Acid Peptic DisordersAcid Peptic DisordersThe Spotlight is On!The Spotlight is On!

Charmaine Rochester, Charmaine Rochester, PharmD, CDE, CDM, BCPSPharmD, CDE, CDM, BCPS

Asst Professor, University of Maryland Asst Professor, University of Maryland School of PharmacySchool of Pharmacy

ObjectivesObjectives

At the end of this presentation, the student should be At the end of this presentation, the student should be able to:able to:

Review the anatomy and physiology of the Review the anatomy and physiology of the stomach stomach

Discuss the pathophysiology, risk factors, signs Discuss the pathophysiology, risk factors, signs and symptoms, complications and diagnosis of and symptoms, complications and diagnosis of ulcersulcers

Given a drug associated with ulcer formation, Given a drug associated with ulcer formation, discuss the proposed mechanism of ulcerationdiscuss the proposed mechanism of ulceration

Discuss the pathophysiology, risk factors, signs Discuss the pathophysiology, risk factors, signs and symptoms, and complications of and symptoms, and complications of gastroesophageal disease (GERD) gastroesophageal disease (GERD)

Acid Peptic DisordersAcid Peptic Disorders

DyspepsiaDyspepsiaPeptic UlcersPeptic UlcersDuodenal UlcersDuodenal UlcersStress UlcersStress UlcersGastroesophageal Reflux Disease Gastroesophageal Reflux Disease

(GERD)(GERD)Gastric CancersGastric Cancers

DyspepsiaDyspepsia

A constellation of upper abdominal A constellation of upper abdominal symptomssymptoms

Accounts for up 40 - 70% of GI complaints Accounts for up 40 - 70% of GI complaints Significant societal costs Significant societal costs CausesCauses

PUD, GERD, gastric cancerPUD, GERD, gastric cancerFood, medications, but commonly idiopathic Food, medications, but commonly idiopathic

Normal Stomach AnatomyNormal Stomach Anatomy

Gastric AntrumGastric Antrum

Physiology: The Secretory Physiology: The Secretory Epithelial CellsEpithelial Cells

Surface Epithelium

Opening of gastric pit

Parietal cell

Chief Cell

Parietal cell

1. Mucus cells• Mucus

2. Parietal cells• HCL

3. Chief Cells• Pepsinogen

4. G cells• Gastrin

Gastric Acid and its FunctionGastric Acid and its Function

Gastric Acid ContentsGastric Acid ContentsHCl, salts, pepsin, mucus, water, intrinsic HCl, salts, pepsin, mucus, water, intrinsic

factor, bicarbonate factor, bicarbonate

Gastric Acid FunctionGastric Acid Functionto kill micro-organisms to kill micro-organisms to activate pepsinogento activate pepsinogenbreaks down connective tissue in foodbreaks down connective tissue in food

Mucosal Defenses/ProtectionMucosal Defenses/Protection

Mucus layer on gastric surface Mucus layer on gastric surface Mucosal barrier to damageMucosal barrier to damage

Bicarbonate: Abundant in mucus layer Bicarbonate: Abundant in mucus layer Prevent acidic damage and auto digestionPrevent acidic damage and auto digestion

Prostaglandins are cytoprotective Prostaglandins are cytoprotective Increase blood flow and cell regenerationIncrease blood flow and cell regeneration

Mucosal integrityMucosal integrityMaintained by tight cell junctionsMaintained by tight cell junctions

Epidemiology of Peptic Ulcer Epidemiology of Peptic Ulcer Disease (PUD)Disease (PUD)

Development of PUDDevelopment of PUD 4 -10% of Americans4 -10% of Americans Gastric Ulcer peaks Gastric Ulcer peaks

55-6555-65thth year year Duodenal Ulcer Duodenal Ulcer

increases with age increases with age until 60 yearsuntil 60 years

Pathophysiology of Peptic Ulcer Pathophysiology of Peptic Ulcer Disease (PUD)Disease (PUD)

Mucosal Defenses

• Bicarbonate

• Mucus

• Prostaglandin

• Growth factor

• Mucosal regeneration

Luminal Aggressors

• H. pylori

• NSAIDs

• Acid

• Pepsin

Goldin GF, et al. Gastr Endosco Clin Nor Am. 1996;6;505-526. Saggioro A, et al. Ital J Gastroenterol. 1994;269(suppl 1):3-9. Modlin IN, et al. Acid Related Diseases. 1998;317-362.

Risk Factors/Aggressors of PUDRisk Factors/Aggressors of PUD

Major FactorsMajor FactorsHelicobacter PyloriHelicobacter PyloriNSAIDsNSAIDsCigarette smokingCigarette smokingAcid and pepsinAcid and pepsin

Other FactorsOther FactorsGeneticsGenetics?Foods?Foods?Stress?Stress

Helicobacter PyloriHelicobacter Pylori

BacteriaBacteria Gram –ve spiral bacteriumGram –ve spiral bacterium 40% of patients >60 yrs are +ve for H.pylori40% of patients >60 yrs are +ve for H.pylori Transmitted: possibly person to personTransmitted: possibly person to person Most common cause of antral gastritisMost common cause of antral gastritis

Mechanism of gastric injuryMechanism of gastric injury CytotoxinCytotoxin Breakdown of mucosal defensesBreakdown of mucosal defenses Adherence to epithelial cellsAdherence to epithelial cells Increase gastrin releasing peptide (GRP)Increase gastrin releasing peptide (GRP) Decrease bicarbonate secretionDecrease bicarbonate secretion

Drug Induced PUDDrug Induced PUD

DrugDrug ActionAction

Iron, K+, Iron, K+, TetracyclinesTetracyclines

Corrosive to mucosaCorrosive to mucosa

Reserpine. TCA, Reserpine. TCA, AnticholinergicsAnticholinergics

sympathetic, sympathetic, parasympathetic parasympathetic tone – tone – acid output acid output

AlcoholAlcohol acid output (secretagogue)acid output (secretagogue)

Causes gastritis, bleeding is Causes gastritis, bleeding is possible, not thought to possible, not thought to causecause ulcerulcer

CaffeineCaffeine acid production (even acid production (even decaffeinated); No decaffeinated); No in ulcer in ulcer formation, lowers (LES) so may formation, lowers (LES) so may cause GERD symptomscause GERD symptoms

NSAIDSNSAIDS

Inhibits prostaglandin Inhibits prostaglandin synthesis (COX synthesis (COX inhibition) inhibition)

Disrupts functional Disrupts functional mucosal integritymucosal integrity

mucosal blood flowmucosal blood flow cell regenerationcell regeneration Direct GI irritationDirect GI irritation Antiplatelet effect Antiplatelet effect

(causing bleeding)(causing bleeding) Ion trapping Ion trapping acid (basal and acid (basal and

maximal stimulation) maximal stimulation) secretionsecretion

Risk Factors for NSAID-Induced GI Risk Factors for NSAID-Induced GI InjuryInjury

History of ulcer or GI complicationsHistory of ulcer or GI complications Increasing ageIncreasing ageConcomitant anticoagulation therapyConcomitant anticoagulation therapyConcomitant corticosteroid useConcomitant corticosteroid useHigh dose NSAID use or concomitant High dose NSAID use or concomitant

aspirin/NSAID useaspirin/NSAID use

Conditions Associated with Conditions Associated with PUDPUD

Fig. 40-2. Feldman: Sleisenger & Fortran’s Gastrointestinal and Liver Disease, 7th ed.

SmokingSmoking

Impairs ulcer healingImpairs ulcer healing Promotes ulcer recurrencePromotes ulcer recurrence Increases the likelihood of ulcer Increases the likelihood of ulcer

complicationscomplications MechanismsMechanisms

Stimulate gastric acid secretion Stimulate gastric acid secretion Stimulate bile salt refluxStimulate bile salt reflux Causes alteration in mucosal blood flowCauses alteration in mucosal blood flow Decrease mucus secretion Decrease mucus secretion Reduces prostaglandin synthesisReduces prostaglandin synthesis Decrease pancreatic bicarbonate secretionDecrease pancreatic bicarbonate secretion

Acid and PepsinAcid and Pepsin

? Mechanism of damage:? Mechanism of damage: gastrin releasing peptide (GRP) gastrin releasing peptide (GRP) defect in inhibition defect in inhibition

of acid productionof acid production mucosal bicarbonate secretionmucosal bicarbonate secretion

basal acid secretory drivebasal acid secretory drive postprandial acid secretory responsepostprandial acid secretory response sensitivity to secretagoguessensitivity to secretagogues

Effects of Diet and StressEffects of Diet and StressDiet and StressDiet and Stress ActionAction

DietDiet Dyspepsia, may Dyspepsia, may pain - not believed to pain - not believed to cause ulcer or assist healingcause ulcer or assist healing

Physiologic Physiologic stressstress

↓↓ mucosal blood flow, tissue hypoxia, mucosal blood flow, tissue hypoxia, mucosal lining degradation; e.g. ICU, mucosal lining degradation; e.g. ICU, sepsis, burn, trauma. Associated with sepsis, burn, trauma. Associated with multiple erosions & significant bleedingmultiple erosions & significant bleeding

Psychological Psychological stressstress

Similar # stressful events in ulcer vs. Similar # stressful events in ulcer vs. non-ulcer patientsnon-ulcer patients

↓↓ tolerance to discomforttolerance to discomfort

Recent epidemiological data suggest Recent epidemiological data suggest possible rolepossible role

Gastric UlcerGastric Ulcer

Duodenal Peptic UlcersDuodenal Peptic Ulcers

Stages of Ulcer FormationStages of Ulcer Formation

Sclerosis

UlcerErosion Chronic Ulcer

Signs and Symptoms of GU or DUSigns and Symptoms of GU or DU

Epigastric painEpigastric pain Not well localized Not well localized Annoying, burning, gnawing, achingAnnoying, burning, gnawing, aching

Duodenal ulcersDuodenal ulcers On an empty stomachOn an empty stomach During the nightDuring the night Between mealsBetween meals Relieved by food and antacidsRelieved by food and antacids Episodic followed with symptomatic periods then no Episodic followed with symptomatic periods then no

occurrenceoccurrence

Complications of PUDComplications of PUD

HematemesisHematemesisPerforationPerforationDiarrheaDiarrheaObstructionObstructionNauseaNauseaVomitingVomitingWeight LossWeight LossWeaknessWeakness

Stress UlcerStress Ulcer Duodenal UlcerDuodenal Ulcer Gastric UlcerGastric Ulcer

Hemorrhage:Hemorrhage:

Frequent, Frequent, associated associated mortalitymortality

Common in Common in posterior wall of posterior wall of duodenal bulb, duodenal bulb, associated with associated with melenamelena

Less common Less common (associated with (associated with hematemesis, coffee hematemesis, coffee grind emesis), melenagrind emesis), melena

Perforation:Perforation:

CommonCommon

When in anterior When in anterior wall of duodenumwall of duodenum

More common in More common in anterior wall of stomachanterior wall of stomach

Obstruction: ?Obstruction: ? CommonCommon RareRare

Malignancy:Malignancy:

RareRare

RareRare 7%7%

Complications: PUDComplications: PUD

Objective MeasuresObjective Measures

MelenaMelenaHct, HgbHct, Hgb

Microcytic, hypochromic indicesMicrocytic, hypochromic indicesPale conjunctivaPale conjunctiva

BUN/Cr RatioBUN/Cr RatioHeme +ve stoolHeme +ve stool

DiagnosisDiagnosis

Gastric Ulcer/Duodenal UlcerGastric Ulcer/Duodenal UlcerUpper endoscopy (gold standard)Upper endoscopy (gold standard)

H. pyloriH. pyloriNoninvasive: Urea breath test, serologyNoninvasive: Urea breath test, serologyInvasive: biopsy (histology, culture, rapid Invasive: biopsy (histology, culture, rapid

urease)urease)NSAID- inducedNSAID- induced

History History Still need to rule out H pylori infection Still need to rule out H pylori infection

Gastroesophageal Reflux Disease Gastroesophageal Reflux Disease (GERD)(GERD)

Reflux of gastric or intestinal contents Reflux of gastric or intestinal contents Results in heartburn, “burping” bitter tasteResults in heartburn, “burping” bitter taste

Signs and Symptoms Signs and Symptoms

Heartburn - hallmark symptomHeartburn - hallmark symptom Typical: Belching, regurgitation Typical: Belching, regurgitation Alarm symptoms: AtypicalAlarm symptoms: Atypical

Weight loss Weight loss Bleeding Bleeding Choking Choking Hoarseness, cough, wheezeHoarseness, cough, wheeze Dysphagia (difficulty swallowing)Dysphagia (difficulty swallowing) Odynophagia (painful swallowing)Odynophagia (painful swallowing) Atypical chest painAtypical chest pain Infants: spitting up, vomiting (uncommon: failure to gain Infants: spitting up, vomiting (uncommon: failure to gain

weight, Fe def anemia, recurrent pneumonia, near SIDS)weight, Fe def anemia, recurrent pneumonia, near SIDS)

Spectrum of Gastroesophageal Spectrum of Gastroesophageal Reflux Disease (GERD)Reflux Disease (GERD)

Acid refluxAcid refluxEsophagitisEsophagitisEsophageal Esophageal

ulcerationulcerationBarrett’s Barrett’s

esophagusesophagus

Possible Extraesophageal Possible Extraesophageal Manifestations of GERDManifestations of GERD

ENTENT PharyngitisPharyngitis Otitis mediaOtitis media SinusitisSinusitis Vocal cord granulomasVocal cord granulomas LaryngitisLaryngitis HoarsenessHoarseness Voice changesVoice changes Chronic coughChronic cough Dental enamel lossDental enamel loss

PulmonaryPulmonary Chronic coughChronic cough AsthmaAsthma Idiopathic pulmonary Idiopathic pulmonary

fibrosisfibrosis Chronic bronchitisChronic bronchitis PneumoniaPneumoniaOtherOther Chest painChest pain Sleep apneaSleep apnea Dental erosionsDental erosions

GERD Pathophysiology GERD Pathophysiology Loss of LES pressure

-Inappropriate relaxation

-Increase in intra-abdominal pressure

Aggressive Factors

Composition acid/pepsin

-Volume of refluxate

Defects in defense mechanisms-Anatomical -Mucosal resistance-Esophageal clearance-Gastric emptying

Lower Esophageal SphincterLower Esophageal Sphincter

LES Closed LES Open

Risk Factors Risk Factors

Factors that decrease LES pressureFactors that decrease LES pressureDietDietAlcoholAlcoholSmokingSmokingDrugs Drugs

Factors that increase intra-abdominal Factors that increase intra-abdominal pressurepressureObesityObesityPregnancy Pregnancy Bending overBending over

Foods and Drugs Affecting LESFoods and Drugs Affecting LESRAISE LES RAISE LES PressurePressure

LOWER LES PressureLOWER LES Pressure

FoodsFoods Proteins, Proteins, carbohydratescarbohydrates

Caffeine, Carminatives, Caffeine, Carminatives, Chocolates, Citrus, Garlic, Fat, Chocolates, Citrus, Garlic, Fat, TomatoesTomatoes

DrugsDrugs Alpha-agonistsAlpha-agonists

Beta-blockersBeta-blockers

CholinergicsCholinergics

CisaprideCisapride

MetoclopramideMetoclopramide

Alcohol, Alcohol, άά--antagonists, antagonists, AnticholinergicsAnticholinergics

BarbituratesBarbiturates

Beta-agonistsBeta-agonists

Calcium Calcium channel channel blockersblockers

DiazepamDiazepam

DopamineDopamine

MeperidineMeperidine

MethylxanthinesMethylxanthines

NarcoticsNarcotics

NicotineNicotine

NitratesNitrates

ProgesteroneProgesterone

ProstaglandinsProstaglandins

Tricyclic Tricyclic antidepressantsantidepressants

EstrogenEstrogen

Adapted from Gonzales et al. DICP 1990;24:1065Adapted from Gonzales et al. DICP 1990;24:1065

Non Pharmacologic InterventionsNon Pharmacologic Interventions

Helps 20% of patientsHelps 20% of patients Weight lossWeight loss Small size food portionsSmall size food portions Loose fitting clothesLoose fitting clothes Cigarette smoking cessationCigarette smoking cessation Avoid chocolate, alcohol, peppermint, fatty Avoid chocolate, alcohol, peppermint, fatty

meals, spicy meals, citric juices, cola, beermeals, spicy meals, citric juices, cola, beer Avoid meals 2 hours before lying downAvoid meals 2 hours before lying down Elevate the head of the bed with a 6-8” blockElevate the head of the bed with a 6-8” block

Elevation of Head of BedElevation of Head of Bed

Complications of GERDComplications of GERD Infants: Failure to ThriveInfants: Failure to ThriveEsophagitis (histopathological changes) Esophagitis (histopathological changes)

Gradations Gradations Grade I- erythema, edemaGrade I- erythema, edemaGrade II- isolated erosionsGrade II- isolated erosionsGrade III- confluent erosions, superficial ulcerationGrade III- confluent erosions, superficial ulcerationGrade IV- erosions, deep ulcers, strictureGrade IV- erosions, deep ulcers, stricture

Peptic stricture Peptic stricture Worsening obstructive lung diseaseWorsening obstructive lung diseaseBarrett’s esophagus Barrett’s esophagus MalignancyMalignancy

GERD and Cancer RiskGERD and Cancer Risk

Esophageal adenocarcinoma 8 times higher in Esophageal adenocarcinoma 8 times higher in patients with heartburn, regurgitation, or both patients with heartburn, regurgitation, or both at least once a weekat least once a week

Esophageal carcinoma 11 times higher in Esophageal carcinoma 11 times higher in patients with nighttime symptoms of GERDpatients with nighttime symptoms of GERD

Lagergren J, et al. New Engl J Med. 1999;240:825-831

GERD in Obstructive Lung DiseaseGERD in Obstructive Lung Disease

Lung EffectsLung EffectsAcid aspiration Acid aspiration

irritates airwaysirritates airwaysVagally-Vagally-

mediated mediated bronchospasm bronchospasm via transient via transient acid refluxacid reflux

Reflux EffectsReflux EffectsChronic airflow Chronic airflow

trapping, diaphragmatic trapping, diaphragmatic flattening may reduce flattening may reduce LES competencyLES competency

Lung Dx: -ve Lung Dx: -ve intrathoracic pressure/+ intrathoracic pressure/+ abdominal pressureabdominal pressure

Bronchodilators Bronchodilators LES LES pressurepressure