Medical School, Notes, Pharmacy

Gastrointestinal Diseases And Treatment: A Short Review

Gastrointestinal diseases refer to diseases involving the gastrointestinal tract (GIT). The common medical conditions involving the gastrointestinal tract (GIT) are:

1. Peptic Ulcers Disease (PUD)

2. Gastroesophageal Reflux Disease (GERD)

3. Chemotherapy Induced Emesis

4. Diarrhea and Constipation

1. Peptic Ulcers Disease (PUD)

Ulceration in the gastric mucosa due to acid-pepsin digestion is called Peptic Ulcer disease. Several major causative factors are recognized:

a. Infection with gram-negative helicobacter pylori

b. Use of nonsteroidal anti-inflammatory drugs (NSAIDS)

c. Increased hydrochloric acid (HCL) secretion

d. Inadequate mucosal defense against gastric acid

Treatment Approaches

There are mainly four treatment approaches to treat PUD. These includes;

1. Eradicating the Helicobacter pylori infection by antimicrobial agents. Such as:

a. Tetracycline

b. Metronidazole

c. Clarithromycin etc.

2. We can also reduce the secretion of gastric acid, by using PPI or H2 receptor blockers. Such as:

a. Cimetidine

b. Ranitidine

c. Famotidine and the prazoles. such as;

d. Rabeprazole

e. Pantoprazole etc.

3. Then, we can use antacids to neutralize the secreted acid & pepsin. Such as:

a. Calcium carbonate

b. Sodium bicarbonate

c. Aluminum hydroxide

d. Magnesium hydroxide

4. We can also use, cytoprotective agents, which will protect the gastric mucosa from damage. (Providing agents that protect the gastric mucosa from damage) such as:

a. Sucralfate and

b. Bismuth subsalicylate

1. Eradication the Helicobacter pylori by Antimicrobial agents

If the infection is caused by Helicobacter pylori, then antimicrobial agents should be used. Eradication of Helicobacter pylori results in rapid healing of active peptic ulcers. It also has low recurrence rates.

To document infection with Helicobacter pylori, endoscopic biopsy of the gastric mucosa, serologic tests, urea breath tests and other diagnosis methods are used.

Triple therapy or quadruple therapy used to eradicate the Helicobacter pylori successfully. These are noted below;

a. Triple Therapy

In triple therapy, PPI combined with either metronidazole or amoxicillin plus clarithromycin.

b. Quadruple Therapy

In quadruple therapy, PPI combined with bismuth subsalicylate, metronidazole, and tetracycline are used. These therapies are administered for 2 weeks

c. Bismuth Subsalicylate

Bismuth salts do not neutralize stomach acid, but inhibit pepsin and increase mucus secretion. This increased mucus secretion helps to form a barrier against the diffusion of acid in the ulcer. They gives cytoprotective actions.

GERD does not respond to the treatment with antibiotics. Because it is not associated with Helicobacter pylori infection.

2. H2-receptor antagonists and regulation of gastric acid secretion

Gastric acid secretion by parietal cells of the gastric mucosa is mainly stimulated by the acetylcholine, histamine, and gastrin. The receptor mediated binding of acetylcholine, histamine, or gastrin results in the activation of protein kinases, which in turn stimulates the H+/K+ adenosine triphosphatase (ATPase) proton pump to secrete hydrogen ions in exchange for K+ into the lumen of the stomach. On the contrary, receptor binding of prostaglandin E2 and somatostatin diminish gastric acid production.

Histamine binding causes activation of adenylyl cyclase, whereas binding of prostaglandin E2 inhibits this enzyme. Gastrin and acetylcholine act by inducing an increase in intracellular calcium levels.

When Histamine binds with the specific receptor, it causes activation of adenylyl cyclase. This activation converts ATP to cAMP. Which results in activation of protein kinase. When protein kinase is activated, acid secretes from parietal cell to the lumen of the stomach.

Antagonists of the Histamine H2 Receptor

Histamine H2 receptor antagonists block the effects of histamine on all H2 receptors, but their primary clinical use is to inhibit gastric acid secretion and are particularly effective against nocturnal acid secretion.

By competitively blocking the binding of histamine to H2 receptors, these agents reduce the intracellular concentrations of cyclic adenosine monophosphate (cAMP) and, thereby, secretion of gastric acid.

Adverse effects

Cimetidine acts as a non-steroidal anti-androgen and may have endocrine effects. These effects include gynecomastia and galactorrhea (continuous release/discharge of milk). Cimetidine can inhibit some cytochrome P450 isozymes and affect the metabolism of many other drugs such as warfarin, phenytoin, and clopidogrel. All H2 antagonists can reduce the effectiveness of drugs that require an acidic environment for absorption, such as ketoconazole.

3. PPIs: Inhibitors of the H+/K+-ATPase proton pump

Proton Pump

H+/K+ adenosine triphosphatase (ATPase) proton pump. Which secretes hydrogen ions in exchange for K+ into the lumen of the stomach.

Proton Pump Inhibitors

The PPIs bind to the H+/K+-ATPase enzyme system (proton pump) and suppress the secretion of hydrogen ions into the gastric lumen. The membrane-bound proton pump is the final stage of gastric acid secretion

Mechanism of action

PPIs are prodrugs with an acid resistant enteric coating which protects them from premature degradation by gastric acid in the stomach. PPIs inhibit both basal and stimulated gastric acid secretions.

This enteric coating is removed in the alkaline duodenum, and the prodrug is absorbed and transported to the parietal cell canaliculus.

There, it converted to its active form, which reacts with a cysteine residue of the H+/K+ ATPase, forming a stable covalent bond.

Omeprazole + sodium bicarbonate = faster absorption

Therapeutic uses

a. Prevention of recurrence of nonsteroidal anti-inflammatory drug (NSAID) associated gastric ulcers in patients who continue NSAID use.

b. Reducing the risk of the duodenal ulcer recurrence associated with H. pylori infections.

c. Peptic Ulcer – Gastric and duodenal ulcers.

d. Gastroesophageal reflux disease (GERD).

e. Zollinger Ellison Syndrome.

f. Aspiration Pneumonia.

g. Bleeding peptic Ulcer.

Adverse effects

a. PPIs decreases the effectiveness of clopidogrel because they inhibit CYP2C19.

b. PPIs increase the risk of fractures (Osteoporosis) in elderly on prolonged use.

c. Prolonged acid suppression with PPIs may result in low vitamin B1.

d. Nausea, loose stools, headache abdominal pain, and constipation.

e. Muscle & joint pain, dizziness, rashes.

f. Hypomagnesemia.


Prostaglandin E, produced by the gastric mucosa, inhibits secretion of HCl and stimulates secretion of mucus and bicarbonate (cytoprotective effect). Misoprostol, a stable analog of prostaglandin E1, as well as some PPIs used in the prevention of gastric ulcers induced by NSAIDs. Dose related diarrhea and nausea are the most common adverse effects and limit the use of this agent.

Why Esomeprazole Is Better Than Omeprazole?

Compared to omeprazole, esomeprazole provides greater acid control in patients with GERD and keeps stomach pH at higher than 4 for a longer period of time. Note that, higher pH = less acidity = less pain. Esomeprazole provides more effective acid control than omeprazole. A single pill of esomeprazole can raise intragastric pH faster than omeprazole. Patients treated with Esomeprazole experienced faster symptom relief than patients treated with omeprazole. Esomeprazole’s drug interactions are fewer than omeprazole.

4. Antacids

Antacids are weak bases that react with stomach acid to form water and salt to reduce stomach acid. Pepsin is inactive at a pH greater than 4, antacids increases the pH value thus reduce pepsin activity.

Therapeutic uses

a. Aluminum and magnesium containing antacids are used for symptomatic relief of peptic ulcer disease and GERD. It also promote healing of duodenal ulcers.

b. They are used as last-line therapy for acute gastric ulcers.

c. Calcium carbonate preparations sometimes are used as calcium supplements for the treatment of the osteoporosis.

Adverse effects

a. Aluminum hydroxide tends to cause constipation, and magnesium hydroxide tends to cause diarrhea. Formulations that combine these active ingredients help normalize bowel function.

b. The binding of phosphate by aluminum containing antacids can lead to hypophosphatemia.

c. Absorption of the cations from antacids (Mg2+, Al3+, Ca2+) is usually not a problem in patients with normal renal function. But, accumulation and adverse effects may occur in patients with renal impairment.

d. The sodium content of antacids can be an important consideration for patients with hypertension or congestive heart failure.

e. Systemic absorption of sodium bicarbonate [NaHCO3] can produce transient metabolic alkalosis.

5. Mucosal protective agents

Mucosal protective agents also known as cytoprotective compounds, these agents have several actions that enhance mucosal protection mechanisms, thereby preventing mucosal injury, reducing inflammation, and healing existing ulcers.

a. Sucralfate

This complex of aluminum hydroxide and sulfated sucrose binds to positively charged groups in proteins of both normal and necrotic mucosa. By forming complex gels with epithelial cells, sucralfate impairs the diffusion of HCl and creates a physical barrier that prevents pepsin and acid from breaking down mucus. It also stimulates prostaglandin release as well as mucus and bicarbonate output, and it inhibits peptic digestion. Sucralfate effectively heals duodenal ulcers and is used in long-term maintenance therapy to prevent their recurrence. Because it requires an acidic pH for activation, sucralfate should not be administered with PPIs, H2 antagonists, or antacids.

Sucralfate does not prevent NSAID-induced ulcers, and it does not heal gastric ulcers.

b. Bismuth subsalicylate

Preparations of this compound effectively heal peptic ulcers. In addition to the antimicrobial actions of bismuth subsalicylate, they inhibit the activity of pepsin, increase secretion of mucus, and interact with glycoproteins in necrotic mucosal tissue to coat and protect the ulcer crater.

2. Gastroesophageal Reflux Disease (GERD)

Gastroesophageal reflux disease, or GERD, is a digestive disorder. Gastroesophageal reflux disease (GERD) occurs when stomach acid frequently regurgitates into the duct that connects the mouth to the stomach (esophagus).

Pathophysiology of GERD

Primary barrier to gastroesophageal reflux is the lower esophageal sphincter (LES). It normally works in conjunction with the diaphragm. If barrier disrupted, acid goes from stomach to esophagus.

Factors That Can Aggravate GERD

a. Diet: Caffeine, fatty foods or spicy foods, chocolate, peppermint, citrus, alcohol etc.

b. Position/Activity – Bending, straining, External Pressure pregnancy, tight clothing etc.

Treatment Approaches

1. Antacids

a. Quick but short-lived relief

b. Neutralize HCl acid

c. Approximately 1/3 of patients with heartburn related symptoms use at least twice weekly

d. More effective than placebo in relieving GERD symptoms

2.Histamine H2-Receptor Antagonists

a. More effective than placebo and antacids for relieving heartburn in patients with GERD

b. Faster healing of erosive esophagitis when compared with placebo – Can use regularly or on-demand

3. Proton Pump Inhibitors

a. Better control of symptoms with PPIs vs H2RAs and better remission rates

b. Faster healing of erosive esophagitis with PPIs vs H2RAs

4. Prokinetic Drugs:

a. Increase gastric emptying (Erythromycin, Cisapride, Metoclopramide, Domperidone)

Complications of Untreated GERD:

a. Erosive esophagitis

b. Stricture

c. Barrett’s esophagus

d. Adenocarcinoma

3. Chemotherapy Induced Emesis

There are two brainstem sites that plays key roles in the vomiting reflex pathway. The first one is chemoreceptor trigger zone, which is located in the area postrema. It is outside the blood-brain barrier and it can respond directly to chemical stimuli in the blood or cerebrospinal fluid.

The second important site is the vomiting center, which is located in the lateral reticular formation of the medulla. It coordinates the motor mechanisms of vomiting.

The vomiting center also responds to afferent input from the vestibular system, the periphery, and higher brainstem and cortical structures.

Emetic actions of chemotherapeutic agents

Chemotherapeutic agents directly activates the medullary chemoreceptor trigger zone, or vomiting center. Several neuroreceptors, such as, dopamine receptor Type 2 and serotonin Type 3 (5-HT3), play critical roles.

The color or smell of chemotherapeutic drugs can activate higher brain centers and trigger emesis. Chemotherapeutic drugs can also act peripherally by causing cell damage in the GI tract and releasing serotonin from the enterochromaffin cells of the small intestinal mucosa. The released serotonin activates the 5-HT3 receptors on vagal and splanchnic afferent fibers, which then carry sensory signals to the medulla, which in turn leading to the emetic response.

Antiemetic drugs

Anticholinergic drugs, such as scopolamine (muscarinic receptor antagonist) and H1-receptor antagonists, such as dimenhydrinate, meclizine, and cyclizine, are very useful in motion sickness. Some of the major categories of drugs used to control the chemotherapy induced nausea and vomiting are given below:

1. Phenothiazines

Phenothiazines, such as prochlorperazine act by blocking dopamine receptors. These are effective against low or moderately emetogenic chemotherapeutic agents. Such as, fluorouracil and doxorubicin.

2. Butyrophenones

Butyrophenones act by blocking dopamine receptors. Such as, droperidol and haloperidol. They are moderately effective antiemetics.

3. 5-HT3 receptor blockers

The specific antagonists of the 5-HT3 receptor are, ondansetron, granisetron, palonosetron, and dolasetron. They selectively block 5-HT3 receptors in the periphery (visceral vagal afferent fibers) and in the brain (chemoreceptor trigger zone).

4. Corticosteroids

Dexamethasone and methylprednisolone, are effective against mildly to moderately emetogenic chemotherapy.

5. Combinations

Antiemetic drugs are often used combinedly to increase antiemetic activity or decrease toxicity.

Corticosteroids, most commonly used dexamethasone, can give increase antiemetic activity when given with high-dose metoclopramide, along with a 5-HT3 antagonist, such as phenothiazine, butyrophenone, or a benzodiazepine.

Antihistamines such as diphenhydramine are often given in combination with high doses of metoclopramide to reduce extrapyramidal reactions.

Diphenhydramine may also administered in combination with corticosteroids to counter the metoclopramide induced diarrhea.

4. Diarrhea and Constipation

Diarrhea is a condition when the stool is soft and watery. Constipation, on the other hand, occurs when bowel movements are inadequate (less than three times a week) or difficult to pass.

Antidiarrheal agents

Increased gastrointestinal motility and decreased absorption of fluid are the main causes of diarrhea. Antidiarrheals used to treat acute diarrhea includes antimotility agents, adsorbents, and drugs that modify fluid and electrolyte transport

1. Antimotility agents

Two commonly used drugs to combat diarrhea are diphenoxylate and loperamide. Both are analogs of meperidine and have opioid-like effects on the intestines. They activate presynaptic opioid receptors in the enteric nervous system, inhibit acetylcholine release, and reduce peristalsis. At normal doses, they lack an analgesic effect.

Side effects include drowsiness, abdominal cramps, and dizziness. Because these drugs can contribute to toxic megacolon, they should not be given to young children or patients with severe colitis.

2. Adsorbents

Adsorbents, such as aluminum hydroxide and methylcellulose, are used to control diarrhea. Presumably, these agents act by adsorbing toxins or microorganisms in the gut and/or by coating or protecting the intestinal mucosa.

They are much less effective than antimotility agents and they can interfere with the absorption of other drugs.

3. Agents that modify fluid and electrolyte transport

Bismuth subsalicylate, used in the treatment of traveler’s diarrhea, decreases fluid secretion in the bowel.

Its action may be due to its salicylate component as well as its coating actions. Adverse effects includes black tongue and black stools.