Treatment of Acid-Treatment of Acid-peptic Disorderspeptic Disorders
Dr. Yuri Clement
Pharmacology Unit, FMS
OverviewOverview• Acid-peptic disorders:Acid-peptic disorders:
– Peptic ulcer disease (PUD)• Helicobacter pylori-associated ulcer• NSAID-associated ulcer
– Gastroeosphagal reflux disease– Dyspepsia
• Drug therapyDrug 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)
PROTECTIVEPROTECTIVEFACTORSFACTORS
Mucus layer
Ionic gradient
Bicarbonate layer
Prostaglandins
Surface epithelialcells
Mucosal bloodsupply
H. pyloriPepsinGastricacid
AGGRESSIVE FACTORSAcidic
environment
Neutral environment
Aggressive and Protective Factors in Aggressive and Protective Factors in gastroduodenal mucosagastroduodenal mucosa
Tx directed at restoring balance by aggressive factors and mucosal defenses
Acid-peptic diseaseAcid-peptic disease
Classification:Classification: • Peptic ulcer disease (PUD)
– H. pylori-associated ulcer– NSAID-associated ulcer
• Gastroeosphageal reflux disease (GERD)
• Dyspepsia
PPeptic eptic uulcer lcer ddisease (PUD)isease (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 pyloriHelicobacter pyloriH. 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’
DetectionDetection
Endoscopy-based invasive tests:Endoscopy-based invasive tests: Rapid urease test, Direct microscopy, histology, Culture, DNA probes/PCR
Non-invasive tests:Non-invasive tests: 13/14C-urea breath test (UBT), Serology (lgG, lgA), PCR in saliva and faeces
NSAID-associated ulcerNSAID-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
10–30% of chronic users develop peptic ulcerNSAIDs:
Aspirin, Ketoprofen, Indomethacin, Ibuprofen, Naproxen, Diclofenac, Fenoprofen
GGastroastroeeosphageal osphageal rreflux eflux ddisease isease (GERD)(GERD)
Retrosternal burning, or heartburn, is the most frequent symptom experienced by ‘acid-reflux disease’ patients in general practice
20–40% 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 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 sphinctermuscle or as a last resort a minor surgery (laparoscopy) to tighten the muscles.
DyspepsiaDyspepsia
… 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 • 2–5% of all GP consultations for dyspepsia
• ‘Acid-reflux disease’ is frequently misdiagnosed as dyspepsia
Treatment of Acid-peptic Treatment of Acid-peptic diseases: A Historical Perspectivediseases: 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 Drug Glossary
AntacidsAntacids
HH22-receptor antagonists-receptor antagonists
Proton pump inhibitorsProton pump inhibitors
H. pyloriH. pylori eradication eradication
•Al(OH)3
•CaCO3
•Mg(OH)2
•NaHCO3
•Cimetidine•Famotidine•Ranitidine•Nizatidine
•Amoxicillin•Bismuth compounds•Clarithromycin•Metronidazole•Tetracycline
•Omeprazole•Esomeprazole•Lansoprazole•Rabeprazole•Pantoprazole
Mucosal protection Mucosal protection
•Bismuth compounds•Sucralfate•Misoprostol
Acid suppressionAcid suppression
The gastric parietal cell: The key to acid secretionThe gastric parietal cell: The key to acid secretion
GastrinHistamine
Acetylcholine
Ca2+
HCI
Protein kinasesProtein kinasesProteinkinasesProteinkinases
Ca2+Ca2+
Release of Ca2+ from
intracellular stores
Release of Ca2+ from
intracellular stores
cAMPcAMP
ProteinkinasesProteinkinases
Release of Ca2+ from intracellular stores
Release of Ca2+ from intracellular stores
ACh (M3)
Ca2+Ca2+
H+
K+
K+
Cl-
Cl-
HCl
AcidAcidpumppump
AntacidsAntacidsAl(OH)3 CaCO3 Mg(OH)2 NaHCO3
Generic formulation Trade nameAl(OH)3 + MgCO3 Gaviscon ®
Al(OH)3 + Mg(OH)2 Maalox ®
Al(OH)3 + Mg(OH)2 + simethine Myanta ®, Gelusil ®
CaCO3 Tums ®
Preparations vary widely in chemical composition and potencyRelatively inexpensive and safe
Mechanism of action:
Weak bases that neutralize gastric acid
Al(OH)3 + 3HCl AlCl3 + 3H2OCaCO3 + 2HCl CaCl2 + H2O + CO2
Mg(OH)2+ 2HCl MgCl2 + 2H2ONaHCO3 + 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
AntacidsAntacids
AntacidsAntacidsClinical 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 pH2. ↑ urinary pH3. Antacid-drug binding• ↓ absorption of fluoroquinolones, tetracyclines, itraconazole, iron
HH22-Receptor -Receptor
Antagonists (H2RA)Antagonists (H2RA)
Generic Dosage forms (mg) Trade names
Cimetidine* 100, 200, 300, 400, 800 Tagamet®
Famotidine 10, 20, 40 Pepcid®
Nizatidine 150, 300 Axid®
Ranitidine 75, 150, 300 Zantac®
H2RAH2RA
Mechanism of action: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.
H2RAH2RA• 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
H2RAH2RA acid secretion results in:1. reduced ulcer pain 2. 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% healingNon-ulcer dyspepsia bleeding in stress-related gastritis
H2RA: Adverse EffectsH2RA: 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: H2RA: Drug-drug interactions/PrecautionsDrug-drug interactions/Precautions
CimetidineDrug-drug interactions: theophylline, warfarin, tricyclic antidepressants,
triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine.
Elderly patients may experience confusional states
Famotidine, Ranitidine, NizatidineMinimal CYP450 interaction. May ketoconazole and itraconazole effects
RanitidineMay alter plasma levels of ferrous sulfate, diazepam, nondepolarizing muscle
relaxants, and oxaprozin
Proton Pump Inhibitors (PPI)Proton Pump Inhibitors (PPI)
Generic Dosage forms (mg) Trade names
Omeprazole* 10, 20, 40 Prilosec®
Lansoprazole 15, 30 Prevacid®
Pantoprazole 40 (40 mg inj) Protonix®
Rabeprazole 20 Aciphex®
Esomeprazole 20, 40 Nexium®
Chemically similar, largely displaced H2-blockers as 1st line therapy
PPIsPPIs
Mechanism of action:Mechanism of action:
Irreversible inactivation of parietal cell H+, K+-ATPase (H+ pump) from transporting H+ into gastric lumen.
(Distinct to gastric parietal cells)
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 PPIs
All inactive prodrugs, administered as acid-resistant enteric-coated capsule or tablet formulations.
bioavailability with food, given 1hr before meals; duration of action 24hrs.
PPIsPPIs
Precaution: Precaution: Symptomatic relief with PPIs may mask symptoms of gastric malignancy
PPIsPPIsClinical Uses: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
Adverse Effects:Adverse Effects:
• Well tolerated; ADR in ~1-5%.Well tolerated; ADR in ~1-5%.• GI Effects - diarrhea, abdominal pain, constipationGI Effects - diarrhea, abdominal pain, constipation• CNS Effects – headache, dizziness, somnolenceCNS Effects – headache, dizziness, somnolence
Drug-drug interactions: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
PPIsPPIs
Mucosal Protective AgentsMucosal Protective AgentsBismuth Compounds, Sucralfate, Misoprostol
Mucosal Protective Agents: Mucosal Protective Agents: Bismuth CompoundsBismuth Compounds (Pepto-Bismol®, Tritec®)(Pepto-Bismol®, Tritec®)
Bismuth subsalicylate (US) and bismuth subcitrate (Europe) complex bismuth salts of salicylate and citric acids respectively
Mechanism of Action: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 CompoundsBismuth Compounds
Clinical Uses (not 1Clinical Uses (not 1stst line): 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:Adverse Effects:• Dark colouration of oral cavity and faeces (short use recommended)
Drug-drug interactions: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®)Sucralfate (Carafate®)
– Complex of Al(OH)3 and octasulphated sucrose.
– Protects against gastric and duodenal mucosa acid-pepsin attack.
• Mechanism of Action: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
SucralfateSucralfate
Limited clinical uses (largely replaced by PPIs):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:Adverse effects:– Well tolerated, constipation due to Al (2%)
Drug-drug interactions:Drug-drug interactions:– May bind to ketoconazole, ciprofloxacin, tetracycline, phenytoin,
warfarin, quinidine, theophylline, and norfloxacin to reduce effects
Prostaglandins:Prostaglandins:Misoprostol (Cytotec®)Misoprostol (Cytotec®)
Mechanism of Action: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 PGE1PGs stimulate intestinal electrolyte and fluid secretion, intestinal motility, and uterine contractions
MisoprostolMisoprostol
Clinical Uses: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:Adverse Effects:• Diarrhea (30%)• Abdominal cramps
Contraindication:Contraindication:• Induces uterine contraction - should not be used in pregnancy or in women
trying to conceive
Drug regimens for Drug regimens for H. pyloriH. pylori eradication eradication
H. pyloriH. pylori eradication eradication is central to long-term is central to long-term remission of ‘acid-remission of ‘acid-pyloripylori disease’ disease’
Dyspepsia: Evaluation and treatment Dyspepsia: Evaluation and treatment
GERD: 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
Top Related