Pharm 46
Introduction
 Peptic ulcer – break in mucosa of stomach (gastric ulcer) or duodenum (duodenal ulcer)
Physiology of Gastric Acid Secretion
 HCl secreted into stomach by parietal cells, located in oxyntic glands in fundus and body of stomach
o Parietal cell actively transports H+ across apical canalicular membranes via H+/K+ ATPases (proton
pumps) that exchange intracellular H+ for extracellular K+
o Regulated by histamine, gastrin, and ACh; each binds to and activates specific receptors on basolateral
membrane of parietal cell, initiating biochemical changes necessary for active transport of H+ out of cell
 Histamine – released by enterochromaffin-like (ECL) cells located in and adjacent to oxyntic
glands and by mast cells in lamina propria; binds to histamine H2 receptors on parietal cell
 H2 receptor activation stimulates adenylyl cyclase and increases intracellular cAMP,
which activates cAMP-dependent protein kinase (PKA)
 PKA phosphorylates and activates proteins responsible for trafficking of cytoplasmic
tubulovesicles containing H+/K+ ATPase to apical membrane of cell
 H+/K+ ATPase doesn’t pump H+ into tubulovesicles because permeability of vesicular
membrane to K+ is low; after fusion of tubulovesicles with apical membrane, availability
of extracellular K+ allows H+/K+ ATPase to pump H+ from parietal cell into gastric lumen
 Cellular activation mobilizes apical membrane K+ channel to provide extracellular K+
 Gastrin – secreted into bloodstream by G cells in gastric antrum; has minor role in stimulating
release of histamine by ECL cells
 ACh – released from postganglionic nerves with cell bodies located in submucosa (Meissner’s
plexus)
 Both gastrin and ACh bind to their respective G protein-coupled receptors on parietal cell and
thereby activate phospholipase C and increase intracellular Ca2+
o Somatostatin-secreting D cells and prostaglandins limit extent of gastric acid secretion
 Somatostatin decreases acid secretion via
 Inhibition of gastrin release from G cells by paracrine mechanism
 Inhibition of histamine release from ECL cells and mast cells
 Direct inhibition of parietal cell acid secretion
 Prostaglandin E2 (PGE2) enhances mucosal resistance to tissue injury by
 Reducing basal and stimulated gastric acid secretion
 Enhancing epithelial cell HCO3- secretion, mucus production, cell turnover, and local
blood flow
 Phases of gastric acid secretion
o Cephalic phase – responses to sight, taste, smell, and thought of food; chewing but not swallowing
triggers increase in acid secretion mediated by vagal stimulation and increased gastrin secretion
o Gastric phase – stimulated by mechanical distension of stomach and ingestion of amino acids and
peptides; distension activates stretch receptors in wall of stomach that linked to short intramural nerves
and vagal fibers
 Luminal nutrients, such as amino acids, strong stimulants for gastrin release
 Gastrin travels via blood to oxyntic mucosa and stimulates ECL cells to release histamine
 Negative feedback on acid secretion is acid-mediated (pH <3) inhibition of gastrin release from
antral G cells
 Acid secretion inhibited by release of somatostatin from antral D cells
o Intestinal phase – stimulation of gastric acid secretion by digested protein in intestine; gastrin plays
major role in mediating this phase as well
 Epithelial cells of stomach secrete mucus, which acts as lubricant that protects mucosal cells from abrasions;
composed of hydrophilic glycoproteins that are viscous and have gel forming properties that enables formation
of uninterrupted layer of water at luminal surfaces of epithelium
o Together mucus and water layers attenuate potential damage due to acidic environment of gastric
lumen
o
Prostaglandins stimulate mucus secretion, whereas NSAIDs and anticholinergic medications inhibit
mucus production
o HCO3- protects gastric epithelium by neutralizing gastric acid; HCO3- secreted by epithelial cells at luminal
surface of gastric mucosa, in gastric pits, and at luminal surface of duodenal mucosa
 Restitution – ability of gastric mucosa to undergo repair; damage repaired through migration of undamaged
epithelial cells along basement membrane to fill defects created by sloughing or injured cells
 Blood flow to gastric mucosa removes acid that has diffused across damaged mucus layer
Pathophysiology of Peptic Ulcer Disease
 Peptic ulcer – break in lining of stomach or duodenum; can involve mucosa, muscularis mucosa, submucosa, and
in some cases, deeper layers of muscle wall
o Compromise of mucosal integrity can cause pain, bleeding, obstruction, perforation, and death
o Caused by imbalance between protective factors and damaging factors in GI mucosa
 Helicobacter pylori – Gram-negative, spiral-shaped bacterium; most common cause of non-NSAID-associated
peptic ulcer disease; eradication of H. pylori leads to lower recurrence and relapse rates in patients with ulcers
o Lives in acidic environment of stomach; initial infection usually transmitted by oral route
o Upon ingestion, microaerophilic bacterium uses 4-6 flagellae to move in corkscrew fashion through
gastric mucus layer
o Attaches to adhesion molecules on surface of gastric epithelial cells
o In duodenum, H. pylori attaches only to areas containing gastric epithelial cells that have arisen as result
of excess acid damage to duodenal mucosa (gastric metaplasia)
o Produces enzyme urease, which converts urea to ammonia, which buffers the H+ and forms NH4OH,
creating alkaline cloud around bacterium and protecting it from acidic environment of stomach
o Virulence factors cause damage to host; urease is damaging because it’s an antigen that causes strong
immune response
o NH4OH produced by urease causes gastric epithelial cell injury
o Other virulence factors include lipopolysaccharides (endotoxins, components of bacteria’s outer
membrane) as well as a lipase and protease that are secreted by bacteria and degrade gastric mucosa
o Cytotoxicity also linked to cagA and vacA (proteins associated with vacuolating cytotoxins)
o Acid secretion increased in patients with H. pylori-associated duodenal ulcers due to increased levels of
circulating gastrin, causing parietal cell proliferation and increased acid production; gastrin elevated by
 Ammonia produces alkaline environment near G cells and thereby stimulates gastrin release
 Number of antral D cells lower than normal in H. pylori-infected patients, resulting in decreased
somatostatin production and increased gastrin release
o Decreases duodenal HCO3- secretion and thereby weakens protective mechanisms of duodenal mucosa
o Presence of H. pylori infection can be detected using 13C-urea breath test, based on organism’s
production of urease; urease converts ingested 13C-urea to 13CO2 if H. pylori present in stomach, and
13
CO2 detected in breath; currently best diagnostic test
 Other methods of detection include histologic examination of gastric mucosal biopsy, serologic
testing for H. pylori antibodies, and stool antigen test
 NSAIDs – GI tract is most common target for adverse effects of NSAID use; damage attributable to both topical
injury and systemic effects
o Most NSAIDs are weak organic acids; in acidic environment of stomach, they are neutral compounds
that can cross PM and enter gastric epithelial cells
o In neutral intracellular environment, drugs are re-ionized and trapped; resulting intracellular damage
responsible for local GI injury associated with NSAID use
o Cause systemic injury, largely because of decreased mucosal prostaglandin synthesis
o 2 cyclooxygenase enzymes catalyze formation of prostaglandins from arachidonic acid
o In general cyclooxygenase-1 (COX-1) constitutively expressed and produces gastric prostaglandins
responsible for mucosal integrity, whereas COX-2 induced by inflammatory stimuli
o Inhibition of COX-1 by NSAIDs can lead to mucosal ulceration because inhibition of PGE2 synthesis
removes one of protective mechanisms maintaining integrity of gastric mucosa
o COX-2 selective NSAIDs (coxibs) may carry lower risk of ulcer formation than nonselective NSAIDs, but
coxibs associated with increase in MI and stroke
o
Adverse cardiovascular effects of coxibs may result from suppression of prostacyclin production by
vascular endothelial cells (catalyzed by COX-1 and COX-2), allowing thromboxane produced by platelets
(catalyzed by COX-1) to exert unopposed prothrombotic effect
o NSAIDs increase expression of intercellular adhesion molecules in vascular endothelium of gastric
mucosa, and increased adherence of neutrophils to vascular endothelium causes release of free radicals
and proteases that damage mucosa
 Zollinger-Ellison syndrome – gastrin-secreting tumor of non-beta cells of endocrine pancreas that leads to
increased acid secretion
 Cushing’s ulcers – seen in patients with severe head injuries, heightened vagal (cholinergic) tone causes gastric
hyperacidity
 Pepsin – digestive enzyme secreted by gastric chief cells
o Cigarette smoking associated with peptic ulcer disease because of its impairment of mucosal blood flow
and healing and its inhibition of pancreatic HCO3- formation
o Caffeine ingestion (increased acid secretion), alcoholic cirrhosis, glucocorticoid use, and genetic
influences all associated with peptic ulcer disease
o Chronic psychological stress may occasionally be a cause of peptic ulcer disease
Agents That Decrease Acid Secretion
 H2 receptor antagonists – reversibly and competitively inhibit binding of histamine to H2 receptors, resulting in
suppression of gastric acid secretion; indirectly decrease gastrin and ACh-induced gastric acid secretion
o Available H2 receptor antagonists include cimetidine, ranitidine, famotidine, and nizatidine
o Absorbed rapidly from small intestine; peak plasma concentrations achieved in 1-3 hours
o Elimination involves both renal excretion and hepatic metabolism; important to decrease dose of these
drugs for patients with liver or kidney failure (nizatidine primarily eliminated by kidney, so don’t have to
worry about liver here)
o All four drugs well tolerated in general; occasional minor adverse effects include diarrhea, headache,
muscle pain, constipation, and fatigue
o May induce confusion and hallucinations in some patients, but uncommon and typically associated with
IV administration of H2 receptor antagonists
o Cimetidine inhibits many cytochrome P450 enzymes and thus can interfere with hepatic metabolism of
numerous drugs; can decrease metabolism of lidocaine, phenytoin, quinidine, theophylline, and
warfarin, facilitating accumulation of these drugs to toxic levels
 Cimetidine inhibits P450 enzymes to a greater extent than other H2 receptor antagonists, so is
not recommended for use during pregnancy or when nursing
 Can have anti-androgenic effects because of action as antagonist at androgen receptor,
resulting in gynecomastia in men and, rarely, galactorrhea (discharge of milk) in women
 Proton pump inhibitors – block parietal cell H+/K+ ATPase (proton pump); superior to H2 receptor antagonists at
suppressing acid secretion and promoting peptic ulcer healing
o Omeprazole, esomeprazole (S-enantiomer of omeprazole), rabeprazole, lansoprazole, dexlansoprazole
(R-enantiomer of lansoprazole), and pantoprazole
o All proton pump inhibitors (PPIs) are prodrugs that require activation in acidic environment of parietal
cell canaliculus; oral formulations enteric-coated to prevent premature activation
o Prodrug converted to active sulfenamide form in acidic canalicular environment, and sulfenamide reacts
with cysteine residue on H+/K+ ATPase to form covalent disulfide bond
o Covalent binding of drug inhibits activity of proton pump irreversibly, leading to prolonged and nearly
complete suppression of acid secretion
o In order for acid secretion to resume, parietal cell must synthesize new H+/K+ ATPase molecules
o Available PPIs have similar rates of absorption and oral bioavailability
 Rabeprazole and lansoprazole have significantly faster onset of action than omeprazole and
pantoprazole
 Esomeprazole inhibits acid secretion more effectively than other proton pump inhibitors at
therapeutic doses
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Used to treat H. pylori-associated ulcers and hemorrhagic ulcers and to allow continued use of NSAIDs
in patients with known peptic ulcers; preferred for treatment of peptic ulcer with H. pylori infection
because they contribute to eradication of infection by inhibiting growth of H. pylori
Effective in preventing recurrent hemorrhagic ulcers; clot formation involves processes impaired in
acidic environments, and profound suppression of gastric acid secretion by proton pump inhibitors
helps maintain clot integrity in ulcer bed
Superior to H2 receptor antagonists for healing NSAID-associated gastric and duodenal ulcers when
patient continues NSAID use because proton pump inhibitors better able to sustain constant increase in
gastric pH
H2 receptor antagonists may be better in pregnant women because H2 receptor antagonists (with
exception of cimetidine) proven to be safe in pregnancy, whereas safety of proton pump inhibitors in
pregnancy is less certain
 H2 receptor antagonists generally less expensive than proton pump inhibitors
Long-term proton pump inhibitor may cause gastric carcinoid tumors, but association has not been
observed in humans
Omeprazole, esomeprazole, lansoprazole, and pantoprazole available in IV dosage forms; IV
formulations useful because it allows drug to bypass harsh acidic environment of stomach and upper
duodenum and allows more drug to reach its site of action in parietal cell canaliculus without
degradation; approved for patients with erosive esophagitis unable to take oral medications
 IV pantoprazole approved for treatment of gastrin-induced hypersecretory state associated
with Zollinger-Ellison syndrome
 IV formulation should be reserved for patients who require profound acid secretion or who are
unable to take oral medications (patients with erosive esophagitis or compromised GI
absorption)
 Appropriate indication for IV would be upper GI bleed with endoscopic evidence of visible blood
vessel, because gastric acid impairs clot formation; give this patient oral formulation when
bleeding stops
All have similar rates of metabolism; all except rabeprazole metabolized by cytochrome P450 enzymes
in liver (specifically CYP2C19 and CYP3A4)
 Rabeprazole largely metabolized through nonenzymatic reduction pathway
Individual’s response to treatment with PPI varies; pharmacogenetics of drug metabolism is major
factor responsible for variation
 PPIs extensively metabolized in liver to less active or inactive metabolites
 Omeprazole is most extensively metabolized; pantoprazole is least extensively metabolized
 CYP2C19 responsible for major metabolism of PPIs; this is the enzyme that has different
polymorphisms in people with different rates of metabolism and clearance of PPIs
 CYP2C19m1 and CYP2C19m2 associated with decreased enzyme activity; carriers of 2
copies of polymorphisms are poor metabolizers of PPIs
 Carriers of one copy ofpolymorphisms are intermediate to extensive metabolizers
 Polymorphisms exist most commonly in Asian populations (20% of Asians versus 2-6%
of Caucasians)
 Poor metabolizers exhibit decreased clearance of PPI, leading to higher plasma
concentrations of drug and greater degrees of acid suppression
 Most patients reach sufficient degree of acid suppression regardless of variability in
metabolism of drugs because standard recommended doses take this into account
 CYP3A4 functions as ancillary metabolic pathway when main pathway saturated
 Pharmacogenetic differences in PPI metabolism can lead to potentially significant drug-drug
interactions
 Only omeprazole interacts with other drugs metabolized by CYP2C19
 Clinically significant interactions don’t generally occur, but be highly aware if patients
taking omeprazole with warfarin, phenytoin, diazepam, or carbamazepine

In future, screening for presence of CYP2C19 polymorphisms could allow physicians to
determine which PPI is most appropriate for each patient and what dosage should most
effectively favor acid suppression while avoiding drug-drug interactions
o After metabolism of PPIs by liver, metabolites excreted via kidney; patients with chronic kidney disease
generally don’t require adjustment of standard dose, but patients with liver failure should be treated
with lower doses of drugs
 Elderly patients don’t generally require dose reduction even though plasma clearance reduced
because plasma half-life is short and accumulation typically doesn’t occur
 Elderly patients with concomitant renal and liver dysfunction should receive lower doses to
avoid increased risk of adverse effects
o PPIs cross human placental barrier; no increased rate of malformations in children born to women who
took PPIs during first trimester of pregnancy
o Generally well tolerated; adverse effects may include headache, nausea, disturbed bowel function, and
abdominal pain
 Potential concern is large increase in plasma gastrin associated with PPI use; because gastric
acid is physiologic regulator of gastrin secretion by G cells in gastric antrum, decreased acid
secretion caused by PPI therapy leads to increased gastrin release
 Trophic effects of gastrin can induce hyperplasia of ECL cells and parietal cells in gastric mucosa
 Rats treated with omeprazole for long periods developed gastric carcinoid tumors, but they
haven’t been observed in humans
 Patients with Zollinger-Ellison syndrome usually develop ECL and parietal cell hyperplasia, and
some develop carcinoid tumors, but no increase in carcinoid tumors found in Zollinger-Ellison
patients taking PPIs
 Hypergastrinemia can also result in rebound hypersecretion of acid upon discontinuation of PPI
o PPIs may decrease clinical efficacy of antiplatelet agent clopidogrel
 PPIs and clopidogrel share common metabolic pathway mediated by CYP2C19 in liver (most
PPIs metabolized by this enzyme, and clopidogrel converted from prodrug to active drug form
by same enzyme)
o PPI therapy may decrease gstric absorption of insoluble calcium by raising gastric pH, but some studies
say omeprazole decreases bone resorption by inhibiting osteoclastic vacuolar H+/K+-ATPase
o Use of PPIs during hospital admission increases risk for hospital-acquired pneumonia, C. difficile
infection, and enteric infections with Salmonella and E. coli
 Increased risk related to compromise of normal defense mechanism (i.e., gastric acid) by PPI,
allowing ingested organisms to escape acid-mediated destruction
 Anticholinergic agents such as dicyclomine antagonize muscarinic ACh receptors on parietal cells and thereby
decrease gastric acid secretion
o Seldom used in treatment of peptic ulcer disease because they’re not as effective as H2 receptor
antagonists or PPIs
o Have many adverse effects, including dry mouth, blurred vision, cardiac arrhythmia, and urinary
retention
Agents That Neutralize Acid
 Antacids – used on as-needed basis for symptomatic relief of dyspepsia; neutralize HCl by reacting with acid to
form water and salts
o Most widely used antacids are mixtures of Al(OH)3 and Mg(OH)2; OH- reacts with H+ in stomach to form
water, while Mg2+ and Al3+ react with HCO3- in pancreatic secretions and phosphates in diet to form salts
o Common adverse effects include diarrhea (Mg) and constipation (Al)
o When antacids containing Al and Mg used together, constipation and diarrhea may be avoided
o Antacids containing Al can bind phosphate; resulting hypophosphatemia can cause weakness, malaise,
and anorexia
o Patients with chronic kidney disease should avoid Mg-containing antacids because they can lead to
hypermagnesemia
 NaHCO3 reacts rapidly with HCl to form H2O, CO2, and NaCl; in paitents with hypertension or fluid overload,
sodium-containing antacids can result in significant sodium retention

CaCO3 – less soluble than NaHCO3; reacts with gastric acid to produce CaCl2 and CO2; can serve as calcium
supplement for prevention of osteoporosis; high calcium content may cause constipation
Agents That Promote Mucosal Defense
 Coating agents
o Sucralfate – complex salt of sucrose sulfate and Al(OH)3; has little ability to alter gastric pH
 Forms viscous gel that binds to positively charged proteins and thereby adheres to gastric
epithelial cells (including areas of ulceration)
 Gel protects luminal surface of stomach from degradation by acid and pepsin
 Little systemic absorption and no systemic toxicity because it’s poorly soluble
 Constipation is one of few adverse effects
 May bind to drugs such as quinolone antibiotics, phenytoin, and warfarin and limit their
absorption
o Colloidal bismuth – salts combine with mucus glycoproteins to form barrier that protects ulcer from
further damage by acid and pepsin
 May stimulate mucosal HCO3- and PGE2 secretion and thereby protect mucosa from acid and
pepsin degradation
 Impedes growth of H. pylori
 Prostaglandins – can be used in treatment of peptic ulcer disease, specifically in treatment of NSAID-induced
ulcers; NSAIDs are ulcerogenic because they inhibit prostaglandin synthesis and thereby interrupt
gastroprotective functions of PGE2, which include reduced gastric acid secretion and enhanced HCO3- secretion,
mucus production, and blood flow
o Misoprostol – prostaglandin analogue used to prevent NSAID-induced peptic ulcers
 Most frequent adverse effects are abdominal discomfort and diarrhea; often interfere with
patient adherence
 Contraindicated in women who are (or may be) pregnant because of possibility of generating
uterine contractions that could result in abortion
Agents That Modify Risk Factors
 Diet therapy typically involves recommendations to avoid caffeine-containing products because of their ability
to increase acid secretion
 Avoidance of alcohol and cigarette smoking advised; excessive alcohol intake directly toxic to mucosa and
associated with erosive gastritis and increased incidence of peptic ulcers
o Cigarette smoking decreases production of duodenal HCO3- and diminishes mucosal blood flow, leading
to delay in ulcer healing
 Treatment of H. pylori infection uses broad-spectrum antibiotics, such as amoxicillin or tetracycline combined
with metronidazole or clarithromycin, together with bismuth citrate and a PPI or ranitidine
o Common regimens involve triple therapy (amoxicillin, clarithromycin, and PPI) or quadruple therapy
(tetracycline, metronidazole, PPI, and bismuth)
o H. pylori may develop resistance to antibiotic therapy; metronidazole resistance reported; resistance to
clarithromycin less common
 3 point mutations in clarithromycin-binding site on H. pylori 23S rRNA responsible for
clarithromycin resistance (A2143G mutation specifically associated with very low bacterial
eradication rate)
 Levofloxacin suggested as alternative drug in second-line therapeutic regimens in patients with
resistance to clarithromycin
o Adverse effects include hypersensitivity reactions to penicillin analogues, nausea, headache, and
antibiotic-induced diarrhea caused by superinfection with C. diff
o Adverse effects and complicated dosing schedules of triple and quadruple therapy can lead to
nonadherence
o Resistance to H. pylori is growing concern, and antibiotic regimens need to evolve to meet challenge