1. Things involved in path of peptic ulcer dz (not completely understood.)
    • 1. Heliobacter pylori infxn
    • 2. increased hydrochloric acid secretion
    • 3. inadequate mucosal defense against gastric acid
  2. 3 Treatment approaches for Peptic ulcer dz
    • 1. eradicate H. pylori infxn
    • 2. reduce secretion of gastric acid w/ use of H2 antagonists or PPI's
    • 3. give agents that protect gastric mucosa from damage
  3. Categories of drugs used to treat Peptic Ulcer dz
    • Antimicro agents
    • 1. Amoxicillin
    • 2. Bismuth compounds
    • 3. Clarithromycin
    • 4. Metranidazole
    • 5. Tetracycline
    • H2-Histamine receptor blockers
    • 1. Cimetidine
    • 2.Famotidine
    • 3. Nizatidine
    • 4. Ranitidine
    • Inhibitors of Proton Pump
    • 1. Esomeprazole
    • 2. Lansoprazole
    • 3. Omeprazole
    • 4. Pantoprazole
    • 5. Rabeprazole
    • Prostaglandins
    • 1. Misoprostol
    • Antimuscarinic agents
    • 1. Dicyclomine
    • Antacids
    • 1. Aluminum hydroxide
    • 2. Calcium hydroxide
    • 3. Magnesium hydroxide
    • 4. Sodium bicarb
    • Mucosal protective agents
    • 1. Bismuth subsalicylate
    • 2. Sucralfate
  4. Antimicrobial agents percent eradicated and the 2 types of therapy?
    80-90% eradicated with antimicrobe therapy and low recurrence rate!

    2 types of therapy

    1. Triple therapy: PPI+metronidazole or amoxicillin+clarithromycin

    2. Quadruple therapy: bismuth subsalicylate+metronidazole+tetracycline+PPI

    • Both administered for 2 wk course
    • Note: bismuth salts inhibit pepsin and up mucus secretion
  5. Is H. Pylori associated with GERD?
  6. How are Gastric secretions regulated?
    Gastric acid secreted by parietal cells of gastric mucosa.

    stimmed by acetylcholine, histamine, and gastrin.

    Stim results in activated protein kinases, these stim H+/K+ ATPase proton pump, secrete H+ ions in exchange for K+ into stomach lumen. A Cl- channel couples chloride efflux with release of H+.

    In contrast, receptor binding prostaglandin E2 and and somatostatin downs gastric acid production.

    • Note: Histamine activated adenylate cyclase (E2 inhibits this enzyme.
    • Note: Gastrin and Ach induce increase in intracell Ca2+
  7. H2 receptor antagonist overview.
    cimetidine, ranitidine, famotidine, and nizatidine

    block action of histamine at al H2 receptors, but most impt is hinhibit gastric acid secretion (most effective during sleep.)

    competitively blocks Hist, reduces intracell cAMP, thus reduce gastrin secrete.

    all potently inhibit (90%) basal, food generated, and night acid after 1 dose.
  8. Describe H2 receptor antagonists actions?
    act selectively on H2 receptors in stomach, BV's, etc.

    But, no effect on H1 receptors.

    Fully reversible, comp antagonists of histamine

    completely inhibit gastric acid induced by hist or gastrin

    But, only partial inhibit Ach or bethanechol induced
  9. Therapeutic uses of H2 blockers
    Their use has declined b/c of PPI's

    Peptic ulcers: all 4 promote healing of duodenal and gastric ulcers. But, recur common after treat stopped. Pts with NSAID ulcers=PPI's (heal AND prevent future ulcers better.)

    Acute Stress ulcers: useful for ulcers ass w/ major physical trauma in high risk ICU pts. Usually I.V.

    Gastroesophageal reflux dz: low dose effective in prevent and treat heartburn. But, 50% don't benefit, and now PPI's used. H2's may not give relief for about 45 min (antacids quicker at neutralize acid already in stomach, but short lived.) Tolerance for H2 therapy seen after 2 wks.
  10. Cimetidine Pharmacokinetics
    all H2's given or5ally, distribute widely (includes breast milk and placenta), and excreted mainly in pee.

    Cimetidine has short serum half life, this is increased in renal fail.

    30% of dose inactivated slowly by liver, rest secrete unchanged in pee.

    dosage of all 4 decreased w/ hepatic or renal fail.

    Cim inhibits P450 and slows metablism of other drugs (ex: warfarin, diazepam, phenytoin, quinidine, carbamazepine, theophylline, and imipramine)
  11. Ranitidine Pharmakokinetics
    Compared to cimetidine, ran is longer acting and 5-10X more potent.

    minimal side efx, does not produce antiandrogenic or prolactin stim efx of cimetidine.

    no drug interaction
  12. Famotidine and Nizatidine Pharmacokinetics
    Famotidine: is similar to ran in action, but 20-50x MORE POTENT than cimetidine, and 3-20x more than ran.

    Nizatidine: similar to ran in action and potency. Unlike the other 3, Nizat not metabbed in liver at all! All Kidney. So bioavailability orally is 100%. No I.V. available b/c of this.
  13. H2 antagonists adverse efx
    mostly cimetidine

    usually minor and ass w/ major pharm activity of drug. Side efx in small number pts and usually don't discontinue

    most commone: HA, dizzy, diarrhea, and muscle pain.

    Other CNS efx: usually in elderly. confusion and hallucination.

    Cim also has endocrine efx b/c acts as nonsteroidal antiandrogen. Gynecomastia, galactorrhea, and low sperm count.

    except for fam, all inhibit gastric first pass metab of ethanol

    ketoconazole depends on acid for gastric absorb, not effective when taken with H2's
  14. PPI's: names and actions
    Omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole.

    Actions: prodrugs with acid resistant coating. in alkaline duodenum, coat removed and prodrug (weak base) absorbed and transport to parietal cel canaliculus.

    Once there, converted to active form, which reacts w/ cysteine residue of H+/K+ ATPase, forms covalent bond.

    18 hrs for enzyme to be resynthed. Acid inhibit starts in 1-2 hrs with lanso and earlier with omep.
  15. PPI Therapeutic uses
    preferred drugs for treating erosive esophagitis and active duodenal ulcer and long term treat of pathologic hypersecretory conditions (ex: zollinger ellison)

    Used to treat GERD

    Used in conjunction w/ antimicrobial in H. Pylori

    for max effect: take 30m before breakfast or largest meal of day.
  16. PPI pharmacokinetics and adverse efx
    Pharmacokinetics: all delayed release and effective orally. some can give IV. Metabolites excreted in urine and feces

    Adverse efx:

    Generally well tolerated, but concern about long term safe b/c increased gastrin secretion. Gastic carcinoid tumors up in animals.

    Omeprazole inhibits drug metab of warfarin, phenytoin, diazepam, and cyclosporine, other PPI's no problem here.

    Long-term gastric acid suppression may lead to low B12 (acid required for it's absorption.) Also calcium carbonate needs acid for full absorption, so up pH in upper int is an issue. Calcium citrate is often used b/c it doesn't need acid to absorb.

    increased reports of diarrhea and Clostridium difficie colitis in pts, so discontinue if diarrhea for a few days and see doc.
  17. Prostaglandins and Misoprostol
    E2 is produced by gastric mucosa. it inhibits secr4etion of GCl and stims secreation of mucus and bicarb.

    deficient E2 is involved in peptic ulcer formation.

    Misoprostol: stable analog of E1, it along w/ some PPI's approved for preventing NSAID gastric ulcers.

    Miso less effective than H2's and PPI's on peptic ulcers.

    Miso prophylactic in pts at risk for NSAID ulcers (elderly or ulcer complications.)

    Miso reduces serious GI complications in pts with rheum arth getting NSAID's

    Miso, like all prostaglandins, causes uterine contraction. No in preggers.

    Most common miso SE: dose related diarrhea and nausea. these limit miso's use.
  18. Antimuscarinic Agents: Dicyclomine
    Musc receptor stim ups GI motility and secretion activity. A chol antagonist (dicyclomine) used as adjunct in managing pept6ic ulcer dz and Zollinger Ellisons syn.

    Especially in pts refractory to standard therapy.

    Many side efx however: cardiac arrythmia, dry mouth , constipate, urinary retention. This limits its use.
  19. Antacid names, Chemisty, and Therapeutic uses
    Aluminum hydroxide, Calcium carbonate, Magnesium hydroxide, and Sodium bicarb

    Antacids are weak bases. React w/ gastric acid to form water and salt, and rais pH. Also reduce pepsin activity b/c pepsin is inactive at ph>4.

    Chemistry. Actions vary widely. effectiveness depends on it's ability to neutralize and whether stomach is full or empty.

    Note: Calcium carbonate reacts w/ HCl to form CO2 and CaCl2.

    Note: Systemic absorb Sodium bicarb can cause metabolic alkalosis for short time, this limits it for long term use.

    • Therapeutic Uses:
    • 1. Symptomatic relief of peptic ulcer dz and GERD.
    • 2. may promote ulcer heal in duodenum, but iffy for gastric, so last line therapy.
    • Note: Calcium carbonate preps also used for Ca supplements to treat osteoporosis
  20. Antacids adverse efx
    • Aluminum hydroxide: constipating
    • Magnesium hydroxide: diarrhear
    • Combine above in preps to normalize bowels.

    binding of phosphate by aluminum containing ones: hypophosphatemia

    Sodium bicarb: systemic alkalosis, liberates CO2 and causes belching and farting.

    Extra cations can be a problem w/ CHF, htn, or HF pts.

    renal impaired: accumulate cations. bad.
  21. Mucosal protective agents
    cytoprotective compounds. prevent mucosal injury, down inflammation, and reduce ulcers.

    1. Sucralfate: complex of AlOH. binds to pos charge proteins in both normal and necrotic mucosa. creates physical barrier that impairs HCl diffusion and prevents mucus degradation by pepsin and acid. also stims prostaglandin release, mucus, and bicarb output. Requires acidic env to activate, so CANT BE USED W/ H2'S OR PPI'S. DOES NOT prevent NSAID ulcers or heal gastric ulcers.

    2. Bismuth subsalicylate: effectively heal peptic ulcers. Also inhibit pepsin activity, up mucus, and interact w/ glocyproteins in necrotic mucosa to coat and protect ulcer crater
  22. Categories of Drugs used to Treat Chemo induced N/V
    • Phenothiazines
    • 1. Prochlorperazine
    • 5HT3 serotonin receptor blockers
    • 1. Dolasetron
    • 2. Granisetron
    • 3. Ondansetron
    • 4. Palonosetron
    • Substituted Benzamides
    • 1. Metoclopramide
    • Butyrophenones
    • 1. Droperidol
    • 2. Haloperidol
    • Benzodiazepines
    • 1. Alprazolam
    • 2. Lorazepam
    • Corticosteroids
    • 1. Dexamethasone
    • 2. Methylprednisolone
    • Cannabinoids
    • 1. Dronabinol
    • 2. Nabilone
    • Substance p/ neurokinin1 receptor blocker
    • 1. Aprepitant
  23. Mechanisms that trigger vomiting
    2 brainstem sites have key roles

    • 1. chemoreceptor trigger zone: located in area postrema.
    • it's outside BBB, so so can repond directly t6o chem stimuli in blood and CSF.

    • 2. Vomiting center: located in lateral reticular formation of medulla.
    • coordinates motor mech of vomiting.
    • also responds to afferent input from vestibular system, periphery, and higher brainstem and cortical places.
    • Vestibular system=motion sickness
  24. Emetic actions of chemo agents
    Chemo agents can directly activate medullary chemo receptor or vomiting center. dopamine type 2 and serotonin type 3 (5HT3) receptors play key roles. color or smell of chemo drugs can trigger high brain centers and cause emesis.

    chemo drugs can act peripherally: damage GI tract and release serotonin from enterochromaffin cells in sm int mucosa. serotonin hits 5HT3 receptors on vagal and splanchnic afferents, carry to medulla, emesis.
  25. Potencies of the antiemetic drugs
    • High Potency:
    • Serotonin antagonist
    • Substituted benzamide
    • Phenothiazine

    • Med Potency:
    • Butyrophenone
    • Corticosteroid
    • Cannabinoid
    • Low Potency:
    • Antihistamine
    • Anticholinergic
    • Benzodiazepine
  26. Phenothiazines: Prochlorperazine
    blocks dopamine receptors.

    effective against low or moderate ematogenic chemo drugs (ex: flourouracil and doxorubicin.)

    Upping dose ups antiemetic activity, but side efx are dose limiting

    Side efx: hypotnsn and restlessness, extrapyramidal, sedation.
  27. 5-HT3 receptor blockers: Ondansetron, granisetron,palonosetron, and dolasetron
    important in treating chemo emesis b/c long duration of action.

    selectively block 5HT3 receptors in periphery (visceral and vagal afferents) and in brain (chemo trigger zone.)

    can be used single dose before chemo (IV/oral) or after.

    All these extensively metabbed in liver

    Hydroxydolasetron is active metabolite of dolas

    adjust dose in hep insufficiency

    Elim through urine

    HA common SE

    In dolas: prolonged QT changes.
  28. Substituted benzamides: metoclopramide
    highly effective at high doses against cisplatin.

    Antidopaminergic side efx: sedation, diarrhea, and extrapyramidal. Limits high dose use.
  29. Butyrophenones: droperidol, haloperidol
    block dopamine receptors.

    moderately effective.

    Droper used for sedation in endoscopy and surgery, comboed w/ opiates or benzos.

    Droper may prolong QT interval

    High dose halo good w/ cisplatin
  30. Benzodiazepines: Alprazolam and Lorazepam
    low potency

    useful in anticipatory vomiting
  31. Cotrticosteroids: Dexamethasone and methylprednisolone
    alone, effective against mild to mod emetic chemo drugs.

    Usually, though, used in comgbo.

    Mech not known for anti emesis.

    Side efx: insomnia, hyperglycemia in diabetes pts
  32. Cannabinoids: dronabinol, and nabilone
    Marijuana derivatives

    effective against moderately emetic chemo.

    seldom first line b/c serious side efx.

    Side efx: dysphoria, hallucinate, sedate, vertigo, disorient.
  33. Sub P/Neurokinin-1 receptor blocker: Aprepitant
    new family of antiemetics

    Targets neurokinin receptor in blrain and blocks action of natural substance.

    usually given oraly with dexamethasone or palonosetron.

    Extensive metabolism: CYP3A4. Can effect other drugs

    use with warfarin can shorten half life of anticoagulant

    Side efx: constipation and fatigue
  34. Combo Antiemetic regimens
    Dexamethasone ups antiemetic activity when given with high dose metoclopramide, phenothiazine, butyrophenone, or benzodiazepine.

    Antihistamines like diphenhydramine, given in combo with high dose metoclopramide to reduce extrapyramidal rxns, or with corticosteroids to counter metoclopramide induced diarrhea
  35. Drug categories for diarrhea and constipation
    • Antidiarrheals:
    • Aluminum hydroxide
    • Bismuth subsalicylate
    • Diphenoxylate
    • Loperamide
    • Methylcellulose

    • Laxatives:
    • Bisacodyl
    • Bran
    • Castor oil
    • Docusate sodium
    • Docusate calcium
    • Glycerin suppositories
    • Hydrophilic colloids
    • Lactulose
    • Magnesium citrate
    • Magnesium hydroxide
    • Magnesium sulfate
    • Methylcellulose
    • Mineral oil
    • Polyethylene glycol
    • Psyllium seeds
    • Senna
    • Sodium phosphate
  36. Antidiarrheals: Antimotility agents
    diphenoxylate and Loperamide

    Both analogs of meperidine, have opioid actions on gut.

    Activates presynaptic opioid receptors in enteric NS to inhibit ACh release and down peristalsis.

    Dose too low for analgesic efx

    Side efx: drowsy, ab cramps, dizziness.

    both can CONTRIBUTE TO TOXIC MEGACOLON and not used in young kids or pts w/ sever colitis
  37. Antidiarrheals: Adsorbents
    Bismuth subsalicylate, methylcellulose, and aluminum hydroxide.

    act by adsorbing intestinal toxins, or bacteria, or coating/protecting the int mucosa.

    much less effective than antimotility agents.

    Can interfere w/ absorb of other drugs
  38. Antidiarrheals: agents that modify fluid and electrolyte transport
    Bismuth subsalicylate, used for travelers diarrhea, downs fluid secretion in bowel.

    action b/c of coating action or maybe salicylate component
  39. Laxatives: General
    All laxatives can be HABIT FORMING

    up potential loss of pharm efx of some agents

    may cause electrolyte imbalance when used chronically
  40. Laxatives: Irritants and stimulants
    • 1. Senna: widely used stim laxative.
    • Its active ingredient is group of sennosides, natural complex of anthraquinone glycosides.

    If take orally: causes bowel evac in 8-10h. also cause water and electrolyte secretion into bowel.

    in combo with docusate stool softener, usefel for opioid induced constipation.

    2. Bisacodyl: suppository or tablets

    colon stimulant: acts on nerve fibers in mucosa of colon.

    Side efx: ab cramps and possible atonic colon w/ chronic use.

    Antacid can't be taken at same time: cause coated tablet to dissolve to early. Stomach irritate and pain.

    3. Castor oil: broken down in sm int to ricinolenic acid, very irritating to gut, ups peristalsis.

    avoid in preggers, may stim uterine contractions
  41. Laxatives: Bulk Laxatives
    1. hydrophilic colloids: from indigestible parts of fruit and veggies.

    form gels in lg int, cause water retention and int distention. Ups peristaltic activity.

    2. Methylcellulose, psyllium seeds, and bran: all similat to above.

    All should be avoided in bed bound pts: intestinal obstruct.
  42. Laxatives: Saline and Osmotic Laxatives
    1. Saline Cathartics: Mag citrate, Mag sulfate, Sodium phosphate, and Mag hydroxide.

    All non absorbable salts that hold wter in int by osmosis and sisten bowel. this ups Int activity and causes defecation.

    2. Electrolyte solutions: contain polyehtylene glycol (PEG)

    used as colonic lavage solution to prep gut for radiologic or endo preocedures.

    3. Lactulose: semi synth disaccharide sugar. also acts as osmotic laxative.

    Cannot be hydrolyzed by int enzymes.

    oral doses degraded in colon by colon bac into lactic, formic, and acetic acids. this ups osmo pressure, accumulate fluid, distend colon, create soft stool, and cause pooping!
  43. Laxatives: Stool softeners
    Emmolient Laxatives or surfactants

    Surface active agents that become emuslified in stoll.

    causes softer poo.

    • 1. docusate sodium
    • 2. docusate calcium
    • 3. docusate potassium

    all may take days to be effective.

    Not taken together with mineral oil b/c potential for absorption of mineral oil.
  44. Laxatives: Lubricant laxatives
    • 1. Mineral oil
    • 2. glycerin suppositories

    facilitate passage of hard stools.

    Mineral oil should be taken oral in upright position to avoid aspiration and possible lipid or lipoid pneumonia.
Card Set
Lippincotts Ch 28 GI and Antiemetic drugs