenomeno interferisca con i processi digestivi o di assorbimento.

Farmacocinetica dei PPI Eur J Clin Pharmacol (2008) 64:935–951 Il lansoprazolo è il farmaco più biodisponibile (80-90%) mentre l’omeprazolo è il meno biodisponibile (205-40%). L’omeprazolo e il pantoprazolo hanno una clearance inalterata indipendentemente dalla funzionalità renale.

Metabolismo dei PPI Dalla figura si può notare che i PPI vengono metabolizzati nel fegato tramite il CYP2C19 inizialmente e poi dal CYP3A4 in maggior misurca rispetto al contrario.

Uso terapeutico Gli inibitori di pompa protonica vengono usati nelle condizioni in cui si richiede la riduzione della secrezione acida gastrica quali il reflusso gastro-esofageo, il reflusso non-erosivo, ulcere gastro-duodenali e nella sindrome di Zollinger-Ellison . Sono usati nella terapia dell’eradicazione dell’ Helicobacter pylori un microrganismo patogeno implicato nellosviluppo di ulcere gastro-duodenali. Il rabeprazolo ha il vantaggio di non interagire con altri farmaci in quanto non segue una via metabolica enzimatica coinvolgente i vari CYP.

THERAPEUTIC REGIMENS Dual therapy Dual treatments including a PPI with either clarithromycin or amoxicillin or metronidazole were popular during the previous decades. Dual therapy is now obsolete due to lack of efficacy of clarithromycin and metronidazole. On the contrary, worldwide primary and secondary resistance to amoxicillin of H. pylori is generally low and rare respectively, although it is a usual medication in standard triple therapy and therefore it is suitable for use in the dual therapy of H. pylori infection. Triple therapy Triple H. pylori therapy comprising a PPI, amoxicillin and clarithromycin is used as the firstline therapy. Clarithromycin or metronidazole resistance has been related to a reduction of success rates, making it a significant reason leading to treatment failure of H. pylori. The other factors such as rapid metabolism of PPIs by CYP2C19, poor patient compliance, high acidity of stomach and bacterial load seem to be the main causes of eradication failure. World J Clin Cases 2016 January 16; 4(1): 5-19

Quadruple therapy Quadruple therapy comprising bismuth subcitrate, PPI, metronidazole and tetracycline has been accepted better than standard triple therapy in several studies. Ten days quadruple therapy containing bismuthate dicitrate, esomeprazole, levofloxacin and tetracycline showed success rate of 95.8% after the failure of sequential therapy. This regimen could be used as a good choice in high clarithromycin resistance areas. In a similar study 14-d therapy with esomeprazole, amoxicillin, levofloxacin, and bismuth achieved more than 90% eradiation rate after the failed sequential or concomitant therapies. World J Clin Cases 2016 January 16; 4(1): 5-19

Terapia di eradicazione dell’ H. pilori Eur J Clin Pharmacol (2008) 64:935–951 La terapia di prima scelta nell’eradicazione è l’uso di un PPI, amoxicillina e claritromicina o metronidazolo. Il trattamento di seconda scelta è basata sull’uso di bismuto in aggiunta alla terapia di prima scelta. Il trattamento di terza scelta è basato sui test di suscettibilità del microorganismo per l’uso dell’antibiotico.

Scarpignato et al. BMC Medicine (2016) 14:179 Abstract Background: The introduction of proton pump inhibitors (PPIs) into clinical practice has revolutionized the management of acid-related diseases. Studies in primary care and emergency settings suggest that PPIs are frequently prescribed for inappropriate indications or for indications where their use offers little benefit. Inappropriate PPI use is a matter of great concern, especially in the elderly, who are often affected by multiple comorbidities and are taking multiple medications, and are thus at an increased risk of long-term PPI-related adverse outcomes as well as drug-to-drug interactions. Herein, we aim to review the current literature on PPI use and develop a position paper addressing the benefits and potential harms of acid suppression with the purpose of providing evidence-based guidelines on the appropriate use of these medications.

Results: Twenty-five years after their introduction into clinical practice, PPIs remain the mainstay of the treatment of acid-related diseases, where their use in gastroesophageal reflux disease, eosinophilic esophagitis, Helicobacter pylori infection, peptic ulcer disease and bleeding as well as, and Zollinger–Ellison syndrome is appropriate. Prevention of gastroduodenal mucosal lesions (and symptoms) in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) or antiplatelet therapies and carrying gastrointestinal risk factors also represents an appropriate indication. On the contrary, steroid use does not need any gastro-protection, unless combined with NSAID therapy. In dyspeptic patients with persisting symptoms, despite successful H. pylori eradication, short-term PPI treatment could be attempted. Finally, addition of PPIs to pancreatic enzyme replacement therapy in patients with refractory steatorrhea may be worthwhile.

Conclusions: Overall, PPIs are irreplaceable drugs in the management of acid-related diseases. However, PPI treatment, as any kind of drug therapy, is not without risk of adverse effects. The overall benefits of therapy and improvement in quality of life significantly outweigh potential harms in most patients, but those without clear clinical indication are only exposed to the risks of PPI prescription. Adhering with evidence-based guidelines represents the only rational approach to effective and safe PPI therapy.

Esomeprazole 20 mg is the only step-down dose PPI able to maintain a significantly higher proportion of GERD patients in symptomatic remission, as compared to lansoprazole 15 mg or pantoprazole 20 mg. Scarpignato et al. BMC Medicine (2016) 14:179

PROBIOTICS The probiotics, live microorganisms mostly within Lactobacillus, Bifido bacterium and Saccharomyces genus which, when administered in sufficient amounts, exert a health benefit on the host beyond inherent basic nutrition. A randomized, prospective, double-blind, placebo controlled study corresponding to 100 H. pylori-positive naive patients demonstrated Lactobacillus reuteri combination alone is capable of exerting an inhibitory activity against H. pylori, and when administered with eradication therapy, it increases eradication rates by about 9% and cause a significant reduction in antibiotic related adverse events

PHOTODYNAMIC THERAPY Photodynamic inactivation of microorganisms is on the basis of the combination of a dye known as a sensitizer or photo sensitiser and harmless visible light of an appropriate wavelength to generate the triplet excited state (3O2) of the dye molecules which, in turn, may react with molecular oxygen which lead to production of different cytotoxic reactive oxygen species such as superoxide radical-anion (O2•-) and singlet molecular oxygen (1O2).

VACCINE All known gastric H. pylori species are urease positive that catalyze the hydrolysis of urea. UreB is the relatively conserve urease activity unit and It has very strong antigenicity and is the critical for the bacterial survival and colonization under acidic condition of the stomach. UreI, a H. pylori urea channel protein, is a key factor for bacterial colonization in acidic mammalian stomach. In a research, a multi-epitope vaccine was designed by coupling two antigenic fragments (UreB and UreI ) of H. pylori and cholera toxin B subunit (CTB), resulting considerable protection effects against H. pylori challenge in BALB/c mice.

Anti-istaminici antiulcera I farmaci antistaminici antiulcera sono diretti nei confronti dei recettori H2. Questi sono cimetidina, ranitidina e famotidina. Lancet 2009; 374: 119–25

Meccanismo di azione della curcumina Several studies have demonstrated that H. pylori infection induces the secretion of matrix metalloproteinases from a range of gastric cells in vivo as well as in cultured cells, which in turn contribute to the pathogenesis of gastric ulcer and gastric cancer. Curcumin suppresses matrix metalloproteinases.