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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)
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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
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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
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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
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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
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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
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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