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IC Week 2
Overview of GI Diseases
o Disorders principally of either Altered secretion or altered motility o Most common secretory disorder is acid-peptic disease which includes: Peptic (gastric & duodenal) ulcer disease [PUD] Gastroesophageal reflux disease [GERD, dyspepsia or heartburn] Hypersecretory states [Zollinger-Ellison syndrome] o Lifetime prevalence of peptic ulcer is ~ 10%, while heartburn occurs in about 50% of healthy individuals o Goals for treatment of acid-peptic disease:
fo
1. relieve pain esophageal chemoreceptors 2. promote healing 3. prevent recurrence 1. neutralize gastric acid 2. reduce gastric acid secretion 3. enhance mucosal defenses by cytoprotective or antimicrobial activity
o In antrum of stomach, signaling through absorption of dietary intake will gate gastrin release which will be modified by para inputs & somatostatin locally o What drives acid secretion via proton pump 1. Signalling from Muscarinic receptor 2. ECL cells release gastrin & histamine
muscarinic gastrinCCK B H2
o Anti-muscarinic drugs Parasympathetic system Agents like atropine will inhibit para drive Seen as acute tx or as adjuncts to other therapies
(H2 antagonists) if approaches not working
Relatively weak inhibitors of acid secretion because they act at only one site No selective CCK antagonists but ultimately gastrin stimulates acid production through histamine. So blocking Histamine will prevent Family of peptide hormones formed by gastric mucosal cells Stimulates gastric motility, HCl & pepsin secretion No direct gastrin antagonists
o Inhibit gastric secretion, Reduce amount of acid (antacids) o Agents that helps establish/maintain gastric layer
o Gastrin:
o H2 antagonists
Reduce gastrin secretion Block histamine-induced cAMP & proton pump activation (gastric acid secretion) Histamine (via H2 receptor) enhances parietal cell Affinity for both gastrin & acetylcholine o H2 blockers are more effective than anti-
H2-Antagonists
o Four Preparations:
o Clinical Use: Most effective drugs for suppressing gastric acid secretion b/c gastric response to all stimuli is inhibited o A single daily dose inhibits gastric acid secretion by 95100% w/o affecting pepsin secretion or gastric motility o Inhibition of gastric acid secretion persists after withdrawal of drug: Irreversible inhibitors: time required to synthesize new proton pumps (H+/K+ATPase) o Generally well tolerated without producing serious adverse effects
OTC preparations inhibit acid secretion for < 6 hours Prescription doses inhibit 60-70% of total 24-hour acid secretion o Are all equally effective, rapidly & well absorbed orally, & generally well tolerated with few side effects o Are structural histamine analogs that block H2 receptors selectively to reduce gastric acid & pepsin secretion without affecting H+/K+ ATPase, H1, or any other receptors o Are especially effective against nocturnal secretion which is largely driven by histamine (i.e., reduced by 90% as compared with 60-80% inhibition of daytime acid secretion)
famotidine > nizatidine = ranitidine > cimetidine o H2-Receptor Antagonists: ADVERSE EFFECTS
Are extremely safe with minor & infrequent adverse effects DO NOT give to pregnant or nursing womenthey cross placenta & secreted into breast milk Most common side effects: diarrhea, headaches, fatigue, myalgias, constipation, & bradycardia Mental changes: confusion, hallucinations, & agitation may occur w/ IV administration in Elderly or pts w/ renal or hepatic dysfunction
o o o o o
GI effects (nausea, colic, flatulence, constipation, & diarrhea), CNS effects (headache, dizziness, somnolence), & skin rashes with prolonged use diarrhea often occurs due to GIT bacterial overgrowth from removal of natural acid barrier hypergastrinemia occurs in 5-10% of long-term users Hepatic metabolism with negligible renal clearance Intestinal absorption is rapid, but bioavailability of the absorbed form depends on activation at gastric acid pH Will promote peptic ulcer healing & prevent ulcer recurrence Are often effective in patients unresponsive to H2 antagonists More effective than H2 antagonists for GERD or NSAIDinduced peptic ulcers
o Clinical Uses:
impotence in men, & galactorrhea in women Inhibitis binding of dihydrotestosterone to androgen receptors & conversion of estrogen to dihydrotestosterone. Increases serum prolactin interferes with cytochrome P450 pathways
All are equally effective for healing & preventing recurrence of PUD Given once daily at bedtime to suppress nocturnal acid secretion will produce ulcer healing rates of > 80-90% after 6-8 weeks of treatment Their use declined markedly following the discovery of proton pump inhibitors & the role of H. pylori in
PUD 20% failure in smokers & elderly Should NOT be used in combo w/ PPI b/c they efficacy of by reducing acid activation Combine w/ antibiotics & bismuth for tx of pts w/ H. pylori infection
Antacids
o Directly chelate acid & turn it into water & salt neutralize the acidity: o Preparation: aluminum hydroxide, calcium carbonate, combo aluminum hydroxide & magnesium hydroxide o Seldom used (more convenient & effective drugs) Act by reducing gastric acidity Inactivating pepsin o MOA: Are weak bases that neutralize gastric HCl to form salt & water, & may interfere with absorption of other drugs Provide mucosal protection - stimulates PG synthesis o Aluminum or magnesium hydroxide either alone, or combined with NaHCO3 or a calcium salt o A single effective dose given 1 hr after eating neutralizes Click here to enter Summary for 2 hrs; 2nd dose 3 hrs after eating extend effect for 4 hr
causes inflammatory gastritis that may lead to peptic ulcers o Single antibiotic regimens are ineffective against H. pylori infection o Best txt regimen is 10-14 day triple therapy: Clarithromycin, 500 mg bid Amoxicillin, 1 gm bid Proton pump inhibitor, bid for patients allergic to penicillin, use metronidazole, 500 mg bid instead of amoxicillin
Aluminum salts Constipation Cation absorption & systemic alkalosis in renal patients o Vary widely in neutralizing capacity, taste, & price o Antacid tablets are generally weak, needed in large numbers, & not recommended for active peptic ulcers o Use as needed to relieve pain in esophagitis, peptic ulcer, & GERD
Binds to PG receptors on parietal cells to inhibit acid secretion b/c NSAIDs inhibit PG formation, misoprostol is used to prevent NSAID-induced ulcers exact mechanism uncertain but may be cytoprotective or inhibit histamine-stimulated gastric secretion Adverse effects: diarrhea & abdominal pain may cause abortion stimulates uterine contractions o Bismuth subsalicylate (Pepto-Bismol)-colloidal bismuth Protective coating of ulcers, Antibacterial against H. pylori OTC -- for treating dyspepsia & acute diarrhea Minimal Adverse effects but will darken tongue & stools b/c bismuth sulfide formed is a black solid
o Constipation may refer to: decreased frequency difficult initiation or passage passage of firm or small-volume stools feeling of incomplete evacuation
o LAXATIVES:
Constipation: Up to 25% of US population; most commonly women & elderly Drugs used to promote defecation & treat constipation are referred to as: laxative= cathartic = purgative = aperient = evacuant Laxatives are widely used w/o prescription & often abused by pts w/eating disorders to body weight Laxatives are usually unnecessary as constipation can be resolved by: increasing water & fiber content of diet appropriate bowel habits & training improved physical activity & exercise attention to psychosocial & emotional factors
Poorly absorbed in SI & require activation in colon w/laxative effects 6-12 hrs later Long-term use causes melanomic pigmentation of colonic mucosa & cathartic colon (colon becomes dilated & ahaustral) o Ricinoleic acid (castor oil): a local irritant that increases intestinal secretion & motility; now seldom used due to unpleasant taste & toxic potential
senna
o methylcellulose, lactulose, & polycarbophil Stool Softeners o Mineral oil, glycerin suppositories, & docusate sodium
o AVOID IN :
Nondigestible sugars & alcohols o Glycerin trihydroxy alcohol that acts in the rectum as
a lubricant & hygroscopic agent water retention stimulate peristalsis Moves water into stool & helps ease of passage
o Agents that soften stools & facilitate expulsion o Given orally or rectally o Docusate Na+ is often prescribed to prevent straining in hospitalized patients Important for cardiac/abdominal procedure pts!
hydrolyzed to organic acids acidify luminal contents draw H2O into lumen colonic propulsive motility o Polyethylene glycol (PEG)-electrolyte solutions poorly absorbed & retain added water by their high osmotic pressure Prepared as mixtures of sodium sulfate, sodium bicarbonate, sodium chloride, & potassium chloride in isotonic solution containing 60 g of polyethylene glycol per liter; Colonoscopy preparation: drink 3-4 liters over 3-4 hrs to produce watery diarrhea & remove solid wastes
o Most widely used are loperamide, diphenoxylate, difenoxin, bismuth subsalicylate, & kaolin/pectin
Produce sedation & antimuscarinic activity Clinical Use: Prevents motion sickness
MOA: act on intestinal opioid receptors (Mu-R) to inhibit Ach release motility (peristalsis) SE includes CONSTIPATION: o Loperamide is 40-50 times more effective than morphine for diarrhea does not cross BBB Opiods that ONLY produce the SE of constipation w/o CNS effects! Acts quickly on oral administration Clinical Use: Travelers diarrhea, should DC if no improvement w/in 48 hrs (prevent constipation) Adverse Effects: few adverse effects & more is effective than diphenoxylate (atropine is added to diphenoxylate as deterrent of abuse)
peak levels at 3-5 hrs Relief of acute, non-specific diarrhea
Have anti-muscarinic activity: CNS centers responsible for nausea & dizziness have both histamine AND muscarinic signaling. Therefore, these drugs prevent motion sickness by blocking both MRs & histamine receptors.
HT3 antagonists:
Clinical Use: Nausea & vomiting during cancer chemo o Phenothiazines & Benzodiazepines - antiemetics
MOA: Absorb compounds & presumably binds potential intestinal toxinsChalk & jelly-- MOA: inhibits intestinal secretions Clinical Use: Management of infectious diarrhea
o Bismuth subsalicylate
Tx of IBD:
Ulcerative Colitis. Crohns Disease.
Gut GI lipase inhibitor Reduces absorption of fats since triglycerid es not split GI: Flatulence, steatorrhe a, fecal incontinen ce
Toxicity
Treatment of IBS
o Tricyclic antidepressants (1st gen)
Low doses of amitriptyline or desipramine Treatment of the abdominal pain Limit nociceptive signalling
Reduce absorption of dietary intake or reduce appetite. Long term use & effectiveness are not as clear
o 5-HT3 antagonist