been “eaten through,” exposing the inner submucosal connective tissue layer. This
mucosal damage is promoted by Helicobacter pylori bacteria that colonize the gastric
lining. The penetrating damage of the digestive acids may erode into blood vessels,
causing life-threatening gastrointestinal hemorrhages (“upper GI bleeds”), or it may
perforate through the stomach, causing either peritonitis (inflammation of the peri-
toneal cavity within the abdomen) or pancreatitis. To facilitate healing, prevent ulcer
recurrence, and relieve pain, the medicinal chemistry approach is multipronged and
involves lowering aggressive acid output, augmenting the mucous-based protection,
and/or eradicating the Helicobacter pylori.
The concentration of acid in the stomach may be reduced either by neutralizing the
acid or by inhibiting acid production. Acid neutralization is inexpensively achieved by
using a nonabsorbable antacid such as CaCO 3 , Mg(OH) 2 , or Al(OH) 3. Inhibition of acid
production may be realized by one of three approaches. First, pirenzepine (4.156) is an
anticholinergic agent (relative M1 receptor specificity) that does not cross the
blood–brain barrier, but which binds to acid-secreting cells in the gut to downregulate
their production. Secondly, omeprazole (4.157) is a proton pump(H+,K+-ATPase)
inhibitorthat blocks the transport of H+into the gut. Thirdly, H 2 histamine antagonists
(e.g., cimetidine, ranitidine) can be used to prevent acid secretion from parietal cells
that are contained within the stomach.
The next major class of drugs for peptic ulcer disease is the mucoprotectants and
other protective agents. Sucralfate (4.158) is a carbohydrate-based drug (chapter 8)
which forms an impenetrable paste that adheres to the stomach lining defect, providing
a protective barrier. Misoprostol (4.159) is a semisynthetic prostaglandin derivative that
promotes mucus production. Carbenoxolone (4.160) has a mineralocorticoid-type
action that also promotes mucus production.
Finally, since the microorganism Helicobacter pylori plays an important role in the
pathogenesis of ulcers, antibacterial agents such as amoxicillin (4.161), metronidazole
(4.162), or even colloidal bismuth compounds (e.g.,4.163) may also be used.
The nonsurgical treatment of peptic ulcer is a superb example of how multiple mole-
cular approaches can be used to therapeutically attack a single clinical problem from
multiple directions. Also, the medical management of peptic ulcer disease demonstrates
how antagonists of neurotransmitter messenger molecules (acetylcholine, histamine) can
be used to treat nonneurological disorders. The role of β-adrenergic agonists and antag-
onists in the treatment of cardiopulmonary diseases is a similar example. Since these
messenger molecules are useful both inside and outside the CNS, the drug designer must
268 MEDICINAL CHEMISTRY