Drugs Used in the Treatment of Gastrointestinal Disorders

Chapter 21 Drugs Used in the Treatment of Gastrointestinal Disorders



I. Peptic Disorders

A. Pathology; diseases include

1. Ulcers of the stomach, esophagus, and duodenum


Helicobacter pylori often responsible for causing ulcers.


2. Zollinger-Ellison syndrome

3. Gastroesophageal reflux disease (GERD)

4. Gastritis

5. Esophagitis

B. Physiology; (Fig. 21-1) physiologic stimulants of gastric acid secretion include:

1. Gastrin

2. Acetylcholine

3. Histamine

4. Prostaglandins

II. Drugs That Decrease Gastric Acidity (Box 21-1)

A. Histamine H2-receptor antagonists

1. Cimetidine


a. Mechanism of action


(1) Blocks histamine action at the H2-receptor site on parietal cells, thus inhibiting gastric acid secretion (see Fig. 21-1)

(2) Decreases production of pepsin

(3) Inhibits postprandial and basal gastric acid secretion

b. Uses


(1) Healing of duodenal and gastric ulcers and prevention of their recurrence

• Intractable peptic ulcers may require higher doses or combination therapy.

(2) Control of secretory conditions such as Zollinger-Ellison syndrome and GERD

• Especially effective against nocturnal secretion (i.e., 90% reduced)

c. Adverse effects

• Antiandrogenic effects (gynecomastia and male sexual dysfunction)

image

21-1 Gastric acid secretion and sites of drug action. ATPase, adenosine triphosphatase; cAMP, cyclic adenosine monophosphate; G, gastrin receptor; H2, histamine H2-receptor; M3, muscarinic M3 receptor; PG, prostaglandin receptor.



BOX 21-1 Drugs that Decrease Gastric Acidity



H2-Receptor Antagonists


Cimetidine


Famotidine


Nizatidine


Ranitidine



Proton Pump Inhibitors


Esomeprazole


Lansoprazole


Omeprazole


Pantoprazole


Rabeprazole



Antacids


Aluminum hydroxide


Calcium carbonate


Magnesium hydroxide


Sodium bicarbonate



Cimetidine can cause gynecomastia in men.


d. Drug interactions

• Inhibition of liver microsomal metabolism of many drugs that utilize the cytochrome P450 system (e.g., beta blockers, benzodiazepines, calcium channel blockers, opioid agonists, tricyclic antidepressants)


Cimetidine extends the half-life (t1/2) of many drugs that are metabolized in the liver.


2. Other H2-receptor antagonists


a. Examples


(1) Ranitidine

(2) Famotidine

(3) Nizatidine


Note common ending -tidine for all H2-receptor antagonists


b. Therapeutic effects are similar to cimetidine

c. Drug interactions and antiandrogenic effects occur much less frequently than with cimetidine

d. All three are more potent than cimetidine


(1) Control of secretory conditions such as Zollinger-Ellison syndrome and GERD; especially effective against nocturnal secretion (i.e., 90% reduced)


H2-receptor blockade: more than 90% reduction in basal, food-stimulated, and nocturnal gastric acid secretions.


(2) Use

• Treatment of duodenal ulcers associated with Helicobacter pylori (given with a bismuth compound and an antibiotic)

(3) Adverse effect

• Thrombocytopenia

(4) Famotidine

• Most potent H2-receptor antagonist

B. Proton pump inhibitors (PPIs) (see Box 21-1)

1. Examples


a. Esomeprazole

b. Lansoprazole

c. Omeprazole

d. Pantoprazole

e. Rabeprazole


Note common ending -prazole to all PPIs; but aripiprazole is a partial D2 agonist


2. Mechanism of action (see Fig. 21-1)


a. Intragastric pH is higher and remains elevated longer than with H2-receptor antagonist therapy.

b. These drugs are benzimidazole compounds that irreversibly inhibit H+/K+ ATPase (adenosine triphosphatase), the parietal cell proton pump.

c. These drugs are prodrugs without inhibitory activity at neutral pH.


(1) Activation requires an acid environment

(2) They should be taken with meals so that food can stimulate acid secretion required for bioactivation.

d. Because these drugs are unstable at a low pH


(1) Dosage forms are supplied as enteric coated granules.

(2) Dissolve only at alkaline pH thereby avoiding degradation by acid in the esophagus and stomach


PPIs are administered as enteric coated formulations to prevent dissolution and bioactivation in the acidic stomach prior to absorption.


(3) After passing through the stomach

(4) The enteric coatings dissolve

(5) The prodrug is absorbed in the intestines.

(6) Carried by the circulation to the parietal cells

(7) Accumulates in the secretory canaliculi

(8) Activated at acid pH to form sulfonamide or sulfenic acid

(9) It binds to sulfhydryl groups on H+/K+ ATPase.


PPIs are prodrugs that are bioactivated in the acidic environment of the parietal cell to an intermediate that irreversibly binds to the proton pump.


e. These drugs will promote peptic ulcer healing and prevent ulcer recurrence

f. These drugs are more effective than H2 antagonists for GERD or nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcers.

3. Uses


a. Drugs of choice for Zollinger-Ellison syndrome resulting from gastrin-secreting tumors

b. Most effective agents for GERD


Proton pump inhibitors are more effective than H2-receptor blockers for treatment of peptic ulcer disease and GERD.


c. Duodenal ulcer, esophagitis, and gastric ulcer


(1) When used to treat peptic ulcer disease, these drugs promote healing, but relapse may occur.

(2) Proton pump inhibitors must be given in combination with agents that eliminate H. pylori.

C. Antacids: weak bases

1. Examples


a. Sodium bicarbonate

b. Aluminum hydroxide

c. Magnesium hydroxide

d. Calcium carbonate


Antacids affect the absorption of many drugs, such as fluoroquinolones and tetracyclines.


2. Mechanism of action

• Neutralize gastric hydrochloric acid and generally raise stomach pH from 1 to 3.0 to 3.5

3. Uses

• Symptomatic relief of acid indigestion, heartburn, GERD

4. Adverse effects


a. Diarrhea for magnesium

b. Constipation for aluminum and calcium


Magnesium salts produce diarrhea while aluminum and calcium salts produce constipation.


c. Cation absorption producing systemic alkalosis in patients with impaired renal function

d. Sodium bicarbonate causes reflex hyperacidity; contraindicated in peptic ulcer disease.

III. Cytoprotective Agents (Box 21-2)

• These drugs act by binding to ulcers; providing a protective coating against digestion by acid and pepsin

A. Sucralfate (aluminum sucrose sulfate)

1. Pharmacokinetics


a. Poorly soluble molecule that polymerizes in acid environment

b. No significant absorption and no systemic effect

2. Mechanism of action


a. Selectively binds to necrotic ulcer tissue

b. Acts as barrier to acid, pepsin, and bile

c. Allows duodenal ulcers time to heal


BOX 21-2 Cytoprotective Drugs


Sucralfate


Prostaglandin analogues (e.g., misoprostol)


Colloidal bismuth compounds (e.g., bismuth subsalicylate)




Sucralfate requires acid pH for activation and should not be administered with antacids, H2-receptor antagonists, or PPIs.


d. Stimulates synthesis of prostaglandins, which have cytoprotective effects on the gastrointestinal tract

3. Uses


a. Treatment of active peptic ulcer disease

b. Suppression of recurrence

B. Misoprostol

• Synthetic, oral prostaglandin E1 analogue

1. Mechanism of action


a. Inhibits secretion of gastrin

b. Promotes secretion of mucus and bicarbonate

2. Uses


a. Prevention of NSAID and steroid-induced gastric ulcers

b. Medical termination of pregnancy of 49 days or less (in combination with mifepristone)


Don’t use misoprostol during pregnancy; it can cause the fetus to abort.


c. Unlabeled uses


(1) Cervical ripening and labor induction

(2) NSAID-induced nephropathy

(3) Fat malabsorption in cystic fibrosis

3. Adverse effects


a. Abdominal cramps

b. Diarrhea


Misoprostol causes severe gastrointestinal (GI) effects.


c. Vaginal bleeding

d. Contraindication

• Pregnancy (can induce labor and uterine rupture)

C. Colloidal bismuth compounds

1. Example

• Bismuth subsalicylate

2. Mechanism of action


a. Selectively binds to ulcer coating

b. Protects the ulcer from gastric acid

3. Uses


a. Control of nonspecific diarrhea

b. Prophylaxis of traveler’s diarrhea, dyspepsia, and heartburn

c. Control of H. pylori (in combination therapy)

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Apr 8, 2017 | Posted by in PHARMACY | Comments Off on Drugs Used in the Treatment of Gastrointestinal Disorders

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