Final exam notes PDF - Dr. kiel PDF

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1 of 9 Final exam notes 4/1/19

Drugs to treat Irritable Bowel Syndrome • alosetron (Lotronex) • eluxadoline (Viberzi) • lubiprostone (Amitiza) • linaclotide (Linzess) Irritable bowel syndrome IBS, is a condition that is predominantly found in women. Different types of IBS constipation form and diarrhea form. GI tract spasms, painfulness and bloating these symptoms are common between both and may alternate between two types. Diagnoses is based on the symptoms. Treatment for IBS, Anti muscarinic like dicyclomine reduce GI tract spasms and relax GI tract can be useful. Hyoscyamine available as oral or sublingual tablet can be rapid delivery of the drug to the blood steam and be helpful for GI spams. Constipation or diarrhea OTC products like laxatives or fiber. Drugs for diarrhea like imodium or limotal reduces diarrhea activate MU opioid receptors in GI tract act peripherally. Some anti depressant can be useful nothing to do with effects on mood, IBS D diarrhea form of IBS may use TCAS block muscarinic receptors as off target effect and reduce spasms and slow GI tract down. Low doses of TCAS like amytriptaline or imipramine can be used, also if patient doesn’t have depression won’t effect mood it will only reduce the diarrhea. We will see effect very quickly because it is an adverse effects. IBS constipation form use low doses of SSRIs used one adverse effect of these is N/V and diarrhea is commonly seen as well. Serotonin in the GI tract there are 5HT 3 on neurons and are activated by serotonin and leads to increase movements of the GI tract. Also serotonin the GI tract will cause increase secretions into the GI tract increase

2 of 9 in fluids and increase the N/V and diarrhea. Using SSRIs block re uptake of serotonin into neurons, more activation go 5HT3 receptors on neurons and increase secretions in GI tract and will help treat constipation. Latronex and Viberzi used for IBS D are 5HT 3 receptor antagonist block them reduce secretions in GI tract and diarrhea. Latronex may cause ischemic colitis the blood flow to the colon is reduced or stopped. Use chronically for IBS off target adverse effect of this drug or just from chronic use it requires monitoring of patients. This drug is only for woman use for IBS from testing from trials. Viberzi is a MU and kappa opioid receptor agonist and delta opioid antagonist, Activating Mu and kappa receptors in the GI tract leads to slowing of Gi tract movements leads to constipation. Not indicated for generalized diarrhea just for IBS D Antagonists at the delta opioid receptors not known for this effects. Doesn't cross BBB wont see central effects of opioid receptor activation. Amitizia and Linzess are used for IBS C, in the lumen of the GI tract there is UROG or uroguaniline and peptide and is secreted by goblet cells. UROG activates a guanylate cyclase on cells on their surface. Guanylate cyclase it converts GTP into cyclic GMP and activates protein kinase G and then this phosphorylates and CL transporter and leads to increase activity of CL transporter and causes efflux of CL from the cell and into the lumen and water follows. Increases secretions from Gi tract cells into the lumen of the GI tract. Take advantage of this to treat IBS C useful for constipation more fluid in lumen causes GI tract to move. Linzess works by activating the guanylate cyclase mimics UROG. A drug that is a peptide and is given orally and take on an empty stomach. This increase CL secretions and fluid secretion, Amitezia directly activates the CL channel doesn't go through guanylate cyclase by effect is the same increase release fo CL into

3 of 9 the lumen and water follows increase fluid secretion. Do not see a lot of adverse effects not increased systemically. 4/3/18 FDA panel approves Tegaserod to treat IBS constipation in woman with low CV risk. Treatment of IBS C or D, role of serotonin increase sections in GI tract and movements lead to diarrhea and lead to N/V. Tegaserod comes back on market is an agonist at the 5HT4 receptor and it is found in the GI tract and activation of this receptor increase secretions into the GI tract and increase GI motility. Serotonin can lead to N/V and diarrhea and part of that is activation of 5HT4 receptors and 5HT3 plays an important role and have Lotronex an antagonist at 5HT3 used for diarrhea IBS blocks serotonin and causes less secretions and motility in GI tract. Tegaserod used for constipation IBS, want to increase fluid into the GI tract, also the drug Zelnorm 5HT4 agonist can also do that as well. Tegaserod was takin off the market 10 or 12 years ago because it increased risk of strokes and MI, 5HT4 agonist on platelets there are 5HT2 receptors and serotonin can stimulate platelets and stimulate platelets to aggregate increase the risk of MI and stroke. Now the risk is still there but minimal and back on the market now.

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Anti-ulcer drugs • PGE2 receptor agonist – misoprostol (Cytotec) • sucralfate • H2 receptor antagonists – cimetidine (Tagamet) – ranitidine (Zantac) – nizatidine (Axid) – famotidine (Pepcid)

• Proton pump inhibitors – omeprazole (Prilosec/Zegerid) – esomeprazole (Nexium) – lansoprazole (Prevacid) – dexlansoprazole (Kapidex) – rabeprazole (Aciphex) – pantoprazole (Protonix)

When we ingest food the stomach stimulates the release of acid in the stomach to break down food, there are cells called G cells and they are stimulated by food or distention of the stomach and stimulates G cells they secret a peptide called gastrin. Gastrin a peptide is also known as CCK cholecystokin, Following ingestion of food there is a release of gastrin into the blood stream from the G cells and gastrin travels through blood stream and stimulates release of gastrin or CCK receptors onto ECL cells and then these cells secrete histamine. Histamine will also activate H2 receptors on the parietal cells and activate NA K atpase or proton pump and release acid hydrogen ion into the stomach to break down food. Ingestion of food causes acid build up in the stomach to break it down.

5 of 9 Gastrin not only stimulates the receptor on the ECL cells and can also directly stimulate the same receptor on the parietal cells also stimulating acid release.

Also the vegas nerve the parasympathetic system it enervates both eh ECL cells and the parietal cells releasing ACH onto the M3 muscarinic receptors found on both of these cells and activation of the M3 receptors on ECL cells also stimulates histamine release and activation of M3 receptors on partial cells also drives the proton pump.

We know the parasympathetic nervous system is involved in digestion and muscarinic receptors are involved with secretions from glands and mediate acid secretion in the stomach. Muscarinic agonist increase acid secretions and antagonist block acid secretion.

Other cells called chief cells release bicarbonate and mucus and line the stomach and the mucus is what forms the protective layer along the stomach lining and when acid is released it will digest food and wont damage the stomach lining. Mucus and bicarbonate production is under control PGE2, so PGE2 receptor when stimulated by PGE2 increase secretion of bicarbonate and mucus. Any time we have unbalance between the acid and mucus that can lead to an ulcer a gastric or duodenal ulcer. If we increase acid or decrease mucus the area where the mucus is decrease there is not protection and now the acid can eat away at the stomach lining and results in an ulcer. This leads to pain or can cause bleeding reduction in mucus or increase in acid can lead to an ulcer.

Class of drugs that leads to ulcers are COX inhibiters aspirin or NSAIDS there MOA causes a decrease in PGE2 and lead to reduction of mucus in the stomach with chronic usage leads to ulcers.

6 of 9 Food or stress can increase stomach acid also H. Pylori bacteria is involved in ulcers. Use antibiotics like tetracycline or amoxicillin to eradicate H. pylori.

Bacteria can cause ulcers, H. pylori can damage D cells, D cells are also found along the stomach lining and are stimulated by acid and results in D cells release of somatostatin on the G cells and the somatostatin reduces the release of gastrin. The body make sure too much acid wont be released in the stomach and less gastrin means less acid release.

H. pylori damage D cells without these due to bacteria you cant put break on acid release and can lead to excess acid. Antibiotics can kill off H. pylori and protect D cells.

Misoprostol a PGE2 receptor agonist, activates receptor in the stomach and will increase bicarbonate and mucus release in the stomach will protect lining o the stomach with mucus and bicarbonate will neutralize the acid. But it can cause severe diarrhea and PGE2 on uterine tissue and stimulation leads to contractions and it is contraindicated in woman who are pregnant will cause evacuation. Not use often but is available.

Sucralfate more commonly used and it is administered orally and doesn't get absorbed from the GI tract and it activated by acid in the stomach and turns into a thick polymer cross linking and this polymer will adhere to proteins in the lining of the stomach and protects the stomach or ulceration. Ulcer can heal and shrink and after a few weeks it will protect the ulceration from acid allowing for healing. Have to take this drug up to 4 times a day on a empty stomach 1 hr before or 2 hrs after a meal, don't want to take it around the time there are other drugs it can get bound by sucralfate polymer and wont be absorbed. Do

7 of 9 not want to take sucralfate with antacids it needs acid to form the polymer. Only taken for a few months not used chronically waits for stomach to heal then stop taking it.

Next two classes can be helpful in treating ulcers and GERD gastro esophageal reflex disease. Lower esophageal muscle weakens over time and acid can reflux into the esophagus and cause damage over time and increase risk of esophageal cancer.

H2 antagonist and PPIs treat ulcers and GERD by reducing stomach acid

H2 antagonists by blocking H2 receptor, reduces stomach acid by around 70%. Blocking H2 receptor, the gastrin stimulates please of histamine from ECL cells and muscarinic receptor stimulates release of histamine and the histamine activates the H 2 receptor and drives proton pump. Get reduction of stomach acid by 70%, adverse effects when we block H2 receptor reducing stomach acid and body tries to compensate, if taking on a chronic bases can develop hyper gastrinemia body is trying to overcome inhibition of acid release and makes more gastrin from G cells and more histamine release and more stimulation of gastrin receptor on parietal cells. If used chronically can get tolerance a reduced effectiveness of the medication with continued use. Need dose escalation to get therapeutic effect. Hypergastrinemia if pt suddenly stops taking H2 receptor antagonist has a lot of gastrin in circulation and lots of histamine receptor no longer blocked then get a lot fo acid being release a rebound acidity now have worse symptoms compared to before. If pt stops taking the drug taper them down. These are no OTC need to counsel pts. Cimetidine was the first to come onto the market and it can block the androgen receptors some what can get gynoclomastia and it also is a good CYP450 inhibiter and

8 of 9 can cause drug interactions and cause elevation of other drugs. Don't see this with other H2 antagonists.

Can use muscarinic receptor antagonists to reduce stomach acid but can lead to a lot of adverse effects.

PPIs, directly inhibit NAK atpase reduce stomach acid by 90% are more effective, They are taken orally absorbed from intestines into the blood stream and then the drug is secreted into the parietal cells and drug is activated by acid and now it binds to the Proton pump and inhibits it and it is irreversible. If it were exposed to acid in the stomach it will be activated there and wont reach intestine where it needs to be absorbed. These drugs are all administered with an enteric coating or acid stable coating or administered along with bicarbonate a basic substance to neutralize stomach acid. Can have oral solution and compounded in sodium bicarbonate. Needs to be protected form stomach acid so it's not activated reach GI tract intestine and absorbed and into the blood stream reached parietal cell the n activated by acid and inhibit proton pump.

Zegerid is a formulation of omeperazole with sodium bicarbonate, all are protected form stomach acid.

See some tolerance with these, however they act irreversibly when stop using drug still have that target bound by the drug. Takes few weeks for new proton pump to be synthesized do not see rebound acidity.

9 of 9 Well tolerated, see HA, constipation, diarrhea and GI effects. Pts who take these drugs chronically have higher risk of osteoporosis and bone fractures, CA absorption can depend on a cidic environment and reducing acidity and prevent optimal CA absorption.

Chronic use of these can have increase risk of CAP acid in the stomach protects us form bacteria and acid reduction can be too much.

H2 antagonist and PPIs commonly used for ulcers and GERD

Metoclopramide can block D2 receptors and 5HT3 receptors can be used for GERD by blocking D2 get tightening of lower esophageal sphincter less acid will reflux into esophagus. Given along with drugs that reduce acid. GERD is chronic condition, D2 antagonist can cause movement disorder tardive diskinisia....