Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Lecture 15 Last lecture we said in regard to GERD there are three different clinical presentations: 1. Classic (Typical ) GERD 2. Extraesophageal (Atypical) GERD 3. Complicated GERD And we also discussed the signs and symptoms of each one of them. - Classic GERD presentations: 1. Substernal burning (heartburn) and/or regurgitation: the most common symptoms of GERD but alone they are not specific and not necessarily giving indications for GERD. 2. Postprandial: the symptoms are aggravated by meals, i.e. patients experience more pain after meals. 3. Aggravated by change in position. 4. Quick or prompt relief by antacids If these four criteria presented in the patient, we should start empiric therapy without the need of diagnostic tests to confirm GERD. There are indications for the diagnostic tests for GERD but if the patient already has classic GERD presentations we directly start the treatment and its nature will depend on the severity of the condition/symptoms. Extraesophageal (Atypical) GERD: the symptoms are exceeding the stomach and esophagus, extending to pulmonary symptoms, ENT symptoms, chest pain and dental erosion. Dental erosion: Discoloration of teeth due to the presence of acid in the dental cavity. (Look at the figure in the slides) So, even though GERD cannot be confirmed solely based on clinical symptoms, the guidelines recommend starting clinical empiric treatment based on the symptoms. Q: When to perform diagnostic tests? 1. 2. 3. 4. Uncertain diagnosis Atypical symptoms Symptoms associated with complications Inadequate response to therapy: the symptoms did not alleviate to the required acceptable level. 5. Recurrent symptoms: patient adhered to his medications, and the symptoms alleviated, but when he stopped taking his medications a quick relapse happened. Quick relapse could indicate more advanced phase of the disease 6. Prior to anti-reflux surgery / Fundoplication Diagnostic tests for GERD: 1. Barium swallow : Or called Barium emptying, ideal test if the patient has structural changes like narrowing in the esophagus. Barium dye can adequately show structural changes like: Stricture, Mass, Bird’s beak (narrowing in the esophagus with curvature) and Hiatal hernia. Limitations: if there were erosive esophagitis (inflammation in the esophagus) or change in the type of cells like in the case of Barrett’s esophagus with NO structural changes, they cannot be detected by Barium imaging. 2. Endoscopy: - direct test - allows for visual inspection of the esophageal mucosa so if there is inflammation (reddish area) it can be detected easily with endoscopy. For this reason it is considered the goal standard test and the most significant test. Indications for Endoscopy: 1. Alarm symptoms 2. Empiric therapy Failure (any signs or symptoms of GERD complications). 3. Preoperative evaluation 4. Detection of Barrett’s esophagus Actually, they are the same indications of the diagnostic tests mentioned earlier. Although in practice, unfortunately the patient goes for a specialized doctor and will be directly advised for endoscopy which is really not necessary in probably the majority of the cases. A student said that in Istishari hospital, they do a test in which they take sample from saliva and measure the concentration of Sodium Bicarbonate which is indicative for body reflex mechanism for excess acid secretion. But the Doctor said it is not going to be neither sensitive nor accurate test. Otherwise, it would have been added to the guidelines for the management of GERD. It is indirect test Concentration of Sodium bicarbonate in saliva is high in case of GERD in order to neutralize the acidity. Inflammation in the esophagus is classified /categorized into four grades. (Refer to the table 32 -3 in the slides). Grade 0: Normal esophageal mucosa /no inflammation. Grade 4: The worst and most severe inflammation, pronounced structural changes in the patient. 3. Ambulatory pH monitoring: we have to know the concept only. A tube on its tip there is small probe which can measure pH value in the lower esophagus area. Incubation is made through the nose not the mouth in order to prevent gag reflux and then it sends signal regarding the pH readings to the detector which is normally handled at the patient body. (Look at the figure in the slides). When the acid get up to the lower esophagus, the pH will become acidic “below 4”. Because the patient can use his mouth during the test, sometimes it can be done for 48 hours instead of 24 hours. For that reason it is called ambulatory, the patient is not obligated to sit on the bed all the time during the test. The main goal of that test is to determine the period of time of the day during which the most exposure to acid happened, because in some severe conditions, the patient experience pain throughout the whole day, but the actual contact between the esophageal mucosae and gastric content is few hours, so it determines the actual time in which the contact / regurgitation happened regardless of heartburn and other symptoms. Can be used in uncertain diagnosis if we are unsure if the acid reaches the esophagus/acid reflux. Limitation: doesn’t give visual inspection and examination >>>> limited / slight use. Refer to the figure in the slides In GERD curve, we can see that the time of the day during which the pH was below 4 is from 11:30 AM to 1:30 AM. This indicates excess acidity in the lower esophagus resulting from contact with gastric contents. Notice in the normal curve there are deep regions during which the pH is below 4 and this is normal transient condition and depends on several factors like the the type of meals :fatty meals, heavy meals , spicy meals etc. GERD disease differs from normal reflux in the duration and severity of the condition, pain throughout the day, and as it gets worse it starts to affect the quality of patient’s life. So, the pH value remained lower than 4 from 11:30 AM to 1:30 AM and this is not transient regurgitation! It is a persistent contact which is indicative of GERD, and this would confirm GERD if it was uncertain diagnosis. The condition is more severe and worse for the patient If the time period during which the pH value below 4 was longer. Ambulatory 24 hour pH monitoring is a sufficient test to confirm GERD in a particular patient but alone doesn’t give us sufficient information about the severity of the case. It is true that the severity depend on the duration of time during which the pH value was below 4 but if we have two patients the pH value was below 4 for 2 hours , we can’t say that they have the same severity , maybe one will be more severe than the other . So alone it is insufficient to evaluate the severity. 4. Esophageal Manometry: The main goal of this test is to assess the peristaltic movements in the esophagus and to quantitate the pressure in the LES. * Pressure in the smooth muscles of the esophagus changes with food ingestion. * Problems in the peristaltic movements of the esophagus can weaken the defensive mechanism regarding GERD symptoms. Sometimes there is certain neurological deficit (nerve damage) causes defects in the peristaltic movements of the esophagus. So in that case, you can’t guarantee adequate control of GERD symptoms unless you solve this deficit. Advantage of Esophageal Manometry test: supply us with quantitative figures or numbers of LES pressure (not just released or decreased pressure), as well as information regarding the severity of the case in the patient. Refer to table 2 in the slides: There are other tests or procedures that can be used sometimes for the diagnosis of GERD: PPI trial: proton pump inhibitor trial: we give the patient PPI for 2 weeks, if the symptoms alleviated this favors the diagnosis of GERD. Limitation: negative trial does not rule out GERD: which means if the symptoms in the patient didn’t alleviate, this does not nessciarily indicate something other than GERD because maybe it was severe GERD and didn’t respond to PPI dose used in the test. An example of procedures is Esophageal biopsy: used for suspected Barrett’s esophagus (change in the type of cells) or suspected cancer. This test is used if there is mass in the esophagus which can be detected easily during Endoscopy or Barium swallow tests. So they do biopsy later on to know the type of cells. Treatment goals for GERD: 1. 2. 3. 4. Eliminate symptoms Heal esophagitis Manage or prevent complications Maintain remission Nonpharmacological Treatments of GERD with life style modifications: not all of them of are applicable at home. Refer to the table 32-5 in the slides 1. Elevate the head of the bed (increases esophageal clearance).Use 6- to 8- inch blocks under the head of the bed. Sleep on a foam of wedge: What is meant here not to increase the number of pillows. The bed itself can be elevated * fancy bed*. Most homes don’t have fancy beds so it is applicable only in hospitals or specialized clinics. The concept is we use the gravity force to pull the gastric contents downward and reduce the symptoms of regurgitation. 2. Dietary changes: a. Decrease the amounts of food. b. The time period between the last meal and bedtime should be at least 3 hours. 3. Weight reduction: The intra-abdominal pressure in obesity can increase reflux, so in case of GERD patient it would increase the symptoms. >>>> weight loss would help 4. Stop smoking: until 2013 it was considered as standard nonpharmacological treatment for GERD but recently it was discovered that smoking has nothing to do with modifying the symptoms. It is true that it increases the inflammation in the body but if a heavy smoker person which has already GERD stopped smoking, the same symptoms will remain. Conclusion: smoking cessation is no longer considered a non-pharmacological treatment of GERD. 5. Avoid tight –fitting clothes: they increase the pressure on the stomach which in turn pushes the gastric contents upwards. 6. In regard to drugs, if the patient can stop them it would be better. If not, the last dose should be taken late afternoon- early evening. Refer to Table 3 in the slides and notice: Tobacco and alcohol cessation box. GERD is classified based on the severity of the symptoms into three phases: Phase I: Mild /occasional symptoms. Most patients do not seek medical help they just rely on OTC medications. The symptoms (Regurgitation/ Heartburn) will occur more than in normal condition but they are nor severe neither annoying for the patient. Phase IIa: Persistent symptoms, mucosal damage. Inflammation in the esophagus, symptoms would increase in duration, heartburn for several hours. Phase IIb: Severe mucosal damage, heartburn can persist throughout the day. Psychological problems: in which the patient may reach a point that he don’t eat anything because he will be afraid of postprandial symptoms. Phase III: Refractory disease: Even with optimum treatments, the symptoms still exist. It is refractory to standard pharmacological treatment. Typically, there are two approaches: First choice is: doubling of the standard doses especially for PPIs and we try it for 1 -2 months. If the Symptoms didn’t alleviate or no acceptable response was noticed we go for surgery because the standard treatments would not be effective in this case. Refer to the Table 32-4: Therapeutic Approach to GERD PHASE I A. Life style changes ( for all phases ) Dietary changes Avoid tight-fitting clothes Separate between the last meal and bedtime by at least 3 hours Decreasing the amounts of food and beverages that can worsens the symptoms PLUS B. Antacids AND/OR C. Low-dose OTC H2 blockers Famotidine: 10 mg once daily (up to 20 mg still considered low dose).Maximum daily dose is 80 mg (40 mg twice daily) Ranitidine: 75 mg once to twice daily (150 mg still considered low dose).Maximum daily dose: 600 mg( 300 mg twice daily or 150 mg four times daily) Nizatidine :75 mg Cimetidine :200 mg OR D. OTC PPI (with doses lower than the standard doses) If the symptoms are unrelieved with lifestyle changes and OTC medications after 2 weeks (PPI trial), begin pharmacologic therapy (phase II therapy) because it is unlikely to be phase I. it is likely to be more advanced GERD. Q: Why we start with low doses of H2 blockers? Can we start with High doses? A: in case of suspected Phase I GERD, the main reason is to avoid Tolerance/Tachyphylaxis that develops after the use of H2 blocker for more than 2-3 weeks. This explain why some patients experience GERD symptoms after month or month and a half of treatment on H2 blockers >>>> because of tolerance development. So using H2 blockers daily for more than 3 weeks is likely to result in tolerance. The solution is to increase the dose until we reach the maximum daily dose if we are talking about H2 blockers. We don’t switch from agent to another from the beginning! If a patient developed tolerance for Ranitidine, can we replace it with equipotent dose of Famotidine? The answer is NO because they act on the same binding site of the receptor, so we should increase the dose of Ranitidine. The Duration of the effect of Famotidine doesn’t really correlate with the half-life. It’s half –life is 24 hours, so it is supposed to be taken once daily but the clinical duration is 8 -10 hours which means if a patient wants to take 40 mg Famotidine, it is better to take 20 mg twice daily rather than 40 mg once. In case of once daily, at best its duration will be 10 hours so there is a period of time not protected. Q: When is it the best time to take H2 blockers? A: 30 min to an hour before meals. Time of administration/dosing is critical to improve the response. If a patient forgot to take them before meals, and he took it after, efficacy will be very low, maybe one third or quarter of the efficacy if it was taken before meals. Onset of action of H2 blockers: 30 min to an hour. Cimetidine is the least commonly used H2 blocker because of: 1. The large potential for drug –drug interactions because it is an inhibitor of Cytochrome P450 2. At higher doses can cause Gynecomastia 3. Higher doses required (200 mg...) The most two commonly used H2 blockers are: Famotidine and Ranitidine Both of them can be used for children less than 1 year of age Ranitidine: from the age of one month Famotidine: from the age of three months Notice that in Phase I, patient is treated for 2 -4 weeks and after that there is NO need to continue with maintenance therapy. In case of Phase II or III maintenance therapy is a must. If the treatment was abruptly discontinued, quick relapse will happen. PHASE IIa A. Life style modifications PLUS B. Standard doses of H2 blockers for 6 -12 weeks Given daily not prn. Either the symptoms exist or not. Cimetidine 400 mg twice daily Famotidine 20 mg twice daily Nizatidine 150 mg twice daily Ranitidine 150 mg twice daily Nizatidine found in the Jordanian market under the brand name Axid, its price is more than double the price of Ranitidine with no advantage in terms of efficacy. So its use is very limited OR C. PPI for 4-8 weeks. All are given once daily PHASE IIb A. Life style modifications PLUS B. PPI for 4 -16 weeks OR C. High-dose H2 blockers for 8 -12 weeks General information: The most effective treatment by far is PPI. It would be a disaster if we convert from PPI to H2 blocker and vice versa especially in patients with severe GERD, because the treatment will be interrupted and this would lead to therapy failure in patients. Clinically, it is not recommended at all to discontinue PPI treatment and go for H2 blockers taking into consideration that the course of treatment of PPI is variable depending on the severity of GERD. Mild up to 4 weeks - Moderate 8 weeks –Severe 16 weeks If the patient stopped PPI before the course of treatment, there will be no complete healing in the lower esophagus and this will create refractory GERD in the patient. In Medicinal Chemistry: Famotidine is three times the potency of Ranitidine. Clinically it is NOT. Because here in Clinical Pharmacy we look at the efficacy which is real life data, the information obtained from clinical practice which is evidence based. So in terms of efficacy they are similar. The body needs 54 hours to synthesize a new proton pump after irreversible inhibition. In case of using PPI, the time decreases to 24 hours and this time differs from PPI agent to another. Fastest with Omeprazole and slowest with Pantoprazole. The reason is the way of binding to the proton pumps at the parietal cells. Done by: Hamza Kiswani