Transcription
Drugs used in peptic ulcer disease.
Now, peptic ulcer is a lesion of the gastrointestinal tract, typically the stomach and the duodenum, caused by damage to the mucosa and deeper tissues due to acid and pepsin. The acid is secreted by the parietal cells, and the pepsin is secreted by the chief cells.
Now, the causes of peptic ulcer can include three major things. First, it can be due to an H. pylori infection. Secondly, it can be caused due to stress in chronic disease patients. And thirdly, it can also be induced by NSAIDs.
Now, to understand the physiology of gastric acid release from parietal cells, I'll draw here a parietal cell along with some of the stomach mucosa, and the red lesion will show the stomach ulcer, a peptic ulcer.
Now, the final step of gastric acid release is the activity of the hydrogen potassium ATPase, which is basically an antiport which secretes hydrogen in exchange for potassium. The four receptors I have drawn here are to be acted upon by different stimuli to increase or inhibit the gastric acid secretion. First is the histamine, which acts on H2 receptors, increasing gastric acid secretion. Acetylcholine acting on M1 also increases it. PGE2, on the other hand, will inhibit gastric acid secretion, and gastrin will also increase gastric acid secretion.
Now, I'll mention the drugs and their site of action on this diagram. Firstly, we can use H2 antagonists, which will act on the site labeled as 1. Secondly, we can use M1 antagonists, which will act on the site labeled as 2. Thirdly, we can use prostaglandin analogues, which will act on the site labeled as 3. Sadly, we do not have any gastrin antagonists. Next, we can use proton pump inhibitors, which will inhibit the proton pump. We can also use sucralfate, which will act on the site 6 and cover the ulcer and promote healing. Lastly, we can use antacids, which will neutralize the acid in the lumen.
Coming to the classification of the drugs used in peptic ulcer disease, we have the drugs which inhibit gastric acid secretion, then we have drugs which are also protective, next our acid neutralizing agents, and lastly, we have anti-H. pylori agents.
The four classes of drugs that inhibit gastric acid secretion are proton pump inhibitors, H2 receptor antagonists, antimuscarinic agents, specifically M1, and prostaglandin analogs.
The acid neutralizing agents can be non-systemic as well as systemic.
The first class of drugs which will inhibit gastric acid secretion are proton pump inhibitors. What they do is basically they inhibit the proton pump, that is, hydrogen potassium ATPase, irreversibly. That is, they are non-competitive inhibitors, that increases their duration of action, although they have a short half-life. How they reach this site is that they are absorbed in the small intestine because they are given in enteric-coated tablets. They diffuse to the blood, and then they diffuse back to the parietal cells, and in the acidic pH, they are converted into the active charged form known as self-amide. They are the most powerful and most commonly used drugs for peptic ulcer.
Now, two important food interactions regarding proton pump inhibitors: food will decrease the absorption of proton pump inhibitors, so they need to be administered 30 minutes before food because food will increase acid secretion and thus the active form of the drug will be in high concentration when it is diffused from the blood into the parietal cells. They have a short half-life and a long action because they are non-competitive irreversible antagonists. They are highly bound to plasma proteins, and they're used in peptic ulcers, all forms of peptic ulcers. They also decrease the risk of aspiration and pneumonia. They are also used in Zollinger-Ellison syndrome because there is hypergastrinemia leading to peptic ulcers, and they also are the drug of choice for gastroesophageal reflux disease.
Now, you need to remember three important side effects. One is decreased vitamin B12 absorption because parietal cell release of acid and intrinsic factor is inhibited. And on chronic use, it can lead to hypergastrinemia because we are inhibiting gastric acid production, so the body increases gastrin production, which can lead to gastric tumors. And lastly, and the most important one is hyperprolactinemia. How that happens is that the P450 is inhibited by PPIs, which lead to inhibited metabolism of estrogen, increased estrogen in the body leads to increased prolactin, and thus in males, we can see gynecomastia and erectile dysfunction, while in females, there is dysmenorrhea and menstrual disturbances. The chief drugs are omeprazole, which is the prototype, esomeprazole, lansoprazole, and pantoprazole. The esomeprazole, lansoprazole, and pantoprazole are present in parenteral formulations as well, and pantoprazole has minimum drug interactions.
Now, coming to the H2 receptor antagonists, they act chiefly on the H2 receptors on the parietal cell and block them competitively and reversibly. So they are less potent than proton pump inhibitors. Their main use is to inhibit the nocturnal acid secretion. The chief drugs that are involved in this category are cimetidine, which is a prodrug. Ranitidine is a longer-acting, more potent with rare drug interactions. It does not cross the blood-brain barrier, has no anti-adrenergic action, and there's no hyperprolactinemia. Famotidine has also no adrenergic effect and higher bioavailability. Nizatidine has higher availability.
Now, the use of H2 receptor antagonists are basically in peptic ulcer disease, Zollinger-Ellison syndrome, GERD, and post-operative use to prevent aspiration pneumonia. But they are overall less effective than proton pump inhibitors.
Next, we can use antimuscarinic agents, which are specifically selective for M1, and they are not usually used because they have decreased efficacy and serious side effects, which are atropine-like side effects. The chief drugs are pirenzepine and telenzepine.
Next, we can use prostaglandin analogues such as misoprostol, which is a PGE1 analog. It inhibits gastric acid secretion, increases the secretion of mucus, increases bicarbonate secretion, and also increases the mucosal blood flow. So it has a cytoprotective effect.
Now, any drug which has a "prost" in it means it's a prostaglandin analog, and it is contraindicated in pregnancy because it will cause uterine contraction and abortion.
Now, the peptic ulcer protective drugs include two drugs mainly. First is sucralfate. What it does is that in acidic pH of the stomach, it polymerizes to form a sticky polymer that adheres to the ulcer base to protect it. It also precipitates proteins at the site to wall off the ulcer from further damage. It also increases prostaglandin release, mucus release, it releases epidermal growth factor, and increased bicarbonate secretion. They should be taken one hour before meals, so they have a protective effect. Antacids, H2 blockers, and PPIs should not be used along with sucralfate because it needs acidic pH to work. It can be used in GERD with esophagitis.
The second ulcer protective agent is bismuth preparations, such as bismuth subsalicylate and colloidal bismuth subcitrate. The mechanism of action is not clear, but the side effects include blackening of tongue and stools.
Now, acid neutralizing agents. What is an ideal antacid? It should be insoluble and not absorbed. It should not liberate carbon dioxide. It should not disturb the acid-base balance of the body. It should be quick, prolonged action, inexpensive. The buffer range should be between 1 and 6, and less drug interactions should be there.
Now, non-systemic acid neutralizing agents include magnesium hydroxide, aluminum salts, magnesium salts, and calcium carbonate. They react with the HCl in the stomach to produce salts, and that is their antacid action, basically. But to prevent alkalosis, they in the intestine, they neutralize the bicarbonate which is not absorbed, so they do not cause metabolic alkalosis. Aluminum salts will cause constipation, and they are slow acting, while magnesium salts will cause diarrhea, and they are fast-acting. Calcium can be absorbed. The calcium salts can be absorbed and cause hypercalcemia. The chief drug interaction will be due to the increased pH of the stomach, which decreased absorption of some drugs such as iron, tetracycline, which is a chelator, and ketoconazole.
The systemic acid neutralizing agents chiefly are sodium bicarbonate and sodium citrate. Sodium bicarbonate disadvantages are that it is short-acting, it has a high water solubility, so it is rapidly absorbed, causing metabolic alkalosis. It releases carbon dioxide. It has a rebound acidity. The systemic acid neutralizing agents should be avoided in hypertensives and congestive heart failure patients because they cause sodium retention.
Lastly, we have anti-H. pylori agents, which fight the H. pylori infection associated with gastritis, duodenal ulcers, gastric ulcers, and even gastric carcinoma.
Now, the mechanism of how H. pylori causes ulcers is not clear, but maybe the ammonia produced by the organism can cause the damage. To treat this type of infection, multidrug regimens are used, which are for about one to two weeks to prevent recurrence of the infection and to prevent drug-resistant forms of H. pylori.
Now, the triple regimen includes lansoprazole, clarithromycin, and amoxicillin, while the quadruple regimen includes omeprazole, colloidal bismuth sulfate, tetracycline, and metronidazole. The amoxicillin should be tested for hypersensitivity because some patients are allergic to penicillin. Resistance is not rapidly developed to amoxicillin. After the patient has completed the triple or quadruple regimen, the patient should continue proton pump inhibitors for about six weeks to let the gastric mucosa heal.
That's what about the drugs used in peptic ulcer disease.