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Author: Paul Abourjaily
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1. Acid Suppressive Therapy

Medications to combat gastric acidity include the following:

  • Antacids:
    Usually a mix of magnesium, aluminum, and/or calcium salts. Examples include:

    • Mix of magnesium hydroxide + calcium carbonate

    • Mix of aluminum and magnesium hydroxides

    • Calcium carbonate

  • Cytoprotectants:

    • Carafate

    • Bismuth compounds (eg, bismuth subsalicylate )

    • Cytotec

  • Histamine-type 2 receptor antagonists (H2As):

    • Cimetidine

    • Ranitidine

    • Famotidine

    • Nizatidine

  • Proton pump inhibitors (PPIs):

    • Omeprazole

    • Lansoprazole

    • Rabeprazole

    • Pantoprazole

    • Esomeprazole

  • Prokinetics:

    • Bethanechol

    • Metoclopramide

    • Tegaserod

    • Cisapride – compassionate use only

    • Domperidone – not commercially available in the United States

Please refer to the following texts for supplemental reading material on the drugs covered in this lecture:

  • Goodman LS, Gilman A, Brunton LL, Lazo JS, Parker KL. Goodman & Gilman's the Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill; 2006 - Section VI, Chapters 36 & 37.

  • Katzung BG. Basic & Clinical Pharmacology. Los Altos, Calif.: Lange Medical Publications; 1982 – Chapter 63.

Antacids
Antacids usually contain mixtures of aluminum, magnesium, and/or calcium salts. Ingredients are highly variable both between products (Mylanta vs Maalox) and even within the same brands (eg, Mylanta vs Mylanta ES). Antacids are available without a prescription.

Antacids work locally within the GI lumen to neutralize acid. They provide quick relief of symptoms, but duration of action is limited to just a few hours at the most. The most common side effects are GI related. They are very likely to be involved in pharmacokinetic interactions of drug absorption. For example, when an antacid is taken in combination with the antibiotic ciprofloxacin, less antibiotic is absorbed due to binding with the aluminum, magnesium, and/or calcium found in the antacid product.

2. Cytoprotectants

Cytoprotectants - These are medications that serve to reinforce the physical barrier between the lining of the stomach and the acid content in the lumen. They typically do little to alter gastric pH. Drugs in this category include:

Sucralfate - A sulfated polysaccharide formulated as an aluminum salt that adheres to epithelial cells and ulcer craters. Sucralfate is often the cause of the same types of pharmacokinetic interactions of drug absorption as seen with antacids. Constipation is the most common side effect. It requires a prescription and is usually administered by mouth 2-4 times per day as either tablets or dissolved in a slurry.

Bismuth compounds (eg, bismuth subsalicylate ) - These products also bind to the base of ulcers and allow healing by limiting acid exposure. Additionally, they tend to possess antibacterial effects and also promote mucin and bicarbonate production within the stomach. Drug interactions of absorption may occur as with other binding agents. The most common side effects include constipation and a reversible darkening of the toungue and/or stool. Bismuth subsalicylate is available without a prescription and is usually dosed multiple times per day as needed. It is a salicylate derivative and should be avoided in patients with a history of hypersensitivity to aspirin.

Misoprostol - A prostaglandin E1 analog. It stimulates gastric secretion of mucin and bicarbonate, increases mucosal blood flow, and weakly suppresses acid production by serving as an agonist to a prostaglandin receptor located on the basolateral membrane of the parietal cell. However, it’s main benefit is derived by replacing GI prostaglandins. It is particularly useful in patients with, or at risk for, NSAID-induced gastric ulcerations. It is not a common cause of drug interactions of absorption. The most common side effects are GI-related (usually diarrhea, abdominal pain and cramping). It also may increase uterine contractility and is contraindicated during pregnancy. It sometimes is used to assist with labor induction and as part of a combination regimen for medical termination of pregnancy. Misoprostol requires a prescription and is usually dosed 2-4 times per day by mouth.

3. Histamine type 2 receptor antagonists (H2As)

H2As compete with endogenous histamine for binding to H2 receptors on the basolateral membrane of parietal cells. They tend to have a longer duration of action (6-12 hours depending on which agent is used) than the traditional antacids and are more effective at increasing gastric pH. Their onset of action is not as fast as antacids, but still usually quick enough (30-60 minutes) to allow for use on an as needed basis.

In general, H2As are extremely well tolerated medications with few side effects. H2As may reduce the bioavailability of other drugs requiring an acidic environment for optimal absorption (eg, ketoconazole, atazanavir).

Cimetidine stands out among this class as being the shortest acting, most prone to drug interactions involving the cytochrome P450 system, and has more side effects in general. Side effects sometimes seen with cimetidine and not with other H2As include gynecomastia in men and galctorrhea in women.

Low dose oral formulations are available for all of the agents in this class. Higher doses sometimes still require a prescription. There are also injectable formulations available for some of them that require a prescription (eg, cimetidine, famotidine, and ranitidine).

4. Proton pump inhibitors (PPIs)

PPIs are highly potent acid suppressive drugs. They irreversibly bind to and inactivate the H+,K+-ATPase “pump” within the parietal cell to turn off acid production. While they may produce large increases in gastric pH, onset of action is typically delayed. Maximal effect is often not seen until after 2-5 days of consecutive use. These drugs have relatively short plasma half-lives, but very long intracellular half-lives. The typical duration of effect is 24-48 hours, which usually allows for once daily dosing.

Like H2As, PPIs are well tolerated medications. The most common side effects are mild and tend to be GI-related (nausea, diarrhea, abdominal pain). Chronic use may cause a reduction in vitamin B12 absorption, and contribute to B12 deficiency in those susceptible. PPIs may reduce the bioavailability of other drugs requiring an acidic environment for optimal absorption (eg, ketoconazole, atazanavir). Earlier concerns of gastric tumors first seen in animal models administered supraphysiologic doses have not been appreciated in humans.

The medications in this class are available in various oral formulations (eg, tablets, capsules, oral powder for suspension, orally disintegrating tablets). Some are also available for intravenous administration. Most require a prescription, although omeprazole tablets are available in “prescription strength” without a prescription.

5. Prokinetic agents

Drugs in this category do not alter gastric acid production, but can be helpful for reducing symptoms related to gastroesophageal reflux disease and other disorders of GI motility. These drugs use a variety of mechanisms to enhance acetylcholine activity and smooth muscle contractions in the GI tract, which in turn promotes peristalsis. The precise mechanisms by which the individual drugs do this varies.

Bethanechol is a direct agonist of acetylcholine receptors. Use is limited due to the host of cholinergic side effects that accompanies administration. It is available as tablets for oral administration and requires a prescription.

Metoclopramide is probably the most commonly used prokinetic in the U.S. today. The mechanism of action involves a combination of serotonin and dopamine receptor modulation. One drawback to its use is potential blockade of central dopamine receptors in the nigrostriatal pathway. Extrapyramidal side effects are thus sometimes encountered as a side effect. It requires a prescription and is available in both oral and injectable formulations.

Tegaserod is currently only approved for use in women with constipation-predominant irritable bowel syndrome. As such, it is not usually considered a typical prokinetic agent although its mechanism bears some similarity to other agents in this category. Tegaserod works as a partial agonist at select serotonin receptors (5HT4), which in turn promotes motility throughout the GI tract. It also stimulates chloride secretion, which may help increase the fluid content of the stool. The most common side effects are diarrhea and headache. It is relatively free of major drug-drug interactions.

Note: Use became restricted by FDA in 2007 due to cardiovascular safety concerns. Use requires a prescription and it is usually dosed twice a day by mouth.

Cisapride possesses similar activity at serotonin receptors in the GI tract as does metoclopramide but exhibits minimal effects on dopamine receptors. As such, extrapyramidal side effects are not encountered. However, this drug inhibits cardiac repolarization in a dose dependent manner. The potential for it to cause cardiac arrhythmias associated with QT prolongation limits use. A few years ago the drug was removed from the U.S. market, and is now only available through compassionate use protocols.

Domperidone is a drug that is very similar to metoclopramide in its ability to modulate serotonin and dopamine receptors in the GI tract, but lacks the CNS penetration into the nigrastriatal pathway and tends not to cause movement disorders as a side effect. However, this drug is not currently licensed for use in the U.S.