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Acid reducing medications

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Acid reducing medications

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Content Reviewers:

James Schurr, PharmD

Acid reducing medications include antacids that directly lower the acidity of stomach contents, and antisecretory medications that act on parietal cells in the stomach to decrease acid secretion. They are used to treat conditions like gastroesophageal reflux disorder and peptic ulcer disease by decreasing the acidity of the stomach and allowing the epithelial linings to heal. 

Now, the stomach is composed of four regions: the cardia, the fundus, the body, and the pyloric antrum. There’s also a pyloric sphincter, or valve, at the end of the stomach, which closes while eating, keeping food inside for the stomach to digest. The epithelial layer of the stomach contains a variety of gastric glands which secrete a variety of substances. Starting with the cardia, it contains mostly foveolar cells that secrete a protective mucus, which is mostly made up of water and glycoproteins. The fundus and the body contain both the parietal cells and enterochromaffin-like cells, and the antrum and pyloric areas contain G-cells. Now gastric acid is mainly composed of HCl, or hydrochloric acid, which is mainly secreted by the parietal cells. Parietal cells have M3, CCK2, and H2 membrane receptors, which modulate its secretory behavior. When food enters the stomach, it causes the stomach walls to expand, which leads to the activation of these receptors. First, stomach expansion causes the branches of the vagus nerve that innervates the stomach to release acetylcholine, which activates M3 receptors. Next, the G cells in the antrum of the stomach release gastrin, which activate the CCK2 receptors. Gastrin and acetylcholine activate the enterochromaffin-like cells, which release histamine, that activates H2 receptors. Activation of M3, CCK2, and H2 receptors increases the conversion of H20 and CO2 to H+ and HCO3- by carbonic anhydrase. The H+ is then pumped out of the cell and into the stomach via the H+/K+-ATPase pump. These H+ ions combine with Cl- ions to form hydrochloric acid and decrease the pH in the stomach. Normally, the stomach is protected from the acidic environment by the mucus secreted by foveolar cells. 

However, if there’s an imbalance between mucus and acid secretion, like in Zollinger-Ellison syndrome, which is caused by a gastrin secreting tumor, it could lead to damage of the stomach. This could manifest as chronic gastritis and gastric, or peptic ulcers. Now, in the esophagus, the lower esophageal sphincter prevents most of the gastric acid from coming back up when the stomach is full or when you’re laying down. If this sphincter is loose, the acid could reflux into the lower esophagus and erode the esophageal lining. This is called GERD, or gastroesophageal reflux disease, more commonly known as heartburn. One way to mitigate the harmful effects of gastric acid in these disorders is to decrease its acidity through medications. 

Let’s start with the H2 receptor antagonists like cimetidine, raNITIdine, famotidine, and nizatidine. H2 antagonists end up with the suffix -tidine, so remember, they enable you t(w)o dine! These medications are competitive, reversible antagonists of H2 receptors, meaning they bind to these receptors so histamine can’t. These medications are able to decrease night time and food stimulated acid secretion by over 90%. They generally take effect within an hour of ingestion and last for around 12 hours, so they can be taken one hour before meals or before bedtime, if taken once per day. They are generally given orally, but intramuscular and IV formulations are available. Now, common indications of H2 receptor antagonists include peptic ulcers, prevention of ulcers and stress ulcers, gastroesophageal reflux disease (GERD), and Zollinger-Ellison syndrome, which is a rare condition caused by gastrin-secreting tumors. But, since they are less effective than proton pump inhibitors (PPIs), they are often classified as second-line treatment. Generally, H2 antagonists are safe medications, so side effects are rare.  But, if they occur, they typically include headache, fatigue, myalgias, diarrhea, and constipation. Now, cimetidine is a strong inhibitor of cytochrome P450 enzymes in the liver.  These enzymes are responsible for the metabolism of a variety of medications and toxins in our body. So, if taken with other medications like benzodiazepines or warfarin, cimetidine could reduce their rate of elimination and cause them to build up in the body. Cimetidine also has anti-androgenic effects and could cause gynecomastia, sexual dysfunctions like decreased libido, and loss of hair, or alopecia. These side effects are reversible and they typically resolve over time once the medication is discontinued. Since it crosses the blood brain barrier, it could also cause confusion and dizziness. In kidneys, cimetidine and raNITIdine compete with creatinine for renal tubular secretion. This way, they can decrease renal excretion of creatinine and increase serum creatinine levels; therefore, individuals with renal impairment require dose reduction! Finally, H2 antagonists can cross the placenta. But, even though there are no known harmful effects for a fetus, they should be avoided during pregnancy and breastfeeding. If necessary, the preferred medication during pregnancy is raNITIdine; and during breastfeeding is famotidine

Next we have the proton pump inhibitors, or PPIs, which include oral medications like omeprazole, lansoprazole, dexlansoprazole, and medications available in IV, like pantoprazole and esomeprazole. The oral forms of these medications are absorbed in the small intestine in their inactive form and get metabolized in the liver. Next they travel through the blood to the parietal cells where the acidic environment helps protonate them so they become fully active. These activated PPIs irreversibly bind to and inhibit the H+/K+-ATPase, or proton pumps, found within parietal cells. Since the proton pump is the terminal step in acid secretion, proton pump inhibitors are better at inhibiting acid secretion than H2 histamine receptor antagonists, with a decrease of up to 99% of gastric acid secretions. Because of this, they are more useful for the treatment of peptic ulcers, gastroesophageal reflux disease (GERD), and Zollinger-Ellison syndrome. On the flip side, they are equally effective in the prevention of ulcers. Furthermore, they have a weak antibacterial effect against the peptic ulcer causing H. Pylori, so they are used in combination with antibiotics like amoxicillin, clarithromycin, or metronidazole. It takes 3-4 days for proton pump inhibitors to decrease stomach acidity, and they remain effective for 2-3 days. With continual daily dosages, an increased antisecretory effect can be achieved for up to 5 days. 

Side effects of proton pump inhibitors are uncommon, but can include gastrointestinal disturbance such as nausea, abdominal pain, and diarrhea. Also, prolonged acid suppression can decrease the absorption of iron, calcium, magnesium, and vitamin B12, or cobalamin. When the gastric juices are less acidic, it also allows more ingested pathogens, like Clostridioides difficile, to survive and invade the GI tract. Therefore, individuals treated with PPIs are more susceptible to Clostridioides difficile infection; but, they are also associated with an increased risk of pneumonia. Other side effects include headaches, rashes, and osteoporosis. Now, as far as drug interactions go, this change in the gastric pH can reduce the absorption of certain medications like digoxin and ketoconazole. Now, omeprazole is an inhibitor of cytochrome P450 enzymes in the liver. So, if taken with other medications like warfarin, it can reduce their rate of elimination and cause them to build up in the body. Finally, since omeprazole inhibits the enzyme CYP 2C19, it can reduce the activation of the antiplatelet medication clopidogrel

Finally, we have the antacids which are weak bases like aluminum hydroxide and magnesium hydroxide. These two medications are not well absorbed in the GI tract so once they get to the stomach, they can neutralize some of the acidity by binding to H+. In general, they are less effective in raising the pH of gastric acid when compared to H2 receptor antagonists and PPIs, and are mainly used for symptomatic relief in GERD. Antacids also include calcium carbonate and sodium bicarbonate, but these medications are less popular since they are well absorbed from the GI tract and associated with severe systemic side effects, such as milk-alkali syndrome. This syndrome is associated with metabolic alkalosis, hypercalcemia, and renal insufficiency. For side effects, aluminum hydroxide inhibits smooth muscle contraction in the GI tract, leading to constipation. Magnesium hydroxide on the other hand, works as a laxative by drawing water from surrounding tissue, leading to diarrhea. In rare cases, this could lead to hypotension. Now, in healthy individuals, absorption of small amounts of aluminum and magnesium is not associated with serious side effects; but in individuals with renal insufficiency, they can accumulate and cause serious side effects. Moreover, aluminum hydroxide can cause hypophosphatemia, proximal muscle weakness, osteoporosis, and even seizures; while magnesium hydroxide can cause hypermagnesemia, hyporeflexia, and cardiac arrest. Finally, all antacids can cause hypokalemia

Summary
Proton-pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available. This group of drugs followed and largely superseded another group of medications with similar effects, but a different mode of action, called H2-receptor antagonists.
Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  3. "Rang and Dale's Pharmacology" Elsevier (2019)
  4. "Peptic ulcer disease" Am Fam Physician (2007)
  5. "Proton Pump Inhibitors, H2-Receptor Antagonists, Metformin, and Vitamin B-12 Deficiency: Clinical Implications" Advances in Nutrition (2018)
  6. "25 Years of Proton Pump Inhibitors: A Comprehensive Review" Gut and Liver (2017)