Pharmacology Ch 46 807-819
Peptic ulcers are breaks in the gastric mucosa that affect 10% of the population. The break can
affectthe mucosa, muscularis mucosa, submucosa, and deeper layers. Can cause pain, bleeding,
obstruction, perforation, and death.
-caused by imbalance between protective factors and damaging factorsin GI mucosa
-most common causes are H. pylori infection and NSAID use
Neurohormonal Control of Gastric Acid Secretion
-HCl is secreted by parietal cells in oxyntic glands in fundus and body of stomach
-H+ is transported across apical, canalicular membrane by H+/K+ ATPases
-Histimine, Gastrin, and Acetylcholine regulate gastric acid secretion
1. Histamine – released by enterochromaffin-like cells (ECLs) (oxyntic glands/mast cells
-bind to H2 receptors on parietal cell
-H2Receptoradenylyl cyclase (cAMP)protein kinase A (PKA)traffic
cytoplasmic vesicles containing H+/K+ ATPase to apical membrane
-allows H+ to be pumped out and K+ in, (can’t happen without receptor)
2. Gastrin – secreted by G cells in gastric antrum
-binds G proteins on parietal cellphospholipase Cincrease CaH+/K+
ATPase activation
-Stimulates histamine release by ECL cells
3. Acetylcholine – secreted by postganglionic nerves in Meissner’s Plexus
-binds G proteins on parietal cellphospholipase Cincrease CaH+/K+
ATPase activation
-Somatostatin-secreting D cells and Prostaglandins inhibit gastric acid secretion by:
1. inhibition of G cells in a paracrine fashion
2. inhibition of histamine release from ECL and mast cells
3. direct inhibition of parietal cell secretion
-Prostaglandin E2 (PGE2) – enhances mucosal resistance to injury by:
-reducing basal and stimulated gastric acid secretion
-enhancing epithelial bicarbonate (HCO3-) secretion, mucus production, cell turnover,
and local blood flow
Phases of Gastric Acid Secretion – 3 phases
1. Cephalic Phase – responses to sight, taste, smell of food trigger gastric acid secretion
2. Gastric Phase – mechanical distension activates stretch receptors in wall of the stomach
linked to vagal nerve fibers. Ingestion of amino acids, stimulate gastrin release, which
travels in the blood and stimulates ECL release of histamine
a. Acid is an inhibitor of this process, as well as somatostatin
3. Intestinal Phase – stimulation of gastric acid secretion by protein in the intestine
Protective Factors – factors such as gastric mucus, prostaglandins, gastric/duodenal bicarb,
repair, and blood flow protect the gastric mucosa
-mucus acts as lubricant to protect stomach from abrasions
-composed of hydrophilic glycoproteins that are viscous and have gel-properties and
allows formation of water layer on top of mucosa to attenuate potential damage
-prostaglandins – stimulate mucus secretion (NSAIDs and anticholinergic meds inhibit it)
-bicarbonate – protects gastric epithelium by neutralizing gastric acid
-secreted by luminal cells of gastric mucosa, gastric pits, and duodenal mucosa.
-restitution – ability of gastric mucosa to undergo repair through epithelial cells migrating along
basement membrane to fill the damaged area
-blood flow – blood flow to gastric mucosa removes acid diffused across damaged layer
Helicobacter pylori – gram-negative bacteria is most common cause of non-NSAID peptic ulcer
disease.
-H. pylori is found in stomach antrum in many patients with duodenal and gastric ulcers
-bacterium survives in acid environment and is transmitted orally
-H. pylori, after ingestion, travels along mucosa and attaches to gastric epithelial cells by
adhesion molecules
-it is able to live in acid environment by secretion of the enzyme urease, which converts urea to
NH3, buffering H+ to form NH4OH to form an alkaline cloud around bacteria.
-Virulence factors secreted by H. pylori cause damage:
-urease is a damaging factor that causes strong immune response
-NH4OH causes gastric epithelial cell injury
-Lipopolysaccharides (endotoxins) – components of bacterial membrane
-Cytotoxicity has been linked to 2 proteins associated with vacuolating cytotoxins (cagA and
vacA)
-persistence of H. pylori can be attributed to change in normal immune response against the
infection
-normally, a T helper type 2 (TH2 response) occurs, but H. pylori causes a TH1, which
induce inflammation and epithelial cell damage
-Acid secretion increases in H. pylori infection, resulting from increased levels of circulating
gastrin, causing parietal cell proliferation and increased acid production.
-gastrin secretion occurs due to ammonia that is generated causing an alkaline
environement to stimulate release
-number of antral D cells is lower than normal in H. pylori patients, resulting in
decreased somatostatin and increased gastrin released
-H. pylori decreases duodenal HCO3 secretion and weakens protective mechanism
-H. pylori can be detected using 13C-urea breath test based on production of bacterial urease.
Urease converts ingested 13C to 13CO2, which can be detected in the breath
NSAIDs – GI damage from NSAIDs attributed to topical injury and systemic effects of NSAID
-NSAIDS normally weak acids which are neutral in stomach acid and can traverse membrane,
where they are re-ionized and trapped in the cellsintracellular damage
-can also cause systemic injuryto GI lining because of decreased mucosal prostaglandin synthesis
-2 cyclooxygenase (COX) enzymes catalyze formation of prostaglandins from arachidonic acid
-COX1 always expressed and produces gastric prostaglandins for mucus integrity
-COX2 is induced by inflammatory stimuli
-COX1 inhibition by NSAIDs lead to mucosal ulceration because of inhibition of PGE2
synthesis, removing one of protective mechanisms for integrity of gastric mucosa
-COX2 selective NSAIDs (coxibs) carry lower risk of ulcer formation compared to
nonselective NSAIDs, but COX2 selective NSAIDs carry risk for MI and stroke
-adverse effects of COX2 NSAIDS may stem from suppression of prostacyclin
from vascular endothelial cells allowing thromboxane to produce unopposed
thrombotic effect
-NSAIDs may also increase expression of cell adhesion molecules in vascular endothelium of
gastric mucosa to cause adherence of neutrophils and release of free radicals that damage it
Acid Hypersecretion – important causative factor in patients with peptic ulcer disease
-Zollinger-Ellison Syndrome and Cushing’s Ulcers two clinical examples where hyperacidity
leads to peptic ulcer disease
-gastrin-secreting tumor in Zollinger-Ellison syndrome; head injury with increased vagal
tone in Cushing’s ulcers
-Cigarette smoking associated with peptic ulcer disease because of its impairment of mucosal
blood flow and healing and its inhibition of pancreatic bicarb.
Pharmacological Agents that Decrease Acid Secretion
1. H2 Receptor Antagonists – called H2 blockers reversibly and competitively inhibit binding of
histamine to H2 receptors, resulting in suppression of gastric acid secretion and indirectly
decrease gastrin and acetylcholine-induced gastric acid secretion
-cimetidine, ramitidine, famotidine, nizatidine are available
-absorbed from small intestine and peak plasma concentrations are reached 1-3 hrs
-excretion is both hepatic and renal (nizatidine almost all renal)
-occasional side effects include diarrhea, headache, muscle pain, constipation
-several drug-drug interactions can occur with H2 blockers: Ketoconazole, drug that
requires acid medium for absorption, has reduced uptake in alkaline environment
created by H2 blockers
-Cimetidine inhibits cytochrome P450 enzymes and interferes with hepatic metabolism
of drugs (decrease metabolism of lidocaine, quinidine, theophylline, warfarin.)
2. Proton Pump Inhibitor – blocks parietal cell H+/K+ ATPase, which is a superior method of
decreasing gastric acid compared to H2 receptor blockers.
-omeprazole is the prototype proton pump inhibitor, others are: esomeprazole,
rabeprazole, lansoprazole, dexlansoprazole, and pantoprazole
-all are prodrugs that require activation of acidic environment of parietal cell canaliculus
-prodrug is converted to its active sulfonamide in acidic environment, and reats with
cysteine on the proton pump to form covalent disulfide bond (irreversible)
-used to treat H. pylori associated ulcers and hemorrhagic ulcers and to allow continual
use of NSAIDs
-5 out of the 6 proton pump inhibitors metabolized by cytochrome P450 and excreted
by the kidney. The last inhibitor is metabolized non-enzymatically
-adverse affects include headache, nausea, disturbed bowel, and abdominal pain
-concern is excess gastrin release with the use of PPIs, which can produce
hyperplasia of ECL and parietal cells in the gastric mucosa
3. Anticholinergic Agents – antagonize muscarinic acetylcholine receptors on parietal cells to
decrease gastric acid secretion, but they aren’t as effector as H2 blockers or PPIs. One such
agent is dicyclomine
Agents that Neutralize Acid – antacids used for dyspepsia relief which neutralize HCl, most
widely used are aluminum hydroxide and magnesium hydroxide
-adverse effects: diarrhea (Mg), constipation (Al)
-NaHCO3 reacts with HCl as an antacid, and Ca(HCO3)2 is less soluble than NaHCO3 and reacts
with gastric acid to neutralize it
Agents that Promote Mucosal Defense –
1. Coating Agents –
a. Sucralfate – salt composed of sucrose sulfate and aluminum hydroxide that is
used to alleviate symptoms of peptic ulcer disease by altering gastric pH –
makes viscous gel, which protects mucosa by forming a positively charged
coating on it protecting it from the acid and pepsin
b. Colloidal Bismuth – coating agent that is used in peptic ulcer disease by forming
a barrier that protects ulcer from further damage: busmith salts bind mucus
glycoproteins, and may stimulate mucosal bicarb and PGE2 secretion to protect
mucosa
2. Prostaglandins – used in treatment of NSAID-induced ulcers (NSAIDs ulcerogenic
because they inhibit prostaglandin synthesis and thereby interrupts protective functions
of PGE2 (gastric acid secretion, bicarb secretion, mucus production, blood)
a. Misoprostol is a prostaglandin analogue used to prevent GI ulcers
i. May cause ab discomfort and diarrhea, contraindicated in
Agents that Modify Risk Factors
1. Diet, tobacco, alcohol – caffeine increases gastric acid secretion, alcohol toxic to
mucosa, smoking decreases duodenal bicarb
2. Treatment of H. pylori infection – uses broad spectrum antibiotics such as amoxicillin or
tetracycline combined with metronidazole or clarithromycin with bismuth citrate and
PPI or ranitidine.
a. Commone treatment is called triple therapy – amoxicillin/clarithromycin/PPI
b. H Pylori can develop resistance, and levofloxin has been suggested as an
alternative