3.26.12 Treatment of GI Disorders

7/30/2019 3.26.12 Treatment of GI Disorders

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Treatment of GI disordersIC Week 2

Monday, March 26, 2012

McCarson

oIn antrum of stomach, signaling through absorption of dietaintake will gate gastrin release which will be modified by pa

inputs & somatostatin locally

oWhat drives acid secretion via proton pump1. Signalling from Muscarinic receptor2. ECL cells release gastrin & histamine

oInhibit gastric secretion, Reduce amount of acid (antacidsoAgents that helps establish/maintain gastric layer

Overview of GI DiseasesoDisorders principally of either

Altered secretion or altered motilityoMost 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]

oLifetime prevalence of peptic ulcer is ~ 10%, whileheartburn occurs in about 50% of healthy individuals

oGoals for treatment of acid-peptic disease:1. relieve pain esophageal chemoreceptors2. promote healing3. prevent recurrence

oAnti-ulcer drugs act to:1. neutralize gastric acid2. reduce gastric acid secretion3. enhance mucosal defenses by cytoprotective

or antimicrobial activity

3 Pathways Regulating Gastric Acid Secretion

PATHWAY MEDIATOR RECEPTORS ANTAGONIST

1)

neural

acetylcholine muscarinic anti-

muscarinic

2)

endocrine

gastrin gastrin-

CCK B

H2 blocker

3)

paracrine

histamine H2 H2 blocker

oAnti-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

oGastrin: No selective CCK antagonists but ultimately gastrin

stimulates acid production through histamine. So

blocking Histamine will prevent

Family of peptide hormones formed by gastric mucosalcells

Stimulates gastric motility, HCl & pepsin secretion No direct gastrin antagonists

oH2 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

oH2 blockers are more effective than anti-


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Proton Pump InhibitorsoBenzimidazole compoundsirreversibly inhibit

parietal cell proton pump, H+/K+ATPase

oAre 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 coatingsdissolve & 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 sulfenicacid which binds sulfhydryl groups on H+/K+ ATPase

oPreparations include: esomeprazole, omeprazole, lansoprazole,

pantoprazole, rabeprazoleoClinical Use:

Most effective drugs for suppressing gastric acidsecretion b/c gastric response to all stimuli is

inhibited

oA single daily dose inhibits gastric acid secretion by 95-100% w/o affecting pepsin secretion or gastric motility

oInhibition of gastric acid secretion persists afterwithdrawal of drug:

Irreversible inhibitors: time required tosynthesize new proton pumps (H+/K+ATPase)

oGenerally well tolerated without producing seriousadverse effects

oAdverse effects of PPI: 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 usersoHepatic metabolism with negligible renal clearanceoIntestinal absorption is rapid, but bioavailability of the

absorbed form depends on activation at gastric acid pH

oWill promote peptic ulcer healing & prevent ulcerrecurrence

oAre often effective in patients unresponsive to H2antagonists

oMore effective than H2 antagonists for GERD or NSAID-induced peptic ulcers

H2-AntagonistsoFour Preparations:

cimetidine, famotidine, nizatidine,&ranitidine

OTC preparations inhibit acid secretion for < 6 hours

Prescription doses inhibit 60-70% of total 24-hour acid secretion

oAre all equally effective, rapidly & well absorbed orally, &generally well tolerated with few side effects

oAre structural histamine analogs thatblock H2 receptorsselectively to reduce gastric acid & pepsin secretion

without affecting H+/K+ ATPase, H1, or any other receptors

oAre especially effective against nocturnal secretion whichis largely driven by histamine (i.e., reduced by 90% as

compared with 60-80% inhibition of daytime acid

secretion)

oRelative potency varies over a 50-fold range: famotidine > nizatidine = ranitidine >

cimetidine

oH2-Receptor Antagonists: ADVERSE EFFECTS Are extremely safe with minor & infrequent adverse

effects

DO NOT give to pregnant or nursing womentheycross 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

Cimetidine: (longest on the market) Endocrine Side Effects:Gynecomastia or

impotence in men, & galactorrhea in women

Inhibitis binding of dihydrotestosterone toandrogen receptors & conversion of estrogen

to dihydrotestosterone.

Increases serum prolactin interferes with cytochrome P450 pathways

oClinical Uses: All are equally effective for healing & preventing

recurrence of PUD

Given once daily atbedtime to suppress nocturnalacid secretion will produce ulcer healing rates of

> 80-90% after 6-8 weeks of treatment

Their use declined markedly following the discoveryof proton pump inhibitors & the role ofH. pyloriinPUD

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 ptsw/ H. pylori infection


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AntacidsoDirectly chelate acid & turn it into water & salt

neutralize the acidity:

oPreparation: aluminum hydroxide, calcium carbonate, combo

aluminum hydroxide & magnesium hydroxide

oSeldom used (more convenient & effective drugs) Act by reducing gastric acidity Inactivating pepsinoMOA:Are weak bases that neutralize gastric HCl to form

salt & water, & may interfere with absorption of other

drugs

Provide mucosal protection - stimulates PG synthesisoAluminum or magnesium hydroxide either alone, or

combined with NaHCO3 or a calcium salt

oA single effective dose given 1 hr after eating neutralizesfor 2 hrs; 2nd dose 3 hrs after eating extend effect for 4 hr

oAdverse effects: Magnesium saltsDiarrhea Aluminum salts Constipation Cation absorption & systemic alkalosis in renal patientsoVary widely in neutralizing capacity, taste, & priceoAntacid tablets are generally weak, needed in large

numbers, & not recommended for active peptic ulcers

oUse as needed to relieve pain in esophagitis, peptic ulcer,& GERD

Mucosal Protective AgentsoProtective coating on peptic ulcers

Limits exposure to acid & pepsinoSucralfate (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

oMisoprostol - methyl analog of PGE1 Binds to PG receptors on parietal cells to inhibit acid

secretion

b/c NSAIDs inhibit PG formation, misoprostol is usedto prevent NSAID-induced ulcers

exact mechanism uncertain but may be cytoprotectiveor inhibit histamine-stimulated gastric secretion

Adverse effects: diarrhea & abdominal pain may cause abortion stimulates uterine contractionsoBismuth 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

Antimicrobial Drugs

oHelicobacter pylori Gram-negative bacterium,causes inflammatory gastritis that may lead to peptic

ulcers

oSingle antibiotic regimens are ineffective against H.pylori infection

oBest 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


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Stimulant or Irritant LaxativesoDrugs that act directly on enterocytes, enteric

neurons, & muscle to induce low-grade inflammation

water & electrolytes accumulate increaseintestinal motility

oDiphenylmethane derivativeslike: Bisacodyl;

Enteric coated, take at bedtime Tablets should be swallowed without chewing or

crushing. Avoids activation in the stomach (causinggastric irritation & cramping)

Phenolphthalein (withdrawn due to potentialcarcinogenicity)

oAnthraquinonesaloe, cascara sagrada orsenna

Poorly absorbed in SI & require activation in colonw/laxative effects 6-12 hrs later

Long-term use causes melanomic pigmentationof colonic mucosa & cathartic colon (colon

becomes dilated & ahaustral)

oRicinoleic acid (castor oil):a local irritant thatincreases intestinal secretion & motility; now seldomused due to unpleasant taste & toxic potential

Bulk Forming LaxativesoBulk-Forming Laxatives are dietary supplements

that add bulk & hold water to intestinal contents

oPolymers that hold water Ex. Metamucilomethylcellulose, lactulose, & polycarbophilStool Softeners

oMineral oil, glycerin suppositories, &docusate sodium

oAgents that soften stools & facilitate expulsionoGiven orally or rectallyoDocusate Na+ is often prescribed to prevent

straining in hospitalized patients

Important for cardiac/abdominal procedurepts!

Motility Disorders: CONSTIPATIONoThe word constipation comes from two Latin words: con

stipare crammed together

oExact definition is difficult butat least 3 times a weekoConstipation may refer to: decreased frequency difficult initiation or passage passage of firm or small-volume stools feeling of incomplete evacuationoLAXATIVES: Constipation: Up to 25% of US population; most

commonly women & elderly

Drugs used to promote defecation & treat constipationare 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 canbe resolved by:

increasing water & fiber content of diet appropriate bowel habits & training improved physical activity & exercise attention to psychosocial & emotional factors

Osmotically Active Laxatives

oSaline laxativesnonabsorbable salts containingmagnesium 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 addingcitrus juices

are usually well toleratedoAVOID IN :

renal insufficiency heart disease electrolyte imbalance diuretic drug co-treatment Nondigestible sugars & alcoholsoGlycerin trihydroxy alcohol that acts in the rectum as

a lubricant & hygroscopic agent

water retention stimulate peristalsis Moves water into stool & helps ease of passageoLactulose, sorbitol, & mannitol-

nonabsorbable sugars hydrolyzed to organic acids acidify luminal

contents draw H2O into lumen colonicpropulsive motility

oPolyethylene glycol (PEG)-electrolytesolutionspoorly absorbed & retain added water bytheir high osmotic pressure

Prepared as mixtures of sodium sulfate, sodiumbicarbonate, sodium chloride, & potassium chloride in

isotonic solutioncontaining 60 g of polyethylene glycol

per liter; Colonoscopy preparation: drink 3-4 liters over 3-4 hrs

to produce watery diarrhea & remove solid wastes


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Anti-emetic Drugs

oHistamine H1 Antagonists First-generation H1 blockersDimenhydrinate,

diphenhydramine, cyclizine, & meclizine Produce sedation & antimuscarinic activity

Clinical Use: Prevents motion sickness Have anti-muscarinic activity:

CNS centers responsible for nausea &dizziness have both histamine ANDmuscarinic signaling.

Therefore, these drugs prevent motionsickness by blocking both MRs & histaminereceptors.

oDopamine D2 & Serotonin 5-HT3 Antagonists

Mechanism of anti-emetic action: Unclear D2 antagonists: Metoclopramide, trimethobenzamide

HT3 antagonists: Ondansetron, granisetron, & dolasetron

Clinical Use: Nausea & vomiting during cancerchemo

oPhenothiazines & Benzodiazepines - antiemetics phenothiazines: Chlorpromazine, prochlorperazine

benzodiazepines: Lorazepam, alprazolam (anxiety)

oMarijuana Derivatives Tetrahydrocannabinol (THC) or dronabinol Also antiemetic but MOA unknown

dronabinol used as prophylactic in patientsreceiving cancer chemotherapy

Adverse effects: central sympathomimeticactivity in form of marijuana-like highs (moodchanges, laughing, paranoid reactions, & thinking

abnormalities)

Motility Disorders: DIARRHEAAnti-diarrheal DrugsoAcute-onset diarrhea is usually self-limited & seldom

requires specific chemotherapy; drug therapy is often

nonspecific

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

Opioid Drugs

oLoperamide, difenoxin & diphenoxylate MOA: act on intestinal opioid receptors (Mu-R) toinhibit Ach release motility (peristalsis)

SE includes CONSTIPATION:oLoperamide is 40-50 times more effective than

morphine for diarrhea does not cross BBB

Opiods that ONLY produce the SE ofconstipation w/o CNS effects!

Acts quickly on oral administration peak levels at 3-5 hrs Relief of acute, non-specific diarrhea

Clinical Use: Travelers diarrhea, should DC if noimprovement w/in 48 hrs (prevent constipation)

Adverse Effects: few adverse effects & more iseffective than diphenoxylate (atropine is added to

diphenoxylate as deterrent of abuse)

oKaolin (chalk) & pectin Kaopectate MOA: Absorb compounds & presumably binds

potential intestinal toxinsChalk & jelly---

oBismuth subsalicylate MOA: inhibits intestinal secretions Clinical Use: Management of infectious diarrhea

Motility Disorders: VOMITINGoNausea & vomiting occur in various conditions

pregnancy, motion sickness, GI obstruction, &

cancer chemotherapy

oVomiting is a complex process coordinated by amedullary vomiting center that activates efferent

pathways in vagus, phrenic nerves, & spinal

innervation of the abdominal muscles

oEmetic signals are mediated by variousneurotransmitters dopamine, serotonin,

histamine, substance P, & others

oCNS chemoreceptor trigger zone and othermodulator zones all give input to the NTS (nucleus

of tractus solitarius).

NTS drives the vomiting reflex!oThere are chemoreceptors/mechanoreceptors in GI

and gut that also give afferents to these centers.


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Newer Anti-Obesity Drugs

Orlistat Sibutramine Rimonabant

Target

organGut CNS CNS

(peripheral ?)

Target

moleculeGI lipase

inhibitor

SERT and NET

inhibitor

CB1 receptor

antagonist

MOA Reducesabsorption

of fats

since

triglycerid

es not split

Reducesappetite

Reducesappetite

Toxicity GI:

Flatulence,

steatorrhe

a, fecal

incontinen

ce

Cardiovascular

: Tachycardia,

hypertension

CNS:

Depression,

anxiety,

nausea

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

Tx of IBD: Ulcerative Colitis. Crohns Disease.

Step up therapy starting w/ topical corticosteroidsand going up till IMMUNOSUPPRESSION.

Treatment of IBSoTricyclic antidepressants (1stgen) Low doses ofamitriptyline or desipramine Treatment of the abdominal pain Limit nociceptive signallingoAntispasmodics Anticholinergics: dicyclomine, hyoscyamine

o5-HT4 partial agonist Tegaserod Emergency treatment only (IBS with

constipation) where no alternative exists

Serious cardiovascular events can occuro5-HT3 antagonist Alosetron Conventional therapy failed Diarrhea-predominant IBS Serious cardiovascular events can occur

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3.26.12 Treatment of GI Disorders