GI Drugs

  1. omeprazole, esomeprazole, lansoprazole
    • Proton Pump Inhibitor
    • prodrug that requires acid activation - irreversibly inhibits proton pumps
    • 1st line treatment for hyperacidity and ulcers (80-95% reduction in H+ production)
    • Mode of action: does not act directly within gastric lumen, enters parietal cells from systemic circulation, activated within acidic environment around the proton pump
    • acid labile - must be absorbed into blood and at higher pH
    • administered as: gelatin capsules, (also, enteric coated, mixed with bicarb, or given parenterally)
    • dosed daily, active for 2 hours, relies on slow turnover of ATPase at luminal surface of epithelial cells and slow replacement of ATPases irreversibly inhibited by PPIs. 
    • only reacts with active proton pumps - treatment req's 2-5 days to reach max efficiency
    • best taken 30 minutes before food to allow for absorption and circulation of the PPI
    • Uses: GERD, erosive esophagitis, peptic ulcers, NSAID induced gastric ulcers, Zollinger-Ellison syndrome, part of H. pylori treatment
    • liver clearance
    • adverse effects: nausea, abd. pain, constipation, flatulence, diarrhea
    • - hepatic failure reduces clearance, especially esomeprazole and lansoprazole
    • - rare: myopathy, arthralgia, headaches, and skin rashes
    • - rebound hypergastrinemia and gastritis can occur with sudden withdrawal possibly b/c excessive gastrin secretion by increased gastric pH
    • - drug interactions through altered CYP activity: inc. serum warfarin [c], dec. activation of clopidogrel
  2. cimetidine, ranitidine, famotidine
    • H2 receptor antagonist on parietal cells - blocks base level of acid secretion maintained by ECL cells
    • less effective vs PPI, but still decreases acid secretion over 70% over 24 hrs with daily dosing
    • particularly useful for nocturnal acid secretion (up to 90% nocturnal acid)
    • important for duodenal ulcers and Zollinger-Ellison syndrome
    • renal excretion via OCT system
    • adverse rxns rare: minor effects such as diarrhea, headache, drowsiness, fatigue, m pain
    • - CNS effects in parenteral admin. and the elderly (hallucinations, delirium, confusion, slurred speech, headaches)
    • - long term use of cimetidine at high doses decreases testosterone binding to androgen receptor (dec. sperm count, impotence, gynecomastia) and hydroxylation of estradiol (galactorrhea in women)
    • decrease pepsin and intrinsic factor output
    • tolerance can develop in 3 days
    • acid rebound if discontinued suddenly
  3. misoprostol
    • prostaglandin analog (PGE1 analog)
    • reduces 80-90% basal or food-induced acid production
    • short acting - up to 3 hrs
    • generally only used to prevent NSAID-induced injury
    • - replaces prostanoids lost due to COX1 inhibition 
    • - PPIs and H2 antagonists more commonly used for this purpose
    • adverse effects: diarrhea (30%), exacerbates IBD, can increase uterine contraction (contraindicated during pregnancy)
  4. sucralfate
    • octasulfate of sucrose w/ Al(OH)3
    • forms sticky neutral pH polymer coating that swells and covers epithelium
    • used for stress ulcers (sticks better to duodenal than gastric ulcers)
    • acid activated - take before food and avoid antacids and PPIs
    • adverse effects: constipation (2%), can block absorption of other drugs through the stomach
  5. Al(OH)3, Mg(OH)2, CaCO3
    • antacids - neutralize pH of gastric contents
    • fast acting, with effects lasting up to 2-3 hours with food
    • largely supplanted by PPIs, but common OTC
    • Mg2+ is fast acting (stimulates gastric emptying and motility), Al3+ is slower acting (delays emptying and slows motility) - combination is preferred
    • surfactant simethicone is sometimes added to reduce gas
    • adverse effects: rebound acid secretion, may interfere with GI absorption of other drugs (generally take 2 hrs before or after other drugs)
    • Al3+ - constipation, nausea, may contribute to osteoporosis and encephalopathy with renal insufficiency
    • Ca2+ - hypercalcemia (transient in normal pts)
    • Mg2+ - contraindicated in renal disease
  6. pirenzepine
    • M1 selective muscarinic antagonist
    • blocks neurotransmission in intramural ganglia resulting in less vagal stimulation of parietal and ECL cells
    • reduces basal acid production 40-50%
    • significant anticholinergic side effects
    • rarely used
  7. tegaserod
    • 5-HT4 serotonin partial agonist in the gut
    • used for females with constipation predominant IBS - can improve lower bowel motility in cases with chronic constipation and bloating
    • only mildly effective, restricted distribution program
  8. cisapride
    • 5-HT4 receptor agonist and AC stimulant
    • used for GERD and gastroparesis
    • adverse effects: fatal cardiac arrhythmias
  9. bethanechol
    • muscarinic agonist - cholinergic derivative
    • **simply activating muscarinic receptors does not activate coordinated motility so this is not a front line approach for pro kinetic therapy
    • more commonly used to help urination in post-surgical pts
    • selectively activates M2 and M3 receptors to promote circular smooth muscle constriction - relatively uncoordinated = little net propulsive activity
    • adverse effects: bradycardia, flushing, diarrhea, cramps, salivation, blurred vision
  10. neostigmine methylsulfate
    • acetylcholinesterase inhibitor
    • **simply activating muscarinic receptors does not activate coordinated motility so this is not a front line approach for pro kinetic therapy
    • promotes accumulation of ACh, potentiates contractions induced by ACh release
    • Can be used to counter an ileus
  11. metoclopramide
    • dopamine receptor antagonist (dopamine at D2 receptors decrease ACh release, so enhances normal ACh response)
    • long used
    • increases lower esophageal sphincter tone and upper GI motility
    • can relieve GERD symptoms but does not promote healing
    • now used for nausea and vomiting in dysmotility syndromes and as an antiemetic
    • can be used as a laxative
    • adverse effects: extrapyramidal side effects, dystopias, Parkinson's like symptoms, tar dive dyskinesia with chronic use
    • anti-emesis effects_______________
    • general dopamine receptor antagonist with 5-HT3 antagonism as well
    • strongly affect CTZ, while also increasing forward motility (stops emesis, promotes defecation)
    • preferred agent for chemotherapy induced nausea
  12. erythromycin (and oleadomycin, azithromycin, and clarithromycin)
    • motilin agonist - 22 aa peptide hormone that amplifies motor activity through effects on enteric neurons and smooth m
    • macrolide antibiotics
    • typically causes gastric dumping which can move bezoars and improve gastric emptying with ileus, scleroderma, and pseudo-obstructions
    • fast dumps can be painful, not recommended for chronic use
  13. polyethylene glycol
    • alcohol osmotic laxative
    • non-absorbable agent
    • causes water retention
    • really cathartics causing bowel emptying with watery stool, but low dosage acts as laxative
  14. magnesium hydroxide
    • salt osmotic laxative
    • non-absorbable agent, causes water retention
    • really cathartics causing bowel emptying with watery stool, but low dosage acts as laxative
    • Mg may stimulate CCK receptors and increase motility
    • should be avoided by individuals with renal insufficiency, cardiac disease, electrolyte abnormalities, or with diuretic use
  15. lactulose (and sorbitol and mannitol)
    • sugar osmotic laxative
    • non-absorbable agent
    • causes water retention
    • really cathartics causing bowel emptying with watery stool, but low dosage acts as laxative
    • used for constipation associated with opioid use and vincristine
    • bacterial fermentation of lactulose also drops luminal pH and can trap NH4 (increased in colon of patients with severe hepatic disease)
  16. glycerin
    • absorbed in the upper GI tract, so does not work as an osmotic laxative when given orally
    • when administered as a suppository - acts as a hydroscopic agent and lubricant
    • increases water retention, which stimulates peristalsis and produces an evacuation reflex
    • rectal administration can produce a bowel movement within an hour
  17. docusate salts
    • stool wetting agents
    • surfactants that allow mixing of fatty substances and water in stool
    • effective as stool softeners
    • does not increase freq. of defecation
  18. bisacodyl
    • irritant laxative given orally or rectally
    • thought to induce moderate inflammation leading to reduced water absorption and increased motility
    • generally safe but overdose causes catharsis
    • warn patients not to chew tablets or mix with milk or antacids to ensure that the tablet reaches the site of action in the small intestine and to avoid gastric irritation
  19. castor oil
    • a general smooth muscle stimulant 
    • used as a laxative, cathartic and to induce labor
    • sold as castor oil, purge, neolid
    • made from Ricinus communis (castor bean)
    • this produces both ricin (deadly toxin only in soluble fraction) and oil full of triglyceride and ricinoleic acid (not toxic)
    • ricinoleic acid speed motility in the small bowel. 4 ml produces laxative effect in 4 hours, 16 ml for cathartic effect
  20. methylcellulose, psyllium, polycarbophil
    • bulk forming laxative
    • generally fiber based - not broken down / absorbed, bulk material stimulates peristalsis and mass action
    • great for regular soft stools
    • may exacerbate intestinal obstructions
    • may adsorb other drugs
    • also acts as anti-diarrheal - absorbs water w/in GI tract decreases stool fluidity which reduces discomfort
    • only provides symptomatic relief for diarrhea
  21. diphenoxylate
    • opioid antidiarrheal agent
    • effects on enteric nervous system: motility decreased via μ opioid receptors, secretions are decreased via δ opioid receptors
    • both receptors increase absorption
    • difenoxin is the active metabolite of diphenoxylate
    • piperidine derivatives
    • can have CNS effects - packaged with sub-therapeutic doses of atropine to discourage abuse
  22. loperamide
    • opioid antidiarrheal agent
    • effects on enteric nervous system: motility decreased via μ opioid receptors, secretions are decreased via δ opioid receptors
    • both receptors increase absorption
    • μ opioid receptor agonist that stops bowel motility
    • 40-50x more potent than morphine
    • does not enter CNS
  23. octreotide
    • parenteral octapeptide derivative of somatostatin 
    • used to combat secretory diarrhea of hormone secreting tumors
    • used for post-surgical gastric dumping syndrome and diarrhea associated with chemotherapy
    • used to rest the pancreas in pancreatitis
    • reduces secretion of many hormones, including serotonin, gastrin, insulin, and secretin
    • adverse effects: nausea, bloating, injection site pain
    • long term therapy may result in gallstones
  24. bismuth subsalicylate (Pepto Bismol)
    • bismuth - 99% unabsorbed and eliminated in feces
    • has antisecretory, anti-inflammatory, anti-microbial activities
    • commonly included in H. pylori treatments
    • salicylate release in acidic environment (stomach) - NSAID activity that is absorbed systemically
    • magnesium aluminum silicate (clay) - may have bulk forming effects
  25. alosetron
    • 5-HT3 ANTAGONIST used for diarrhea, predominantly IBS
    • generally produce effects opposite of 5-HT4 agonists, but also may reduce visceral sensitivity by reducing sensory and vagal nerve signaling
    • can produce serious constipation and potentially fatal ischemic colitis
    • use only after failing other constipation/diarrheal therapies and only available through restricted distribution programs
  26. ondasetron, granistron, dolasetron, palonosetron
    • 5-HT3 antagonists used in chemotherapy induced nausea and emesis
    • 5-HT3 antagonists reduce motility (acting peripherally in small intestine)
    • Act centrally at CTZ and NTS to reduce emesis
    • all are oral or parenteral except palonosetron which is parenteral only
    • excretion primarily via liver (except palonosetron which is also excreted by kidney)
    • adverse effects: generally well tolerated, commonly headache, constipation, diarrhea, light-headedness
  27. prochlorperazine and chlorpromazine
    • phenothiazine - originally used as antipsychotics, no longer used as such
    • primarily targets D2 receptors in CTZ and H1 receptors
    • preferred as general purpose anti-nauseant and anti-emetic
    • can be useful for chemotherapy induced nausea
    • not as uniformly effective as metoclopramide or 5-HT3 antagonists
    • also good for motion sickness (H1 effect)
    • adverse effects: parkinson-like symptoms, extrapyramidal side effects with long term use, may cause dissociative dysphoria in psychiatrically normal patients
  28. cyclizine, promethazine, hydroxyzine, diphenhydramine
    • antihistamines - H1 receptor antagonist
    • widely used for motion sickness - can be used for post-op emesis
    • act primarily on brainstem and vestibular apparatus
  29. scopolamine
    • anticholinergic - muscarinic ACh receptor antagonist
    • used parenterally, but more commonly administered as a trans-dermal patch
    • very effect for short / long-term prevention of motion sickness
    • can be used for post-op emesis
    • act primarily on vestibular apparatus
    • not effective for chemotherapy-induced nausea b/c minimal CTZ effects
    • adverse effects: dry mouth and blurred vision, may induce outburst of uncontrolled behavior when used in the presence of pain or anxiety
  30. syrup of ipecac
    • emetic - given orally shortly after ingesting toxin/drug
    • act on CTZ
    • largely superseded by activated charcoal, because of danger of aspiration during vomiting
    • activated charcoal absorbs toxins/drug and allows safe passage through the gut
  31. apomorphine
    • emetic - D2 agonist, acts locally and on CTZ
    • given sub-q
    • also largely superseded by activated charcoal
    • more commonly used in veterinary medicine
Card Set
GI Drugs
MOHD3 GI drugs lectures 84, 86