- Ali Yaghi. - Sara Yaghi. - Alia Shatnawi. 1 P a g e

Transcription

1 -2 - Ali Yaghi - Sara Yaghi - Alia Shatnawi 1 P a g e

2 We ended the previous lecture with H2 receptor antagonists, which work by selectively inhibiting H2 receptors. They are widely used to treat: 1- GERD, but here PPI are more preferred because of their superior action and higher efficacy. 2- Non ulcer dyspepsia. 3- Stress related gastritis, can prevent bleeding, usually given IV. 4- Peptic ulcer disease, but H2 receptor antagonists become ineffective if: A) H. Pylori is the causative agent, in this case PPI are used. B) If NSAID is continued. Note: NSAIDS inhibit COX and decrease the prostaglandins, so we lose the protective action of the prostaglandins over the stomach. So they can cause peptic ulcer. We can only use H2 inhibitors if the patient stops taking NSAIDS. If the patient can t stop taking NSAIDS, we use PPI. PPI with the continuation of NSAIDS have better ability to heal the ulcer caused by the NSAIDS. The father of H2 receptor antagonists is Cimetidine (Tagamet). H2 receptor antagonists side effects: Extremely safe drugs, but can (in 3% of patients) cause diarrhoea, headache, fatigue, myalgia and constipation. Cimetidine has a lot of side effects. It inhibits cytochrome p450. We know that the metabolism of the drugs causes deactivation of the drug. As example, if a person is using digoxin (a drug used for treating heart failure), and I give him cimetidine, cimetidine will inhibit CYP450, which leads to a longer activity time for digoxin (because digoxin is deactivated by CYP450, which is in this case is inhibited by cimetidine). << Digoxin has a narrow therapeutic index, which means if we prescribe a higher dose than permitted, or if we inhibit its deactivation, we reach toxicity level. <<We use newer drugs such as Ranitidine, which has less ability and affinity to bind with CYP450. So it has less inhibitory effect. << Other new drugs like Nizatidine and Famotidine have negligible biding affinity to CYP450, so they are considered safer with regard to drug-drug interaction. Cimetidine has antiandrogenic activity. People who take this drug have high level of estradiol especially in men. Because it causes loss of libido, erectile dysfunction, increases secretion of prolactin which causes gynecomastia (breast enlargement in male). Cimetidine causes CNS effects in elderly, such as excitation, confusion and agitation. 2 P a g e

3 Duration of action: The duration of action is 12 hours, so these drugs are given 2 times a day. They are given before meals, and they are mainly effective in decreasing acid secretion during night (nocturne), and somehow effective in daytime and meal stimulated acid secretion. HCL secretion can be affected by: 1) H2 receptors antagonists. (We have finished talking about them). 2) Muscarinic muscle antagonists, which are not used a lot because of their side effects. 3) Proton pump inhibitors (PPI), which directly inhibit acid secretion. Proton pump inhibitors mechanism of action: 1- Drug must be absorbed in small intestine and delivered to parietal cell through the blood. They do not work directly in the stomach like antacids, they need to be absorbed first. 2- Drug is protonated and trapped in acidic canaliculi of parietal cells. The drug that we take is a prodrug, (it has to be activated in order to do its function). PPI are weak bases and they are acid labile (destroyed easily by the acidic environment). To protect the PPI from destruction in the stomach (as they are taken orally), they are ENCAPSULATED BY MICROENCAPSULATION. Then after reaching the small intestine, PPI are disintegrated and they are absorbed to the blood stream, (They enter easily because they are lipophilic). 3- Trapping of protonated drug within the acidic canaliculi next to target enzyme. Once the PPI which are weak bases- are in the canaliculi-where HCL is secreted-, the PPI will be protonated (charged), therefore the drug will not be able to get out of the canaliculi. This is good because that s where we want the drug to work. 4- It is an irreversible inhibition. (Covalent bond with amino acid cystine in the protein of the pump). 5- Full inhibition with 2:1 ratio of (drug: enzyme). Note: In order to stop the action of the drug, the pump must be recycled by degrading it then synthesizing a new one. Therefore, restoring the highest action of the pump (diminishing the activity of the drug) needs long time, around 4-5 days, and the duration of action of the drug is 24h. 3 P a g e

4 Half-lives of these drugs are very short (the unbound drug will be degraded quickly). Notes: 1- PPI : given once a day (twice in case of severe illness). 2- H2 antagonist: twice a day. 3- Antacids: many times a day (its duration of action is 2 hours maximum). That s why PPI are better because they are stronger and they are taken only once daily. Some PPI's : Omeprazole (oral). Rabeprazole (oral). Lanzoprazole (oral and IV). Pantoprazole (oral and IV). Esmoprazole (oral and IV). Note: The Reason for naming these drugs (-prazoles) is because they are benzyemidazole. Rabeprazole and immediate release omeprazole have faster onsets of action. So it should be given one hour before meal (opposite of antacids which are given after meals). Have short half-lives but their effect lasts for 24 hours due to irreversible inhibition. Pharmacodynamics: Proton pump inhibitors inhibit both fasting and meal-stimulated acid secretion because they block the final common pathway of acid secretion (90-98% of 24-hour secretion). Notes: 1- H2 receptor antagonists are preferable for night time acid secretion. 2- Night time acid secretion can be caused by the indigestion of food. 3- PPI are preferable for other acidity causes (especially during the daytime). 4 P a g e

5 Clinical Uses for PPI: 1- Gastroesophageal Reflux (GERD): PPI are better than H2 receptor antagonist 2- Non ulcer Dyspepsia: (can happen after heavy meals): - Modest activity % more beneficial than a placebo. 3- Stress- Related Gastritis: - If a patient has nasogastric tube, we can give him Oral immediate- release omeprazole. - For patients without a nasoenteric tube, IV H2-antagonists are preferred because of their proven efficacy. 4- Gastrinoma and other Hypersecretory Conditions: - Usually high doses of omeprazole are used. Although omeprazole can induce gastrin release, it still has a good activity for inhibiting HCL release. 5- Peptic Ulcer Disease: - They heal more than 90% of cases within 4-6 weeks. Especially good for: A- H. pylori- associated ulcers: - PPI eradicate H. pylori by direct antimicrobial activity and by lowering MIC (minimum inhibitory concentration) of the antibiotics. Note: PPI are used in triple therapy (we will talk about this later in this sheet). B- NSAID-associated ulcers: -PPIs promote ulcer healing despite continued NSAID use. (Remember H2 antagonist in this sheet). -Also used to prevent ulcer complications of NSAIDs. C- Rebleeding peptic ulcer: -Oral or IV PPI administration. -High ph may enhance coagulation and platelet aggregation. 5 P a g e

6 Adverse Effects of PPIs: General side effects: - Diarrhoea, headache, abdominal pain, not teratogenic in animals, but not used in pregnancy. - Reduction of cyanocobalamine absorption. - Increased risk of GI and pulmonary infection. - Atrophic gastritis and intestinal metaplasia. - Chronic inflammation in gastric body - They increase serum gastrin level which can cause: Carcinoid tumours in rats. Hyperplasia of parietal cells (ECL cells). Increase proliferative rate of the colonic mucosa but without cancer development. Drug Interactions: - Some drugs needs gastric acidity to be absorbed, so PPIs may affect absorption of drugs (like digoxin and ketoconazole and vitamin b12 complex) due to decreased gastric acidity. - It is noted that people who are along term use of PPI have a decreased level of vitamin B12. The solution for that is giving vitamin B12 injections or changing the drug. - Omeprazole can inhibit metabolism of coumadine, diazepam and phenytoin. - Rabeprazole and pantoprazole have no significant interactions with other drugs. Note: Long term use of PPI increases the risk of a hip fracture. It can be due to reduced amount of Ca2+ dissolved in the stomach (because calcium needs high acidity to be absorbed) OR because they interference with the breakdown and rebuilding of bone by interfering with the acid production of osteoclasts. Beware of using these drugs with osteoporotic patients. That s it for PPI. Muscarinic antagonists Atropine Pirenzepine 6 P a g e

7 Side effcets: urinary retention xerostomia blurred vision Now we will talk about Mucosal Protective Agents GI mucosal defence mechanisms: 1- Mucus secretion. 2- Cell-cell tight junctions (Restrict back diffusion of acid and pepsin). 3- Epithelial bicarbonate secretion. 4- Restitution: migration of some gland neck cells seals small erosions to re-establish intact epithelium. 5- Mucosal prostaglandins: Stimulate mucus and bicarbonate secretion. DRUGS that enhance mucosal protection 1.Sucralfate 2.Prostaglandin analogs (misoprostol, cytotec) 3.Bismuth compounds 1. Sucralfate: Is a salt of sucrose complexed to sulphated aluminium hydroxide. Has a negatively charged sucrose sulphate, which binds to positively charged proteins in the base of ulcer or erosions, forming a physical barrier that restricts further caustic damage and stimulates prostaglandin and bicarbonate secretion. In the stomach, it forms a viscous, tenacious paste that binds selectively to ulcers or erosions for up to 6 hours. Clinical Use: - 1 gm, four times daily on an empty stomach. - Reduces the incidence of GI bleeding in critically ill patients. - Acid inhibitory therapies may increase the risk of nosocomial pneumonia. 7 P a g e

8 Adverse Effects: It is not absorbed, so devoid of toxicity. Constipation in 2% of patients. Caution in renal insufficiency. Drug Interactions: May bind to other medications, thus impairing their absorption (wait 6 hours period). 2. Misoprostol: Prostaglandin analogue, a methyl analogue of PGE1. Half-life 30 minutes, so it s given 3-4 times daily. Stimulates mucus and bicarbonate secretion and enhances mucosal blood flow. Binds to prostaglandin receptor on the parietal cells, reducing the histaminestimulated camp production and causing modest acid inhibition. Also, stimulates electrolyte and fluid secretion, motility and uterine contractions. (Contraindicated with pregnancy because it causes abortion). Used in labour to facilitate delivery (Uterine rupture might occur). Mechanism of action: Misoprostol binds to prostaglandin receptor and reduces acidity, and enhance mucus and bicarbonate secretion. 8 P a g e

9 Which drug will target NSAID stimulated peptic ulcer pharmacologically? The answer is Misoprostol, because it will counteract the effect of NSAID. What is the best drug to treat NSAID stimulated peptic ulcer? The answer is PPI, because we do not like to use Misoprostol a lot because: A- It has a lot of side effects. B- Need for multiple daily dosing. C- PPI may be as effective and better tolerated. Note: Cyclooxygenase2-selective NSAIDs are an option for such patients. Side effects: 1- Can cause diarrhoea and abdominal cramping in 10-20% of patients. 2- Should not be used in pregnancy. 3. Colloidal Bismuth Compounds: 1- Bismuth subsalicylate. 2- Bismuth subcitrate. 3- Bismuth dinitrate. They coat the ulcers and make a protective layer inside the stomach, but they are additive. May stimulate prostaglandins, mucus and bicarbonate secretion. Bismuth subsalicylate inhibits intestinal prostaglandins and chloride secretion, so useful in infectious diarrhoea (travellers diarrhoea) leading to reduced liquidity and frequency of diarrhoea. Have direct antimicrobial effects and binds enterotoxins, so useful in travellers diarrhoea. Have direct activity against H. Pylori. Adverse effects: 1- Black stools and tongue. 2- Encephalopathy: headaches, ataxia, confusion and seizures. Note: they are not absorbed, but when they are absorbed, they cause the encephalopathy. 9 P a g e

10 Helicobacter pylori H pylori characteristics: 1- Helix-shaped Gram-negative bacterium. 2- Produces large amounts of the enzyme urease 3- It produces other enzymes including protease, vacuolating cytotoxin A (VacA), and certain phospholipases damage the mucosal epithelial cells. Note: The inflammatory response to the bacteria induces G cells in the antrum to secrete the hormone gastrin, which travels through the bloodstream to the fundus of stomach. Antibiotics to eradicate Helicobacter pylori: Clarithromycin Amoxicillin Metronidazole Tetracycline Clarithromycin-based triple therapy: PPI+ clarithromycin + amoxicillin or metronidazole for 14 days. (we give options because of the allergy to amoxicillin in some patients). Bismuth quadruple therapy (for penicillin allergic patients) : PPI or H2 Receptor antagonist + bismuth + metronidazole + tetracycline for days. GOOD LUCK 10 P a g e