Gastrointestinal Pharmacotherapy

Objectives

Discuss the process of acid secretion in the gastrointestinal tract Differentiate medications used to suppress gastric acid secretion Explain the role of gastrointestinal motility in disease states Differentiate medications used to account for impaired gastrointestinal motility

Gastrointestinal tract

Disorders of the Esophagus and Stomach

Gastroesophageal Reflux Disease (GERD)

Dyspepsia/Non-erosive reflux disease (NERD) Esophagitis (erosive)

Peptic ulceration
H. pylori associated peptic ulcers

Gastric Secretion

Stomach Anatomy

Defense Mechanisms

Lower esophageal sphincter

Secretion of gastric mucus
Stimulated by prostaglandin E2 and I2

Secretion of bicarbonate ions

GERD

Definition: when the reflux of stomach contents causes troublesome symptoms or complications Diagnosis:
Presence of symptoms Demonstration of reflux Identification of existing damage from reflux

Epidemiology

44% of adults in the US experience heartburn 1 time/month Up to 15-18% of adults in the US experience heartburn weekly Heartburn or substernal burning is the most commonly recognized manifestation of GERD

Risk Factors for GERD

Obesity Food (spicy, chocolate, peppermint) Age Smoking Caffeine Alcohol Pregnancy

Stages of GERD
Stage
I (NERD)

Description
sporadic 2-3 episodes/wk

Medical Management
Lifestyle

modification Antacids/H2 RA as needed

PPI

II III

Frequent

symptoms +/- esophagitis

Chronic,

vs. H2RA

unrelenting PPI once or twice Immediate relapse off daily therapy Esophageal complications

Treatment of GERD

Decrease acidity of stomach contents

Antacids H2 receptor antagonists Proton pump inhibitors

Protect gastric mucosa

sucralfate

Chemically neutralize stomach acid

Base (OH)3 or CO3 + Al, Ca, or Mg
CaCO3= calcium carbonate (Tums) Al (OH)3 + Mg (OH)2 = Maalox

Some contain simethicone (a surfactant)

Al (OH)3 + Mg (OH)2 + simethicone = Mylanta

Site GI chapter

Antacids
Mechanism of Action: Antacid + HCl salt + water Examples

Al(OH)3 + 3 HCl CaCO3 + 2 HCl

Site GI chapter

AlCl3 + 3H2O CaCl2 + 2H20 + CO2

Antacids

Side Effects
Constipation (Al containing products) Diarrhea (Mg containing products) Electrolyte imbalances Decreases absorption of other drugs

Place in Therapy
Minor, infrequent dyspepsia With other acid suppressants on an as needed basis Calcium supplementation

H2-Receptor Antagonists

Block histamine from binding to H2 receptors on parietal cell

Decrease rate of activation by histamine decreased acid secretion

Blocks basal and bolus acid secretion

Basal: continuous acid secretion Bolus: secretion in response to stimuli (food, etc)

H2-Receptor Antagonists

Cimetidine (Tagamet)
Not used often due to drug interactions

Ranitidine (Zantac)
150-300mg by mouth twice daily

Famotidine (Pepcid)
20-40mg by mouth twice daily

Nizatidine (Axid)
150-300mg by mouth twice daily

H2-Receptor Antagonists

Side Effects
Well tolerated Many drug interactions, esp. with HIV medication Tolerance can develop with long term use

Place in Therapy
As needed for minor dyspepsia Daily to control frequent symptoms

Low dose for symptoms w/o esophagitis High dose for symptoms w/ esophagitis

Proton Pump Inhibitors

Most potent inhibitors of acid secretion

Decrease daily acid secretion 80-95%

Require activation by acid in stomach Irreversibly binds and inactivates the H+/K+-ATPase
H+/K+-ATPase is the pump molecule that secretes acid from the parietal cell into the lumen of the stomach

Proton Pump Inhibitors

Drug
Omeprazole (Prilosec) Esomeprazole (Nexium) Lansoprazole (Prevacid) Pantoprazole (Protonix) Rabeprazole (Aciphex)

Healing
20-40mg daily 20-40mg daily 15-30mg daily 40mg daily 20mg daily

Prevention
20mg daily 20mg daily 15 mg daily 20-40mg daily 20mg daily

Proton Pump Inhibitors

Side Effects
Well tolerated Takes multiple doses to get full effect

Place in Therapy
Symptomatic GERD with esophagitis Promote healing of gastric ulcers Hypersecretory conditions Prevent NSAID-associated gastric ulcers

Miscellaneous

Other medications used for GERD

Prostaglandin analogues (i.e. misoprostol)

Bind a EP3 receptor on parietal cells, decreasing cAMP (energy) available for H+/K+-ATPase

Sucralfate
Sucrose + Al(OH)3 which forms a viscous layer on the gastric mucosa Prevents acid from contacting mucosa

Metoclopramide

Stimulates gastric motility clearance of stomach acid

increased

Complications of GERD

Ulceration (w/ or w/o H. pylori) Asthma exacerbations Esophageal strictures Adenocarcinoma Barrett Esophagus

H. Pylori Infection

Gram-negative rod Not always associated with an active ulcer Associated with gastritis, leads to:
Gastric/duodenal ulcers Gastric adenocarcinoma Gastric B-cell lymphoma

Eradication is standard of care to promote healing of ulcer and to prevent recurrence

H. Pylori Infection

3 Drug Combination
Proton pump inhibitor (high dose) 2 antibiotics (clarithromycin + amoxicillin OR metronidazole

4 Drug Combination
Proton pump inhibitor (high dose) 2 antibiotics (metronidazole + tetracycline OR amoxicillin OR clarithromycin) Bismuth subsalicylate

All regimens 14 days in duration

Patient compliance is difficult with intense regimens

Acid-rebound Phenomenon

Chronic suppression of acid secretion leads to hypergastrinemia

Gastrin stimulates ECL cells to release histamine increased acid secretion from activation of histamine receptor on parietal cell

Disorders of the Lower GI Tract

Constipation
Diarrhea

Gastrointestinal Motility

The GI tract is in a continuous contractile, absorptive, & secretory state Muscle, CNS, ENS (enteric nerve system), and humoral pathways control GI movement 4 phases to movement in the GI tract
Peristalsis is most important, moves contents through GI tract

GI Motility
increased transit time
- Increased water absorption constipation decreased transit time -Decreased water and nutrient absorption diarrhea

Constipation

Affects up to 27% of Americans Accounts for 2.5 mil. physician visits/year $400 million spent on OTCs annually
Definition
Unsatisfactory defecation that results in infrequent stool, difficult stool passage, or both

Constipation

Causes of Constipation

GI disorders
Irritable bowel syndrome, hernia, anal fissures

Metabolic disorders
Diabetes with neuropathy, hypothyriodism

Pregnancy Psychogenic disorders Medications

Analgesics, antacids, iron preparations

Treatment of Constipation

Lifestyle modifications

Medications

Fiber-rich diet Adequate fluid intake Appropriate bowel habits and training Exercise Bulk-forming laxatives Stimulant laxatives Hyperosmotic laxatives Stool softeners

Bulk-Forming Laxatives

3 kinds
Psyllium (Metamucil) Methylcelluose (Citrucel) Calcium polycarbophil (Fibercon)

Increases colonic mass which triggers peristalsis Increases water content of stool via hydrophilic forces

Stimulant Laxatives

Induce low-grade inflammation in the small and large intestine Promotes accumulation of water and stimulates motility Provides soft or semifluid stool in 6-12 hours Bisacodyl (Dulcolax) 5-15 mg by mouth daily; 10mg rectally daily (rectal administration effective within 1 hour) Castor Oil Senna (Senokot) 8.6mg sennosides 1-2 times per day (1-2 tablets once or twice daily)

Hyperosmotic Laxatives

Osmotically mediated water retention (via cations-Al, Mg, etc) which stimulates peristalsis Provides watery fecal evacuation in 1-6 hours Magnesium hydroxide (Milk of Mag)
5-15mL by mouth four times daily

Polyethylene glycol (Miralax)

Dose used depends on level of evacuation

Sodium phosphate (Fleets Phosphosoda)

Stool Softeners/Lubricants

Docusate (Colace)

Stool softener Mixes aqueous and fatty material in the intestinal tract, leading to increase stool water content Used to prevent constipation or straining

Mineral Oil (Nujol)

1-2 capsules by mouth once or twice daily

Lubricant Coats stool and allows for easier passage 15-30mL orally as needed Causes softening and passage of stool in 1-3

days

Diarrhea

Prevalence of diarrhea varies in developed vs. non-developed countries

1.3 billion episodes/yr in developing countries 4 million deaths

Can be associated with an infectious cause

Shigella, Salmonella, E. Coli among most common

Most diarrhea is self-limiting Defined as an increase in stool frequency or water content

Diarrhea

Opioid Derivatives

Bind the -receptor on enteric nerves, epithelium, and muscle

Decrease GI motility Increase absorption of water from the bowel

Diphenoxylate (Lomotil)
5mg by mouth 4 times daily (max 20mg/day)

Loperamide (Immodium)
4mg by mouth first, then 2mg by mouth after each loose stool (max 16mg/day)

Adsorbents

Non-selectively absorbs intestinal fluid

Regulates stool texture and viscosity Bind bacterial toxins and bile salts

Attapulgite (Kaopectate)
30-120mL after each loose stool

Can bind other medications, must space out from others by 2 to 3 hours

Bismuth Salicylate

Anti-secretory, anti-inflammatory, antimicrobial effects Used for the prevention and treatment of travelers diarrhea PeptoBismol
30mL (2 tabs) every hour as needed (up to 8 times/day) Excessive use can lead to salicylate poisioning

Probiotics

Replaces normal colonic microflora

Restores intestinal function and suppresses the growth of pathogenic bacteria

Lactobacillus acidophilus (Lactinex)

2 tabs or 1 packet of granules 3-4 times daily

Dairy Products
200-400 grams of lactose Special lactobacillus containing yogurts

Conclusion

Approximately 1/3 of your patients will be taking a medication for GERD Approximately of your patients will be taking a medication for constipation GERD, constipation, and diarrhea affect a patients quality of life

Questions?