GI medications

what is gastric acid?

• HCl

• secreted by parietal cells in the stomach by the H+ pump (H+/K+ ATPase)

what is acid secretion stimulated by?

• histamine (H2 receptors)

• ACh (M3 receptors)

• gastrin (promotes histamine secretion by ECl cells)

what is acid secretion inhibited by?

PGE2

what do epithelial cells secrete?

• cytoprotective mucous and bicarbonate that blanket the mucosa and neutralize acid
• stimulated by ACh and PGI2

what are the causes of peptic ulcer disease (PUD)?

• helicobacter pylori infection (HPI)
• chronic use of NSAIDs: including low-dose aspirin
• other drugs: biphosphonates, corticosteroids, clopidogrel, warfarin, potassium chloride supplements
• hypersecretion of gastric acid: e.g. Zollinger-Allison syndrome - gastrin-secreting pancreatic tumor
• stress ulcers

what can lead to ulcer formation?

• critically ill patients not being fed orally or enterally
• decreased mucosal blood flow and disruption of normal mucous and bicarbonate secretion rapidly

what is HPI?

gram (-) bacteria that colonize gastric mucosa beneath the mucous/bicarbonate blanket

how is PUD managed?

• acid suppression
• acid neutralization (antacids): provide temporary and very rapid pain relief; used prn
• cyto-protection: sucralfate, misoprostol: synthetic PGE1

what drugs are used for acid suppression?

• H2-receptor antagonists (H2RAs): "tidine" drugs
• H+ pump inhibitors (PPIs): "prazole" drugs
• potassium-competitive acid blockers (PCABs)

what are the 4 first-line regimens for the eradication of HPI?

• optimized bismuth quadruple for 14 days
• rifabutin triple 4 FDC capsules po TID for 14 days: contains amoxicillin
• vononprazan Dual for 14 days: contains amoxicillin
• vonoprazan triple for 14 days: contains amoxicillin

what is the dose-related inhibition of gastric acid secretion of H2RAs for management of PUD?

• onset 1 hour; duration 6-10 hours

• secondary inhibition of vagal (ACh) and gastrin-stimulated acid secretion

• basal and nocturnal acid secretion are inhibited more effectively than post-prandial acid secretion

what is the treatment regimen of H2RAs for the management of PUD?

• 6-8 weeks for duodenal ulcer (DU), full 8 weeks for gastric ulcer (GU)
• additional 2-4 weeks for elderly patients or smokers
• equally effective given twice daily or once daily at bedtime for an ulcer
• OTC use is not indicated to treat an ulcer

what are the adverse effects of H2RAs?

cimetidine is much more likely to cause AEs than famotidine or nizatidine:

• most common in GI: diarrhea, constipation, nausea, vomiting

• community-acquired pneumonia is most common during first 30 days of use: diabetes, immune compromise, asthma, COPD, children, elderly

what H2RAs are used for management of PUD?

cimetidine, nizatidine, famotidine

what are the drug interactions with H2RAs?

• cimetidine inhibits hepatic CYP enzymes
• nizatidine and famotidine do not inhibit CYP enzymes
• cimetidine: additive myelosuppression (alkylating agents, antimetabolites, radiation therapy)

what are PPIs?

• approved to treat PUD
• more potent than H2RAs, heal ulcers more rapidly
• effectively inhibit basal and post-prandial acid secretion
• onset of action ~ 1 hr
• full acid secretion returns after 4-7 days: H+ pump inhibition is irreversible; have to synthesize new pumps

what PPIs are approved to treat PUD?

omeprazole, omeprazole/NaHCO3, lansoprazole, rabeprazole

what are the adverse effects of PPIs in the GI?

abdominal pain, bloating, nausea, vomiting, diarrhea (increased risk of Clostridium difficile-associated diarrhea), constipation, flatulence, dysphagia, anorexia, irritable colon, esophageal candidiasis, mucosal atrophy of the tongue, taster perversion, dry mouth, stomatitis, benign gastric fundic polyps, ECL hyperplasia

what are the adverse effects of PPIs on the respiratory system?

upper respiratory tract infection, community-acquired pneumonia

what are the adverse effects of PPIs on the musculoskeletal system?

muscle cramps, myalgia, muscle weakness, joint pain, osteoporosis, and hip, wrist, or spine fracture

what are the adverse effects of PPIs in hypomagnesemia?

• use > 1 year
• tetany, seizures, atrial fibrillation, supraventricular tachycardia, paresthesia, muscle weakness, muscle cramps, lethargy, inhibition of parathyroid hormone secretion (hypocalcemia)

what are the adverse effects of PPIs?

• most common in GI

• dose-dependent decrease in vitamin B12

• respiratory and musculoskeletal systems

• hypomagnesemia

what are the drug interactions of PPIs with CYP enzymes?

• inhibition of CYP enzymes
• omeprazole: increased levels of diazepam, warfarin, phenytoin, cyclosporine, saquinavir
• rifampim. St. John's wort: decreased levels of omeprazole
• lansoprazole, rabeprazole: only minimal CYP inhibition

what are other drug interactions of PPIs?

• decreased bioavailability of ketoconazole, ampicillin, iron salts, digoxin, and atazanavir
• may increase risk of digoxin-associated cardiotoxicity secondary to hypomagnesemia
• sucralfate: delays absorption and decreases oral bioavailability of PPI

what is miSORPROStol?

• used for prevention of GI ulcers

• synthetic PGE1: inhibits acid secretions and stimulates mucus/bicarbonate secretion and mucosal blood flow

what are the adverse effects of miSOPROStol?

• GI: dose-related diarrhea (up to 40% of patients), abdominal pain, nausea, vomiting, constipation

• headache

• genitourinary: menstrual irregularities (cramps, dysmenorrhea, hypermenorrhea, spotting), postmenopausal vaginal bleeds, spontaneous abortion (contraindicated during pregnancy)

• hematologic: anemia, thrombocytopenia

what are the drug interactions of miSOPROStol?

food and antacids decrease the rate of absorption

what is sucralfate?

used for treatment and prevention of GI ulcers

what are the adverse effects of secralfate?

• constipation (most common)

• diarrhea, nausea, vomiting, flatulence, indigestion, dry mouth, headache, dizziness, insomnia, vertigo

• bezoars (risk factors: delayed gastric emptying, enteral tube feedings)

what are the drug interactions of sucralfate?

• decreased oral bioavailability of cimetidine, digoxin, ketoconazole, phenytoin, ranitidine, tetracycline, theophylline, warfarin (binding in the gut)

• decreased oral absorption of ciprofloxacin, norfloxacin secondary to aluminum content

• antacids, H2RAs, or PPIs can decrease the activation of sucralfate (give at least 2 hrs after sucralfate)

what are the classic symptoms of gastroesophageal reflux disease (GERD)?

• heartburn and acid regurgitation

• usually worse after eating, especially if you lay down within a couple of hours after a meal

what are the atypical symptoms of GERD?

epigastric bloating/pain (can present as chest pain), early satiety, dyspepsia

what are the alarm symptoms of GERD?

dysphagia, chronic sore throat, bleeding or anemia, unexplained weight loss

what are the extraesophageal symptoms of GERD?

chronic cough, laryngitis, erosion of tooth enamel, asthma

what are the triggers of reflux symptoms of GERD?

• obesity
• alcohol or tobacco use
• fatty or spicy foods, chocolate, mints, caffeine, carbonated beverages
• drugs: anticholinergics, β-agonists, ⍺-antagonists, narcotics, oral contraceptives, xanthine derivatives (caffeine). CCBs

what can be seen in GERD?

sphincter open, allowing reflux

what are the 4 GERD phenotypes?

• non-erosive reflux disease (NERD)
• erosive esophagitis (EE)
• eosinophilic esophagitis (EoE)
• barrett's esophagus

what is non-erosive reflux disease (NERD)?

• 70% of synptonatic patients; normal endoscopy
• 30% less likely to respond to PPIs

what is erosive esohpagitis (EE)?

• endoscopy reveals erosions in the esophagus
• more likely to be male, Caucasian, obese
• virtually all patients respond to PPI therapy (esophageal healing and symptomatic control)

what is eosinophilic esophagitis (EoE)?

allergic reaction to food or environmental allergen resulting in immune reaction (production of eosinophils) that causes esophageal inflammation

what is barrett's esophagus?

• risk factor for esophageal cancer
• response to PPIs does not reduce underlying cancer risk

what are the concerns about long-term use of PPIs?

• osteoporosis and bone fracture (decreased Ca2+ absorption)
• community-acquired pneumonia
• C. difficle colitis
• ischemic heart disease and acute MI (PPIs may decrease NO synthesis)
• dementia (in mice, PPIs increase amyloid-beta proteins in brain)
• chronic renal failure (mechanism unclear)
• gastric carcinoid tumors in mice

what are gastric carcinoid tumors in mice?

• occur secondary to chronic hypergastrinemia/ECL hyperplasia
• ECL hyperplasia also occurs in humans (most common with HPI), but carcinoid tumors have not been reported

what is vonoprazan (voquenza)?

• K-competitive acid blocker (PCAB)
• competitive (non-covalent) binding to H+, K+-ATPase (H+ pump) in parietal cell leading to decreased basal and stimulated gastric acid secretion
• AEs, DIs

what is competitive binding of PCAB?

• not dependent on activation by stomach acid: works more rapidly, often within hours of first dose
• longer t_1/2 (effects last longer than with PPIs)

what are the AEs of PCAB?

• common (4-5%): diarrhea, dysgeusia
• occasional (2-3%): vuvlovaginal candidiasis, nasopharyngitis
• rare (<2%): QTc prolongation, neutropenia, depression, insomnia, tubulointerstitial nephritis

what are the DIs of PCAB?

• vonazapram is metabolized by hepatic CYP3A4, CYP2B6, CYP2C9, CYP2D6, and UDPGT
• avoid use with moderate-to-strong CYP3A4
• vonazapram is a CYP2C19 inhibitor: caution when used with clopidogrel or citalopram

what is the recommended dose of PCAB?

• healing of EE: 20 mg po QD for 8 weeks

• maintenance of healed EE: 10 mg po QD for up to 6 months

• heartburn associated with NERD: 10 mg po QD for 4 weeks

what are serotonin (5HT3) receptor antagonists the most effective agents for?

• chemotherapy-induced nausea and vomiting (CINV)
• radiation-induced nausea and vomiting (RINV)
• post-operative nausea and vomiting (PONV)

what are neurokinin receptor antagonists?

• e.g. aprepitant

• most effective against cytotoxic drug-induced emesis (delayed vomiting)

what are serotonin (5HT3) receptor antagonists?

• e.g. ondandsetron
• most effective against cytotoxic drug-induced emesis
• block serotonin peripherally (GI vagal nerve terminals) and in the CNS (chemoreceptor trigger zone)

what are histamine H2 and muscarinic receptor antagonists?

• e.g. cyclizine, hyoscine
• vestibular emesis (motion sickness)

what are the common adverse reactions of 5HT3 receptor antagonists?

headache, fatigue, malaise, constipation

what are the uncommon (1-10%) adverse reactions of 5HT3 receptor antagonists?

drowsiness, sedation, dizziness, agitation, anxiety, paresthesia, pruritus, skin rash, diarrhea, gynecologic disease, urinary retention, transient increase in liver enzymes, injection site reaction, hypoxia, gever

what are the rare (<1%) adverse reactions of 5HT3 receptor antagonists?

• cardiovascular: hypotension, syncope, ischemic heart disease, atrial fibrillation, bradycardia, prolonged Q-T interval (can cause torsades de poitnes, acute MI, and sudden cardiac death), second-degree atrioventricular block
• respiratory: bronchospasm, dyspnea
• skin: stevens-johnson syndrome, toxic epidermal necrolysis
• misc: chills, dystonic reaction, extrapyramidal reaction, serotonin syndrome, flushing, neuroleptic malignant syndrome, tonic-clonic seizures

what are the doses of ondansetron (Zofran, GlaxoSmithKline) used to prevent CINV?

• oral (moderately emetogenic chemotherapy in adults and children ≧12 yrs of age): 8 mg po 30 minutes before chemo, 8 hrs after the initial dose; 8 mg po q12hr x 1-2 days following completion of chemotherapy

• oral (highly emetogenic chemotherapy in adults): single 24 mg dose po 30 minutes before chemotherapy

• IIV (adults and pediatric patients ≧6 months of age): 0.15 mg/kg (16 mg max) by 15-minute infusion beginning 30 minutes before chemotherapy at 4 and 8 hrs after chemo

what are the doses of ondansetron (Zofran, GlaxoSmithKline) used to prevent PONV?

• adults receiving total body irradiation (TBI) or single high-dose fraction or daily fractionated radiation to the abdomen: 8 mg po 3 times daily

• TBI: one 8 mg dose 1-2 hrs before each fraction

what are the doses of ondansetron (Zofran, GlaxoSmithKline) used to prevent RINV?

• adults: single 4 mg IV dose immediately before induction of anesthesia; may repeat postoperatively for nausea or vomiting shortly after surgery

• children 1 month to 12 yrs of age: single 4 mg IV dose (>40kg) or 0.1 mg/kg IV dose (≦40kg) immediately before or after induction of anesthesia; may repeat postoperatively as above

what are the doses of granisetron (Kytril, Roche) used to prevent CINV?

• adults and children 2-16 yrs of age

• IV: 10 mcg/kg (5 min infusion or IV injection) within 30 minutes of chemotherapy

• oral: 1 mg po twice daily (within 12 hrs of chemotherapy and 12 hrs after) or 2 mg po once daily (within 1 hr of chemotherapy)

what are the doses of granisetron (Kytril, Roche) used to prevent PONV?

• adults

• TBI or daily fractionated radiation to the abdomen: 2 mg once daily (within 1 hr of radiation)

what are the doses of granisetron (Kytril, Roche) used to prevent RINV?

• adults

• single 1 mg IV dose by IVP 30 sec before induction of anesthesia or immediately before reversal of anesthesia

what is dolasetron mesylate (Anzemet, Sanofi-Aventis) indicated for?

• CINV and PONV

• NOT RINV

what is granisetron (Kytril, Roche) indicated for?

• CINV: adults and children 2-16 yrs of age; IV, oral

• RINV: adults; TBI or daily fractionated radiation to the abdomen

• PONV: adults

what is ondansetron (Zofran, GlaxoSmithKline) indicated for?

• CINV: oral, IV

• RINV: adults, TBI

• PONV: adults, children 1 month-12 yrs

what are the doses of dolasetron mesylate (Anzemet, Sanofi-Aventis) used to prevent CINV?

• oral: 100mg dose (adults) or 1.8 mg/kg (100mg max) in children 2016 yrs of age within 1 hr of chemotherapy

• IV: due to the risk of dose-dependent QT interval prolongation, IV dolasetron should NOT be used to prevent CINV

what are the doses of dolasetron mesylate (Anzemet, Sanofi-Aventis) used to prevent PONV?

• IV: single 12.5mg dose (adults) or 0.35 mg/kg (12.5mg max) in children 2-16 yrs of age 15 min before cessation of anesthesia (prevention) or as soon as nausea and/or vomiting develops (treatment)

what are the doses of palonosetron hydrochloride (Aloxi, Helsinn) used to prevent CINV?

• adults: single 0.25mg dose by IVP over 30 sec, approximately 30 min before chemotherapy

• children 1 month to <17 yrs: single 20 mcg/kg (1.5mg max) dose by IVP over 15 min, approximately 30 min before chemotherapy

what are the doses of palonosetron hydrochloride (Aloxi, Helsinn) used to prevent PONV?

adults: single 0.075mg dose by IVP over 10 sec immediately before induction of anesthesia

what is aprepitant/fosaprepitant dimeglumine (Emend, Merck)?

• selective antagonist at substance P/neurokinin-1 (NK1) receptors
• highly emetogenic chemotherapy regimens: American Society of Clinical Oncology (ASCO) guidelines recommend a 3-drug regimen NK1 receptor antagonist, 5HT3 receptor, and dexamethasone
• moderately emetogenic chemotherapy regimens: ASCO recommends a 2-drug regimen (palonosetron and dexamethasone is preferred; granisetron or andansetron plus dexamethasone is second-line)

what are the adverse effects of aprepitant/fosaprepitant dimeglumine (Emend, Merck)?

fatigue, dizziness, disorientation, nausea, anorexia, constipation, diarrhea, dyspepsia, stomatitis, gastritis, hiccups, perforating duodenal ulcer, enterocolitis, neutropenia, alopecia, bradycardia, hypotension, hypertension, sinus tachycardia, hot flush, pharyngolaryngeal pain, preuritus, dehydration

what is the recommended dose for aprepitant/fosaprepitant dimeglumine (Emend, Merck)?

• CINV: adult, 125mg po 1 hr before chemotherapy on day 1, then 80mg po on days 2 and 3 of the treatment regimen

• PONV: adult, single 40mg oral dose withing 3 hrs of anesthesia induction