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Proton Pump Inhibitors and What You Need to Know

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Proton Pump Inhibitors and What You Need to Know PROTON PUMP INHIBITORS SAFETY: A LITERATURE REVIEW CHARLENE LEPANE DO MSPH FACOI FACG FASGE ASST PROFESSOR MEDICINE UCF SCHOOL OF MEDICINE, LECOM BRADENTON, NSUCOM AND KCUMB CENTRAL FLORIDA HEPATOLOGY AND GASTROENTEROLOGY AT CELEBRATION HEALTH PROTON PUMP INHIBITORS SAFETY: A LITERATURE REVIEW AGENDA Background of PPIs Literature review of PPIs and blood thinners Pharmacokinetics of PPIs Current Use of PPIs PURPOSE OF THIS PRESENTATION Literature review of long term side effects of PPIs PROVIDE CLINICAL Osteoporotic fractures BASED DATA TO Renal damage ASSESS CURRENT Infection Rhabdomyolysis CLINICAL RELEVANCE MI/Cardiac events OF PPI THERAPY TO Electrolyte and Nutrienal deficiencies REINFORCE BEST Anemia and thrombocytopenia PRACTICE Drug interactions RECOMMENDATIONS PPIS Pharmaceutical agents that target H+/K+-ATPase located in the gastric parietal cells PPIS: PHARMACOKINETICS AND PHARMACODYNAMICS PPI is a prodrug which is activated by acid Activated PPI binds covalently to the gastric H+, K+-ATPase via disulfide bond Cys813 is the primary site responsible for the inhibition of acid pump enzyme, where PPIs bind PPIs share the core structures benzimidazole and pyridine but their PK and PD are a little different PPIS: PK AND PD Several factors must be considered in understanding the pharmacodynamics of PPIs, including: accumulation of PPI in the parietal cell the proportion of the pump enzyme located at the canaliculus de novo synthesis of new pump enzyme metabolism of PPI amounts of covalent binding of PPI in the parietal cell the stability of PPI binding PPIs have about 1hour of elimination half-life Area under the plasma concentration curve and the intragastric pH profile are very good indicators for evaluating PPI efficacy PPIS First available in 1989 with discovery of omeprazole Has become one of the most widely prescribed drugs Available in the USA as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole and dexlansoprazole Their high potency in increasing the pH of the stomach coupled with an excellent safety profile has made this class of drugs become one of the most commonly prescribed drugs in primary and specialty care AVAILABLE PPIS APPROVED BY FDA Liquid or Drug Dosages, mg IV suspension Generic Over-the-counter Omeprazole 10, 20, 40 Yes No Yes Yes Esomeprazole 20, 40 Yes Yes Yes Yes Lansoprazole 15, 30 Yes Yes Yes Yes Dexlansoprazole 30, 60 No No No No Pantoprazole 20, 40 Yes Yes Yes No Rabeprazole 20 No No Yes No STUDIES A study conducted in 2010 Ann Arbor, MI Veterans Administration hospital determined that of 946 patients: only 35% were prescribed PPI therapy for an appropriate documented upper GI diagnosis 10% received PPIs empirically for symptomatic treatment based on extraesophageal symptoms 18% received PPIs for gastroprotection 36% had no documented appropriate indication for PPI therapy Subgroup analysis demonstrated 49% of patients across all four categories received PPIs without documentation of re-evaluation of upper GI symptoms Disavowing the potential for on-demand or step-down therapy and this total cost of inappropriate PPI use was US$1,566,252 based upon average wholesale price (AWP) costs Heidelbaugh et al 2010 STUDIES Boston, MA health plan evaluated prescription patterns via pharmacy audit data in 2003 of both PPIs and histamine 2 receptor antagonists (H2RAs) in patients taking for more than 90 days Study of 168,727 adult patients found an: appropriate upper GI diagnosis in 61% of the study population; most common diagnoses of dyspepsia (42% of total) and GERD (38% of total) Approximately 39% of patients in this study lacked appropriate documentation for any upper GI diagnosis Almost 50% had documented symptoms of extraesophageal manifestations of potential upper GI disease Nearly 19% of subjects had diagnoses or symptoms commensurate with atypical GERD or dyspepsia no subgroup analysis with regard to defined gastroprotection with PPIs Jacobson et al. 2003 PHARMACOKINETICS PPIs are mainly eliminated by the hepatic route and cytochrome P450 (CYP450) system Polymorphic CYP2C19 and CYP3A4 are the primary enzymes involved in their metabolism Omeprazole and pantoprazole are metabolized mainly thorough CYP2C19 and therefore will interact with other drugs metabolized by same enzyme Warfarin and clopidogrel Lansoprazole is equally metabolized by both CYP2C19 and CYP3A4 Rabeprazole combines with H+/K+-ATPase reversibly causing 2-3X anti-secretory activity than omeprazole Mainly metabolized through non-enzymatic pathways and therefore little interaction with other meds PPIS AND EOSINOPHILIC ESOPHAGITIS Eosinophilic esophagitis (EoE) is now recognized as a chronic allergic inflammatory reaction involving an abnormal Th2-type immunological response A growing body of evidence has shown that PPIs might benefit both GERD and EoE patients and has recognized a new potential phenotype of the disease termed PPI-responsive esophageal eosinophilia (PPI-REE) A systemic review containing 10 randomized clinic trials (RCTs) enrolling 437 patients was performed to assess the efficacy of topical steroids + placebo vs PPIs for management of EoE Budesonide > fluticasone (OR.96; 95% CI .09-3.92) PPI > fluticasone (OR.61; 95% CI .13-1.86) but not to budesonide (OR 1.64;95%CI .08- 8.5) 3.Lipka et al. Dis Esophagus 2016;29(6):700-703 4.Lipka et al. Aliment Pharmacol Ther. 2016;43(6):663-673 PPIS AND EOSINOPHILIC ESOPHAGITIS These findings from the meta-analysis even showed there is no difference between topical steroids and PPIs for most of the symptoms of EoE Multiple plausible mechanisms of why PPI benefit EoE: Acid suppression as well as anti-inflammatory effects of PPIs might decrease acid injury-related cytokines, pain and esophageal permeability PPIs can inhibit Th2 cytokine-induced eotaxin-3 secretion in esophageal epithelial cells potentially reducing eosinophil recruitment PPIs can also exhibit antioxidant properties and inhibit certain functions of immune cells that may contribute to EoE PPIs would benefit at least 1/3 of patients with EoE Orel et l. Acta Gastoenerol Belg 2016;79(2):245-250 PPIS AND HELICOBACTER PYLORI H. pylori is a gram-negative bacillus that parasitizes the stomach and main pathogenic bacterium is protracted gastritis and PUD Closely connected to chronic gastritis, PUD, MALT (mucosa-associated lymphoid tissue lymphoma) Plays role in pathogenesis of gastric cancer therefore eradication reduces risk of gastric cancer A multicenter, open-label , randomized controlled trial (RCT) in 2003 with 544 patients with early gastric cancer indicated prophylactic eradication of H. pylori prevented potential development of metachronous gastric cancer OR .35 (95%CI.16-.76;P=.009) for development of metachranous gastric cancer Fukase et al. Lancet 2008;372(9636):392-397 Gatta et al. J Antimicrobial Chemother. 2003;51(2):439-442 PPIS AND HELICOBACTER PYLORI PPIs not only suppress the bacteria directly but also increase the pH which allows better penetration of the antibiotics Other PPIs showed a better eradication effect compare to omeprazole; the most effective combination studied is that with lansoprazole Replacement with pantoprazole resulted in few adverse reactions Substitution with rabeprazole led to increased rate of ulcer healing A clinical trial involving 80 patients with gastritis reported H. pylori eradication rate of esomeprazole-based triple therapy was similar to those based on first generation PPI Saito et alWorld J Gastoenerol. 2015;21(48):13548-13554 PPIS AND CANCER PPI-induced tumor cell apoptosis has become an area of interest A study 2010 suggested that PPIs exert selective apoptosis induction and cytoprotective actions, in addition to acid suppression PPIs showed a significant antitumor effect as a single agent in treating melanomas, lymphomas and gastric adenocarcinomas B cell tumors, Multiple Myeloma, colon cancer, pancreatic cancer and metastatic breast cancer Because of the acidic environment, it seems conceivable that PPIs may be able to impact the tumor site Various studies have been conducted to prove the antitumor effect of PPIs in vitro 2007 PPIs combined with vinblastine could increase the sensitivity to vinblastine Kim et al. Cancer Prev Res 2010;3(8)963-974 DeMilito. Can Res. 2007;67(11):5408-5417 PPIS AND CANCER Faulk et al. in Gastroenterology 2012 confirmed that PPIs + 325 mg ASA prevented esophageal adenocarcinoma in patients with Barretts’ esophagus The proposed mechanism was the PPIs combined with ASA may eliminate acid and bile salt reflux or block the activation of gastrin-CCK-cyclooxyygenase-2 (COX-2)-mediated pro-carcinogenic signal pathways and regulate PGE2 production The most probable mechanism of the antitumor effects of PPIs is demonstrated by the inhibition of the acidic environment PPIs are excellent at disturbing the acidic environment inhibits phosphorylation of the extracellular signal in turn regulates kinases contributes to the induction of apoptosis in cancer cells Faulk et al. gastroenterology. 2012; 143(4):917-926 PPIS AND TYPE 2 DM Suggested role of PPI with management of blood sugar in type 2 DM Gastrin is a peptide secreted mostly by antral G cells PPI indirectly elevate serum gastrin levels via negative feedback Gastrin promotes B cell neogenesis in the pancreatic ductal complex, modest pancreatic B cell replication, and improvement of glucose tolerance in animal models in a published study 2015 World J Diabetes Remodeling of pancreatic tissue is seen
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