GI pharm

  1. Bismuth Salicylate
    • MoA: Reacts with HCl to produce bismuth oxychloride and salicylic acid, forming physical protection; also allows HCO3- secretion
    • Actions: Anti-microbial, anti-inflammatory, and decreased motility/secretion; coats ulcers and erosions and creates a protective layer against acid and pepsin
    • Use: To increase ulcer healing and for travelers diarrhea
    • Note: Stools may appear dark brown because bismuth is excreted 99% unchanged
  2. Octreotide
    • MoA: Synthetic somatostatin analog
    • Actions: Inhibit intestinal secretion; high doses also inhibit motility
    • Use: Diarrhea caused by AIDs/dumping syndrome/vagotomy, acute variceal bleeds, and for GI tumors (VIPoma and caricinode tumors)
    • Side effects: Nausea, cramps, steatorrhea
  3. Loperamide (Imodium)
    • MoA: Mew agonist that decreases ACh release
    • Actions: Increased GI transit time and increased anal sphincter tone
    • Use: Anti-diarrheal medication
    • Penetrates the CNS poorly so is safe opioid to use
    • Note: Do not use in IBD as leads to toxic megacolon
  4. Diphenoxylate
    • MoA: Mew agonist that decreases ACh release
    • Action: Increases GI transit time
    • Use: Anti-diarrheal medication
    • Note: Given with atropine as has CNS effects
    • Note: Also contraindicated in IBD because it leads to toxic megacolon
  5. Clonidine
    • MoA: alpha2-agonist that causes presynaptic inhibition of the myenteric plexus
    • Action: Slows/decreases both secretory and motility reflexes
    • SE: Profound hypotension, depression, fatigue
    • Use: Diarrhea, especially that caused by diabetic nephropathy and from opiate withdrawal
    • Note: Because of the side effects, clonidine is not the preferred drug for diarrhea; in the above cases, however, it is very ideal and works really well
  6. Alosetron
    • MoA: 5-HT3 antagonist
    • Action: Competitively inhibits 5HT3 receptor to increase transit time in colon; has long duration of action
    • SE: Ischemic colitis (rare but serious)
    • Use: Restricted to diarrhea-predominant IBS
  7. Fiber: Hydrophilic colloids, Psyllium (metamucil), and polycarbophil (fibercon)
    • MoA: Bulk-forming agents that contain fiber, a non-digestible element that is delivered to the colon unchanged, and that rely on osmotic gradient driven by fiber to pull water into stool
    • Use: Constipation
    • Note: Lignin (from wheat bran) is most effective as it is not easily fermented (versus fruits or vegetables)
  8. Saline Laxatives: Magnesium sulfate and sodium phosphate
    • MoA: Provide osmotic load to bowel, causing water retention and initiating peristalsis
    • Use: Constipation
    • SE: Diarrhea and dehydration
    • Note: May be abused by bulemics
    • Caution: Careful using in patients with renal insufficiency, cardiac disease, or electrolyte abnormalities (esp. for bowel prep)
  9. Polyethylene glycol
    • MoA: Non-absorbable osmotically active polymer
    • Use: As a laxative because it doesn't cause cramping (versus sorbitol; also cannot be fermented by colonic bacteria) and as bowel prep with added salts to compensate for electrolyte shifts
    • Note: Safe for use as bowel prep in patients with cardiac problems
  10. Lubriprostone
    • MoA: Prastanoic acid derivative that stimulates CCl2 channels in the intestinal epithelial cells, causing excretion of chloride-rich water
    • Use: Chronic, indiopathic constipation and constipation predominant IBS in women
  11. Bethanechol
    • MoA: M3R agonist that activates bowel and bladder smooth msucle
    • Use: Post operative and neurogenic ileus and urinary retention (no longer used for constipation due to cholingergic side effects)
    • SE: Cramps (because of uncoordinated or spasmodic contraction)
    • Contraindicated in pt with BPH or spasmotic bladder contractions
    • Note: Resistant to AChE
  12. Neostigmine
    • MoA: AChE inhibitor the increases [ACh]
    • Action: Improves gastric, small intestine, and colonic emptying
    • Use: Pseudobstruction, paralytic ileus (be careful), IV for acute bowel distension, postoperative and neurogenic ileus, urinary retention, myasthenia gravis, and postop reversal of NMJ block
    • SE: Cholinergics, espeically muscle hyperactivity, diaphragm paralysis, and death
  13. Metoclopramide and Domperidone
    • MoA: D2 antagonists
    • Action: Stimulates coordinated contractions and increases resting tone/contractility/LES tone/motility but does NOT influence colon transport time
    • Use: Postoperative ileus, GERD, daibetic gastroparesis
    • SE: Increased Parkinsonian effects (restlessness, nausea, diarrhea, drowsiness, fatigue)
    • Contraindicated in patients with Parkinson's or small bowel obstruction
  14. Cisapride
    • MoA: 5HT4 agonist
    • Use: Constipation
    • Note: No longer in use as causes hypokalemic arrythmias, incr QT interval, v-tach, and v-fib
  15. Tergaserod maleate
    • MoA: 5HT4 agonist
    • Use: Constipation preodminant IBS (NOT diarrhea)
    • Note: No longer in use due to stroke and cardiac risks
  16. Prucalopride
    • MoA: 5-HT4 agonist
    • Use: Constipation
    • Note: Safer as lacks activity at cardiac K+ channels and 5H1B receptors
  17. Treating constipation predominant IBS
    Lubiprostone and 5HT4 agonists (with caution)
  18. Treating diarrhea predominant IBS
    Alosetron and 5HT3 antagonists (with caution)
  19. Treating symptomatic and non specific symptoms of IBS
    Fiber, antispasmodics (Calcium channel blockers, anticholinergics, opioid receptor antagonists)
  20. Treating visceral sensitivity in IBS
    Serotonin antagonists and antidepressants
  21. Antacids
    • Weak bases that combine with HCl to form salt and H20
    • They alter the gastric/urinary pH and may delay gastric emptying, which effects the absorption, bioavailability, and urinary excretion of drugs
  22. Calcium Carbonate (Tums)
    • MoA: Weak base that combines with and neutralizes HCl to produce water and salt
    • Overuse: can cause hypercalcemia (kidney failure) and increased rebound acid; it also chelates certain drugs and decreases their effectiveness (ex. tetracyclin)
    • Note: They alter the gastric/urinary pH and may delay gastric emptying, which effects the absorption,  bioavailability, and urinary excretion of drugs
  23. Sodium Bicarbonate (alka seltzer)
    • MoA: Weak base that combines with and neutralizes HCl to produce water and salt
    • Overuse: Systemic alkalosis and fluid retention
    • Note: These are very soluble, fast acting, and rapidly removed
    • Also: They alter the gastric/urinary pH and so may delay gastric emptying, which effects absorption, bioavailability, and urinary excretion of drugs
  24. Aluminum Hydroxide
    • MoA: Weak base that combines with HCl to produce water and salt
    • Overuse: causes constipation (because aluminum is insoluble) and hypophosphatemia; may also cause proximal muscle weakness
    • Note: Will alter gastric/urinary pH -> delayed gastric emptying -> effects on absorption, bioavailability, and urinary excretion of drugs
  25. Magnesium hydroxide
    • MoA: Weak base that combines with and neutralizes HCl to produce acid and salt
    • Overuse: causes laxative effect (diarrhea), hyporeflexia, hypotension, and cardiac arrest
    • Note: These are relatively insoluble, longer acting with little Mg2+ absorption
    • Note: Alter the gastric and urinary pH, delaying gastric emptying, and affecting the absorption, bioavailability, and urinary excretion of drugs
  26. Maalox and Mylanta
    Combinations of Aluminum Hydroxide and Magnesium Hydroxide to prevent the constipation/diarrhea caused by each medication
  27. H2R Antagonists
    • MoA: Block H2R on basolateral membrane of parietal cell, decreasing cAMP, decreasing PKA, decreasing activity of the potassium channel (no hyperpolarization occurs so no chloride efflux occurs)
    • Recognize: "tidine"
    • Examples: cimetidine and ranitidine
    • Rapidly absorbed with little protein binding
    • 10-35% are metabolized by the liver, and both metabolized and unmetabolized parts are excreted by the kidney
    • Use: Promotes ulcer healing and treats GERD
    • Inhibits P450 metabolism (watch out for warfarin + cimetidine!!)
  28. Cimetidine
    • MoA: H2R antagonist that decreases chloride excretion out of parietal cells by blocking the basolateral histamine receptor
    • Use: to promote ulcer healing and for GERD
    • SE: Gynecomastia, impotence, galactorrhea, impotence; can cross blood brain barrier (confusion, dizziness, headaches), and placenta
  29. Muscarinic Antagonists
    • MoA: Prevents effects of vagal ACh release on submucosal neurons in the stomach (i.e. no stimulation)
    • Example: Pirenzepine (big one for acid secretion), scopolamine (more for anti-emetic), atropine
    • SE: Significant cholinergic effects
    • Note: there is a problem with patient compliance as the effect is generalized
  30. Pirenzepine
    • MoA: Muscarinic antagonist with some M1 selectivity that prevents the effects of vagal ACh release on the submucosal neurons of the stomach (i.e. no stimulation)
    • Use: Prevent gastric acid secretion (GERD?)
    • SE: Significant cholinergic effects
  31. Proton Pump Inhibitors (PPI)
    • MoA: Irreversibly bind H+/K+/ATPase in tubulovesicles of parietal cells
    • Example: Omeprazole (it is a prodrug)
    • Steps to activation/use of drug:
    • 1: Accumulation in canaliculi-drug enters cell from circulation and, because is a weak base, accumulates in the acidic secretory canaliculi
    • 2: Activation-Once in the canaliculi, the drug is converted via proton-catalyzation into the sulfenamide
    • 3: Pump inhibition-irreversible covalent modification of the pump at the sulfhydryl group of cysteines on the extracellular domain
    • Pharmakokinetics:
    • 1: Delivery of the drug-Because it is unstable at low pH, delayed-release is necessary to prevent degradation (capsule only dissolves in alkaline pH, allowing small intestinal absorption)
    • 2: Absorption is rapid and highly protein-bound
    • 3: Metabolism occurs extensively in liver via cytochrome P450
    • SE:
    • 1: Increase drisk of hip/wrist/spine fractures due to decreased acid causing decreased calcium absorption and/or decreased osteoclast function
    • 2: Pneumonia/other infections because decreased acid leads to increased bacterial colonization of the stomach and intestine, including Clostridium difficile and community-acquired respiratory infections)
    • 3: B12 absorption problems
    • 4: Gastric carcinoma because the decreased acid causes hypergastrinemia and ECL derived tumors
    • 5: Hypomanesemia in prolonged use
  32. Omeprazole
    • MoA: Proton pump inhibitor the blocks the H+/K+/ATPase in tubulovesicles of the parietal cell membrane
    • Use: Peptic ulcer, gastritis, esophageal reflux, Zollinger-ellison syndrome
    • Pharma
    • SE: Increased hip/wrist/spine fractures, increased infections (pneumonia, Clostridium dificile), B12 absorption issues, gastric carcinoma, and hypomanesimia (prolonged use)
  33. PPIs vs. H2 antagonists
    • Mechanism: PPIs are irreversible pump modification, H2 are competitiv receptor antagonist
    • Effectivity: PPIs effective regardless of stimulus to parietal cell; H2 antagonists effect in noctural acid secretion
    • Time to effective inhibtion: PPIs take 2-5 days, H2 antags take minutes
    • Metabolism: PPIs extensively in liver, H2 antags excreted mostly un-metabolized in urine
    • Protein binding: PPIs have extensive binding, H2 antags have very little
    • Resumption of acid secretion: after 24-48 hours with PPI; after 6-8 with H2 antag
    • GERD healing rate: 80-90% with PPI; 50-75% with H2 antag
    • Cost: PPIs are expensive while H2 antag are cheap
  34. Gastric mucosal defense
    Includes sucralfate, misoprostol, and bismuth subsalicylate
  35. Misoprostol
    • MoA: Modified synthetic PGE1 that stimulates mucus and bicarb secretion and mucosal blood flow
    • Action: Can provide significant decrease in basal or food stimulated parietal cell acid secretion
    • Use: Preventing mucosal injury caused by NSAIDs
    • SE: diarrhea, cramping
    • Contraindicated: in pregnancy because causes uterine contractility
  36. Sucralfate
    • MoA: A sulfated polysaccharide that crosslinks and polymerizes in acidic environments, causing a viscous sticky gel that adheres to epithelial cells (use on an empty stomach)
    • Action: Binds selectively to ulcers or erosions for 6 hours, inhibiting mucosal erosion and ulceration; negatively charged sucrose sulfate binds to positively charged proteins at the ulcer base
    • Use: Increase ulcer healing and traveler's diarrhea
    • SE: Constipation (due to aluminum absorption and for this also a risk of renal insufficiency)
  37. Therapy for H. Pylori infection
    • Triple therapy: omeprazole or ranitine (2x per day) plus 2 antibiotics 2x per day (amoxicillin, clarithromycin, metronidazole)
    • Quadruple therapy: omeprazole (2x per day), tetracycline (4x per day), bismuth subsalicylate (4x per day), metronidaxole (3x per day)
  38. Mechanism of nausea and vomitting
    • It is a protective thing that aims to rid the stomach and intestine of toxic substances and prevent further ingestion
    • It consists of multiple phases:
    • Pre-ejection phase: gastric relaxation and retropreistalsis
    • Retching: Rhythmic action of respiratory muscles the precedes vomiting. It consists of contraction of abdominal, intercostal, and diaphragmatic muscles against the closed glottis
    • Ejection: Intense contraction of the abdominal muscles and relaxation of UES
  39. Important inputs for the vomiting relflees
    • Three main inputs to a central emetic center: 1. Chemotriggerzone (CTZ) with 5HT3, D2, and NK1 receptors 2. Solitary Tract Nucleus (STN) with 5HT3, M1, H1, and NK1 receptors 3) The cerebellum with H1 and M receptors
    • Pathway of CTZ: Blood-borne emetics and cytotoxic drugs trigger 5HT3, D2, and NK1 receptors in the CTZ, which relays to the vomiting center
    • Pathway of STN: Two routes. 1) Gagging in the pharynx leads to activation of glossopharyngeal and trigeminal afferents that go to 5HT3, M1, H1, and NK1 receptors in the STN and then the vomiting center 2) Vagal and sympathetic afferents from the stomach and small intestine activate 5HT3, NK1, M1, H1 receptors in STN
    • Pathway of cerebellum: Motion in the inner ear leads to activation of H1 and M receptors in the cerebellum which relays to the vomitting center
  40. CTZ
    • Pathway:Blood-borne emetics and cytotoxic drugs trigger 5HT3, D2, and NK1 receptors in the CTZ, which relays to the vomiting center
    • Pharmacology: 5HT3 receptors, D2 receptors, NK1 receptors
  41. Solitary tract nucleus (STN) or nucleus tract soltarus (NTS)
    • Pathway of STN: Two routes.
    • 1) Gagging in the pharynx leads to activation of glossopharyngeal and trigeminal afferents that go to
    • 5HT3, M1, H1, and NK1 receptors in the STN and then the vomiting center
    • 2) Vagal and sympathetic afferents from the stomach and small intestine activate 5HT3, NK1, M1, H1 receptors in STN
    • Pharmacology: 5HT3, M1, H1, and NK1 receptors
  42. 5-HT3 antagonists and nausea
    • Most effective for chemotherapy-induced emesis because 5HT receptors play a role in motility reflexes and vagal afferents
    • 1: 5HT is released from ECL cells to act on the 5HT3/4 receptors of intrinsic sensory neurons (initiating peristalsis) and on 5HT3 receptors of vagal neurons (mucosal disruption that leads to nausea via the CTZ and STN pathways)
    • 2: 5HT is also released from neurons in the myenteric plexus, which modulates motility reflexes and stimulates motility
  43. Ondansetron
    • MoA: Blocks 5HT3 receptors in several locations, preventing 5HT signaling from enterchromaffin cells (no stimulation of vomittijng reflexes) and also inhibiting 5HT's effect in STN and CTZ
    • Use: Very effective for chemo-induced nausea and vomitting, also used for nausea secondary to upper abdominal irradiation, hyperemesis of pregancy, postoperative nausea (although less effect) but NOT motion sickness
    • Pharmacokinetics: long lasting effects, is well absorbed from GI tract, and is given in single IV dose (or orally)
    • SE: headache and constipation
  44. Cerebellum
    Pathway: Motion in the inner ear leads to activation of H1 and M receptors in the cerebellum which relays to the vomitting center
  45. Scopolamine
    • MoA: MR antagonist that blocks muscarinic input from inner ear to vomiting center via the cerebellum
    • SE: Dry mouth, blurred vision, drowsiness, amnesia
    • Use: preventing and treating motion sickness (significantly more effective at preventing), some use in postoperative nausea and vomiting, NOT used for chemo-induced nausea
    • Note: Given as transdermal patch
  46. Promethazine
    • MoA: First generation H1 receptor antagonist that works via the STN pathway
    • Actions: Crosses blood brain barrier
    • Use: antiemetic
    • SE: significant muscarinic receptor antagonism (sedation) and drowsiness
  47. Dimenhydrinate
    • Aka Dramamine
    • MoA: First generation H1 receptor antagonist
    • Use: antiemesis (effective for motion sickness)
    • SE: Has less D2 effect than promethazine but still has antimuscarinic effects
  48. Dopamine receptor antagonists for antiemesis
    • Among most commonly used for general purpose antinauseants and anti-emetics
    • Examples: Phenothiazines, chlorpromazine (high doses cause thorazine shuffle and extrapyramidal side effects), and meoclopramide
    • MoA: D2 antagonists that reduce inputs to CTZ
    • Use: Not as uniformly effective with chemo induced emesis BUT are valuable in motion sickness due to antihistamine and anticholinergic activity; some also have prokinetic effects (like metoclopramide)
  49. Phenothiazine
    • MoA: D2 receptor antagonist
    • Use: Antiemesis, especially motion sickness
  50. Chlorpromazine
    • MoA: D2 receptor antagonist
    • Use: anti-emesis especially motion sickness
    • SE: Thiazine shuffle and extra pyramidal effects
  51. Aprepirant
    • MoA: Non-peptide inhibitor of NK1 receptors that crosses the blood-brain barrier and acts in the CTZ and STN
    • Use: Chemotherapy induced nausea, especially in combination with 5HT3 antagonists; can be very effective for preventing delayed emesis
  52. Dronabinol (delta-9-tetrahydrocannabinol or delta9-THC)
    • MoA: CB1 cannabinoid receptor agonist that causes presynpatic inhibition of NT release on neurons in/projecting to the vomiting center (non-specifically shuts down all the inputs)
    • Pharmacokinetics: Highly lipid soluble with a large volume of distribution
    • Use: Prophylactic antiemetic in chemo patients who don't respond well to other medications, stimulates appetite (useful in some cases)
    • SE: Abuse potential and significant side effects
  53. Emetics
    • Drugs that induce vomiting
    • Examples: Ipecac and apomorphine
    • Risks generally outweigh the benefits of using these because they can induce seizures, pneumonitis, and pneumonia
  54. Ipecac
    • MoA: a local irritant of the duodenum that also stimulates the CTZ
    • Note: Because of the intestinal action, it is effective even when antiemetic drugs are present
  55. Apomorphine
    • MoA: D1 and D2 receptor agonist that stimulates CTZ
    • SE: Respiratory depressant, so be careful with some types of poisoning
    • Note: Because it is unstable, is prepared just prior to use via the subcutaneous route
  56. Inflammatory Bowel Disease
    • Consists of Ulcerative Colitis or Crohn's Disease
    • Ulcerative colotis: a chronic but superficial inflammatory process that is confined to the colon where involvement begins with the rectum and moves proximally
    • Crohn's diease: a transmural inflammatory process that can involve any part of the GI tract from mouth to anus and is characterized by skip lesions, fistulas, granulomas, and abscesses; note that the ileocecal valve region is most commonly affected
    • Both present with secretory diarrhea, ulceratoin, exudation with protein-losing enteropathy, bleeding, and malabsorption
  57. Pharmacotherapy of IBD
    • A complex process that aims for symptomatic relief, induction of remission, prevention of relapse, healing of fistulae, and avoidance of emergent surgery
    • Mild disease: 5-aminosalicylates
    • Moderate disease: glucocorticoids (prednisone)
    • Advanced disease: Infliximab (TNA alpha antagonists)
    • Recurring disease: Purine analogs (6MP/Azothioprine) and methotrexate
    • There is also supportive therapy, including analgesic, anticholinergic (useful for intense muscle pains and constrictions seen in Crohn's), and antidiarrheal agents
  58. Sulfasalazine
    • MoA: a 5-aminosalicylate that inhibits the cyclooxygenase and 5-lipoxygenase pathways of AA metabolism
    • Pharmacokinetics: Parent compound is cleaved by bacterial azoreductases found the colon to form 5-ASA (active compound) and sulfapyridine (causes side effects)
    • SE: malaise, myalgia, general unhappiness, sulfonamide toxicity, reversible oligospermia
    • Use: Effective in UC but not very effective in Crohn's (because it affects small intestine, where drug is inactive; nevertheles speople are still started on this for Crohn's)
  59. Prednisone
    • MoA: Glucocorticoid that is an effective inflammatory agent
    • Causes remission in up to 90% of UC pt and 69-90% of pt with active Crohn's
  60. Azathioprine and 6-Mercaptopurine (6-MP)
    • MoA: Immunosuppressive purine antimetabolites that inhibit cell division and proliferation
    • Causes 50-60% remission in both UC and Crohn's patients in 3-6 months, with 80% of those maintaining remission
    • SE: Nausea, vomiting, bone marrow depression, hepatotoxicity
  61. Methotrexate
    • MoA: Inhibites production of purines and thymidine, preventing cellular proliferation; also interferes with inflammatory responses such as IL1 and t-lymphocytes
    • Effective in Crohn's but use in UC is not clear
    • Note: Folate supplementation is recommended
  62. Infliximab
    • MoA: TNF-alpha antagonist that binds and neutralizes activity of TNF-alpha; also promotes complement activation and apoptosis of activated T lymphocytes
    • IV infusion
    • Causes symptomatic relief in 70% of Crohn's and UC patients, with remission in 30%; effective in 2 weeks
    • SE: Infection (esp respiratory) because of immune suppresion, fever, hypotension
Card Set
GI pharm
GI pharm