-Mohammad Ashraf. -Anas Raed. -Alia Shatnawi. 1 P a g e

Transcription

1 -1 -Mohammad Ashraf -Anas Raed -Alia Shatnawi 1 P a g e

2 Dr. Alia started the lecture by talking about subjects we are going to cover through this course; you can refer to the record if you are interested. Peptic ulcers Definition: Defect in the lining of the stomach or the duodenum. In the stomach we have specialized cells which secret HCl. HCl is very harmful and irritant acid for any part of the body. So, to protect the stomach from it we have several defensive mechanisms, like epithelial cells lining the stomach which have specialized cells that secret mucous to protect the inside of the stomach. If we have a decrease in the mucous secretion because of a defect in the epithelial cells, we have more potential to develop an ulcer, so the inner layer will be exposed to the acid and this acid will damage the innermost layers, which can lead to perforation or bleeding in the stomach. We have different ways to treat peptic ulcers: Inhibition of proton pumps (H + pumps). HCl = H + + Cl -, so what secretes HCl in the stomach is a hydrogenpotassium ATPase pump that secrets protons in the lumen of the stomach. So, drugs that stop these pumps, will result in decreasing the secretion of HCl. Increasing bicarbonate (HCO 3 - ) or mucosa This can be done by giving bicarbonate to the patient in a form of drugs called antacids. Antacids are bases, so when react with HCl they decrease the acidity.this is called chemical antagonism (if you remember, last semester we talked about different types of antagonism, which are pharmacological, physiological and chemical antagonism). CaCo 3 is one of these antacids which chemically antagonizes HCl, so it s a chemical antagonist because it diminishes the effect of HCl without binding to a receptor nor an enzyme. 2 P a g e

3 Also, we can increase bicarbonate or mucous secretion. So, we can use agents that will help the body to produce more mucous and bicarbonate. Prostaglandins stimulate production of mucous and bicarbonate, so if we use a prostaglandin analogue (a drug resembles the structure of prostaglandins), this will activate prostaglandins receptors in the stomach and secrete more mucous which is a protector for the lining of the stomach and the duodenum. Also, we can give the patient material that will cause lining inside the stomach called mucoprotective agents; this will help in decreasing discomfort that happens from excessive acid secretion. Causes of peptic ulcers: The most common cause is a bacteria called H. pylori, we need to give antibiotics to patients with H. pylori to eradicate this microorganism. Ulcers also can be caused or worsened by some drugs such as aspirin, ibuprofen or NSAIDs. These drugs inhibit the production of prostaglandins all over the body by inhibiting cyclooxygenase and by using these drugs we get rid of pain, headache, inflammation or fever, but we also we get rid of the protective effect of prostaglandins which is protection of the stomach. That s why if someone has to take NSAIDs, he should take drugs to treat peptic ulcers during NSAIDs course if he suffers from peptic ulcers. Some people have to take NSAIDs the whole duration of their lives like people with rheumatoid arthritis or other autoimmune diseases, so we either give them proton pumps inhibitors (PPIs),or instead of NSAIDs, we give them COX2 selective inhibitors (like celecoxib or rofecoxib) if the patient cannot benefit from the use of peptic ulcer treatment. Other causes of peptic ulcers including stress, smoking, spicy food and alcohol, all of these increase the risk of developing peptic ulcers. Gastrinoma: Tumors that secret gastrin. In the stomach we have canaliculi where acids being secreted, there are mucous cells in the neck of these canaliculi which secrete mucous. 3 P a g e

4 Inside the wall of the canaliculi we have parietal cells which secret HCl, G cells which secret gastrin, ECL cells which secret histamine and chief cells which secret pepsin. All of these cells affect acid secretion, how? Quick review of stomach physiology: Parietal cells have hydrogen potassium ATPase pumps, they can be activated by different kinds of stimuli, like histamine receptor, muscarinic receptor and CCK receptor.so, if acetylcholine binds to muscarinic receptor, or histamine binds to histamine type 2 receptor, or gastrin binds to CCK receptor, it will cause translocation of the resting pumps. These pumps usually present in the cytoplasm and once they are activated they need to translocate to the luminal side of the membrane where they function (production of protons) then secreting HCl.So, by inhibiting one of these 3 mentioned pathways, HCl secretion will be decreased. Some groups of drugs that are used to treat peptic ulcer can work on the muscarinic receptors (muscarinic antagonists).they block acetylcholine from binding to M receptors, so activating acid secretion. Vagal stimulation and parasympathetic pathway affect most of secretory cells in the stomach.vagal stimulation and parasympathetic pathways are activated when we see or smell food, so acetylcholine is released. Acetylcholine will stimulate G cells to secret gastrin, gastrin will go to the antrum blood vessels and bind to parietal cells to secret HCl, but also, gastrin will bind to ECL cells receptors to stimulate histamine release. In addition, we have D cells which secrets somatostatin, somatostatin have the opposite effect in acid secretion. So vagal stimulation will suppress acetylcholine receptor, as a result suppressing somatostatin release, and this will stimulate G cells to secrete gastrin, so HCl secretion increase. Actually, we don t use muscarinic receptor antagonists a lot unless we don t have alternatives, because muscarinic receptors are part of parasympathetic pathways and they present all over the body. So, when 4 P a g e

5 muscarinic receptors are inhibited in the stomach, the drug used is not selective for that subtype of the receptors, so not only receptors of the stomach are inhibited, and we will have a lot of side effects like blocking histamine pathways all over the body. We said that ECL cells release histamine to stimulate acid secretion. Histamine binds to H 2 -receptor and Ca i and camp rises activating phosphokinases.so, to treat peptic ulcers by anti-histamines is done by blocking histamine from binding to H 2 -receptor only. This will minimize the side effects. Side note: Treatment of allergy by anti-histamine targets H 1 -receptor (H 1 antagonists).h 1 -receptors exist all over the body. H 2 -receptors exist mainly in the stomach. Antacids: They are kind of safe, over the counter (sold without prescription), weak bases, neutralize acidity by reacting with acids to form salt and water. They can stimulate mucosal prostaglandin production. These drugs are given after a meal. Their efficacy varies according to rate of dissolution. One thing to be cautious about is that they could affect absorption of other medications (e.g. tetracyclines no absorption, and so no effect against bacteria). So, don t give tetracyclines with or after antacids, wait at least 2 hours. Examples of antacids: Sodium Bicarbonate (Baking Soda): Reacts with HCl to produce CO 2 + NaCl. Side effects: Might exacerbate water retention (because of NaCl production). That doesn t usually happen in healthy patients, but we should be careful about using this drug in patients with congestive heart failure (CHF). 5 P a g e

6 People with CHF have retention of fluids on their hearts or lungs, so usually we give them diuretics to help the body to get rid of excessive salts and water. It can stimulate acid secretion by stimulating gastrin secretion. Systemic absorption leads to metabolic alkalosis. CO 2 leads to gastric distension and belching. Magnesium Hydroxide & Aluminum Hydroxide Both of them react slowly and don t produce CO 2. Metabolic alkalosis is also uncommon. Side effects: Mg salts can cause diarrhea. Aluminum salts cause constipation. Usually we give these 2 drugs in combination to avoid diarrhea and constipation. Contraindicated in renal insufficiency because excretion of the salts happens through the kidney. Aluminum antacids absorb or chelate many drugs; most common used. Magnesium antacids have laxative action causing diarrhea. Calcium antacids stimulate acid rebound by promoting gastrin release. Sodium antacids should be avoided because they aggravate CHF and counteract diuretic therapy for high blood pressure (HBP). Fast drugs have faster onset of action, so they relieve the symptoms earlier, but their duration of action is lower. 6 P a g e

7 We don t want from these drugs to be absorbed because we want them to work in the stomach, so the more they stay in the GI system the more the duration of action they have. Though, antacids in general don t have long duration of action (maximum is 1-2 hours), so they are not helpful for patients with chronic peptic ulcers. H 2 -receptor antagonists Were the most commonly prescribed drugs in the world (1970s-1990s). Examples: Cimetidine, Ranitidine, Famotidine and Nizatidine. Famotidine is the strongest; potency is 100x more than Cimetidine. The rest are stronger than Cimetidine by 4-10 times. Cimetidine is the prototype, has many problems (side effects). Mechanism of action: There drugs are selective competitive inhibitors of the parietal cells H 2 - receptors, this will suppress acid secretion. They also decrease volume of secretion and pepsin concentration. So, they decrease secretion stimulated by: Histamine, Gastrin and Acetylcholine. A lot of systems in our body are affected by the circadian rhythm (timing of the day), for example, acid secretion increases at night (highest peak), so usually symptoms are at their peak at night. H 2 -receptor antagonists are very useful in treating 90% of nocturnal acid secretion and 60% of day-time and meal-stimulated acid. 7 P a g e

8 This chart shows HCl secretion measured within 24 hours. As we can see after every meal how much secretion increases (control), and the highest increase is being at night. Notice from the chart how much H 2 -receptor antagonist decreases acid secretion. They work so much better at night time that after lunch or dinner for example. 8 P a g e