3.26.12 Treatment of GI Disorders

Monday, March 26, 2012

Treatment of GI disorders IC Week 2

McCarson

Overview of GI Diseases Disorders principally of either •  Altered secretion or altered motility 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] Lifetime prevalence of peptic ulcer is ~ 10%, while heartburn occurs in about 50% of healthy individuals Goals for treatment of acid-peptic disease:

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1. relieve pain   esophageal chemoreceptors 2. promote healing 3. prevent recurrence o

 Anti-ulcer drugs act to:

1. neutralize gastric acid 2. reduce gastric acid secretion 3. enhance mucosal defenses by cytoprotective or antimicrobial activity

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In antrum of stomach, signaling through absorption of dietary intake will gate gastrin release which will be modified by para inputs & somatostatin locally 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

1) neural

MEDIATOR

RECEPTORS

ANTAGONIST

acetylcholine

muscarinic

antimuscarinic

2) endocrine

gastrin

gastrinCCK B

H2 blocker

3) paracrine

histamine

H2

H2 blocker

 Anti-muscarinic drugs  Anti-muscarinic • Parasympathetic system • Agents like atropine will inhibit para drive • Seen as acute tx or as adjuncts to other therapies

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(H2 antagonists) if approaches not working • o

Gastrin: •

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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

H2 antagonists • •

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Relatively weak inhibitors of acid secretion secretion because because they act at only one site

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 H2 blockers are more effective than anti-

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Inhibit gastric secretion, Reduce amount of acid (antacids) Agents that helps establish/maintain gastric layer

Proton Pump Inhibitors Benzimidazole compounds irreversibly inhibit 

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parietal cell proton pump, Are pro-drugs that are inactive at neutral pH environment (take w/ food) •  Activated in an acid environment (take • 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 Preparations include:

H2-Antagonists o

H +/K+ATPase

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• esomeprazole, omeprazole, lansoprazole, pantoprazole, rabeprazole Clinical Use: • Most effective drugs for suppressing gastric acid secretion b/c gastric response to all stimuli is inhibited A single daily dose inhibits gastric acid secretion by 95100% w/o affecting pepsin secretion or gastric motility

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• cimetidine, famotidine, nizatidine, &ranitidine

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Are extremely safe with minor & infrequent adverse effects nursing womenthey • DO NOT give to pregnant or nursing cross placenta & secreted into breast milk  effects: • 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

 Adverse effects of PPI: PPI: •

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Relative potency varies over a 50-fold range:

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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 H 2 antagonists More effective than H2 antagonists for GERD or NSAIDinduced peptic ulcers

• OTC preparations inhibit acid secretion for < 6 hours  • Prescription doses  inhibit 60-70% of total 24-hour acid secretion Are all equally effective, rapidly & well absorbed orally, & generally well tolerated with few side effects Are structural histamine analogs that block that block H2 receptors selectively to reduce gastric acid & pepsin secretion without affecting H+/K+ ATPase, H1, or any other receptors Are especially effective against n octurnal 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

Inhibition of gastric acid secretion persists after withdrawal of drug: • Irreversible inhibitors: time required to synthesize new new proton pumps (H+/K+ATPase) Generally well tolerated without producing serious adverse effects

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Four Preparations:

• Cimetidine: (longest on the market)

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Endocrine Side Effects: Gynecomastia or

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impotence in men, & galactorrhea in women dihydrotestosterone to  Inhibitis binding of dihydrotestosterone androgen receptors & conversion of estrogen to dihydrotestosterone.  Increases serum prolactin interferes with cytochrome P450 pathways

Clinical Uses: • •

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All are equally effective for healing & p reventing recurrence of PUD Given once daily at  bedtime to suppress nocturnal acid secretion will produce ulcer healing rates o f  > 80-90% after 6-8 weeks of treatment  Their use declined markedly following th e discovery of H. pylori in pylori in of proton pump inhibitors & the role of H.

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

 Antimicrobial Drugs

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 for 2 hrs; 2nd dose 3 hrs after aft er eating extend effect for 4 hr o

 Adverse effects: • Magnesium salts

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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

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Protective coating on peptic ulcers Limits exposure to acid & pepsin

Sucralfate (aluminum sucrose sulfate) binds selectively to necrotic necrotic ulcer tissue & acts as a barrier barrier

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Polymerizes to produce a v iscous, sticky gel adheres strongly to epithelial cells & ulcer craters in acid environment  Effective in healing duodenal ulcers Side Effect  Constipation Poorly absorbed systemically & has few adverse eff ects Requires acid pH for activation & should not be given together with antacids, H 2 antagonists, or proton pump inhibitors

Misoprostol - methyl analog of PGE 1

Binds to PG receptors on parietal cells to inhibit acid secretion mis oprostol is used • b/c NSAIDs inhibit PG formation, misoprostol 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 (Pepto-Bismol)-colloidal 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 is a black solid

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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

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

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Constipation’ may refer to: • decreased frequency • difficult initiation or passage • passage of firm or small-volume stools • feeling of incomplete evacuation

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Stimulant or Irritant Laxatives Drugs that act directly on enterocytes, enteric neurons, & muscle to induce low-grade lo w-grade inflammation • water & electrolytes accumulate  increase intestinal motility o Diphenylmethane derivatives like: • Bisacodyl;  Enteric coated, take at bedtime o

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LAXATIVES:

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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

Osmotically Active Laxatives o Saline laxatives nonabsorbable salts containing magnesium cations (magnesium citrate) or phosphate anions (sodium phosphate) • • • o

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

 AVOID IN :

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renal insufficiency heart disease electrolyte imbalance diuretic drug co-treatment 

 Nondigestible sugars & alcohols o Glycerin  trihydroxy alcohol that acts in the rectum as • • o

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a lubricant & hygroscopic agent  water retention stimulate peristalsis Moves water into stool & helps ease of p assage

Lactulose, sorbitol, & mannitolnonabsorbable sugars  hydrolyzed to organic acids  acidify luminal contents  draw H2O into lumen   colonic propulsive motility

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 

Tablets should be swallowed without chewing or crushing. Avoids activation in the stomach ( causing gastric irritation & cramping)

• Phenolphthalein (withdrawn due to potential  carcinogenicity ) o

 Anthraquinones  Anthraquinones senna

aloe, cascara sagrada or

• 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

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

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methylcellulose, lactulose, & polycarbophil

Stool Softeners s uppositories,, & o Mineral oil, glycerin suppositories docusate sodium Agents that soften stools & facilitate expulsion Given orally or rectally o Docusate Na+ is often prescribed to prevent  straining in hospitalized patients • Important for cardiac/abdominal procedure  pts!  o o

Motility Disorders: DIARRHEA  Anti-diarrheal Drugs o

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

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

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Opioid Drugs o Loperamide, difenoxin & diphenoxylate (Mu-R) to • MOA: act on intestinal opioid receptors (Mu-R) 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  

peak levels at 3-5 hrs Relief of acute, non-specific diarrhea

• Clinical Use: Traveler’s 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) o

Kaolin (chalk) & pectin Kaopectate

• MOA: Absorb compounds & presumably binds potential intestinal toxins Chalk & jelly--o

 Anti-emetic Drugs Drugs o Histamine H 1 Antagonists

Bismuth subsalicylate

intestinal secretions secretions • MOA: inhibits intestinal • Clinical Use: Management of infectious diarrhea

diphenhydramine, cyclizine, & meclizine 

Nausea & vomiting occur in various conditions   pregnancy, motion sickness, GI obstruction, 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 (nucleus of tractus solitarius). solitarius ). • NTS drives the vomiting reflex! o There are chemoreceptors/mechanoreceptors in GI and gut that also give afferents to these centers. o

Produce sedation & antimuscarinic activity Clinical Use: Prevents motion sickness

 Have anti-muscarinic activity:  CNS centers responsible for nausea &

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dizziness have both histamine AND muscarinic signaling. Therefore, these drugs prevent motion sickness by blocking both MRs & histamine receptors.

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Dopamine D2 & Serotonin 5-HT 3 Antagonists Mechanism of anti-emetic action: Unclear

D2 antagonists: trimethobenzamide de  Metoclopramide, trimethobenzami

• HT3 antagonists:

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Ondansetron, granisetron, & dolasetron

• Clinical Use: Nausea & vomiting during cancer chemo o

Phenothiazines & Benzodiazepines - antiemetics

• phenothiazines:  Chlorpromazine, prochlorperazine • benzodiazepines:  Lorazepam, alprazolam (anxiety) o

Motility Disorders: VOMITING 

First-generation H 1 blockers Dimenhydrinate,

Marijuana Derivatives

Tetrahydrocannabinol abinol (THC) or dronabinol • Tetrahydrocann 

Also antiemetic but MOA unknown  dronabinol  used as prophylactic in patients 

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

Tx of IBD:

Newer Anti-Obesity Drugs

 Ulcerative Colitis.  Crohn’s Disease.

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

Treatment of IBS o

Tricyclic antidepressants (1 st  gen)

of amitriptyline ne or desipramine • Low doses of amitriptyli • Treatment of the abdominal pain • Limit nociceptive signalling

 Antispasmodics  Antispasmodics • Anticholinergics:  dicyclomine, hyoscyamine

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5-HT4 partial agonist 

• Tegaserod • Emergency treatment only (IBS with constipation) where no alternative exists • Serious cardiovascular events can occur o

5-HT3 antagonist 

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 Alosetron Conventional therapy failed Diarrhea-predominant IBS  Serious cardiovascular events events can occur 

Orlistat

Sibutramine

Rimonabant 

Target  organ

Gut 

CNS

CNS (peripheral ?)

Target  molecule

GI lipase inhibitor

SERT and NET inhibitor

CB1 receptor antagonist 

MOA

Reduces absorption of fats since triglycerid es not split 

Reduces appetite

Reduces appetite

Toxicity

GI: Flatulence, steatorrhe a, fecal incontinen ce

Cardiovascular : Tachycardia, hypertension

CNS: Depression, anxiety, nausea

Reduce absorption of dietary intake or o r reduce appetite. Long term use & effectiveness are not as clear