Treatment of Acidpeptic Disorders

Dr. Yuri Clement Pharmacology Unit, FMS

Overview
Acid-peptic disorders:
Peptic ulcer disease (PUD) Helicobacter pylori-associated ulcer NSAID-associated ulcer Gastroeosphagal reflux disease Dyspepsia

Drug therapy: therapy

Acid suppression agents Antacids H2-receptor antagonists (H2RA) Proton pump inhibitors (PPIs) Mucosal protective agents Bismuth compounds Sucralfate Prostaglandins Helicobacter pylori eradication: polypharmacy, including antimicrobials (Mechanisms of action, clinical uses and adverse effects)

Aggressive and Protective Factors in gastroduodenal mucosa

PROTECTIVE FACTORS Mucus layer Ionic gradient Bicarbonate layer Prostaglandins Surface epithelial cells Mucosal blood supply Neutral environment Acidic environment AGGRESSIVE FACTORS Gastric acid Pepsin H. pylori

Tx directed at restoring balance by aggressive factors and mucosal defenses

Acid-peptic disease
Classification: Peptic ulcer disease (PUD)
H. pylori-associated ulcer NSAID-associated ulcer

Gastroeosphageal reflux disease (GERD) Dyspepsia

Peptic ulcer disease (PUD)

A sensitive, raw patch which forms a break in stomach (gastric ulcers) or duodenum (duodenal ulcers) lining Symptoms:
Severe pain in the abdomen:
usually felt at top of stomach, centrally between ribs and sometimes going through to the back often burning often eased by eating often worse at night sometimes accompanied by vomiting.

Helicobacter pylori
H. pylori infection is the leading cause of PUD; associated with virtually all ulcers not induced by NSAIDs.
H. pylori is a short, spiral-shaped, microaerophilic gram-negative bacillus. Closely involved in the pathogenesis of PUD, gastric lymphoma and adenocarcinoma. H. pylori infection causes inflammatory gastritis, and together with gastric acid, is a key factors in acid-pylori disease

Detection
Endoscopy-based invasive tests: Rapid urease test, Direct microscopy, histology, Culture, DNA
probes/PCR

Non-invasive tests: 13/14C-urea breath test (UBT), Serology (lgG, lgA), PCR in saliva and faeces

NSAID-associated ulcer
~ 30 million users daily: osteoarthritis, backpain, rheumatoid arthritis.
40% > 60 years; > 500 million prescriptions yearly, OTC access ~20% of ADRs in US and 25% in UK NSAID-related ~15% - 40% users complain of upper GI symptoms 1030% of chronic users develop peptic ulcer
NSAIDs:
Aspirin, Ketoprofen, Indomethacin, Ibuprofen, Naproxen, Diclofenac, Fenoprofen

Gastroeosphageal reflux disease (GERD)

Retrosternal burning, or heartburn, is the most frequent symptom experienced by acid-reflux disease patients in general practice

2040% experience heartburn; primary symptom of acid-reflux disease

Symptoms negatively impacts quality of life

8% suffer from heartburn or acid reflux 2-3 times/week

Severity of heartburn does not correlate with the severity of any underlying esophagitis

GERD lifestyle changes

Eat >3 hours before bedtime. Stop smoking. Avoid certain foods: fatty, milk, chocolate, spearmint, peppermint, caffeine, citrus fruits and juices, tomato products, pepper seasoning, and alcohol -- especially red wine. portions of food at mealtime, and avoid tight clothing or bending over after eating. Elevate the head of the bed or mattress 6 to 8 inches. Lose weight if overweight..

Further treatment using drugs to reduce acidity, or metoclopramide to tighten sphincter muscle or as a last resort a minor surgery (laparoscopy) to tighten the muscles.

Dyspepsia
is persistent or recurring abdominal pain that is
centered in the upper abdomen that lasts for more than four weeks.
Symptoms - bloating, nausea, burping, feeling of fullness soon after eating, usually soon after having a meal.

~25% annual prevalence in Western countries <50% of sufferers seek medical care 25% of all GP consultations for dyspepsia Acid-reflux disease is frequently misdiagnosed as dyspepsia

Treatment of Acid-peptic diseases: A Historical Perspective

Centuries-old use of antacids Lifestyle modification: bland diet, alcohol consumption, no smoking, no aspirin, avoid stressful situations. Surgery as last resort when deep ulcers cause complications such as bleeding or perforation of the wall of the stomach or duodenum.

Drug Glossary
Acid suppression
Antacids
Al(OH)3 CaCO3 Mg(OH)2 NaHCO3

Mucosal protection
Bismuth compounds Sucralfate Misoprostol

Proton pump inhibitors

Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole

H. pylori eradication
Amoxicillin Bismuth compounds Clarithromycin Metronidazole Tetracycline

H2-receptor antagonists
Cimetidine Famotidine Ranitidine Nizatidine

The gastric parietal cell: The key to acid secretion

HCI

HCl H+
Protein kinases Ca
2+ 2+

ClK+ Cl
+ -

Acid pump

Protein kinases
2+ Ca2+

Release of 2+ Ca2+ from intracellular stores

K
Protein kinases cAMP

Release of 2+ Ca2+ from intracellular stores

Ca2+

ACh (M3) Acetylcholine

Gastrin

Histamine

Antacids
Al(OH)3 CaCO3 Mg(OH)2 NaHCO3

Generic formulation
Al(OH)3 + MgCO3 Al(OH)3 + Mg(OH)2 Al(OH)3 + Mg(OH)2 + simethine CaCO3

Trade name
Gaviscon Maalox Myanta , Gelusil Tums

Preparations vary widely in chemical composition and potency Relatively inexpensive and safe

Antacids
Mechanism of action:
Weak bases that neutralize gastric acid Al(OH)3 + 3HCl AlCl3 + 3H2O CaCO3 + 2HCl CaCl2 + H2O + CO2 Mg(OH)2+ 2HCl MgCl2 + 2H2O NaHCO3 + HCl NaCl + H2O + CO2

(baking soda)

stomach and duodenal bulb acidity do not decrease acid secretion. Pepsin is inactive pH > 4.0. Stimulate mucosal prostaglandin production

Efficacy depends on:

Dissolution rate Water solubility Rxn rate with acid Gastric emptying rate

Antacids
Clinical Use:
Mg and Al antacid mixtures promote healing of duodenal ulcers; gastric - doubtful. GERD; does not affect natural history of disease

Adverse effect:
Mg and Al cause osmotic diarrhea and constipation respectively. Mixtures or alternating Al(OH)3 and Mg(OH)2 avoid bowel function changes. Should not be used chronically in renal insufficiency.

Drug-drug interactions [Al(OH)3 and Mg(OH)2]: 1. gastric pH 2. urinary pH 3. Antacid-drug binding

absorption of fluoroquinolones, tetracyclines, itraconazole, iron

H2-Receptor Antagonists (H2RA)

Generic
Cimetidine* Famotidine Nizatidine Ranitidine

Dosage forms (mg)

100, 200, 300, 400, 800 10, 20, 40 150, 300 75, 150, 300

Trade names
Tagamet Pepcid Axid Zantac

H2RA
Mechanism of action:
Highly selective, dose-dependent, competitive inhibition of histamine action in gastric parietal cell, inhibit basal acid and pepsin secretion (including nocturnal secretion). It also inhibits acid secretion mediated by gastrin, cholinergic agents, food and reflex vagal stimulation. However, they do not act by blocking cholinergic or gastrin receptors.

H2RA
Rapid absorption, equally efficacious Duration of action <6 hours
Cimetidine has a short duration of action; multiple daily dosing. Ranitidine and famotidine has short plasma t1/2, whereas nizatidine has a longer t1/2.

Inhibit 60-70% of total 24-hour secretion:

90% nocturnal; 60-80% daytime

Significant 1st pass metabolism:

~50% bioavailability, except nizatidine (~100%)

Clearance by:
Hepatic metabolism Glomerular filtration Renal tubular secretion

Dramatic decline in use with advent of proton-pump inhibitors

 acid secretion results in:

1. 2.

H2RA

reduced ulcer pain promotes ulcer healing (~80-90%)

Clinical uses: Peptic ulcer disease (PUD) No significant therapeutic role in acute H. pylori-associated PUD In refractory H. pylori-associated PUD, H2RA given to prevent ulcer recurrence In NSAID-associated PUD, rapid healing with discontinuation of NSAID. 1x nighttime dose useful in uncomplicated PUD. GERD Prophylatically with erosive esophagitis <50% healing Non-ulcer dyspepsia bleeding in stress-related gastritis

H2RA: Adverse Effects

Well tolerated (<3% ADR) CNS effects headache, fatigue, dizziness GI effects constipation or diarrhea Cimetidine (high-dose or chronic use) Endocrine effects gynecomastia or impotence in men; galactorrhea in women
Precautions: Adjust dose or discontinue in renal insufficiency, pregnancy and lactating mothers

H2RA: Drug-drug interactions/Precautions

Cimetidine Drug-drug interactions: theophylline, warfarin, tricyclic antidepressants, triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine. Elderly patients may experience confusional states Famotidine, Ranitidine, Nizatidine Minimal CYP450 interaction. May ketoconazole and itraconazole effects Ranitidine May alter plasma levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin

Proton Pump Inhibitors (PPI)

Generic Omeprazole* Dosage forms (mg) Trade names 10, 20, 40 Prilosec Prevacid Protonix Aciphex Nexium

Lansoprazole 15, 30 Pantoprazole Rabeprazole 40 (40 mg inj) 20

Esomeprazole 20, 40

Chemically similar, largely displaced H2-blockers as 1st line therapy

PPIs
Mechanism of action:
Irreversible inactivation of parietal cell H+, K+ATPase (H+ pump) from transporting H+ into gastric lumen.
(Distinct to gastric parietal cells)

PPIs
H+ pump blockade is the most effective way to inhibit acid secretion. (90%-98% 24-hour inhibition) ~18hrs to synthesize new pumps Inhibit both fasting- & meal-induced H+ secretion PPIs relieve pain and heal peptic ulcers > H2 antagonists

PPIs
All inactive prodrugs, administered as acid-resistant entericcoated capsule or tablet formulations. bioavailability with food, given 1hr before meals; duration of action 24hrs.

PPIs
Clinical Uses:
Peptic ulcer disease (PUD) management:
H. pylori-associated triple therapy, followed by PPI for 4-6 weeks. NSAID-associated Remove NSAID to healing time PPI or H2RA - Prevention of rebleed.

Moderate and severe GERD 1st line (superior to H2RA) in controlling

symptoms and healing esophagitis.

Non-ulcer dyspepsia inconclusive Precaution:

Symptomatic relief with PPIs may mask symptoms of gastric malignancy

PPIs
Adverse Effects:
Well tolerated; ADR in ~1-5%. GI Effects - diarrhea, abdominal pain, constipation CNS Effects headache, dizziness, somnolence

Drug-drug interactions:
gastric pH reduces ketoconazole and digoxin absorption Esomeprazole may inhibit metabolism of diazepam Omeprazole may inhibit metabolism of coumadin, diazepam, phenytoin Lansoprazole theophylline clearance No significant interactions with rabeprazole and pantoprazole

Mucosal Protective Agents

Bismuth Compounds, Sucralfate, Misoprostol

Mucosal Protective Agents:

Bismuth Compounds (Pepto-Bismol, Tritec)
Bismuth subsalicylate (US) and bismuth subcitrate (Europe) complex bismuth salts of salicylate and citric acids respectively

Mechanism of Action:
Primary effect: antibacterial activity against H. pylori Secondary effect: chelates proteins at ulcer bases providing cytoprotective against acid back diffusion and peptic digestion at acidic pHs Stimulate HCO3-, mucus and prostaglandin secretions No effect on gastric acidity

Bismuth Compounds
Clinical Uses (not 1st line):
Acute diarrhea (OTC) Dyspepsia (OTC) In refractory H. pylori-associated PUD, useful in quadruple therapy (Promotes gastric and duodenal ulcers healing (as effective as cimetidine) and prevent ulcer recurrence)

Adverse Effects:
Dark colouration of oral cavity and faeces (short use recommended)

Drug-drug interactions:
Patients on large aspirin dose or showing aspirin sensitivity may show sensitivity to salicylate in bismuth subsalicylate bioavailability of oral tetracycline

Sucralfate (Carafate)
Complex of Al(OH)3 and octasulphated sucrose. Protects against gastric and duodenal mucosa acid-pepsin attack.

Mechanism of Action:
Bind +vely charged proteins in ulcer, forming protective viscous adhesive substance for up to 6hrs. Physical barrier backdiffusion of H+ Stimulates mucosal prostaglandin and HCO3- secretion

Sucralfate
Limited clinical uses (largely replaced by PPIs):
Short-term management of H. pylori-associated ulcers, can promote and hasten peptic ulcer healing (Less effective than H2RA and PPIs) Prevention of stress-related bleed

Adverse effects:
Well tolerated, constipation due to Al (2%)

Drug-drug interactions:
May bind to ketoconazole, ciprofloxacin, tetracycline, phenytoin, warfarin, quinidine, theophylline, and norfloxacin to reduce effects

Prostaglandins:
Misoprostol (Cytotec)
Mechanism of Action:
Inhibition of histamine-stimulated adenylyl cyclase activity, reduce activity through the histamine-evoked cAMP-dependent pathway and thereby reduce acid secretion. Stimulate the production of mucus and HCO3- by adjacent superficial epithelial cells and enhance mucosal blood flow. Analog of PGE1
PGs stimulate intestinal electrolyte and fluid secretion, intestinal motility, and uterine contractions

Misoprostol
Clinical Uses:
Moderately effective as 2nd-line drug. Promotes duodenal/gastric ulcer healing Prophylaxis in chronic aspirin and NSAID use with high risk of peptic ulcers. (COX-2 inhibitors alternative for NSAID.)

Adverse Effects:
Diarrhea (30%) Abdominal cramps

Contraindication:
Induces uterine contraction - should not be used in pregnancy or in women trying to conceive

Drug regimens for H. pylori eradication

H. pylori eradication is central to long-term remission of acid-pylori disease

Dyspepsia: Evaluation and treatment

GERD: treatment

Summary
Acid-peptic disorders PUD, GERD, dyspepsia. Rational drug use:
acidity antacids, H2RA, PPIs. Mucosal protection bismuth compounds, sucralfate,
misoprostol

H. pylori eradication triple therapy with PPIs & antibiotics