GI Pharmacology Lecture Notes PDF

GI UNIT PHARMACOLOGY Instructor Wanqing Liu, PhD. Professor, Department of Pharmacology, School of Medicine, Wayne State University. Tel: 313-577-3375; Email: [email protected]. Lecture Learning Objectives By taking this class, you will be able to: Describe pathophysiology of common GI disorder...

GI UNIT PHARMACOLOGY Instructor Wanqing Liu, PhD. Professor, Department of Pharmacology, School of Medicine, Wayne State University. Tel: 313-577-3375; Email: [email protected]. Lecture Learning Objectives By taking this class, you will be able to: Describe pathophysiology of common GI disorders Describe pharmacotherapy treatment for GI disorders Understand the mechanism of action of common medications for GI disorders Describe side effects of GI medications Describe contraindications and other major issues related to the GI medications This lecture does not include learning objectives that are related to the following area. It is expected that other sections of pharmacology will be more specifically focused on these topics: Nausea and Emesis (neurological issues) Oncology Virology Immunology Lecture Content Outline 1. Learning Objectives -------------------------------------------------------------------------------- S. 2 2. GI Function-------------------------------------------------------------------------------------------- S. 3 3. Common GI Disorders and Pharmacology----------------------------------------------------- S. 4 3.1 Gastritis------------------------------------------------------------------------------------------- S. 5 3.2 Gastroesophageal Reflux Disease (GERD)------------------------------------------------ S. 6 3.3 Peptic Ulcer Disease (PUD) and Duodenal Ulcer---------------------------------------- S. 7 3.4 Helicobacter Pylori----------------------------------------------------------------------------- S. 8 3.5 Treatment for Gastritis, Heartburn, GERD & PUD-------------------------------------- S. 9 3.5.1. Antacids----------------------------------------------------------------------------------- S. 10 3.5.2. H2RA--------------------------------------------------------------------------------------- S. 11 3.5.3. Anticholinergics------------------------------------------------------------------------- S. 13 3.5.4. PPIs----------------------------------------------------------------------------------------- S. 14 3.5.4.1. Drug-drug interaction---------------------------------------------------------- S. 16 3.5.5. Prostaglandins---------------------------- ---------------------------------------------- S. 17 3.5.6. Mucosal Protective Agents/Cytoprotective Drugs------------------------------ S. 18 3.5.7. Treatment of H. Pylori------------------------------------------------------------------ S. 20 3.6 Chronic Bowel Disease (CBD)------------------------------------------------------------------ S. 23 3.6.1. Treatment of CBD------------------------------------------------------------------------ S. 24 3.7 Constipation--------------------------------------------------------------------------------------- S. 25 3.7.1. Treatment of constipation------------------------------------------------------------- S. 26 3.7.1.1. Bulking agents--------------------------------------------------------------------- S. 27 3.7.1.2. Stool softners and Stimulant Purgatives------------------------------------ S. 28 1  3.8 Diarrhea--------------------------------------------------------------------------------------------- S. 29 3.8.1. Treatment of diarrhea------------------------------------------------------------------- S. 30 3.9 Clostridium Difficile------------------------------------------------------------------------------- S. 31 4. Additional Readings------------------------------------------------------------------------------------- S. 41 Lecture Notes 2. GI Function The major function of the gastrointestinal tract includes motility, secretion as well as digestion & absorption. The motility is via smooth muscle subunits connected with the gap junction. These subunits are stimulated in either a tonic or a phasic manner. Motility physically facilitates the movement and blending and grinding of food in the GI tract. Under certain conditions (pathological, pharmacological, or toxicological) the GI motility can be overactive (hypermotility), possibly leading to diarrhea or vomiting, or underactive (hypomotility), possibly leading to constipation or vomiting, both of which may lead to abdominal pain. Secretion is the second most important function of the GI tract. Up to 9 liters of fluid are secreted by the GI tract each day, including 2-3L of acids. This fluid is mainly composed of 4 components: ions, digestive enzymes, mucus, and bile. Secretion of these fluids mainly involves salivary glands, pancreas, liver, and GI epithelial cells. The secreted ions primarily contain H+, K+, Cl−, HCO3−and Na+. H+ and Cl− are secreted by the gastric parietal cells into the lumen of the stomach to create the acidic environment, while HCO3− is secreted by the pancrea c acinar cells to neutralize the acid secretions in the intestine. Digestive enzymes are secreted by the epithelial cells of both the stomach and intestine. Mucus is released into the stomach and intestine. The main function of mucus is to lubricate and protect the inner mucosa of the tract. It contains mucins which are glycoproteins. Bile is secreted by the liver and stored in the gall bladder and excreted into the duodenum of the small intestine. Bile contains bile salts, bilirubin, and cholesterol. Food is digested during the movement in the GI tract where large molecules are broken into smaller molecules and further absorbed in the small intestine. The majority of nutrients absorption occurs in the lumen of the canal in the chyme and at the epithelial junction of the cells of the small intestine. The absorption at the small intestine is facilitated by the large surface area of the villi. The majority of small-molecule nutrients are perfused into the membrane of the enterocyte of the intestinal epithelium, while some may be actively taken into the cells via special transporters, i.e. P-glycoproteins. In pharmacology, an orally administered drug will also pass through the GI tract, where the low pH environment in the stomach while higher pH in intestine would affect the absorption of drugs as well, e.g. a weak acid drug has a higher absorption rate in the low pH environment, while a weak base drug 2 is more likkely absorbed d in the intesttine. Howeve er, regardless of the pH, givven the largee surface of th he villi, a considerable amountt of drugs wo ould be still ab bsorbed in th e intestine. OOther factors e.g. drug soluubility, permeability, lipophiliccity, involvem ment of transp porters, etc. ccan also affecct the drug ab bsorption. Therefore e, the impact of gastric pH on overall drrug absorptioon should be cconcluded baased on well- designed pharmacokin netic studies, e.g. PK studie es demonstraated that, alth hough quinidiine is a weak base (pKa=8.5), its absorptioon is still significantly decrreased when ggastric pH is iincreased duee to PPI administration. Likewisse, although warfarin w is a weak w acid (pKKa=5), its absorption can bbe increased w when co-administered with PPI. P This is be ecause increased pH decreeases and incrreases the solubility of quinidine and warfarin n, respectivelyy. However, bothb drugs ar e still mainly absorbed viaa the intestinee. Only the soluble s form can rapidly re each the intesstine and are absorbed. Non-soluble drrugs either would stay in thee stomach for a longer tim me or are even ntually excretted in feces. 3. Comm mon GI disorde ers In this lecture, we will introduce common GI diso orders, their pathophysiollogy and theirr common pharmaco ological treatm ment optionss. For these medications, m w we will brieflyy go over their mechanism m of action, sid de effects, dru ug-drug interraction and co ontraindicatioons. Common GI disorders include gastritis, Gastroessophageal Refflux Disease (GERD), Peptic Ulcer Disease (PUD) and d Duodenal Ulcer, U well as diarrheea and constipation. Chronic Bowel Diseasse (IBD), as w 3.1. Gastritis Gastritis refers r to a con ndition characterized by in nflammation,, irritation, or erosion off the lining off the stomach h. Gastritis is usually chhronic. The histology of gasstritis involve es damages off the epithe elium and gland system off the stomach h, with infiltration of eosinoph hils and neutrrophils, reducced cytoplasm mic mucin, reaactive epithellial changes e.g. e nuclear and nucle eolar enlargem ment. It may also have sub bnuclear vacuolatio on in antral glands or pits. The causes of o gastritis include innfections, which among the e majority of cases is relatted to H. pyloori; injury due to either phyysical and chem mical reasons; drugs that haave particularr side effects e.g. that of aaspirin and otther nonstero oidal anti-inflammmatory druggs, as well as certain disorrders of the im mmune system, e.g. autoim mmune diseaases. Gastritis usually u does not n cause app parent sympto oms, but it caan lead to ulccers, which may cause the symptoms to get worse. 3  3.2 Gastroesophageal Reflux Disease (GERD) GERD is the most common gastric-esophageal disorder with an incidence of 20-40% of common populations. It is a chronic, relapsing condition characterized by the backflow of stomach acid into the esophagus. While the esophagus is not equipped to handle stomach acid, the acid would cause scaring for the esophagus mucosa. Gastric acid can be also refluxed into the throat, which can cause sore throat, dry cough, or asthma-like symptoms. The common symptom of GERD is heartburn, which is an uncomfortable burning sensation behind the breastbone. (Warning: heartburn could be also a symptom of myocardial infarction that could be mistaken for GERD!). More severe symptoms may also be observed as difficulty swallowing or chest pain. Chronic GERD gradually damages the esophagus mucosa and can further lead to complications include esophageal erosions, esophageal ulcer, and narrowing of the esophagus (esophageal stricture (narrowing). Endoscope of Barrett’s Esophagus Among ~10% of patients, the (can become malignant - needs monitoring) normal esophageal lining or epithelium may be replaced with abnormal (Barrett's) epithelium. This condition (Barrett's esophagus) has been linked to cancer of the esophagus. 3.3. Peptic Ulcer Disease (PUD) and Duodenal Ulcer PUD is usually characterized by open sores developed on the inside lining of the stomach or the upper portion of the small intestine i.e. the duodenal part. PUD includes gastric ulcers (GU) and duodenal ulcers (DU). Patients with GU can have painless bleeding or stomach pain. Stomach bleeding may lead to a dark and tar-like stool. It is usually associated with stress, NSAIDs, or H. pylori, especially in a chronic course. GU usually takes longer to heal than DU. When associated with stress, GU can occur at any age. While when associated with H. pylori and NSAIDs, it generally occurs in mid to old ages. Among some cases with benign PUD, there is still normal gastric acid production but the mucosal barrier is weak. Among malignant PUD, excessive secretion of gastric acid usually overwhelms the mucosal barrier. The most common symptom of duodenal ulcers (DU) is chronic abdominal pain. DU can occur at any age, equally in men and women. The common risk factors for DU are cigarette smoking, NSAIDs, and H. pylori. 4  3.4 H.. pylori (HP) HP is unde erlying many of the comm mon disorderss mentioned aabove. HP is the most common chro onic infection n in the world d, with 60-90%% of the entire hum man population were estim mated to be infected. i Aboout 90-100% gastritis and 70-80% GI ulcers are re elated to HP infection. i Epi demiological studies reevealed that HP H infection iss highly corre elated with chhronic gastritis and is associatted with duoddenal ulcer disease, gastri c ulcer disease, and a gastric cancer. The cause e-effect relationship underlying these assocciations was discoovered by two o prominen nt scientists, Barry B Marshall and a Robin Waarren, based on which the tw wo scientists shared the Nobel N Prize in Ph hysiology or Medicine 2005. HP is a graam-negative, gastric bacteerium with a bundle b of flaggellas. HP pro oduces ureasee which enables the organnism to survive in the acidic stomach byy creating an aalkaline micro oenvironmen nt. The diagnoosis ection can be biopsy-based of HP infe d positive cultture (endoscoopy), serologiic tests for the HP antigen, or urea breath tests. Therre is also a sto ool test for HP antigen. Thhe non-invasivve tests are h highly recommended in primary care. The e current standard test rec ommended is urea breath h test, fecal antigen teest, or biopsy-based test at least 4 weeks after antibbiotic therapyy has completted and after PPI therapy has not been given g for 1-2wwks. 3.5 Trreatment for Gastritis, Heaartburn, GERD & PUD The treatm ment principlles for gastritis, heartburn, GERD, and PPUD are focussed on reducing risk factors, neutralizing secreted acid, a decreasing the secrettion of gastricc acid, protecting the muco osa, and controlling the H. Pylorri infection, which w as menttioned abovee is underlyingg 60-70% cases of gastritiss and ulcers. Liffestyle change es are usuallyy recommend ded to adjust tthe diet, conttrol weight, aand reduce smoking anda alcohol in ntake. Besides these lifestyyle modulatioons, medications with diffeerent mechan nisms of action are commonlly prescribed.. Many of the ese drugs are OTC eligible, with commo on use in a larrge number of o patients, atttention should be paid to side effects aand contraind dications. Accordingg to different mechanisms of action, me edications useed to control the upper GI tract disordeers include: antacids which h neutralize the t secreted acid, a drugs foor inhibiting acid secretion by targeting different pathways invvolved in H+ secretion by the gastric parietal cells, e.g. H2 Recepttor antagonissts/blocker (H H2RA) for inhibiting histam mine- based parrietal cell activation, antichholinergic druugs to inhibit vagal nerve signals s mediated by choline, and protoon pump inhib bitors inhibiting the H+/K+ + exchange transporter, as well as dru ugs for protecting the mucosa of GI tract. Given the broad involvem ment of HP amo ong many of these t disordeers, specific or HP is necessary for HP positive patien control fo nts. 5 Below we will go over drugs of each of the categories mentioned above: 3.5.1 Antacids The purpose of antacids is to neutralize the secreted acid. Depending on the mechanism of action, there are systemic antacid and non-systemic antacid drugs. Systemic antacids are absorbed into the circulation system, e.g. sodium bicarbonate (NaHCO3) can be readily absorbed into the general circulation and may alter systemic pH. However, long-term use of systemic antacids may potentially lead to Na+ overload and systemic alkalosis, it is therefore usually limited to use as short- term relief. Excessive sodium bicarbonate administration may also cause hypokalemia as it would push potassium from the extracellular space back into the cells, esp. muscle cells. Therefore, in the clinic, NaHCO3 can be also used to treat hyperkalemia. Non-systemic antacids including aluminum hydroxide, magnesium hydroxide and calcium carbonate which only have very limited absorption in the stomach. They can effectively suppress GERD, and are generally quite safe. But aluminum and calcium could lead to constipation while magnesium may cause diarrhea. They are also contraindicated in patients with impaired renal function as the overload of ions may cause electrolyte imbalance, e.g. hypercalcemia or hypermagnesemia, which could further lead to hypotension, nausea, vomiting, ECG changes, respiratory or mental depression, and coma. 3.5.2 Histamine H2 Receptor Antagonists/Blockers (H2RA) While antacids primarily neutralize the secreted acids, many other drugs are designed to inhibit the acid secretion in the stomach. Acid secretion can be mainly modulated by three stimulating signaling pathways and one inhibitory pathway. The three stimulating pathways include 1) the vagal/enteric neurons-based signaling mediated by acetylcholine, a neurotransmitter; 2) the stimulation by enterochromaffin-like cells (ECLs) mediated by secreting histamine, a paracrine; and 3) gastrin as a hormone secreted by the G cells (endocrine cells in gastric epithelium) stimulates histamine release from ECL cells, thus activating the parietal cells indirectly or directly stimulates parietal cells proliferation. It is worth mentioning here about Zollinger-Ellison syndrome, which is a rare tumor formed in the pancreas or duodenum called gastrinomas. The tumors can secrete large amounts of the hormone gastrin, thus leading to excessive production of gastric acid, which can further lead to PUD and other symptoms. The inhibitory pathway is somatostatin, a hormone or paracrine that is secreted by delta (D) cells and some of the G cells. Somatostatin has inhibitory effects on multiple cells including G, ECL, and parietal cells. This pathway is usually activated when stomach pH is too low, thus plays a role to balance the H+ secretion. This balance can be changed by stress, food, or drugs, leading to gastric issues. 6 The histam mine release has multiple physiologicall functions inccluding stimu ulating the co ontraction of smooth muscle m in the GI G tract, incre easing permeability of cappillaries, increasing sensoryy nerve endin ngs, and strongly stimulatin ng gastric acid d secretion. Vagal V stimulattion causes th he release of histamine froom cells in the stomach, accts on receptors in parietaal cells. Thereefore, drugs caan be used too target the receptorss to block the histamine efffects. Traditio onal antihistaamines or H1 receptor antagonists geneerally reduce the effects of histamine h in the body but do not block histamine efffects on gastrric acid produ uction. The H2 re eceptor inhibitors can competitively inh hibit histamin e H2 receptoors to suppresss the function of parietal ceells such thatt blocking histtamine-, gastrin- and ACh--stimulated gastric acid secretion. Thesse drugs can suppress gasstric secretion n in 24 hrs byy 70%. H2RA usually has low side s effects. One O exception n is cimetidinne, which has neurological effects that m may cause connfusion. Cimetidine shouldd not be used for patients w who has stom mach cancer. Also, cimetid dine is an inhibitor for transpo orters expresssed in the kid dney that are important foor drug secrettion and excretion. It should NOT be used for patients whow has chro onic kidney di sease and red duced kidneyy function. Co o- administration of cime etidine and otther drugs thaat are substraates of these transporters,, e.g. metformmin, can potenntially increasse the blood concentration c n of these druugs, leading to o adverse reaactions. Cimettidine has an antiandrogenic potential and d inhibits estrrogen metaboolism, potenttially causing gynecomastia (swelling breasts e.g. in n men) when overdose. It also inhibits hepatic cytocchrome p450 enzymes (e.gg. 1A2, 2C9, 2D6, 3A4), potentially leaads to metabo olism issue off many other drugs. Over 1 100 drugs inteeract with cimeetidine. Comm mon exampless include: warfarin, tricycl ic antidepres sants, lidocaiine, calcium channel blockers, b quinidine, oral sulfonylureas, phenytoin, p thheophylline, b benzodiazepin nes, and betaa- blockers (metoprolol ( and a propranolol). The drugg may cause im mpairment o of vitamin B122 absorption ((low red bloodd cells, weakness, numbness, fatigue, ettc) as well. (P MID: 313349975) 3.5.3 holinergic drugs Antich As mentio oned above, acetylcholine a is important in the activattion of pariettal cells via binding b to the acetylcholinee receptor. Drugs can bindd to these receptorss thus block th he effect of acetylcholine ono acid secre tion. Examplees of these drugs d include Pirenzepine oro Gastrozepin which are muscarinic M M1 acetylcholine receptorr antagonists. These drugs can be as efffective as H2 blockers. However, the ey are rarely used, u primariily as an adjunnct therapy, partly due e to its antich holinergic side e effects, e.g. anorexia, bluurry vision, constipatiion, dry moutth, sedation, etc. 3.5.4 Proton n pump inhibiitors (PPIs) ough the protton pump on the cell mem H+ secretion by parietaal cells is thro mbrane. The p pump is a hydrogen/potassium ATPase, A exchaanging potasssium from thee stomach lum men with cyto oplasmic 7 hydroniumm, by using ATP A as energy. PPIs can bind irreversiblyy to the gastriic proton pum mps to preven nt the release off gastric acid from f parietal cells. Since the pump is located on the paarietal cells, PPIs P can irreveersibly bind to o the transpo orter and stro ongly suppress acid secretion n in responsee to all primarry stimuli incl uding histam mine, gastrin, aand acetylcho oline. It is thus generally g morre effective th han H2RA and d can make a rapid relief ffor the sympttoms as well aas faster heaaling for ulcerrs and other injuries due too acidic erosi on. PPIs can d decrease acidd secretion byy up to 95% for up to 48 hours. PPIs are used in the prevention p of esophagitis, treatment off H. pylori- associated d ulcers, and are listed as the first choicce in erosive esophagitis, eerosive gastriitis, and Zollin nger- Ellison synndrome. Thesse drugs are usually u prescrribed for 4-8 wweeks coursee of treatmen nt. PPIs are generally g safe with mild sid de effects. Ho owever, it shoould be notedd that the usee of PPIs woulld significanttly increase stomach pH, which w may afffect the abso rption and so olubility of maany drugs thaat are weak base es/acids. Therefore, they are a usually ussed with a 2h r interval fromm/to giving oother prescrib bed drugs. 3.5.4.1 Drrug-drug interractions of PP PIs. PPIs couldd also affect the t metabolissm of other drugs by induccing/inhibitingg CYP450 enzzymes. One tyypical example is omeprazole e (OME) whicch can affect multiple m druggs with narrow w therapeuticc windows, e..g. diazepam, phenytoin, and warfarin. OME is prim marily metaboolized in the liiver by CYP2C C19 whose geene harbors genetic polymorphisms thaat reduce the CYP2C C19 function. These low-fu unction alleles wo ould lead to inncreased OME exposure due to the in ncreased bloo od concentraation. OME caan also inhibitt CYP2C19, thus affectin ng the metabo olism of other drugs or activation of certain prodrugs. For examp ple, clopidogrrel (Plavix) is an antiplatelet prodrug th hat requires activation a by CYP2C19 in the liver. OME inhibition for CYP2 2C19 functionn thus may leaad to insufficiient antiplateelet effect, esp pecially amon ng patients caarrying loss-of-function all eles. Geneticc tests for these alleles aree available before prescrribing the dru uency of the ppoor metabolizers varies aamong differeent ugs. The frequ ethnic grooups, with a 2-5% 2 among Caucasian C and d African poppulations, butt 10-15% amo ong Asians. 3.5.5 Prostaaglandins Mucosal cells c of the stomach and duodenum ECL cells can se cret prostaglaandins e.g. PGE1, that can enh hance the mu ucosal resistance to tissue injury by inhibiting basal and stimulated gastric g acid se ecretion of thee parietal cellls. It can also increase secretion s of mucous m and bicarbonate, b a increase mucosal bloo and od flow and enhance e muccosal repair. Synthetic S PGEE1 analog e.g.. Misoprostol can mimic thiss function and be used to treat gastric acid-related a ddisorders, especiallyy for treating NSAID-induce ed injuries. 8 These druugs are generaally safe but could c have mild m side effeccts e.g. diarrheea, pain, and cramps (~30% of patients). It is also contraindicated in women of childbearing age and during pregnancyy, which may cause birtth defects and d premature birth. 3.5.6 Mucossal Protective e Agents/Cyto oprotective D rugs These druugs are designned as polyme ers to “coat” the lining of tthe stomach to enhance eendogenous mucosal protection p and provide a physical p barrie er over the suurface of the ulcer. Examp ples include Sucralfate e/Carafate/An ndapsin®, which can be ussed to treat o r prevent PUD. The drugs are designed d to form a sticky polymer in an acidic environment and a adhere too the ulcer sitte, thus forming a barrier. It nhibit the seccretion of pep can also in psin and may increase prosstaglandin prroduction. They usually req quire a low pH to t be activate ed. o these drugss may reduce the effective The use of eness of otherr drugs by afffecting absorpption, and whhen using, sho ould avoid co--administratio on of antacid, H2RA, or PPPIs, and shoulld be used twwice daily, and d taken on an a empty stoomach before meals. They should be givven 2 hrs befo ore or after o other drugs. Mucosal protective p ents also include salicylic acid age a derives, ee.g. Bismuth subsalicylate or Bismutth Chelates, byb introducing a Bismuth i nto the salicylic accid. These dru ugs protect th he ulcer crateer and allow hhealing by reducing inflammation i n and inhibitin ng bacterial growth g e.g. H.. pylori. These ageents should not be used re epeatedly or for f more thann 2 months att a time as they could causse salicylism (salicylate ( poisoningg) characterizeed by ringing in the ears, nausea, n and vomiting. It can also caause black tonngue/stools due d to the reaction between b the trace t amountt of sulfur andd bismuth (Bii+S) to form black colored bismuth b sulfid de. 3.5.7 Treatm ment of HP Due to the broad involvement of HP P infection in many GI disorders,, treatment of o HP is one off the primaryy goals in conttrolling the diisorders of th he upper GI trract. Triple therapy is the prrimary combination therap py for HP, whhich usually reequires a commbination of ttwo antimicrobials and one e PPI or one H2RA. H The commmonly usedd antibiotics in n triple therapy include Amoxicillin (Amimox®)) which can diisrupt cell waalls; Clarithrom mycin (BIAXIN N/Klacid®) or Tetracycline that inhibit bacterial protein synthesis; or o Metronidazole (Flagyl®)) that disruptss bacterial DN NA synthesis. Metronidazole is usuallly used when n there is the bacterial res istance to ammoxicillin and tetracycline, or due to inttolerance/alle T choice of PPIs is usually omeprazolee. Adding an H2RA ergy to other antibiotics. The or PPI increases the staability and acctivity of antib biotics and caan accelerate healing. Bismmuth is also ussed which can e antibiotic efffect by disrupting cell wa lls and also in n facilitate the ncrease the HHCO3- and mu ucous secretion. The current (2017) Amerrican College of o Gastroenteerology (ACG) recommend ded first-line prescription of triple th herapy is a 144-day treatme ent using a PPPI + clarithrom mycin + amoxxicillin (metroniddazole if intolerant or allerrgic to Amoxiccillin), which generally hass effectivenesss among Norrth American patients. The e guideline no oted that “should clarithroomycin resistance indeed exceed 15%, clarithrom mycin triple thherapy should d be avoided”” (ACG Guide line, 2017). Due to the increased HP H resistance to triple therrapy, quadrupple therapy iss also increasiingly used by combiningg a PPI or H2R RA, bismuth, metronidazo ole, and tetraccycline for 100-14 days (ACG Guideline, 2017). 9 The side effects of the combined HP therapy are usually small and could vary from drug to drug. For example, metronidazole may cause a metallic taste among some patients, while Clarithromycin & Amoxicillin can lead to nausea, diarrhea, and abdominal cramps. Clarithromycin can interact with many other drugs. One of the commonly used drugs is Lipitor (atorvastatin). Clarithromycin can inhibit the transporter (OATP1B1/SLCO1B1) and enzyme (CYP3A4) that are involved in atorvastatin absorption into the liver and metabolism, respectively, thus can lead to the accumulation of atorvastatin in the blood. This can increase the risk of side effects including liver damage and a rare but serious condition called rhabdomyolysis that involves the breakdown of skeletal muscle tissue. In some cases, rhabdomyolysis can cause kidney damage and even death (drugs.com/interaction). The dose of atorvastatin should be lowered or an alternative lipid-lowering drug should be used. Clarithromycin or other macrolides can also lead to prolonged QT intervals. It should be evaluated for risks and benefits among patients who have known prolongation of the QT interval, history of torsades de pointes, congenital long QT syndrome, or other cardiac conditions. It should be noted that worldwide, there is increased resistance of HP to triple therapy antibiotics. As shown in the figure and table below from a study in the Korean population where gastric cancer incidence is among the highest in the world, the HP control rate by triple therapy keeps dropping in the past decades, and the resistance to various antibiotics keeps increasing. A similar trend was observed among other countries. The bismuth quadruple therapy increasingly becomes a better choice. 10  3.6 Chronic bowel disease Now let’s focus on the common disorders in the lower GI tracct. We will go o over a few disord ders includingg inflammato ory bowel dise ease (IBD), diaarrhea and constipatiion. Among IB BD, there are also Crohn’s disease and ulcerative co olitis. Crohn’s disease and ulcerative colittis are chronicc inflammato ry diseases characterized by diffussed mucosal inflammation which could affect both tthe small and large intestine, witth the ulcerattive colitis lim mited to the c olon. Compared to other com mmon disorde ers, Crohn’s disease d and ulcerative colittis Lee et al., Dig Dis Scci., 2014, 59 (6): 1235–1243 have an in ncidence of approximatelyy 20-250/100,,000 individu als. The causee of IBD is still inco ompletely understood, witth genetic facctors possessiing a high imp pact on etiology. Crohn’s disease primarrily causes ulccerations (bre eaks in the linning) of the sm mall and large intestines, leadinng to patchy transmural infflammation t hat may affecct any part of GI tract. Its sym mptoms includ de chronic diaarrhea with bblood and mucous, weight losss, rectal blee eding, fever, and a night swe eats. Ulcerativve colitis has similar symptom e.g. bloody diarrhea, d coliccky pain, urge ency to defeccate, but moree limited to the colon. 3.6.1 Treatm ment for IBD Despite thhe extensive research duriing the past decades, d ther e is, unfortunaately, no apprroved treatment for IBD. The T current m management ffor IBD is focu used on resollving acute eppisodes and prolong p remisssion. For thiss purpose, a few medicaations are usu ually used for controlling innflammation and bacterial infection. i Inte egrative theraapy should also consider nnutritional support. mmatory age Anti-inflam ents in IBD tre eatment incluude 5-aminosaalicylic acid (5-ASA) foor mild sympttoms, while corticosteroids are used fo r moderate symptoms. Topical anttibiotics include sulfapyridine and ampiicillin, and immunom modulators arre often used to adjust the e inflammatioon as well. For examp ple, thiopurin nes and methotrexate can be used for aactive and chronic syymptoms; Cycclosporine as an immunosuppressant iss also used for active and chronic symptoms that are usuallyy refractory too corticostero oids. A few biologics antib body- based dru ugs to reduce inflammation, e.g. Inflixim mab is used aggainst the tummor necrosis factor-alpha (TNF-α) which w is appro oved to treat autoimmune a diseases alsoo can improvee IBD. The antibody-based d drugs require infusion.. There is also o a compound ded drug by ccombined syn nthesis of 5-A ASA and sulfapyrid dine called sulfasalazine which plays thee dual role off the two druggs. Pharmaco ogenetic issue e is involved for f use of thio opurines. Thioopurine methhyltransfurasee (TPMT) is an enzyme innvolved in thiopurine metaabolism that has a good deeal of geneticc polymorphism. Dependiing on a patie ent’s genetic profile, ustment or avoiding these agents altoge dose adju ether might bbe needed. 1) Extensiive metabolizzers – accumuulate 6-MMP and 6-MMPR R metabolitess which causee hepatotoxxicity and do not produce 6-thioguanine nucleotidess (6-TGNs), th he active t thiopurinees. Do not inccrease dose to metabolittes. These paatients are oftten resistant to get an efffect. Extensivve metabolize ers are prone to develop h epatotoxicityy. 11 2) Poor metabolizers m – produce largge amounts of o 6-TGNs. Higgh intracellullar concentraations of 6-TG GNs are assocciated with myelosuppresssion. Some reeports of successful IBD treatmeent with LOWW doses of AZAA (0.16-0.29 m mg/kg/day) hhave been d. published 3) Currentt recommend dation: Genotype e and phenotyype for TPMTT status prio or to starting AZA or 6-MP to guide dosing d and usse. (Wilhelm SM). Side effeccts for the druugs mentione ed above are e generally mild, e.g. diarrhea; Corticosteroiids have signiificant side efffects includinng W Woillard et al. TTherapies, 20 017 hypertenssion, hyperglyycemia, osteooporosis, glau ucoma etc., w while 5- ASA may lead to salicylate sensitivitty etc., especially in long-t erm use. Advverse effects ccan be minim mized with local administration: via rectal administration (suppositoories, enemass) or the use of budesonid de orally (exttensive first pass p metaboliism with limitted systemic bioavailabilityy offers local GI effects on nly) 3.7 Constipation Constipation is a comm mon chronic bowel b issue characterized by infrequennt stools, hard d stools, and difficulty passing stools. The defecaation process is a neurologgical reflex: wwhen the stom mach and duodenum m are distend ded with food d, gastrocolic and duodenoocolic reflexess are initiated d. The cerebral cortex con ntrols the deffecation refle ex so that defe ecation can ooccur at accep ptable times aand places. Constipation develops when the de ex is inhibitedd or the patieent fails to resspond to the urge efecation refle to defecatte. The manaagement princciple for mild constipation n in the first pplace is focuseed on dietary modification n, which is usually u effectiive for many patients. Onlyy if this fails sshould laxativves be used. It should be n noted that laxative/purgativee abuse has been the majo or cause of coonstipation, w which is now a public healtth problem, especially in elderly peoplle. 3.7.1 ment for consstipation Treatm There aree a few mechaanisms underrlying which the drugs/dietary modificaations are dessigned for tre eating constipatiion. These aggents include bulking agentts to increasee o the stools, osmotic laxattives that can the bulk of n increase thee fluid content of stools,, stool softene ers to lubricate the stool, and stimuulant purgativves to increasse the peristalsis of the bowwel. 3.7.1.1 Bu ulking agents Bulking aggents contain n methylcellullose and extraacts e.g. agarr, bran, which aree insoluble, noon-absorbable, non-digesttible polysacccharide polymers. They can forrm a hydrated d mass in thee gut lumen too promotess peristalsis an nd improvingg fecal consisttency. Bulkingg agents also increase in bowel content volume, triggering stretch receeptors estinal wall to in the inte o causes refle ex contractionn (peristalsis) that propels thhe bowel content forward. 12 The bulking agents may take several days to work and must be taken with lots of water, or otherwise, it would make constipation worse. There is no serious side effect. Although laxatives are sometimes considered the safest kind of laxative, they can still lead to side effects if used too frequently or in high doses. (Cornell Health). 3.7.1.2 Stool Softeners and Stimulant Laxatives Stool or fecal softeners are mainly used to lubricate the stools. Examples include liquid paraffin or mineral oil. They are typically taken with empty stomach, but non-absorbable, making the intestinal walls and stool moist and slippery, thus facilitating defecation. Other softeners also include docusate sodium which is a surfactant or “detergent” to produces softer feces. Glycerin suppository is also used as a lubricant. Osmotic stimulant laxatives can be non-digestible sugars and alcohols, e.g. lactulose which is further broken down by bacteria to acetic and lactic acid, which causes the osmotic effect to stimulate peristalsis. Stimulants also include salts, usually Mg2+, e.g. Milk of Magnesia (Mg(OH)2) (use both as an antacid and laxative), or Epsom Salt (MgSO4). Sodium sulfate (Glauber’s Salt) or sodium phosphates can also stimulate peristalsis. Sodium phosphate and sodium citrate are usually used in enema (rectal wash). Purgative stimulants are drugs that stimulate peristalisis, e.g. Triphenylmethane. Stimulants are usually effective in 1-3 hrs and are often used to purge the intestine e.g. drug overdose or poisoning. When using for treating constipation, they should not be used for more than 3 days. The salts can rapidly increase intestinal electrolytes at the lumen and hence increase water secretion. It has also effects on enteric nerves, thus increasing peristalsis. The side effects are minimal, with abdominal cramping most commonly observed. It should be noted that stimulants may rapidly change the electrolyte balance, thus requires a good renal function must be good. They are contraindicated in patients with heart failure. 3.8 Diarrhea Diarrhea, on the other hand, usually features increased bowel motility, which causes secretion or retention of fluids in the intestinal lumen and bowel contents are rapidly propelled. This way, absorption of fluids and electrolytes is limited. In some cases, diarrhea can cause inflammation or irritation of the GI tract. In developing countries, acute diarrhea is one of the major health issues, which causes of death of malnourished infants. Diarrhea can be a symptom underlying other diseases e.g. anxiety, irritable bowel disease, or food allergy. Infection is a major cause of acute diarrhea, which can be attributed to bacteria, viruses, or parasites. Bacteria secrets toxins, which can block the mucosal cells from absorbing H2O and Na+, increasing the fluid content in the bowel contents; while viruses can cause inflammation of the GI wall, which increases fluid secretion and stimulates peristalsis. Parasites can also cause diarrhea, some are even prolonged diarrhea, e.g. giardia intestinalis is the most commonly identified intestinal parasite in the US, which often affects children. Other causes for diarrhea also include toxins or certain drugs or radiation therapy. 13  3.8.1 Treatment of diarrhea In many cases, diarrhea disappears rapidly without requiring any treatment. Certain conditions indicate a necessary intervention, e.g. persistent diarrhea which continues over 2-3 days, or severe diarrhea in the elderly or small children, diarrhea associated with chronic inflammatory disease, or when specific causes for diarrhea has been determined. The principle of diarrhea treatment is to maintain fluid and electrolyte balance e.g. using NaCl and glucose (Resorb®). When an infection develops, anti- infective agents e.g. antibiotics should be used. Vancomycin for c. Difficile, Azithromycin for Traveller’s diarrhea, and Cipro for E.coli and Shigella are commonly used prescriptions. Absorbents e.g. activated charcoal are often used when poisoning e.g. toxins are suspected. Opioids can activate μ-receptors in the enteric nerve plexus to reduce peristalsis, e.g. loperamide (Imodium®) which is an opioid that does not pass the blood-brain barrier but has 40-50x more potent than morphine. Certain side effects should be noted for opioid antidiarrheal drugs, e.g. risk for constipation, abdominal cramps, drowsiness. It should be also used with caution in inflammatory bowel disease patients. The use of opioids in IBD is associated with heavier use of opioids and increased mortality. The use of opioids in IBD can also lead to toxic megacolon, acute toxic colitis with dilatation of the colon. 3.9. Clostridium difficile (C. difficile) C. difficile is the major cause of diarrhea and colitis in patients exposed to antibiotics (~20%). C. difficile can be transmitted via the fecal-oral route, with three steps to infection: alteration of normal fecal flora, colonic colonization formation of C. difficile, and growth and production of toxins. The C. difficile infection can lead to the formation of colitis and toxic megacolon. The treatment of diarrhea should first discontinue the offending antibiotic to restore the balance of gut microbiota. Antibiotics include metronidazole and vancomycin are often used to suppress the growth of C. difficile. These antibiotics have contraindications in patients with liver or renal impairments. 4.0. References and additional readings 1. Gastrointestinal Pharmacology, Handbook of Experimental Pharmacology. By Beverley Greenwood- Van Meerveld, 2017 (Springer) 2. Pocket Handbook of GI Pharmacotherapeutics: Edition 2; By George Y. Wu, 2016 (Humana Press) 3. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2017;112(2):212-239. doi: 10.1038/ajg.2016.563 4. Ju Yup Lee 1, Nayoung Kim, Min Soo Kim, Yoon Jin Choi, Jung Won Lee, Hyuk Yoon, Cheol Min Shin, Young Soo Park, Dong Ho Lee, Hyun Chae Jung. Factors affecting first-line triple therapy of Helicobacter pylori including CYP2C19 genotype and antibiotic resistance. Dig Dis Sci., 2014;59(6):1235-43. doi: 10.1007/s10620-014-3093-7. 5. CPY2C19 and omeprazole: www.pharmgkb.org 6. Clarithromycin drug-drug and drug-disease interactions: FDA insert for BIAXIN, 2017. 14 7. Woillard JB et al., Pharmacogenetics of immunosuppressants: State of the art and clinical implementation - recommendations from the French National Network of Pharmacogenetics (RNPGx). Therapie. 2017;72(2):285-299. 8. Cornell Health. Laxative abuse: What to know. 15