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GI Drugs Ulcer physiology and pathology Peptic Ulcers: Ulceration of stomach or duodenum commonly caused by H. Pylori Etiology: usually caused by H. Pylori (causes gastritis, peptic ulcers, or rarely MALTomas) o Risk Factors: Acidic pH, excessive pepsin, or NSAID use; treatment focuses on reducing these Pathogenesis: VacA cytotoxin targets the mt induces vacuole formation destroys the epithelium Acid Secretion: 1) stimulation of parietal cells 2) inhibition of parietal cells 3) secretion of HCl from cell Stimulation: increased pH in stomach, sight of food, stretch of stomach due to food o Causes Ach release from ENS and vagus AND gastrin release from G-cells ECL cells: stimulated by Ach and gastrin to release histamine o Parietal cell: Ach (M3), gastrin, and histamine (H2) bind to basolateral parietal cell Increase of IP3 (Ach/gastrin) and cAMP (histamine) increase of H/K transporters Note: Ach also stimulates secretion of bicarbonate and mucus (to protect mucosa) Inhibition: PGE2 and somatostatin inhibit acid secretion by reducing amount of H/K transporters o PGE2 also increases secretion of bicarbonate and mucus AND increases blood flow to mucosa Acid secretion: combined actions of H/K ATPase, K exporter, and Cl exporter (CFTR) H+ secretion Drugs that inhibit acid secretion Antimuscarinics – Pirenzepine and Telenzepine (-enzepine) Use: Limited use due to better drugs; higher affinity for M1 receptors (over M2/M3) limits side effects Side Effects: slow stomach emptying, low mucus secretion, dry mouth, mydriasis, urinary retention H2 blockers – Cimetidine and Ranitidine (-tidine) MOA: H2 antagonist at parietal cells which decrease of H+, pepsin and intrinsic factor o Secretion is blocked irrespective of stimulus – b/c both Ach and gastrin go through histamine Pharmacokinetics: metabolized by liver, with a bioavailability of 50% due to high of first pass metabolism Use: duodenal/gastric ulcer – heal within 4-6 weeks but remit if therapy is stopped b/c H. pylori still present o Other uses: GERD or hypersecretory diseases (ZE syndrome, MEN 1 – pancreatic gastrinoma) Side Effects: few side effects, because H2 receptors are rarely physiologically used o Endocrine effects: causes galactorrea (women); impotence and gynecomastia (men) Cimetidine blocks androgen receptors at high doses o CNS: Cross the BBB and cause confusion, dizziness, and slurred speech Drug interactions: inhibits many CYP450 alters metabolism of many drugs (e.g. warfarin, theophylline) Proton pump inhibitors (PPI) – Omeprazole (-prazole) Mechanism: irreversibly inhibits H/K proton pump; a prodrug that is activated at pH <2 o Enteric-coated capsule protects activation in stomach absorbed in SI travels in blood reaches parietal cell where it activates at pH <2 Pharmacokinetics: Maximum effect in 2 hours; upon cessation Acid secretion returns to normal in 3-5 days Uses: duodenal/gastric ulcer, GERD, hypersecretory diseases (ZE syndrome, MEN1) Side effects: few side effects; elevated gastric pH may increase incidence of C. diff infection o Hypomagnesemia: long term use, along with loop/thiazide diuretic reduces levels of Mg o Osteoporosis: long term use of PPI increases the risk of bone fractures Drug interactions: inhibits CYP2C19 increases plasma concentration of diazepam, warfarin o Clopidogrel requires CYP2C19 for activation of prodrug; do not use with omeprazole o Increased gastric pH decreases bioavailability of –conazoles (antifungals), Fe2+ salts, ampicillin Cytoprotective drugs (drugs that protect the gastric mucosa) Misoprostol o MOA: PGE1 analog that inhibits acid secretion, stimulates HCO3- and mucus secretion, promotes gastric blood flow o Uses: Co-administration with NSAIDs in RA patients to minimize the adverse gastric effects Pregnancy termination in first 90 days, as misoprostol contracts the uterus o Side effects: diarrhea (increased intestinal motility and secretion) and abortion Sucralfate o MOA: if pH <4 it forms a thick, sticky layer that adheres to ulcer proteins, forming a protective layer Don’t administer <30 min before or after antacids, because it wont activate o Uses: treatment of duodenal and gastric ulcer (effective as H2 blockers) Bismuth compounds—Pepto Bismol o Act like sucralfate but also may kill H. Pylori o Used in conjunction with antibiotics and PPIs to treat H. Pylori ulcers Antacids – Mg(OH)2, Al(OH)3, CaCO3, NaHCO3 o MOA: neutralizes gastric acid; acts rapidly, but requires large quantities/frequent dosing to work o Systemic antacids: NaHCO3 and Na citrate alkalinize the urine (used in aspirin overdose) Side effects if NaHCO3, CaCO3 and milk are used together, CaPO4 salts form in kidney Also can alkalinize the blood metabolic alkalosis o Non-systemic antacids: Ca2+, Mg2+, Al3+ are poorly absorbed in the GI tract o Effects/Uses: Raise gastric pH: effect prolonged by food which delays stomach emptying Pepsin is inactivated at pH 5-7 Acid rebound: increased pH gastrin secretion reflex acid release More prominent with CaCO3, as Ca can trigger gastrin release Gastric motility: Al3+ decreases motor activity and causes constipation Mg2+ increases motor activity and causes diarrhea (milk of magnesia is a laxative) o Drug interactions: Mg2+ and Al3+ can decrease absorption tetracyclines and fluoroquinolones, Increase in gastric pH inhibits absorption of antifungals –conazoles and Fe2+ H. Pylori Ulcer Quadruple therapy o Why Multidrug therapy? Ulcers treated with PPI reoccur b/c H. pylori is still present Multiple antibiotics, b/c H. Pylori can become resistant to metronidazole or clarithromycin Low rate of reoccurrence of ulcer after eradication of H. Pylori, so kill it o Quadruple therapy: tetracycline/amoxicillin, metronidazole, bismuth salicylate, PPI E.g. clathromycin, metronidazole, pepto bismol, omeprazole Drugs that affect GI motility (used for irritable bowel syndrome, GERD, prevention of vomiting) Physiology of GI motility Afferent: Bolus of food, mechanically or chemically, activates enterochromaffin cells to release 5-HT Interneurons: 5-HT binds to 5-HT3 receptors on afferent neurons Efferent: interneurons connect to efferent neurons, and activate them by binding to 5-HT4 receptors o Oral segment: the efferent neuron releases Ach and substance P contraction SMC o Aboral segment: the efferent neuron releases NO and VIP relax SMC Physiology of GI Fluid Flow Balance between GI secretion and absorption determines if patient is constipated or has diarrhea o Diarrhea: in general, cAMP stimulates secretion and inhibits absorption diarrhea o Constipation: in general, low cAMP and low Ach reduce secretion constipation (eg opioids) Absorption: mainly done villous cells; Na/H and Cl/HCO3 promote absorption of NaCl and water follows o Continuous absorption of NaCl is maintained by basal Na/K ATPase and Cl channels Secretion: mainly done by crypt cells; basal NKCC2 promotes uptake of Na, Cl, and K o Elevated levels of cAMP activate CFTR and K channels, promoting KCl and thus water secretion Drugs affecting GI motility: Laxatives, Prokinetics, and anti-diarrheals Laxatives General mechanisms: provide hydrophilic substance that is not absorbed to promote water secretion o Increase the gastric motility o Inhibit solute uptake or decrease solute reabsorption increased solute in GI tract water secretion Types: Fiber, Osmotic laxatives, stimulant laxatives, stool softeners Uses of Laxatives: o Idiopathic Constipation: No role in constipation associated with intestinal pathology First step: correct underlying disease or drug causing constipation, increase fiber/water intake Second step: bulk forming agents – psyllium Third step: start low dose stimulant laxative; discontinue ASAP o Prevent straining on defecation as it may cause hernia or hemorrhoid rupture o Evacuation of colon prior to radiological exam of abdomen or GI tract, elective bowel surgery, proctological exam, colonoscopy, and following drug overdose Fiber Composition: Non-digested, non-absorbed hydrophilic material from plant cell walls like cellulose Effects on GI tract: binds water and ions to increase mass of feces GI dissension increase GI motility o Binds bile acid and can serve as a mechanism to lower plasma cholesterol Side effects: few and minor; flatulence or binds other drugs (cellulose binds digoxin) Dietary fiber can be supplemented with psyllium, which should be taken with water to prevent constipation. Saline or osmotic laxatives MOA: non-absorbed molecules increase GI osmolality leading to water retention in the SI and colon. o Rapidly induces laxation – in 1-3 hours. Drugs: MgSO4 (Epsom salt) and Mg(OH)2 (milk of magnesia): may produce Mg toxicity in renal failure o Lactulose: bacteria digest lactulose causing cramps and flatulence Can treat hepatic encephalopathy – acid production by bacteria converts NH3 to NH4+ o K+/Na+ salts of phosphorus: avoid in CHF (Na overdose) and renally impaired (P overdose) o Sorbitol: used in conjunction with charcoal in toxicity; sorbitol doesn't bind to charcoal! Charcoal binds toxin that is overdosed and sorbitol promotes GI emptying to clear drug Whole bowel irrigation: isotonic solution given in large volumes to flush out the GI tract without net absorption or loss of salts or water. o Uses: bowel cleansing prior to colonoscopy, surgery, barium enema X-ray “Stimulant” laxatives MOA: increase salt/water secretion and promote GI tract motility. o Vary in mechanism, but involve generation of NO2, PGE2, and activation of PKC. o Excessive use can lead to fluid and electrolyte deficits o Most act in colon and produce laxation in 6-8 hours Notes for phenolphthalein and bisacodyl: chronic use of these drugs is not recommended o Undergo enterohepatic cycling: Are absorbed in low SI enter liver and are conjugated released into duodenum with bile reaches colon where bacteria deconjugate it drug is active in colon o Drugs are present in saliva, milk, and urine Phenolphthalein: withdrawn due to cancer risk; can turn urine red if pH>9 Bisacodyl: are enteric-coated to prevent action in upper GI; activate in the lower SI where pH is higher o Shouldn't be crushed or taken with antacids because loss of capsule in upper GI induces vomiting Anthraquinones and glycosides of danthron (Senna): promote secretions in GI tract o Side effects: hypovolemia and hypokalemia Castor Oil (Purge): a triglyceride of ricinoleic acid o MOA: Ricinoleic acid stimulates peristalsis and fluid secretion in SI o It causes complete GI emptying in 1-6 hours, and thus is not recommended for common constipation o Side Effects: Can induce uterine contractions in pregnant women Lubiprostone o MOA: Directly activates CFTR Cl- channel promoting secretion and motility o Uses: chronic idiopathic constipation and IBS with constipation in women o Side effects: Nausea, diarrhea, and make sure woman isn’t pregnant before use Linaclotide o MOA: Activating guanylate cyclase C increased cGMP activate CFTR, HCO3/Cl channels increased salt and water secretion promotes GI motility and laxation o Uses: chronic idiopathic constipation and IBS with constipation in adults. o Contraindication: children <6; shown to cause death o Side effects: nausea, diarrhea Stool softeners: Docusate: mild, delayed laxation in 1-3 days; MOA unknown Prokinetics: General Mechanism: direct increase motility GI tract by acting on ENS Uses: reduce acid reflux, treat diabetic gastroparesis, reduce risk of vomiting, and treat chronic constipation Bethanechol o MOA: 4° muscarinic agonist (unabsorbed) and is resistant to hydrolysis by acetylcholinesterase o Uses: post-surgery promotion of GI motility – it causes an uncoordinated, generalized contraction More frequently used to promote bladder emptying in urinary retention or neurogenic bladder o Side effects: increased acid secretion; negligible systemic effects, as its poorly absorbed Cisapride o MOA: 5-HT4 agonist that activates myenteric interneuron Ach release induces motility. Increases clearance of esophagus/stomach and constricts LES – used for GERD Increases motility of SI and LI – used for idiopathic constipation Unlike bethanechol it does not increase gastric acid secretion o Uses: GERD, diabetic gastroparesis, chronic constipation o Drug interactions: metabolized by CYP3A4 so CYP3A4 inhibitors like erythromycin, ketoconazole, grapefruit juice increase the level of drug leading to prolonged QT and arrhythmia Due to this drug interaction, cisapride was withdrawn from the market Tegaserod o MOA: partial 5-HT4 agonist in the myenteric plexus increased motility o Use: treatment of irritable bowel syndrome in women when it is associated with constipation o Side effects: diarrhea leading to hypotension, hypovolemia Increased incidence of serious CV events lead to drug being withdrawn from market Metoclopramide o MOA: 5-HT4 agonist and dopamine D2 antagonist o Uses: GERD, diabetic gastroparesis, antiemetic during chemotherapy o Side effects: Drug induced parkinsonism/TD, hyperprolactinemia Erythromycin – antibiotic that can also be used for diabetic gastroparesis o MOA: binds to motilin receptors and promotes GI peristalsis; SE are NVD Antidiarrheals Antimuscarinic drugs: contraindicated in Glaucoma, GERD/UC (reduced motility promotes acid damage) o MOA: relax GI smooth muscle, leading to decreased motility o L-hyoscyamine: isomer of atropine; may produce antimuscarinic side effects o Dicyclomine: compared to atropine, it has a small effect on CV and salivary/sweat secretion o Glycopyrrolate: quaternary antimuscarinic poor GI absorption thus causes minimal SE Use: IBS and antisialogogue for surgery (prevent bowl movement) Opioid agonists: Diphenoxylate and Loperamide o MOA: inhibits Ach release in myenteric plexus leading to decreased motility and peristalsis and increased tone in sphincters o Diphenoxylate: marketed as mixture with atropine No analgesia/euphoria at recommended doses; high doses produce euphoria/dependence o Loperamide: OTC because it doesn’t enter CNS, so no analgesia, euphoria, or physical dependence o Uses: treatment of diarrhea; half-life of 11 hours allows long duration of action o Contraindication: patients with ulcerative colitis, as reduced motility may cause toxic megacolon Alosetron o MOA: 5-HT3 antagonist blocks afferent neurons in the myenteric plexus leading 1) decrease motility and 2) blocks receptors on vagal afferent pain fibers (reduced pain) o Uses: women with IBS that is mostly diarrhea and have abdominal pain o Adverse effects: severe constipation and ischemic colitis Emesis Mechanism: irritants in GI tract EC cells release 5HT binds to 5-HT3 on vagal afferents stimulates the emetic center in the medulla emesis o Chemoreceptor trigger zone: base of 4th ventricle, can be activated by drugs, activates emetic center o Afferent transmitters to emetic center: 5-HT, dopamine, acetylcholine Drugs that cause emesis: Dopamine, opioids, anti-neoplastic drugs, syrup of ipecac Syrup of Ipecac: o MOA: active ingredient emetine acts on GI afferent and directly on CTZ to induce emesis o Use: rarely used to induce vomiting following drug overdose o Side effects: chronic use/abuse (bulimics) can lead to CHF and myopathy Apomorphine: Dopamine agonist used for 1) Last resort emesis 2) Parkinson’s off episodes Antiemetics for chemotherapy or anesthesia Serotonin HT3 antagonists: Ondansetron (–setron) o MOA: 5-HT3 antagonist in afferent nerves signaling from the GI tract to the CTZ o Use: prevent vomiting with chemotherapy, for maximum effect its used with Used to prevent post-operative nausea and vomiting o Side effects: relatively few but constipation and prolonged QT interval (avoid in patients with RF) Dopamine D2, muscarinic, and Histamine antagonists o Chlorpromazine – typical antipsychotic MOA: D2, muscarinic, H1, α-1 antagonist; Blocks D2 receptors in CTZ for anti-emesis Use: schizophrenia; nausea and vomiting Side effects: dystonia, akathesia, Parkinsonism, TD, and hyperprolactinemia (D2) Sedation (H1), antimuscarinic effects (M2), orthostatic hypotension (α1) o Prochlorperazine MOA: Antagonist at D2, M, H1, 5-HT, and alpha-1 receptors Uses: antiemetic (reserved for vomiting resistant to other drugs) and antipsychotic Side effects: extrapyramidal effects and hyperprolactinemia o Metoclopramide MOA: D2 antagonist (anti-emesis at CTZ) and 5-HT4 agonist (increase GI motility) Uses: nausea and vomiting associated with chemotherapy, GERD, diabetic gastroparesis Side effects: extrapyramidal effects and hyperprolactinemia o Promethazine MOA: antagonist at H1 and muscarinic receptors Uses: antiemesis associated with anesthesia and motion sickness; pre/post-op sedation Side effects: sedation is prominent side effect Contraindications: children <2, due to fatal respiratory depression and sleep apnea Other anti-emetics used during chemotherapy and surgery o Aprepitant MOA: antagonist at substance P/neurokinin receptors in vagal afferent to the emetic center Use: emesis associated with cisplatin chemotherapy (causes acute and delayed emesis) Used with ondansetron and dexamethasone to increases acute and delayed anti-emesis o Fosaprepitant Water soluble prodrug converted to aprepitant; IV infused 30 min before chemo o Dronabinol and nabilone: MOA: synthetic THC that acts as agonist at CB1 receptors in CTZ Uses: antiemetic for chemotherapy when other agents aren’t effective Appetite stimulant in cancer and AIDS patients Drugs for prophylaxis of motion sickness Scopolamine o MOA: Anti-muscarinic drug o Use: Most efficacious drug for motion sickness; also reduces NV associated with surgery o Use limiting aspect: numerous anti-muscarinic side effects Diphenhydramine, dimenhydrinate, promethazine o MOA: Anti-histamines and anti-muscarinic effects prevention of motion sickness Meclizine and cyclizine o MOA: H1 antagonist; produces less sedation than diphenhydramine Prophylaxis of milder cases of motion sickness Drugs for inflammatory bowel disease (Crohn’s and IBD) Glucocorticoids (Budesonide) o Absorption: enteric coated (pH<5.5) to prevent dissolution prior to ileum/colon, is poorly absorbed and has high first pass metabolism (CYP3A4) leading to low o Drug interactions: cyp3A4 inhibitors (grapefruit juice, ketoconazole) increase drug concentration o Side effects: limited due to poor absorption – less acne and moon face than with prednisone Sulfasalazine o MOA: sulfasalazine is a prodrug cleaved by colonic bacteria to release 5-ASA and sulfapyridine 5-amino-salicylic acid: anti-inflammatory agent Sulfapyridine: inactive, but produces hypersensitivity in some patients o Use: mild-moderate ulcerative colitis and rheumatoid arthritis o Olsalazine, Balsalazide, Mesalamine: drugs comprised of 5-ASA, but not sulfapyridine Used in patients who are sensitive to sulfapyridine Infliximab o MOA: monoclonal antibody against TNF-alpha o Uses: moderate-severe CD or UC; Promotes mucosal healing and reduce number of fistulas o Note: all mAb work for few weeks (unless given with methotrexate) b/c antibodies are formed against the foreign mAb o Other anti-TNF-a Abs: Adalimumab and Certolizumab Cromolyn sodium o MOA: prevents activation of mast cells o Use: treatment of UC and systemic mastocytosis