DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Pharmacotherapy of Gastric Acidity,
Peptic Ulcers, and Gastroesophageal
Reflux Disease
John L. Wallace and
Keith A. Sharkey
The acid-peptic diseases are those disorders in which
gastric acid and pepsin are necessary, but usually not
sufficient, pathogenic factors. Although inherently caustic,
acid and pepsin in the stomach normally do not produce
damage or symptoms because of intrinsic defense
mechanisms. Barriers to the reflux of gastric contents
into the esophagus comprise the primary esophageal
defense. If these protective barriers fail and reflux
occurs, dyspepsia and/or erosive esophagitis may result.
Therapies are directed at decreasing gastric acidity,
enhancing the lower esophageal sphincter, or stimulating
esophageal motility (Chapter 46). The stomach is
protected by a number of factors, collectively referred to
as “mucosal defense,” many of which are stimulated by
the local generation of prostaglandins and NO (Wallace,
2008). If these defenses are disrupted, a gastric or duodenal
ulcer may form. The treatment and prevention of
these acid-related disorders are accomplished by decreasing
gastric acidity and enhancing mucosal defense. The
appreciation that an infectious agent, Helicobacter
pylori, plays a key role in the pathogenesis of acid-peptic
diseases has stimulated new approaches to prevention
and therapy.
PHYSIOLOGY OF GASTRIC SECRETION
Gastric acid secretion is a complex, continuous process
in which multiple central and peripheral factors contribute
to a common end point: the secretion of H + by
parietal cells. Neuronal (acetylcholine, ACh), paracrine
(histamine), and endocrine (gastrin) factors all regulate
acid secretion (Figure 45–1). Their specific receptors
(M 3
, H 2
, and CCK 2
, respectively) are on the basolateral
membrane of parietal cells in the body and fundus of
the stomach. Some of these receptors are also present
on enterochromaffin-like cells (ECL), where they regulate
the release of histamine. The H 2
receptor is a
GPCR (Chapters 3 and 32) that activates the G s
–adenylyl
cyclase–cyclic AMP–PKA pathway. ACh and gastrin
signal through GPCRs that couple to the G q
–PLC-
IP 3
–Ca 2+ pathway in parietal cells. In parietal cells, the
cyclic AMP and the Ca 2+ -dependent pathways activate
H + , K + -ATPase (the proton pump), which exchanges
hydrogen and potassium ions across the parietal cell
membrane. This pump generates the largest ion gradient
known in vertebrates, with an intracellular pH of ~7.3
and an intracanalicular pH of ~0.8.
The most important structures for CNS stimulation of gastric
acid secretion are the dorsal motor nucleus of the vagal nerve, the
hypothalamus, and the solitary tract nucleus. Efferent fibers originating
in the dorsal motor nuclei descend to the stomach via the vagus
nerve and synapse with ganglion cells of the enteric nervous system.
ACh release from postganglionic vagal fibers directly stimulates gastric
acid secretion through muscarinic M 3
receptors on the basolateral
membrane of parietal cells. The CNS predominantly modulates
the activity of the enteric nervous system via ACh, stimulating gastric
acid secretion in response to the sight, smell, taste, or anticipation
of food (the “cephalic” phase of acid secretion). ACh also
indirectly affects parietal cells by increasing the release of histamine
from the ECL cells in the fundus of the stomach and of gastrin from
G cells in the gastric antrum.
ECL cells, the source of gastric histamine, usually are in close
proximity to parietal cells. Histamine acts as a paracrine mediator,
diffusing from its site of release to nearby parietal cells, where it
activates H 2
receptors. The critical role of histamine in gastric acid
secretion is dramatically demonstrated by the efficacy of H 2
receptor
antagonists in decreasing gastric acid secretion.
Gastrin, which is produced by antral G cells, is the most
potent inducer of acid secretion. Multiple pathways stimulate gastrin
release, including CNS activation, local distention, and chemical