Rebuilding trust in proton pump inhibitor therapy

Table 1 Type of proton pump inhibitor available

PPI	Omeprazole	Esomeprazole	Lansoprazole	Dexlansoprazole	Pantoprazole	Rabeprazole
Half-life (T1/2) (hrs)[7-9]	0.6-1.0[7]	1.1[8]	0.9-1.6[7]	1-2[9]	0.9-1.9[7]	1[7]
Hepatic metabolism[10]	Major: CYP2C19; minor: CYP3A4	Major: CYP2C19; minor: CYP3A4	Major: CYP2C19; minor: CYP3A4	Major: CYP2C19; minor: CYP3A4	Minor: CYP3A4 CYP2C19	Non-enzymatic reduction minor: CYP2C19 and CYP3A4
Elimination[11]	Renal	Renal	Renal/fecal	Renal/fecal	Renal	Renal
Oral bioavailability (%)[11]	40-50	89	80-90	50-60	77	52
Food effect[14]	30 min before breakfast	60 min before breakfast	30 min before breakfast	Pharmacokinetics unaffected by meals	Pharmacokinetics unaffected by meals (exception oral suspension: 30 min prior to meal)	Pharmacokinetics unaffected by meals (exception capsule sprinkle: 30 min prior to meal)

PPI: Proton pump inhibitor.

Table 2 Guidelines on proton pump inhibitor use

ACG/ACG/CAG/SAGES/European guidelines	Recommendation
GERD[19,20,22]	Trial an 8-wk duration of once daily PPI in patients with heartburn and regurgitation without reflux symptoms
	Once daily dosing-administer PPIs 30 min to 1 h before a meal; twice daily dosing-administer PPIs 30 min to 1 h before breakfast and dinner
	For patients experiencing refractory GERD, optimize PPI therapy with patient compliance, dosage and timing to achieve symptom control before further exploration
	Prescribe continuous daily PPIs over H2RAs for erosive esophagitis maintenance healing
	Continue lifelong PPIs in patients with LA Grade C or D erosive esophagitis
	If patients with normal esophageal mucosa or LA Grade A esophagitis have normal ambulatory reflux monitoring results after 2-4 wk discontinuation of PPI therapy, it is strongly recommended to stop PPI use (low level of evidence)
Dyspepsia[23]	Patients < 60 years old, tested H. pylori negative or symptoms persist after eradication therapy, should start empiric PPI therapy
	Functional dyspepsia patients, tested H. pylori negative or symptomatic after infection treatment, should be on PPIs
H. pylori infection[24]	If active or history of PUD, and tested H. pylori positive, start eradication treatment (10-14 d) with PPIs and antibiotics
	Dyspepsia patients found to be H. pylori positive on gastric biopsy, treat with eradication therapy consisting of PPIs and antibiotics for 10-14 d
	GERD patients who are found H. pylori positive should be offered eradication therapy for 10-14 d course
	Use levofloxacin triple regimen consisting of PPI, amoxicillin and levofloxacin as salvage therapy if first line eradication therapy fails
Barrett’s esophagus[25, 26]	Recommend once daily dosing PPIs primarily indicated for symptomatic relief
	Twice daily dosing can be considered in patients with esophagitis or poor symptomatic relief
EoE [28,29]	Recommend PPI therapy for clinical and histological remission of EoE
NSAIDs[31,32]	PPIs are indicated for patients at risk of GI bleeds for gastroprotection (age > 65 years, high dose NSAID use, previous history of ulcers, concomitant therapy with corticosteroids, anticoagulants and antithrombotics)
	Prescribe continuous or intermittent high dose PPI the following 3 d after GI ulcer bleed was stopped endoscopically

ACG: American College of Gastroenterology; AGA: American Gastroenterological Association; SAGES: Society of American Gastrointestinal and Endoscopic Surgeons; CAG: Canadian Association of Gastroenterology; PPI: Proton pump inhibitor; H. pylori: Helicobacter pylori; H2RA: Histamine 2 receptor antagonist; GERD: Gastro-esophageal reflux disease; PUD: Peptic ulcer disease; LA: Los Angeles; EoE: Eosinophilic esophagitis; NSAID: Nonsteroidal anti-inflammatory drug; GI: Gastrointestinal.

Table 3 Proton pump inhibitor associated side effects

PPI associated adverse risks	Proposed mechanism	Evidence type	Conditional recommendations to reduce risk
Electrolyte abnormalities: Hypomagnesemia, vitamin B12, iron	Decreased acid secretion decreases intestinal absorption of minerals/vitamins	Observational studies, conflicting evidence[33,34,36,37]	Unless other risk factors present, no recommendation to increase intake of vitamins/minerals or have routine screening of levels[19]
Fracture risk/hypocalcemia	Decreased acid secretion decreases calcium carbonate absorption	Observational studies, conflicting evidence[39,40-42]	Without other risk factors for bone disease, no recommendations to increase calcium/vitamin D intake or have routine bone mineral density exam[19]
AIN/CKD/ESRD	Initiate cell mediated immune response in kidneys	Observational studies, conflicting evidence[43-46]	Without other risk factors, there is no recommendation to routinely screen for kidney function in patients on PPIs[19]
Dementia	Increase β-amyloid plaque production and increase affinity of tau proteins	Observational studies, conflicting evidence[48,49]	No recommendations on dementia prevention in patients on PPI
Gastrointestinal infections: C. diff, SIBO, SBP	Alter gut microbiota due to decreased acidic environment	Observational studies, conflicting evidence[34,51-55]	For patients who develop C.diff infection while on PPI, can consider switching to H2 blockers[55]
Community acquired Pneumonia	Increase bacterial colonization in stomach from hypochlorhydria leading to lung micro-aspiration events	Observational studies, RCTs, conflicting evidence[57-59]	No strong recommendation can be made
	Alter respiratory flora
Gastrointestinal malignancies	Hypergastrinemia resultant from decreased acid production increases ECL cell hyperplasia	Observational studies, RCTs, conflicting evidence[60-62,64,65]	Given conflicting data, no recommendation on prevention can be made
Adverse Cardiovascular effects- arrythmias, decreased clopidogrel bioavailability, increased digoxin toxicity	Hypomagnesemia- torsade de pointes	Observational studies, RCTs, conflicting evidence[59,66]	For patients with significant esophagitis (grade C or D) or with poorly controlled GERD, PPI treatment outweighs the debatable cardiovascular risks[19]
	CYP450 inhibitor- decreases drug bioavailability
	Interaction with ATP-dependent P-glycoprotein
	impair endothelial function and platelet induction

GERD: Gastro-esophageal reflux disease; PPI: Proton pump inhibitor; AIN: Acute intestinal nephritis; CKD: Chronic kidney disease; ESRD: End stage renal disease; C. diff: Clostridium difficile; SIBO: Small intestinal bacterial overgrowth; SBP: Spontaneous bacterial peritonitis; ECL: Enterochromaffin-like; RCTs: Randomized control trials.