The longer I live, the more I am convinced that half the unhappiness in the world proceeds from little stoppages, from a duct choked up, from food pressing in the wrong place, from a vexed duodenum or an agitated pylorus.

---Sydney Smith (1771 1845)

Objectives

Understand the indications as well as

contraindications of gastrointestinal agents

Understand the adverse effects as well as the

side effects of these agents

Understand the mechanism of action

Overview

Gastric Acidity, Peptic Ulcers, and Gastroesophageal

Reflux disease

Constipation and anti-diarrheal

Anti-emetics

Irritable Bowel Syndrome

PUD & GERD

Proton Pump Inhibitors

H2 Receptor Antagonists

Agents that enhance mucosal defense

Prostaglandin Analogs

Sucralfate

Antacids

Gastric Secretion Physiology

Chemical Mediators

Ach

Synapse with ganglion of enteric nervous system

Stimulates muscarinic receptors M3

Stimulates histamine from ECL and gastrin from G

cells

Responds to sight, smell, taste, or anticipation of food

Histamine: H2 receptors

Chemical Mediators

Gastrin

Stimulated by CNS activation, local distension, and

components of the gastric contents

Stimulates histamine release from ECL cells

Gastric Defense Against Acid

Primary esophageal defense is the lower

esophageal sphincter

Secretion of a mucus layer that traps secreted

bicarbonate at the cell surface

Coats the mucosal surface of the stomach

Stimulated by PGE2 and PGI2 on EP3 receptors and

also inhibits parietal cell activity

Proton Pump Inhibitors (PPIs)

Omeprazole (Prilosec)

Esomeprazole (Nexium)

Lansoprazole (Prevacid)

Dexlansoprazole (Kapidex)

Rabenprazole (Aciphex)

Pantoprazole (Protonix)

Physiology

PPI: Mechanism of Action

Dose dependent inhibition of basal & stimulated gastric acid secretion

Helps prevent stomach acid production by turning off many of the acid-producing pumps Irreversibly inhibits gastric

acid secretion from parietal cells by binding to H+K+ATPase. molecule (proton pump)..

Block hydrogen ion secretion

Pharmacokinetics of

Proton Pump Inhibitors

Proton pump inhibitors are administered as inactive prodrugs

Acid-labile prodrug

Oral products are formulated for delayed release as acid-resistant, enteric-coated capsule or tablet formulations

Passed through the stomach into the alkaline intestinal lumen

Enteric coatings dissolved

Prodrug is absorbed

PPI cont

All PPIs are equipotent

PPIs inhibit only active proton pumps

Most effective when taken within 30-60 minutes before meals

Tablet or capsule should be swallowed whole

Do not chew or crush tablets

Those with swallowing difficulties can mix contents of

capsule with applesauce and swallow immediately

It is not optimal to open capsules and give via feeding

tubes

Patients with liver disease may need dose adjustments

and should be monitored closely

PPI: Side Effects

PPI are generally well tolerated

Undesirable effects usually mild and transient

Abnormal B12 levels with prolonged therapy

Acid is important in releasing vitamin B12 from food

Most common side effects

HEADACHES

DIARRHEA

NAUSEA

PPI: Drug Interactions

May alter absorption of drugs for which intragastric acidity affects drug bioavailability

Ketoconazole

Digoxin

All proton pump inhibitors are metabolized by hepatic P450 cytochromes

CYP2C19 and CYP3A4

Clinically significant drug interactions are rare

Omeprazole inhibit the metabolism Coumadin, diazepam, and phenytoin

Prevacid SoluTab

Prevacid SoluTab quickly

melts in the mouth

less than 60 seconds

Can be taken anywhere

With or without water

Has a strawberry flavor

Therapeutic Use PPIs PUD

GERD

Erosive esophagitis which is complicated or

unresponsive to treatment with H2 receptor

antagonists

Omeprazole approved for self-treatment of

heartburn

Lansoprazole and esomeprazole approved for

NSAID associated gastric ulcers in patients who

continue taking NSAID

H2-Receptor Antagonists

(H2RA)

Ranitidine(Zantac)

Famotidine(Pepcid)

Nizatidine( Axid)

Cimetidine(Tagamet)

MOA: Reversibly bind to the histamine-2 receptors

of the parietal cells

Physiology

H2-Receptor Antagonists cont

Advantages: Available OTC; inexpensive; few ADRs less then 3% incidence of ADR: CNS, thrombocytopenia

Disadvantages: Drug Interactions Cimetidine Potent Inhibitor of CYP450.

Tolerance can develop within 3 days of starting treatment and may be resistant to increased doses of the medications

Elimination: Predominantly renal Dosage adjustments is required in the presence of renal

insufficiency

Therapeutic uses include PUD, uncomplicated GERD, Stress ulcers

Adverse Effects

Mental status changes occurs less common then

other side effects and occurs primarily in elderly

patients after IV administration

confusion, hallucinations, agitation

more common with cimetidine

Cimetidine

gynecomastia or impotence in men and galactorrhea in

women..

Should not be administered to pregnant women

unless absolutely necessary

Antacids

MOA: neutralizes the acid in the

stomach

Weak bases that react with gastric

hydrochloric acid to form a salt and water

Examples: sodium bicarbonate,

calcium carbonate , magnesium

hydroxide (MgOH), aluminum

hydroxide (AlOH)

Maalox = AlOH + MgOH

Simethicone

surfactant that may decrease foaming and

hence esophageal reflux

Famotidine, calcium

carbonate and magnesium

hydroxide

Antacids

Advantage: Rapid onset

Disadvantage: frequent dosing, poor palatability, abdominal distension (flatulence), electrolyte abnormalities

Magnesium containing antacids cause diarrhea and Aluminum can cause constipation

Patients with renal insufficiency may get accumulation of Mg leading to hypermagnesemia and Al3+ leading to osteoporosis, encephalopathy, and proximal myopathy

Sodium bicarbonate preparations contain considerable sodium - overload can occur CHF patients

Antacids: Drug Interactions

All antacids potentially may increase or decrease the rate

and/or extent of absorption of concomitantly administered oral drugs by changing GI transit time or by binding or chelating the drug Space doses of the drugs as far apart as possible

Digoxin: Possible decreased digoxin absorption

Diazepam: Possible increased diazepam absorption with aluminum hydroxide

Naproxen: Possible increased naproxen absorption with sodium bicarbonate

Tetracyclines: Possible decreased tetracycline absorption

Antacids: Dose and Administration For uncomplicated ulcers

1 and 3 hours after meals and at bedtime

For severe symptoms or uncontrolled reflux As often as every 30 to 60 minutes

Should be administered in suspension form Greater neutralizing capacity than do powder or tablet dosage

forms

If tablets are used, they should be thoroughly chewed for maximum effect

Antacids are cleared from the empty stomach in about 30 minutes Presence of food is sufficient to elevate gastric pH to about 5 for

approximately 1 hour and to prolong the neutralizing effects of antacids for about 2 to 3 hours

Agents that enhance mucosal

defense

Misoprostol (Cytotec)

Sucralfate (Carafate)

Bismuth Subsalicylate (Pepto-Bismol)

Physiology

Prostaglandins: Misoprostol

Synthetic analog of prostaglandin E1 Gastric antisecretory agent with protective effects on

the gastroduodenal mucosa

drug also increases the amplitude and frequency of uterine contractions and stimulates uterine bleeding and total or partial expulsion of uterine contents in pregnant women.

Used for reducing the risk of NSAIDs induced gastric ulcer

Inhibits gastric acid secretion and protects the mucosa from the irritant effects of certain drugs

Misoprostol

Diarrhea with or without abdominal cramps in 30% of patients begins within first 2 weeks and often resolves spontaneously within a week

Indications:

Prevention of NSAIDs-Induced Ulcers

Gastric and Duodenal Ulcer

As an adjunct to mifepristone to terminate pregnancy

DO Not Use in pregnant women

Can cause clinical exacerbations of inflammatory bowel disease and should avoid in patients with this disorder

Sucralfate (Carafate)

It is minimally absorbed into the body

Its actions are entirely on the lining of the stomach and

duodenum

MOA: binds to the surface of ulcers and coats the ulcer

Protects the ulcer surface from further injury by acid

Advantages: inexpensive; few ADRs

Disadvantages: aluminum containing substance; drug

interactions due to chelation; clogs up NG/GT tubes

Dose: 1 gm po qid

on an empty stomach 1 hour before meals

Sucralfate: Adverse Effects

and DI

Constipation (2%)

Should be avoided in patients with renal failure

Aluminum can be absorbed

Sucralfate forms a viscous layer in the stomach that may inhibit absorption of drugs

Phenytoin, digoxin, cimetidine, ketoconazole, and fluoroquinolone antibiotics

Should be taken at least 2 hours after the administration of other drugs

Sucralfate (Carafate)

Bismuth Subsalicylate

Pepto-Bismol : antidiarrheal agent

Used for travelers diarrrhea

Helidac

Combination with tetracycline and metronidazole

Approved in the United States for treatment of H. pylori-associated duodenal ulcer

MOA: Unclear Local protective effects (coating of the stomach)

Stimulate prostagladin production

Anti-diarrheal effects: coating action decreases fluid secretion into the bowel

Bismuth Subsalicylate

ADR:

Poor palatability

Dark stool: may be confused with gastrointestinal

bleeding

Constipation

Contraindication: Salicylate allergy

Should be avoided in patients with renal

insufficiency

Bismuth toxicity

Encephalopathy: ataxia, headaches, confusion, seizures

Constipation: Definition

Persistent, difficult, infrequent, or seemingly

incomplete defecation

low stool frequency alone is not the sole criterion for the

diagnosis of constipation

Surveys say normal stool frequency on a Western diet to be

at least three times a week

Many constipated patients have a normal frequency of

defecation but complain of excessive straining, hard stools,

lower abdominal fullness, or a sense of incomplete

evacuation

Normal Physiology

Primary function of the small intestine

Digestion and assimilation of nutrients from food

Regulate secretion and absorption of water and electrolytes

Storage and subsequent transport of intraluminal contents

Alterations in fluid and electrolyte handling

With decreased motility and excess fluid removal, feces can

become impacted, leading to constipation

When the capacity of the colon to absorb fluid is exceeded, diarrhea

occurs

Alterations in motor and sensory functions of the colon

Irritable bowel syndrome (IBS)

Chronic diarrhea/Chronic constipation

Laxatives

Laxatives generally act in one of the

following ways

Enhance retention of intraluminal fluid by

hydrophilic or osmotic mechanisms

Decrease net absorption of fluid by effects

on small- and large-bowel fluid and

electrolyte transport

Alter motility by either inhibiting segmenting

(nonpropulsive) contractions or stimulating

propulsive contractions

Bulk Laxatives

Psyllium seed (Metamucil), methylcellulose (Citrucel) Natural or synthetic polysaccharides or cellulose derivatives that

primarily exert their laxative effect by absorbing water and increasing fecal mass

Forms gels in large intestines causing water retention and intestinal distension

Effective in increasing the frequency and softening the consistency of stool with a minimum of adverse effects

May be used alone or in combination with dietary changes

May reduce serum cholesterol

Takes 1 3 days to work

Bulk Laxatives

Dose: Usually administered 1-3 times daily Risk of esophageal obstruction in patients receiving

large dosages

Administer in divided doses

Precautions and Contraindications

Potentially severe hypersensitivity reactions

Acute bronchospasm, and anaphylaxis

Occur in susceptible individuals with psyllium sensitivity

Emollients ( stool softeners)

Docusat (Colace)

Calcium and sodium salts of docusate

Lower the surface tension of stool

Allows water to more easily enter the stool

Administration

Orally

Rectally

Softening of the feces generally occurs within 1-3 days

following initiation of oral docusate salt therapy

Osmotic Laxative

Laxatives containing magnesium cations or phosphate anions are commonly termed saline laxatives

Poorly absorbed

Result of osmotically mediated water retention which then stimulates peristalsis

Magnesium hydroxide (Phillips Milkof Magnesia)

Magnesium citrate (Citroma)

Over the counter sodium phosphate products (fleet enema fleet phospho-Soda, Visicol) withdrawn from the market in 2008

Osmotic Laxative

Need a few days to become effective

Will see watery evacuation

May result in electrolyte and volume overload in

patients with renal insufficiency or cardiac dysfunction

Magnesium sulfate

bitter taste

may cause nausea

can be masked by mixing the drug with lemon juice

Poorly Absorbed Sugar Lactulose ( Constulose, Enulose)

Efficacious in the treatment of constipation caused by opioids

Idiopathic chronic constipation

Lactulose nonabsorbable sugars metabolized by colonic bacteria into lactic, formic and acetic acids increase osmotic pressure causing fluid accumulation, colon distension, soft stools, and defecation

Polyethylene glycol and electrolytes (Colyte, GoLYTELY, NuLYTELY) Used to prepare for colonoscopy and other

radiologic procedures

Polyethylene glycol 3350 (Miralax)

PEG (NuLYTELY)

Stimulant Laxatives

Cathartics induce bowel movements through

a number of poorly understood mechanisms

Direct stimulation of the enteric nervous system

and colonic electrolyte and fluid secretion

Long-term use of cathartics could lead to

dependence

Stimulant Laxatives:

Anthraquinone Derivatives

Senna (Ex-Lax, Senokot) Occur naturally in plants

Poorly absorbed and after hydrolysis in the colon

Produce a bowel movement in 612 hours when given orally and within 2 hours when given rectally

Chronic use leads to a characteristic brown pigmentation of the colon known as "melanosis coli

SE: Nausea, vomiting, diarrhea, abdominal cramps

Melanosis Coli

Stimulant Laxatives: Castor

oil

Derived from the bean of the castor plant

Acts primarily in the small intestine to stimulate secretion of fluid and electrolytes and speed intestinal transit

When taken on an empty stomach may produce a laxative effect within 1 to 3 hours

Seldom recommended Unpleasant taste and its potential toxic effects on intestinal

epithelium

Pregnant women should avoid castor oil it may stimulate uterine contractions

Stimulant Laxatives:

Bisacodyl (Dulcolax)

Available as suppositories and enteric-coated tablets

Acts directly on nerve fibers in the mucosa of the colon

Effects after an oral dose usually are not produced in

less than 6 hours

Taken at bedtime, it will produce its effect the next morning

Suppositories work much more rapidly

Within 30 to 60 minutes

Stimulant Laxatives:

Bisacodyl (Dulcolax)

To avoid gastric irritation and the possibility of vomiting Enteric-coated bisacodyl tablets must be

swallowed whole and not crushed, chewed, or taken within 1 hour of antacids or milk

Rectal administration may cause irritation and a sensation of burning of

the rectal mucosa

Stimulant Laxatives

May produce some degree of abdominal discomfort,

nausea, mild cramps

Do not use suppositories or enemas if you have:

abdominal cramps

rectal fissures

ulcerated hemorrhoids

Lubiprostone (Amitiza)

Used for the management of chronic idiopathic

constipation in adults

MOA:

Locally acting chloride channel activator to increase fluid

secretion into the intestinal lumen

Increases the passage of stool and alleviating symptoms of

chronic idiopathic constipation

Drug Interactions

All laxatives Increase intestinal motility

Potentially decrease transit time of concomitantly administered oral drugs decrease their absorption

Mineral oil May impair absorption of many orally administered drugs

including fat-soluble vitamins (i.e., vitamins A, D, E, and K

Bulk forming laxatives Binds orally administered digitalis, nitrofurantoin, and

salicylates in the GI tract

Space apart 3 hours after or before administration of these drugs

Diarrhea: General Principles

Defined as passage of abnormally liquid or unformed

stools at an increased frequency

Stool weight >200 g/d can generally be considered

diarrheal

Diarrhea

acute if 4 weeks in duration

Diarrhea: General Principles

Mechanism of Diarrhea

Decreased absorption

Increased secretion

Increased osmolality of luminal contents, or a change in gut

motility

Antimotility Agents

Diphenoxylate and Loperamide are analogs that

have opioid-like actions on the gut

MOA: They activate presynaptic opioid receptors

in the enteric nervous system to inhibit

acteylcholine release and decrease peristalsis

Atropine sulfate is anti-muscarinic

Can contribute to toxic megacolon, they should

not be used in young children or in patients with

severe colitis

Antimotility Agents: Diphenoxylate + Atropine (Lomotil)

Widely used to control diarrhea

Initial adult dosage: 5mg 4 times daily

Adverse effects: nausea, vomiting, abdominal

discomfort or distension, paralytic ileus,

pancreatitis

Acute toxicity symptoms of atropinism to look for

dryness of the skin and mucous membranes,

tachycardia, miosis, hypotonia, loss of tendon

reflexes, nystamus, and seizures

Antimotility Agent: Loperamide Hydrochloride (Imodium)

As an antidiarrhea agent, loperamide is reported to be

more specific, longer acting, and 2-3 times more potent

than diphenoxylate

Tolerance to the antidiarrheal effect of loperamide has

not been reported

Imodium: Clinical Use

Used in the control and symptomatic relief of acute

nonspecific diarrhea and of chronic diarrhea

associated with inflammatory bowel disease

Combination: Loperamide and simethicone

Used for the control and symptomatic relief of diarrhea with

relief of flatulence, bloating

Imodium: Dosage

Acute Diarrhea

Initial dosage is 4 mg, followed by 2 mg after each

unformed stool

Adult dosage should not exceed 16 mg daily

For self-medication of acute nonspecific diarrhea

in adults

initial dosage 4 mg, followed by 2 mg after each

subsequent unformed stool

however, dosage should not exceed 8 mg in a 24-hour

period unless directed by a physician

Imodium: Acute Toxicity

Manifested by paralytic ileus and CNS

depression

Naloxone may be administered if CNS

depression occurs

Antiemetics

Reverse Peristalsis (Retroperistalsis)

Begins in the small intestines

Gastroesophageal junction relax to permit passage of bolus

Triggered by

Chemical stimuli to brain

Motion sickness, vestibular infection

Increased intracranial pressure

GI tract: afferent fibers, distension, irritation, infection

Drug overview

Antidopaminergic

Anticholinergics

NK1 Receptor antagonist

Serotonin 5-HT3 receptor antagonist

Antidopaminergics

Metoclopramide(Reglan)

Blocks D2-receptors in the CTZ

Prokinetic: enhancing gastric emptying (closes the

esophageal sphincter and opens the pyloric sphincter) thus

relieving nausea and vomiting

Indicated in symptomatic patients with gastroparesis

Prochlorperazine (Compazine)

Warnings: Extrapyramidal reactions such as tardive

dyskinesia, neuroleptic malignant (NMS) syndrome, excess

sedation

Anticholinergics

Antihistamines

Meclizine (Antivert)

Dimenhydrinate (Dramamine)

Scopolamine (Transerm-Scop): muscarinic antagonist

Anticholinergics

Effective in cases of motion sickness or vertigo

Reduce the sensitivity of the labyrinthine apparatus

Scopolamine (Transderm-Scop) causes inhibition of

vestibular input to the CNS

Aprepitant (Emend)

MOA: antagonist of human substance P/ neurokinin 1

(NK1) receptors

FDA approved for prevention of chemotherapy-induced

nausea and vomiting

Adverse effects: associated with diarrhea, constipation,

headache, extreme fatigue and some cases hiccups

Serotonin 5-HT3 receptor

Antagonist

Ondansetron (Zofran)

Dolasetron (Anzemet)

Granisetron (Kytril)

Palonosetron (Aloxi)

Ondansetron (zofran)

Can be administered as a single dose prior to

chemotherapy (intravenously or orally) and are

efficacious against all grades of emetogenic therapy

Prevents emesis in most cisplatin-treated patients

Useful in the management of post operative nausea

and vomiting

Requires dosage adjustment in hepatic insufficiency

Irritable bowel Syndrome

Disease process not fully understood

Symptoms include abdominal pain, altered bowel

frequency and stool consistency (often alternating

diarrhea and constipation), abdominal distenstion or

bloating

Treatment includes:

Antispasmodics/anticholinergics

5-HT3 receptor antagonists

Dicyclomine (Bentyl)

MOA:

Anticholinergic which decrease motility, relax smooth muscle

tone in the GI tract, and decrease secretions

Antispamodic decrease motility by relaxing smooth muscle

tone

CI:

Glaucoma (narrow angle), GI tract obstructive disease,

Myasthenia gravis, CAD, CHF

Alosetron (Lotronex)

Used for women with severe chronic diarrhea-

predominant IBS who is resistant to all other

interventions

Only available through a prescribing program

5 HT3 receptor antagonist

Risk of developing ischemic colitis

THE END

Feel free to email me your questions:

liu_ag@yahoo.com