Escolar Documentos
Profissional Documentos
Cultura Documentos
Joseph Heitman
I. Ulcers
-Gastric physiology
-History and revolution in thought
-Treatment strategies
A) histamine H2 receptor antagonists
B) H+ pump antagonists
C) prostaglandin antagonists
D) surface agents and antacids
E) eradication of Helicobacter pylori with bismuth and antibiotics
II. Other (diabetic gastroparesis, reflux esophagitis, gastric stasis, anorexia nervosa)
III. Nausea and vomiting
-physiology
-treatment
IV. Diarrhea
V. Constipation
VI. Inflammatory bowel disease
Gastric Physiology
The stomach is an outpocket of the gastrointestinal tract in which ingested food undergoes
mechanical and chemical changes that promote absorption in the small and large intestine. The gastric
mucosa contains specialized structures, known as oxyntic glands or gastric pits (which make up the
fundus and corpus). This specialized mucosa produces acid (HCl) (from parietal cells); the proteolytic
enzyme pepsin (from chief cells); mucous (from mucous cells), and hormones (from endocrine cells).
Acid is not absolutely required for digestion because individuals with achlorhydria usually can digest
food without malabsorption.
Lastly, mucous (neutral fluid containing glycoproteins) protects the gastric mucosa from both
mechanical and chemical damage.
About 10 years ago a revolution in thinking about the causes of ulcers began and focused
attention on the role of an infectious agent, the bacterium Helicobacter pylori, in ulcer formation. The
role for Helicobacter pylori in gastric disease, including ulcers and cancer, is now well established and
treatment of this infection is likely to significantly improve the lives of ulcer patients.
This is not to say that this bacterium is the only cause of ulcers, but just that it is by far the
most significant and may account for up to 90% of ulcers. It is certainly the most common cause of
recurrent ulcers. Other causes of recurrent ulcers, such as aspirin/NSAIDs (which weaken mucosal
defenses by both a local irritative effect and systemically by decreasing production of prostaglandins) or a
rare tumor of the pancreas or duodenum that secretes gastrin and overstimulates acid production (ZE or
Zollinger-Ellison syndrome, a non-beta cell islet tumor) are quite distant second and third causes of
ulcers.
We begin by discussing the various pharmacological treatments of ulcers, which still have a quite
important place in therapy, and then return to our discussion of Helicobacter pylori.
Acid Secretion
Parietal cells contain a modified smooth endoplasmic reticulum, called the tubulovesicular and
canalicular structures, which contain pumps that secrete H + ions, derived from dissociation of H2O into H+
and OH-, in exchange for K+ ions. ATP to drive these pumps is supplied by abundant mitochondria. Cl ions are transported from blood into the parietal cell cytoplasm and then into canaliculi. Parietal cells
also contain carbonic anhydrase, which hydrates CO 2 to produce H+ ions to combine with excess OH ions produced by the H+ pump and HCO3- ions that are exchanged for Cl- ions.
Regulation of Acid Production
Acid production by parietal cells is regulated by the nervous system, endocrine system, and a
local paracrine system. These inputs are mediated by receptor-ligand interactions on neurons, endocrine
cells, and parietal cell (see figures).
Neural signals via the vagus impinge on postganglionic neurons (mechanism not yet defined) in
the stomach, which release acetylcholine to stimulate endocrine cells (at as yet undefined muscarinic
receptors) and parietal cells (M 3 receptors) to produce histamine and acid, respectively. This is the basis
for the surgical management of ulcer by vagotomy or partial vagotomy. Histamine released by endocrine
cells binds to parietal cell H 2 histamine receptors and stimulates acid production. Other local paracrine
factors include prostaglandins, which inhibit acid production. Lastly, gastric endocrine cells release
gastrin into the circulation in response to stretch and chemoreceptors. Gastrin returns to the stomach to
act on endocrine cells and increase histamine release, and on parietal cells directly to increase acid
production by histamine. Other endocrine cells secrete somatostatin, which counteracts the stimulatory
effects of gastrin.
In the parietal cell, histamine and prostaglandins act via G-proteins to increase or decrease,
respectively, cAMP production by adenylate cyclase. In contrast, gastrin and acetylcholine increase Ca 2+
concentrations. Activation of these two distinct signalling pathways underlies the phenomenon that: 1)
prostaglandins inhibit histamine action, but not isolated acetylcholine or gastrin signals, 2) gastrin and
acetylcholine potentiate histamine action (by acting on 2 different signals). The second messengers
cAMP and Ca2+ activate protein kinases. The next step in regulating acid production is not clear. H +
secretion requires not only the H +/K+ exchange pump, but also a K +/Cl- cotransporter that allows K+ ions
to enter tubulovesicles and canaliculi and then exchange for H + entry. Some evidence suggests that
insertion of the K+ carrier into the membrane is the regulated step.
H+ Pump Inhibitors
Acid is ultimately secreted from the apical surface of parietal cells by the H +-K+ exchange pump.
Several benzimadazole derivatives inhibit this pump. Omeprazole and a few other H+ pump blockers are
used clinically. Omeprazole is an extremely potent inhibitor of gastric acid secretion and is therefore
invaluable in treating ulcers resistant to histamine H 2 receptor antagonist therapy and ulcers that result
from Zollinger-Ellison syndrome. ZR results from non-beta cell islet tumors of the pancreas or
duodenum which secrete gastrin and overstimulate acid production, resulting in ulcers.
Omeprazoles mechanism of action is unusual. The compound is stable and does not inhibit the
pump at neutral pH. At acidic pH (below 5) in the lumen of parietal cell canaliculi, omeprazole becomes
protonated and rearranges to two active species that covalently react with the H + pump, irreversibly
inactivating it. Omeprazole specifically accumulates in the canalicular lumen when the pH is below 5,
because the protonated species are changed and dont escape the vesicles. As the pump is blocked, pH
rises and, when it reaches 5, omeprazole stops accumulating in the canaliculi.
Omeprazole can reduce acid production by 95% or more. This results in increased gastrin
production, which can cause mucous cells to proliferate, even to the point of carcinoid tumors, in animals.
There is as yet no evidence of this in humans. However, carcinoid tumors are known to occur in patients
with gastrinoma or chronic atrophic gastritis.
Omeprazole is characterized by oral administration, rapid absorption, binding to plasma protein,
hepatic metabolism, short half-life (80-90 min), renal excretion. The drug is well tolerated, even when
given to ZE patients in high dose for long periods. Three percent incidence of GI disturbance, rarer CNS
effects (headache, dizziness).
Prostaglandins
Prostaglandins inhibit histamine stimulation of parietal cells and also protect the mucosa by
enhancing blood flow and mucous secretions. Non-steroidal antiinflammatory drugs (NSAIDs) promote
ulcers by decreasing prostaglandin levels. In some cases, patients on chronic NSAID theapy receive
concomitant treatment with the PGE 1 analog, misoprostol. Misoprostol is also effective in duodenal
ulcer, but offers no advantage over other therapies. Given orally, side effects include diarrhea, cramping,
and potentially abortion. Therefore it should not be given to pregnant or potentially pregnant women.
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Sucralfate
This is a local coating agent (complex of sucrose octasulfate and polyaluminum hydroxide) that
acts locally on the mucosal surface and is highly effective in treating ulcers. It is most effective given
prior to, rather than after, meals. At pHs below 4 (i.e., in the stomach) sucralfate polymerizes to a highly
viscous gel. You can think of this as something like super-mucous that forms where it is needed.
Sucralfate causes constipation in about 10% of patients. It is very commonly used in hospitalized
patients.
Helicobacter pylori, Antibiotics and Pepto-Bismol for Ulcers
Helicobacter pylori is a spiral gram negative microaerophilic (likes low amounts of oxygen)
bacillus, first seen in gastric tissue in 1892, first cultured from gastric biopsies in 1982, that is specially
adapted to survive in the stomach and duodenum (see Peterson, NEJM 324:1043-1048, 1991).
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H. pylori produces a hyperactive form of the enzyme urease, which catalyzes conversion of urea
to ammonia and CO2 and allows the bacterium to partially neutralize the acidity of the stomach. This is
the basis of a simple color assay for the bacterium in which urease in biopsy specimens is detected by a
pH-dependent color change. In random populations, prevalence is 10% for those under 30 years but rises
to 60% for those over 60 years. Prevalence is 100% in patients with duodenal ulcers and 80% in patients
with gastric ulcers. That many individuals infected with H. pylori do not develop ulcers suggests other
factors contribute to ulcer development.
The transmission route is not known. The fecal-oral route has been proposed, but the bacterium
has not been found in stool. Person-to-person transmission is possible, because the bacterium is not
found in food, water, or animals with frequent human contact (pets, livestock). Gastroenterologists have
twice the average prevalence. H. pylori is associated with histological changes of the gastric mucosa
(gastritis, inflammation). The central question is whether the bacterium causes these changes or simply
lives there after the fact. In two human subjects who swallowed H. pylori cultures, both suffered
inflammation of the gastric mucosa. One spontaneously resolved, the other developed chronic gastritis.
In addition to histological changes, H. pylori infection is associated with increased gastrin and
acid secretion.
Recent studies reveal that antibiotic treatment combined with more standard ulcer medication,
such as ranitidine, is highly effective and reduces relapse. For example, patients treated with a two-week
course of ranitidine, tetracycline, metronidazole (antibiotic selective for anaerobic and microaerophilic
bacteria and anoxic cells, undergoes reduction and then damages DNA) and bismuth subsalicylate
(Pepto-Bismol) had only 12% relapse, compared to a 74% (gastric) and 95% (duodenal) relapse rate for
ranitidine treatment alone. Institution of antibacterial treatment for ulcer could largely eliminate the need
to treat relapses and vastly reduce the overall cost of ulcer treatment. Because H. pylori causes chronic
atrophic gastritis in some patients, it may also play a role in the etiology of gastric carcinoma. This would
be the first association of bacterial infection with cancer.
Additional information on Helicobacter pylori from slides
Diagnosis Diagnostic approaches for H. pylori infection include: abnormal histology of gastric
mucosa, serological tests as signs of infection, a breath test in which 13C-labelled urea (ingested) is
metabolized by the bacteria and released as 13C-labelled CO2 in the breath, and finally a color assay of
biopsy specimens that detects a urease-dependent pH change.
Treatment One now-standard therapy is Quadruple Therapy, which consists of tetracycline,
bismuth subsalicylate, metronidazole and a histamine H 2 receptor antagonist (cimetidine or ranitidine).
Alternatives include: substitution of tetracycline by amoxicillin, substitution of metronidazole with
clarithromycin. Alternatively, some results suggest a dual therapy of amoxicillin plus omeprazole (proton
pump inhibitor that also kills H. pylori) may be effective in some cases.
Association with cancer Five links between H. pylori and gastric lymphoma/carcinoma
1. H. pylori present in patients with gastric lymphoma/carcinoma
2. Rate of H. pylori infection increased in these patients.
3. Risk of cancer increased in infected vs. non-infected individuals
4. H. pylori infection precedes diagnosis of carcinoma/lymphoma
5. Eradication of H. pylori caused tumor remission in patients with biopsyproven low-grade gastric MALT lymphomas
Model of the relationship between H. pylori and gastric lymphoma/carcinoma H. pylori
infection leads to chronic gastritis, epithelial cell hyperplasia, and increased risk of malignant
transformation to gastric carcinoma. Lymphoid tissue is normally absent from the stomach. Infection
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Metoclopramide is well absorbed orally and has a short half-life (4 hr). Most (80%) is excreted in
the urine without metabolism.
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The vomit reflex loop begins with receptors in the GI tract, which when stimulated send a signal
through vagal afferents to the vomit center or chemoreceptor trigger zone located in the medulla in the
area
postrema
near
the
fourth
ventricle.
The vomiting center is in the lateral ventricular formation. Several pathways provide input, including the
chemoreceptor trigger zone (CTZ), the vestibular system, cortical regions, and visceral afferents from the
GI tract. The blood-brain barrier is not well-developed around the area postrema, providing it access to
the circulation. Activation of the vomit center initiates the vomit reflex, during which the glottis closes to
protect the lungs, the cardiac sphincter opens, respiratory and abdominal muscles contract the stomach,
and a reverse peristaltic wave ejects the stomach contents.
An array of different antiemetic agents is known. We will consider only the major classes and the
most commonly used.
Antiemetics can be divided into those acting centrally (in the CTZ (vomit center)), those acting
centrally and peripherally, and those acting peripherally. Because nausea and vomiting are reflexes
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mediated by the nervous system, it should not be surprising that antiemetics are neurotransmitter
antagonists.
The precise wiring of the vomit center is not known. Based on the action of antiemetics, it has
been inferred that cholinergic and histaminergic neurons link the vestibular apparatus to the vomit center,
whereas dopaminergic neurons act centrally and peripherally during vomiting.
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The antimuscarinic scopolamine is one of the most potent agents for motion sickness and is also
used in vertigo and to reduce postoperative nausea and vomiting. Scopolamine acts centrally to block the
vomit center by inhibiting acetylcholine actions. Scopolamine is a relative of atropine and shares similar
side affects (dry mouth, blurry vision, urinary retention), but crosses the blood-brain barrier more
effectively. Typically delivered by a transdermal patch behind the ear, which should be placed prior to the
onset of nausea. Most frequent side effects are dry mouth and drowsiness. Advise patients to wash their
hands after applying the patch to avoid contact of the drug with the eyes.
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The second class of centrally acting antiemetics is the H1 histamine receptor antagonists. These
include dimenhydrinate (Dramamine), diphenhydramine (Benadryl), and meclizine (Antivert). These
agents are useful for motion sickness, vertigo, and (in extreme cases) pregnancy. Importantly, they are
not useful for nausea associated with chemotherapy. In some cases, meclizine is effective for radiationassociated nausea and vomiting. The most common side effect, sometimes useful clinically, is
drowsiness.
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The small intestine and colon are gigantic absorptive surfaces. On average, 9 liters of fluid enters
the small intestine every day (the vast majority from secretions). Only 1-1.5 liters of this fluid reaches the
colon. Because the small intestine normally operates at 50% absorptive capacity and the colon can at
most absorb only 4-5 liters/day, temporary loss of absorptive capacity overloads the colon and diarrhea
ensues. Note: You should all be aware (or beware) that there is a large and burgeoning literature about
electrolyte transport and ion channels in GI function that we could consider in depth. However, since
none of the antidiarrheal agents or laxatives we will consider work by taking advantage of this exquisite
physiological information, I have not included this here. You should know however, that infectious
agents cause diarrhea by 1) secreting toxins that inhibit absorption or 2) by directly killing mucosal cells.
Constipation
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For the most part, constipation is an inconvenience and uncomfortable, but not life threatening.
Nonetheless, hospitalized patients are often constipated secondary to changes in environment, immobility,
medications, or procedures (barium sulfate). In some cases (recent MI or GI surgery), one would like the
patient to avoid straining.
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Luckily there are a number of remedies. Laxatives can be divided into several classes: 1) bulk
agents (fiber, such as psyllium in Metamucil), 2) emollient surface agents that soften the stool by
allowing water and fat entry (such as docusate or Colace), 3) stimulant cathartics, such as the
phenolphthalein derivative bisacodyl (Dulcolax) or extracts of cascara or senna (Senecot) that stimulate
peristalsis, 4) osmotic cathartics that contain nonabsorbable salts or sugars that hold water in the bowel
lumen (Milk of Magnesia), 5) lavage agents, used for bowel preps, contain polyethylene glycol
(Golytely).
Diarrhea
The causes of diarrhea are legion. Infectious diarrhea is common and kills 5 million people,
mostly children, every year. We will not have time to consider antibacterial treatment here. Most
diarrhea is self-limiting, if dehydration and electrolyte imbalances are prevented by oral rehydration.
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The mainstay of diarrhea treatment should be 1) oral or parenteral hydration and electrolyte
balance, 2) treatment of the specific underlying disorder, and 3) lastly, use of nonspecific antidiarrheal
agents.
In some cases, such as travelling, it is inconvenient to have diarrhea and a temporary nonspecific
treatment is to slow GI motility, thus promoting absorption, with either of the opioid piperidine analogs
diphenoxylate (Lomotil) or loperamide (Imodium).
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