Proton pump inhibitors (PPI) bid (e.g., omeprazole 20 mg bid or lansoprazole 30 mg bid) plus clarithromycin 500 mg bid and amoxicillin 1000 mg bid for 7 to 10 days
From: Geriatric Clinical Advisor , 2007
Proton Pump Inhibitors
Jai Moo Shin , George Sachs , in Encyclopedia of Gastroenterology, 2004
Introduction
The proton pump inhibitors (PPIs) can be classified into two groups: irreversible and reversible inhibitors. Irreversible covalent inhibitors are either substituted 2-(pyridinemethylsulfinyl)benzimidazoles or a similar structure, pyridylmethylsulfinyl pyrido-imidazole, which inhibit the pump enzyme by covalently binding to the α-subunit of the H+,K+-ATPase. Reversible proton pump inhibitors are mostly K+-competitive inhibitors, which inhibit the gastric H+,K+-ATPase activity by competing with potassium ions.
Since a substituted benzimidazole was first reported to inhibit the H+,K+-ATPase, many PPIs have been synthesized and are now in clinical use. Typical proton pump inhibitors in clinical use are listed in Fig. 1.
FIGURE 1. Chemical structure of irreversible proton pump inhibitors in clinical use.
In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016
General information
Proton pump inhibitors inhibit the H+/K+-ATPase (proton pump) in oxyntic cells of the stomach, the final common pathway in the secretion of gastric acid in response to a variety of stimuli, such as gastrin and histamine. Their use in acid-related disorders has been extensively reviewed [1–3].
General adverse effects and adverse reactions
The adverse reactions profile of the proton pump inhibitors during short-term administration (under 12 weeks) is similar to that reported with short-term use of histamine H2 receptor antagonists. The type and frequency of adverse reactions to lansoprazole, omeprazole, pantoprazole, and rabeprazole are comparable. The most common adverse reactions include headache, diarrhea, nausea, abdominal pain, constipation, dizziness, and rashes. Proton pump inhibitors can interact with other drugs by increasing gastric pH, inhibiting hepatic cytochrome P450, or inducing specific isoforms of this enzyme system. However, drug–drug interactions involving these isoenzymes and omeprazole or lansoprazole are uncommon and generally appear to be clinically unimportant. Pantoprazole seems to have a lower drug–drug interaction potential than either omeprazole or lansoprazole.
William A. SodemanJr. M.D., J.D., F.A.C.P., F.A.C.G., F.A.C.L.M. , Thomas C. Sodeman M.D. , in Instructions for Geriatric Patients (Third Edition), 2005
General Information
Proton pump on inhibitors are powerful drugs that inhibit the production of acid by the stomach. They are commonly used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and infection in the stomach with Helicobacter pylori. Many patients will find that they must remain on this medication for long intervals of time. To obtain the maximum effect of this drug, one must pay particular attention to timing when it is taken.
At the present time in the United States, five different proton pump inhibitors are available as prescription medications. These include Omeprazole (Prilosec), esomeprazole (Nexium), pan to prazole (Protonix), rabeprazole (Aciphex), and lansoprazole (Prevacid). In addition, one of these, omeprazole (Prilosec), is available without prescription as an over-the-counter medication.
This drug should be taken on an empty stomach. It should be taken 30 to 60 minutes before the meal. The tablets or the tiny pills inside the capsules should not be ground or chewed. They must remain intact to protect the drugs from being prematurely activated by the acid in the stomach. The medication must pass through the stomach intact and into the small intestine. The pills are designed to disintegrate in the small intestine to permit the drug to be absorbed into the blood. The circulation then carries the medication throughout the body. It will circulate for 1.5 hours on average before it is metabolized and gone.
Some of the drug is carried to the wall of the stomach to the cells that manufacture the stomach acid. When the cells begin to manufacture acid, which occurs when you eat a meal, the drug becomes activated and turns the acid-producing mechanism off. No further acid will be produced until the stomach manufactures additional acid-producing enzymes.
The timing of taking the medication 30 to 60 minutes before eating a meal permits the maximum effect of the medication in the inhibiting of the production of gastric acid. The customary time to take this medication is in the morning. If your physician recommends taking the dose at another time of day or if your work schedule means that your first meal of the day is not breakfast, you should still take the preparation 30 to 60 minutes before a meal. If the medication is taken and not followed by a meal, it will have little effect.
Some patients may have to take this medication twice daily. If this is the case for you, then the first dose can be taken before breakfast and a second dose taken 30 to 60 minutes before the evening meal.
Bryan M. Tucker , Mark A. Perazella , in Nephrology Secrets (Fourth Edition), 2019
7. What syndromes involving the kidneys are associated with PPIs?
PPIs, regardless of class, can cause AIN. Hyponatremia, likely the result of SIADH, is less common. Most PPIs are metabolized predominantly by hepatic CYP450 enzymes, in particular CYP3A4 and CYP2C19. PPIs can cause CNI toxicity due to their effects to reduce CNI metabolism by these 2 CYP450 enzymes. Hypomagnesemia is another complication of PPIs. This is due to reduced GI absorption rather than magnesium loss via the kidneys. A reduction in TRPM-6/7 function, which are magnesium pores in apical membranes of gastrointestinal (GI) epithelial cells, lead to this effect. Discontinuation of the PPI generally reverses GI magnesium wasting.
R. Bradley Troxler , Susan M. Harding , in Principles and Practice of Pediatric Sleep Medicine (Second Edition), 2014
Proton Pump Inhibitors
Proton pump inhibitors (PPIs) inhibit the hydrogen–potassium ATPase channels that are the final step in gastric acid secretion. PPIs bind covalently with the cysteine residues of the hydrogen–potassium ATPase pump. PPIs are more effective at suppression of acidic secretions than the H2RAs.11 Commonly used PPIs include omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole. There is some variation in the rates of activation and plasma half-life with the different PPIs; however, average half-life approximates 1–2 hours. Due to covalent bonding to the ATPase pump, the duration of action ranges from 15 hours for lansoprazole to 28 hours for omeprazole, and 46 hours for pantoprazole. PPIs are slow to achieve steady-state inhibition and generally require 3 days to achieve maximum impact. Children, ages 1 to 10 years, metabolize PPIs faster than adults and require a higher per kilogram dose compared to adults.48 PPIs should be tapered and not discontinued abruptly as this would result in gastric acid hypersecretion.
Minor side effects occur in 1–3% of patients on PPIs and include headache, diarrhea, abdominal pain, nausea, and rash. Major side effects are rare and include interstitial nephritis with omeprazole, hepatitis with omeprazole or lansoprazole, and visual disturbances with pantoprazole and omeprazole.49
There is a high frequency of nocturnal acid breakthrough among children on PPIs. Pfefferkorn et al. studied 18 children with esophagitis (mean age of 10.3 years) treated with 1.4 mg/kg of PPI divided twice daily and underwent esophageal pH testing after 3 weeks of therapy.50 They demonstrated that 89% of the patients had nocturnal acid breakthrough on the PPI.50
Finally, PPIs are most effective if they are administered as a single daily dose, 30 minutes before breakfast. This dosing corresponds with the timing of activation of stomach proton-potassium pumps after the overnight fast.11
Richard Jewell , in xPharm: The Comprehensive Pharmacology Reference, 2007
Therapeutics
Proton pump inhibitors are prescribed for the treatment of acid related gastrointestinal diseases including gastric and duodenal (peptic) ulcers, reflux esophagitis, and Zollinger-Ellison syndrome. The beneficial acid-reducing properties of PPIs are due to formation of active sulfenamide metabolites. PPIs have also been shown to be effective in combination with antibiotics for the eradication of Helicobacter pylori. Administered orally in the form of enteric-coated "slow release" tablets, PPIs are normally taken before food, with the dose and duration of treatment depending on the PPI prescribed. Not recommended for children. For further information refer to parent pro-drugs including esomeprazole magnesium, lansoprazole, omeprazole, pantoprazole (sodium sesquihydrate), and rabeprazole sodium (sodium salt).
David H. Shaw , in Pharmacology and Therapeutics for Dentistry (Seventh Edition), 2017
Proton Pump Inhibitors
PPIs are drugs that irreversibly inhibit H+/K+-activated adenosine triphosphatase (H+, K+-ATPase, commonly called the proton pump) in the gastric parietal cell (Fig. 28-1), the final common pathway for acid secretion. PPIs have become the drug class of choice for treating acid-related gastrointestinal diseases such as PUD and GERD. PPIs are among the most widely sold drugs because of their outstanding efficacy and safety. Currently, six members of the PPI class are available by prescription in the United States: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole (Table 28-2). Esomeprazole, lansoprazole, and omeprazole are available OTC at a lower dosage. When taken orally, all six agents effectively reduce basal and stimulated acid secretion considerably. They are longer lasting and substantially more potent than histamine H2-receptor antagonists in the short-term treatment of PUD, GERD, and heartburn. Dexlansoprazole is marketed in a longer lasting dual delayed-release formulation, with two types of granules, each with a coating that dissolves at a different pH. This provides two peak plasma times, but the clinical relevance of this form of release has not been firmly established.
PPIs are administered as inactive prodrugs that accumulate selectively in the acid environment of the secretory canaliculus of the gastric parietal cell. The PPI is rapidly protonated and converted to the active form of the drug. Because PPIs bind covalently to active proton pumps, synthesis of new pumps or activation of resting pumps is required to restore activity. This irreversible inhibition of the pump explains why the duration of action of this class extends beyond the elimination half-life of 0.5 to 2 hours (see Table 28-2). Most PPIs are best taken on an empty stomach (food can decrease bioavailability up to 50%) once daily 30 minutes to 1 hour before the first meal of the day so that the peak serum concentration coincides with the maximum activation of the proton pumps. Dexlansoprazole, unlike the other PPIs, lacks the pharmacokinetic and pharmacodynamic drug–food interactions and can be taken with a meal.
The most common adverse effects reported with PPIs are headache, diarrhea, and nausea, but the frequency is only slightly greater than placebo. Long-term use of PPIs may cause a slight increase in serum gastrin. This information led to concerns regarding gastrin-induced neoplasms that have been reported in animal models. PPIs have been used worldwide for close to 40 years and, to date, none have been associated with an increased risk of gastric cancers in patients receiving long-term therapy. Of more recent concern are reports that PPIs, particularly with prolonged therapy, are associated with a decrease in Ca2+ and Mg++ absorption through induction of hypochlorhydria and with an increased risk to develop community-acquired Clostridium difficile–associated disease (CDAD). Acid is also important in releasing vitamin B12 from food, and subnormal B12 levels have been reported with prolonged PPI therapy.
All PPIs increase gastric pH and may alter the absorption of drugs that are weak bases or acids or formulated as pH-dependent, controlled-release products. Absorption of aspirin, digoxin, and midazolam may be increased, and ketoconazole absorption may be decreased when administered with a PPI. The clinical significance of the alterations is unclear. PPIs can also alter the hepatic metabolism of other medications. All PPIs are metabolized to varying degrees by hepatic P450 cytochromes (CYP450), including isoenzymes CYP2C19 and CYP3A4, and may interfere with the medications metabolized by these same enzymes. Omeprazole has been shown to progressively inhibit CYP2C19 activity with repeated administration and may inhibit the metabolism of diazepam, warfarin (coumadin), and phenytoin. In spite of these concerns, few clinically significant drug interactions have been reported given the enormous popularity of PPIs.
One adverse drug interaction that initiated an FDA warning is the potential interaction between clopidogrel and PPIs. Clopidogrel is a prodrug that is activated by hepatic CYP2C19, the same isoenzyme involved, to varying extent, in the metabolism of the PPIs. The concern is that coadministration of clopidogrel and a PPI would reduce the activation of clopidogrel (and its antiplatelet action) in susceptible patients. The clinical relevance of this potential interaction remains a point of debate, but it is recommended that patients taking clopidogrel be prescribed a PPI that has minimal effect on the activity of CYP2C19 (e.g., pantoprazole). The effect of long-term PPI use on cardiovascular health is another area of clinical debate. PPIs may have a negative effect on vascular function leading to an increased risk for myocardial infarction.
PPIs, especially used long-term, may increase the risk of: rebound hypersecretion, bone fracture, and infections, namely, Clostridium difficle-induced diarrhea as well as pneumonia.
Normal Physiology of the Gastrointestinal Tract and Gender Differences
ROBYN G. KARLSTADT MD, FACG , ... AMY FOXX-ORENSTEIN DO, FACG , in Principles of Gender-Specific Medicine, 2004
4. Acid Inhibition by Proton Pump Inhibitors
Proton pump inhibitors are used for the treatment of erosive gastroesophageal reflux disease (GERD). It is possible that gender may influence the degree of gastric acid inhibition afforded by PPIs. In a study conducted to determine the effect of two PPIs on stimulated gastric acid secretion, a subanalysis examined the influence of gender on proton pump inhibition of pentagastrin-stimulated GAO [88]. The results demonstrated that proton pump inhibition of pentagastrin-stimulated GAO was significantly more effective in females compared to males in decreasing both volume and GAO (see Table 36-6). The inhibition of GAO in women was reflective of a significant decrease in gastric volume and H + secretion. Therefore, gender differences may exist in the inhibition of gastric acid secretion induced by PPIs.
Table 36-6. Proton Pump Inhibition of Pentagastrin-Stimulated Gastric Acid Output
N
Age
Cumulative 24 hr GAO (mEq)
% Change
Cumulative 24 hr Volume (ml)
[H+] (mEq/L)
Female
10
20–42
122 ± 35*
65%
1776 ± 297*
61 ± 10*
Male
21
19–46
269 ± 35
22%
2917 ± 227
84 ± 7
Placebo (n = 3 females, 1 male; age 20–38), cumulative (24 hr) pentagastrin-stimulated GAO was 344 ± 28 mEq; cumulative volume was 3100 ± 349 ml; and [H+] was 109 ± 10 mEq/L. Mean ± SEM;
*
= p < 0.05; % change = % decrease from placebo. Data collection after administration of a single dose of PPI.
A Worldwide Yearly Survey of New Data in Adverse Drug Reactions
Kirby Welston , Dianne May , in Side Effects of Drugs Annual, 2017
Drug–Drug Interaction, Pemetrexed
PPIs, specifically lansoprazole, were shown to inhibit pemetrexed transport via human organic anion transporters (hOATs) [40C]. Inhibitors of hOAT3 may delay the elimination of pemetrexed leading to increased hematological toxicities. A study was undertaken to determine the effects of PPIs on hOAT3-expressing cultured cells in vitro, as well as a retrospective review of the incidence of hematologic toxicities in 108 patients with nonsquamous cell small-cell lung cancer who received permetrexed and carboplatin concurrently with a PPI [40C]. In vitro, lansoprazole was found to inhibit hOAT3-mediated pemetrexed uptake more than other PPIs. When retrospectively reviewing the 108 cancer patients, concomitant use of lansoprazole with pemetrexed and carboplatin was an independent risk factor associated with hematologic toxicities (odds ratio: 10.004; P = 0.005). Forty-seven percent of lansoprazole users experienced a hematologic toxicity. This suggests that lansoprazole, but not other PPIs, should be avoided in patients receiving pemetrexed and carboplatin.
Noel Lee , ... Sumona Saha , in Clinical Pharmacology During Pregnancy, 2013
25.1.6 Proton pump inhibitors
Proton pump inhibitors (PPIs) are typically reserved for patients with severe symptoms refractory to lifestyle modification and the older generation medications. Four of the five PPIs (lansoprazole, rabeprazole, pantoprazole, and esomeprazole) are FDA category B. Omeprazole, however, is FDA category C rating due to fetal toxicity in animal studies.
Despite their favorable pregnancy classification, concern over the long-term safety of PPIs has limited their use. However, there is now a large amount of data supporting their safety in pregnancy. A 2009 meta-analysis by Gill et al. which included 1530 PPI-exposed and 133,410 non-exposed controls found no increased risk for major malformations, spontaneous abortions or preterm delivery with first-trimester use of PPIs [19].
A Danish cohort study examining 840,968 live births, of which 5082 were exposed to a PPI between 4 weeks before conception and the end of the first trimester, did find a minor difference in abnormalities in the newborns of exposed (3.2%) and non-exposed (2.6%) women (adjusted prevalence odds ratio, 1.23; 95% CI, 1.05 to 1.44) [20]. The risk of birth defects, however, was not significantly increased in secondary analyses of exposure to individual PPIs during the first trimester.
Thus, based on the available data, PPI use in pregnancy does appear to be safe. First trimester exposure, however, should be avoided when possible due to the possible increased risk for fetal malformations. While most patients can be effectively treated with once-a-day dosing some may need to be dosed twice daily.
The various medical therapies for GERD are summarized in Table 25.1.
Table 25.1. Medications for gastroesophageal reflux disease
Drug
FDA pregnancy category
Recommendations in pregnancy
Recommendations in lactation
Antacids
Calcium-based
NA
Safe
Compatible
Magnesium-based
Avoid in late pregnancy as may arrest labor and precipitate seizures; can cause diarrhea
Aluminum-based
Can cause constipation and possibly fetal neurotoxicity
Alginic acid
Safe
Sodium bicarbonate
Contraindicated due to risk for maternal fluid overload and metabolic alkalosis
Sucralfate
B
Safe
Compatible
Metoclopramide
B
Avoid long-term, high dose use due to risk for tardive dyskinesia
Limited human data: potential toxicity
H2-receptor antagonists
Ranitidine
B
Preferred H2-RA in pregnancy
All safe except nizatidne
Cimetidine
May have anti-androgenic properties
Famotidine
Probably safe
Nizatidine
Probably safe but less preferred H2-RA
Proton pump inhibitors
Omeprazole
All B except omeprazole (C)
Reserve for refractory patients; avoid first trimester use
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