Treatment of GI disorders

IC Week 2

Monday, March 26, 2012 McCarson

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

o Anti-ulcer drugs act to:

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

3 Pathways Regulating Gastric Acid Secretion

PATHWAY MEDIATOR RECEPTORS ANTAGONIST

1) neural 2) endocrine 3) paracrine

acetylcholine gastrin histamine

muscarinic gastrinCCK B H2

antimuscarinic H2 blocker H2 blocker

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-

Proton Pump Inhibitors

o Benzimidazole compounds irreversibly inhibit parietal cell proton pump, H+/K+ATPase o Are pro-drugs that are inactive at neutral pH Activated in an acid environment (take w/ food) Unstable at a low pH, to avoid degradation by acid in esophagus & stomach, dosage forms are supplied as enteric coated granules that dissolve only at alkaline pH (absorbed in intestine) After passing through the stomach, enteric coatings dissolve & the pro-drug is absorbed in intestines Carried by circulation to the parietal cells, where the drug accumulates in secretory canaliculi Activated at acid pH & form sulfonamide or sulfenic acid which binds sulfhydryl groups on H+/K+ ATPase o Preparations include:

H2-Antagonists
o Four Preparations:

cimetidine, famotidine, nizatidine, &ranitidine

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

esomeprazole, omeprazole, lansoprazole, pantoprazole, rabeprazole

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)

o Relative potency varies over a 50-fold range:

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 Adverse effects of PPI:

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

Cimetidine: (longest on the market)

Endocrine Side Effects: Gynecomastia or

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

Antimicrobial Drugs o Helicobacter pylori Gram-negative bacterium,

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

o Adverse effects: Magnesium salts Diarrhea

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

Mucosal Protective Agents

o Protective coating on peptic ulcers o Sucralfate (aluminum sucrose sulfate) binds selectively to necrotic ulcer tissue & acts as a barrier
Polymerizes to produce a viscous, sticky geladheres strongly to epithelial cells & ulcer craters in acid environment Effective in healing duodenal ulcers Side Effect Constipation Poorly absorbed systemically & has few adverse effects Requires acid pH for activation & should not be given together with antacids, H2 antagonists, or proton pump inhibitors Limits exposure to acid & pepsin

o Misoprostol - methyl analog of PGE1

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

Motility Disorders: CONSTIPATION

o The word constipation comes from two Latin words: con stipare crammed together o Exact definition is difficult but at least 3 times a week

Stimulant or Irritant Laxatives

o Drugs that act directly on enterocytes, enteric neurons, & muscle to induce low-grade inflammation water & electrolytes accumulate increase intestinal motility o Diphenylmethane derivatives like: Bisacodyl; Enteric coated, take at bedtime
Tablets should be swallowed without chewing or crushing. Avoids activation in the stomach (causing gastric irritation & cramping)

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

Phenolphthalein (withdrawn due to potential carcinogenicity) o Anthraquinonesaloe, cascara sagrada or

Osmotically Active Laxatives o Saline laxatives nonabsorbable salts containing

magnesium cations (magnesium citrate) or phosphate anions (sodium phosphate)
act by osmotic force to hold H20 inside intestines distend intestines stimulate peristalsis have an intensely bitter taste that is masked by adding citrus juices are usually well tolerated

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

Bulk Forming Laxatives

o Bulk-Forming Laxatives are dietary supplements that add bulk & hold water to intestinal contents o Polymers that hold water Ex. Metamucil

o methylcellulose, lactulose, & polycarbophil Stool Softeners o Mineral oil, glycerin suppositories, & docusate sodium

o AVOID IN :

renal insufficiency heart disease electrolyte imbalance diuretic drug co-treatment

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!

o Lactulose, sorbitol, & mannitolnonabsorbable sugars

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

Motility Disorders: DIARRHEA

Anti-diarrheal Drugs
o Acute-onset diarrhea is usually self-limited & seldom requires specific chemotherapy; drug therapy is often nonspecific

Anti-emetic Drugs o Histamine H1 Antagonists

First-generation H1 blockers Dimenhydrinate,

diphenhydramine, cyclizine, & meclizine

o Most widely used are loperamide, diphenoxylate, difenoxin, bismuth subsalicylate, & kaolin/pectin

Produce sedation & antimuscarinic activity Clinical Use: Prevents motion sickness

Opioid Drugs o Loperamide, difenoxin & diphenoxylate

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.

o Dopamine D2 & Serotonin 5-HT3 Antagonists

Mechanism of anti-emetic action: Unclear D2 antagonists:

HT3 antagonists:

Metoclopramide, trimethobenzamide Ondansetron, granisetron, & dolasetron

Clinical Use: Nausea & vomiting during cancer chemo o Phenothiazines & Benzodiazepines - antiemetics

o Kaolin (chalk) & pectin Kaopectate

MOA: Absorb compounds & presumably binds potential intestinal toxinsChalk & jelly-- MOA: inhibits intestinal secretions Clinical Use: Management of infectious diarrhea

o Bismuth subsalicylate

phenothiazines: Chlorpromazine, prochlorperazine benzodiazepines: Lorazepam, alprazolam (anxiety)

o Marijuana Derivatives

Motility Disorders: VOMITING

o Nausea & vomiting occur in various conditions pregnancy, motion sickness, GI obstruction, & cancer chemotherapy o Vomiting is a complex process coordinated by a medullary vomiting center that activates efferent pathways in vagus, phrenic nerves, & spinal innervation of the abdominal muscles o Emetic signals are mediated by various neurotransmitters dopamine, serotonin, histamine, substance P, & others o CNS chemoreceptor trigger zone and other modulator zones all give input to the NTS (nucleus of tractus solitarius). NTS drives the vomiting reflex! o There are chemoreceptors/mechanoreceptors in GI and gut that also give afferents to these centers.

Tetrahydrocannabinol (THC) or dronabinol

Also antiemetic but MOA unknown dronabinol used as prophylactic in patients

receiving cancer chemotherapy Adverse effects: central sympathomimetic activity in form of marijuana-like highs (mood changes, laughing, paranoid reactions, & thinking abnormalities)

Tx of IBD:
Ulcerative Colitis. Crohns Disease.

Newer Anti-Obesity Drugs

Orlistat
Target organ Target molecule MOA

Sibutramine CNS SERT and NET inhibitor Reduces appetite

Rimonabant CNS (peripheral ?) CB1 receptor antagonist Reduces appetite

Gut GI lipase inhibitor Reduces absorption of fats since triglycerid es not split GI: Flatulence, steatorrhe a, fecal incontinen ce

Toxicity

Cardiovascular : Tachycardia, hypertension

CNS: Depression, anxiety, nausea

Step up therapy starting w/ topical corticosteroids and going up till IMMUNOSUPPRESSION.

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 Antispasmodics Anticholinergics: dicyclomine, hyoscyamine o 5-HT4 partial agonist

Tegaserod Emergency treatment only (IBS with constipation) where no alternative exists Serious cardiovascular events can occur Alosetron Conventional therapy failed Diarrhea-predominant IBS Serious cardiovascular events can occur

o 5-HT3 antagonist