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170 Drugs for the Treatment of Peptic Ulcers

Drugs for Gastric and Duodenal Ulcers

In the area of a gastric or duodenal peptic ulcer, the mucosa has been attacked by digestive juices to such an extent as to expose the subjacent connective tissue layer (submucosa). This “self-digestion” occurs when the equilibrium between the corrosive hydrochloric acid and acid-neutralizing mucus, which forms a protective cover on the mucosal surface, is disturbed. Mucosal damage can be promoted by Helicobacter pylori bacteria that colonize the gastric mucus.

Drugs are employed with the following therapeutic aims: (a) to relieve pain; (b) to accelerate healing; and (c) to prevent ulcer recurrence. Therapeutic approaches are threefold : (I) to reduce aggressive forces by lowering H+ output, (II) to increase protective forces by means of mucoprotectants; and (III) to eradicate Helicobacter pylori.

I. Lowering of Acid Concentration

Ia. Agents for acid neutralization (A). H+- binding groups such as CO32-, HCO3or OH, together with their counter ions, are contained in antacid drugs. Neutralization reactions occurring after intake of CaCO3 and NaHCO3, respectively, are shown in (A). With nonabsorbable antacids, the counter ion is dissolved in the acidic gastric juice in the process of neutralization. Upon mixture with the alkaline pancreatic secretion in the duodenum, it is largely precipitated again by basic groups, e.g., as CaCO3 or AlPO4, and excreted in feces. Therefore, systemic absorption of counter ions or basic residues is minor. In the presence of renal insuf ciency, however, absorption of even small amounts may cause an increase in plasma levels of counter ions (e.g., magnesium intoxication with paralysis and cardiac disturbances). Precipitation in the gut lumen is responsible for other side effects, such as reduced absorption of other drugs due to their adsorption to the surface of precipitated antacid; or

phosphate depletion of the body with excessive intake of Al(OH)3.

Na+ ions remain in solution even in the presence ofHCO3-rich pancreaticsecretions and are subject to absorption, like HCO3. Because of the uptake of Na+, use of NaHCO3 must be avoided in conditions requiring restriction of NaCl intake, such as hypertension, cardiac failure, and edema.

Since food has a buffering effect, antacids are taken between meals (e.g.,1 and 3 hours after meals and at bedtime). Nonabsorbable antacids are preferred. Because Mg(OH)2 produces a laxative effect (cause: osmotic action, p.174, release of cholecystokinin by Mg2+, or both) and Al(OH)3 produces constipation (cause: astringent action of Al3+, p.180), these two antacids are frequently used in combination (e.g., magaldrate).

Ib. Inhibitors of acid production (B). Acting on their respective receptors,the transmitter acetylcholine, the hormone gastrin, and histamine released intramucosally stimulate the parietal cells of the gastric mucosa to increase output of HCl. Histamine comes from enterochromaf n-like (ECL) cells; its release is stimulated by the vagus nerve (via M1 receptors) and hormonally by gastrin. The effects of acetylcholine and histamine can be abolished by orally applied antagonists that reach parietal cells via the blood. Proton pump inhibitors are drugs of first choice for promoting healing of ulcers. Infection with H. pylori should be treated resolutely (p.172) to lower the risk of ulcer recurrence, chronic gastritis, gastric carcinomas, and gastric lymphomas.

The cholinoceptor antagonist pirenzepine preferentially blocks cholinoceptors of the M1 type; its use in peptic ulcer therapy is now obsolete.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

 

Drugs for Gastric and Duodenal Ulcers

171

 

A. Drugs used to neutralize gastric acid

 

 

 

 

 

 

 

CaCO3

 

 

 

Absorbable

Nonabsorbable

 

 

NaHCO3

 

Antacids

 

Mg(OH)2

 

 

 

 

 

 

Al(OH)3

 

 

Na+ HCO3-

 

 

CaCO3

H+

 

 

 

 

H+

 

 

 

 

 

 

 

 

 

 

 

 

 

H+

 

 

 

 

H2CO3

 

 

H2CO3

 

 

 

H2O

 

 

 

 

 

 

 

 

H2O

 

 

 

 

 

CO2

 

 

 

 

 

 

 

 

 

CO2

 

 

 

Na+

 

 

 

Ca2+

 

 

 

 

 

Pancreas

 

 

 

Pancreas

 

 

 

 

 

 

Absorption

 

 

 

 

 

 

HCO3-

 

Na+

HCO3-

HCO3-

 

CaCO3

 

B. Drugs used to lower gastric acid production

 

 

 

 

 

 

 

 

 

 

 

 

N. vagus

 

Acid-resistant

 

 

 

 

 

 

 

 

 

coating

 

 

 

 

 

 

 

 

 

 

 

 

 

Parietal cell

 

 

 

ACh

 

 

 

 

 

 

 

 

 

 

Inactive form

 

 

ATPase

M3

 

 

 

M1

 

Active form

 

 

H+

H2

Histamine

ECL cell

 

of omeprazole

 

 

K+

 

 

 

 

 

 

 

 

 

 

 

 

 

Gastrin

 

Proton pump inhibitors

H

 

 

H2-Antihistaminics

 

 

 

 

 

 

 

 

 

 

 

 

 

N

O

 

H3C

 

 

 

 

 

 

S

 

 

 

 

 

 

 

N

 

N

CH2

O

CH2

S

 

H3CO

 

 

 

CH2

H3C

 

 

 

 

 

 

 

(CH2)2

 

 

 

 

 

 

 

 

 

 

 

 

N

 

 

 

 

NH

 

 

 

 

 

 

 

 

 

 

 

H3C

 

CH3

 

 

 

 

C

NHCH3

 

 

 

 

 

 

CH

NO2

Omeprazole

 

OCH3

Ranitidine

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

172 Drugs for the Treatment of Peptic Ulcers

Histamine receptors on the parietal cells belong to the H2 type and are blocked by H2 antihistaminics (p.118). Because histamine plays a pivotal role in the activation of parietal cells, H2 antihistaminics also diminish responsivity to other stimulants, e.g., gastrin (in gastrin-producing pancreatic tumors, Zollinger–Ellison syndrome). The first H2- blocker used clinically, cimetidine, only rarely produces adverse effects (CNS disturbances such as confusion; endocrine effects in the male such as gynecomastia, decreased libido, impotence); however, it inhibits the hepatic biotransformation of many other drugs. The more recently introduced substances ranitidine, nizatidine, and famotidine are effective at lower dosages. Evidently, inhibition of microsomal enzymes decreases with reduced drug load; thus, these substances are less likely to interfere with the therapeutic use of other pharmaceuticals.

Omeprazole (p.171) can cause maximal inhibition of HCl secretion. Given orally in gastric juice-resistant capsules, it reaches parietal cells via the blood. In the acidic milieu of the mucosa, an active metabolite is formed and binds covalently to the ATP-driven proton pump (H+/K+-ATPase) that transports H+ in exchange for K+ into the gastric juice.

Lansoprazole, pantoprazole, and rabeprazole produce analogous effects. Omeprazole is a racemate. With respect to dosage, the now available (S)-omeprazole (esomeprazole) represents the more potent enantiomer, but this offers no therapeutic advantage.

II. Protective Drugs

Sucralfate (A) contains numerous aluminum hydroxide residues. However, it is not an antacid because it fails to lower the overall acidity of gastric juice. After oral intake, sucralfate molecules undergo cross-linking in gastric juice, forming a paste that adheres to mucosal defects and exposed deeper layers. Here sucralfate intercepts H+. Protected from acid, and also from pepsin, trypsin, and bile acids, the mucosal defect can heal more rap-

idly. Sucralfate is taken on an empty stomach (1 hour before meals and at bedtime). It is well tolerated, but released Al3+ ions can cause constipation.

Misoprostol (B) is a semisynthetic prostaglandin derivative with greater stability than natural prostaglandin, permitting absorption after oral administration. Locally released prostaglandins (PGF2α, PGE2) promote mucus production in superficial cells and inhibit acid secretion of parietal cells (B). Inhibition of physiological PG synthesis by drugs (e.g., NSAIDS, p.200) explains the mucosal injury from these pharmaceuticals: protection by the mucus layer is diminished and acid production is enhanced. Misoprostol mimics the action of the prostaglandins on the mucosal tunic and thus can attenuate the adverse effects produced by inhibitors of PG synthesis, at least as regards the gastric mucosa. Additional systemic effects (frequent diarrhea; risk of precipitating contractions of the gravid uterus) significantly restrict its therapeutic utility.

III. Eradication of Helicobacter pylori (C)

This organism plays an important role in the pathogenesis of chronic gastritis and peptic ulcer disease. The combination of antibacterial drugs and omeprazole has proved effective. If amoxicillin (p.272) or clarithromycin (p.278) cannot be tolerated, metronidazole (p.276) may serve as a substitute. Colloidal bismuth compounds are also effective; however, as they entail the problem of heavymetal exposure, this treatment can no longer be recommended.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Drugs for Gastric and Duodenal Ulcers

173

A. Chemical structure and protective effect of sucralfate

CH2OR

OR

 

 

Sucralfate

H

O

H2C

 

H

O

 

H

 

 

 

 

 

OR

H

H

 

RO

 

RO

 

O

 

CH2OR

 

 

 

H

OR

 

 

RO

 

H

 

 

 

 

 

R = – SO3[Al2(OH)5]

 

Conversion

 

 

 

 

 

in acidic

 

H+

 

 

 

environment

 

 

 

 

pH < 4

 

 

 

 

 

-

 

R = – SO3[Al2(OH)4]

+

– SO3

 

 

 

 

 

 

 

Cross-linking

 

 

 

 

 

and formation

 

 

 

 

 

of paste

 

 

 

 

 

Coating of

 

 

 

 

 

mucosal

 

 

 

 

 

defects

B. Structure and protective effect of misoprostol

Mucus

Surface epithelial cells

 

 

 

 

 

O

 

O

 

 

 

 

 

Supporting cells

 

CH3

OCH3

 

 

 

 

 

 

CH3

 

 

 

 

 

 

HO

OH

 

 

 

Misoprostol

 

H+Cl-

 

 

 

 

O

 

 

 

 

 

 

COOH

CH3

 

 

 

HO

OH

 

Parietal cells

Pepsin-

 

 

 

Prostaglandin E2

Lumen

with proton

producing chief

 

 

 

pumps

cells

 

 

 

 

 

C. Helicobacter eradication

 

 

 

Helicobacter

 

Eradication

 

 

pylori

 

e.g., short-term triple therapy

Reflux

 

 

 

 

esophagitis

 

 

 

 

Gastritis

 

Amoxicillin*

(2 x 1000 mg/day) 7 days

 

Clarithromycin*

(2 x

500 mg/day) 7 days

Peptic ulcer

 

 

Omeprazole

(2 x

20 mg/day) 7 days

 

 

*if intolerable,

 

 

 

 

metronidazole

(2 x

500 mg/day) 7 days

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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