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