Drugs to Treat Gastric Acidity, Drugs to Treat Gastric Acidity, Peptic Ulcer Disease, and Peptic Ulcer Disease, and

Gastroesophageal Reflux DiseaseGastroesophageal Reflux Disease

Michael A. Pezzone, M.D., Ph.D.Michael A. Pezzone, M.D., Ph.D.Assistant Professor of Medicine and Pharmacology Assistant Professor of Medicine and Pharmacology

University of Pittsburgh, Pittsburgh, Pennsylvania USAUniversity of Pittsburgh, Pittsburgh, Pennsylvania USADivision of Gastroenterology, Hepatology and Nutrition and Department of Division of Gastroenterology, Hepatology and Nutrition and Department of PharmacologyPharmacology

Learning ObjectivesLearning Objectives

1.1. Know the major classes of acid-suppressive Know the major classes of acid-suppressive drugs and their mechanisms of action drugs and their mechanisms of action

2.2. Know the common side effects of acid-Know the common side effects of acid-suppressive drugssuppressive drugs

3.3. Know the specific treatment of acid-peptic Know the specific treatment of acid-peptic disordersdisorders

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

A syndrome of symptomatic reflux of gastric contents A syndrome of symptomatic reflux of gastric contents into the esophagus (i.e. into the esophagus (i.e. heartburnheartburn))– Pathologic RefluxPathologic Reflux--reflux esophagitis or abnormal --reflux esophagitis or abnormal

ambulatory pH studyambulatory pH study– Functional HeartburnFunctional Heartburn--non-erosive reflux disease--non-erosive reflux disease

Gastric reflux contains a variety of esophageal irritantsGastric reflux contains a variety of esophageal irritants– Acid (2-3 liters per day)Acid (2-3 liters per day)– PepsinPepsin– BileBile

BackgroundBackground

US US Population Population

AffectedAffectedHeartburn Heartburn FrequencyFrequency

7%7% DailyDaily

14%14% WeeklyWeekly

15%15% MonthlyMonthly

GERD Prevalence and Impact on QOLGERD Prevalence and Impact on QOL

Lifestyle modificationsLifestyle modifications Over-the-counter Over-the-counter medicationsmedications

– Head of bed elevationHead of bed elevation AntacidsAntacids

– Avoidance of tight-fitting clothesAvoidance of tight-fitting clothes HH22 Receptor Antagonists (H Receptor Antagonists (H22RAs)RAs)

– Weight lossWeight loss Proton Pump Inhibitor (PPI)Proton Pump Inhibitor (PPI)

– Restriction of alcoholRestriction of alcohol

– Elimination of smokingElimination of smoking Prescription medicationsPrescription medications– Dietary therapyDietary therapy ProkineticsProkinetics

– Refraining from lying down after Refraining from lying down after mealsmeals HH22RAsRAs

– Avoidance of evening snacks before Avoidance of evening snacks before bedtimebedtime

PPIsPPIs

SurgerySurgery

GERD Treatment OptionsGERD Treatment Options

Classes of AgentsClasses of Agents

1.1. Proton Pump InhibitorsProton Pump Inhibitors

2.2. Histamine HHistamine H22-Receptor Antagonists-Receptor Antagonists

3.3. Prostaglandin AnalogsProstaglandin Analogs

4.4. CytoprotectantsCytoprotectants

5.5. AntacidsAntacids

1. Proton Pump Inhibitors 1. Proton Pump Inhibitors (PPI’s)(PPI’s)

PPIsPPIs

Most potent suppressors of acid secretionMost potent suppressors of acid secretion Diminish basal and stimulated acid production Diminish basal and stimulated acid production

by 80-95%by 80-95% 24-48 hr effects on acid suppression24-48 hr effects on acid suppression Acid-activated pro-drugsAcid-activated pro-drugs

PPIsPPIs

Irreversibly inhibit HIrreversibly inhibit H++/K/K++ATPase function to:ATPase function to:– Block gastric acid secretionBlock gastric acid secretion– Decrease pepsin concentrationDecrease pepsin concentration– Increase gastric pH Increase gastric pH

Secretion of acid only resumes when new proton Secretion of acid only resumes when new proton pumps are deployedpumps are deployed

Steady-state inhibition (affecting 70% of pumps) Steady-state inhibition (affecting 70% of pumps) may take 2-5 daysmay take 2-5 days

Typical dose is once daily (1 hr before breakfast)Typical dose is once daily (1 hr before breakfast)

PPI PharmacologyPPI Pharmacology

Pro-drugs with pKa of approximately 4Pro-drugs with pKa of approximately 4 Activated only when pH decreases below 4Activated only when pH decreases below 4– Occurs only in parietal cell secretory canaliculiOccurs only in parietal cell secretory canaliculi– Achieved only when parietal cell activation occurs Achieved only when parietal cell activation occurs

(after meals)(after meals)– Most effective after a prolonged fast when large Most effective after a prolonged fast when large

amounts of active proton pumps are present (i.e. amounts of active proton pumps are present (i.e. breakfast)breakfast)

Unstable at low pH (enteric coated or gelatin shell)Unstable at low pH (enteric coated or gelatin shell)

Available PPIsAvailable PPIs

Esomeprazole (Nexium)Esomeprazole (Nexium) Lansoprazole (Prevacid) (iv)Lansoprazole (Prevacid) (iv) Omeprazole (Prilosec, Zegerid, generic, OTC)Omeprazole (Prilosec, Zegerid, generic, OTC) Pantoprazole (Protonix) (iv)Pantoprazole (Protonix) (iv) Rabeprazole (Aciphex)Rabeprazole (Aciphex)

**All have equivalent efficacy at comparable doses**All have equivalent efficacy at comparable doses**Choice often based on prescription plan and co-pay**Choice often based on prescription plan and co-pay

**Not necessarily first line therapy**Not necessarily first line therapy**Pregnancy Category B (except omeprazole C)**Pregnancy Category B (except omeprazole C)

PPI StructuresPPI Structures(substituted benzimidazoles)(substituted benzimidazoles)

Activation of Substituted Activation of Substituted BenzimidazolesBenzimidazoles

H+/K+ATPaseH+/K+ATPase

**forms a disulfide bond with the cystine residues within the alpha subunit of the enzyme**forms a disulfide bond with the cystine residues within the alpha subunit of the enzyme

80

1.6

PPI MetabolismPPI Metabolism

Rapidly absorbedRapidly absorbed Highly protein boundHighly protein bound Extensively metabolized in the liver by the Extensively metabolized in the liver by the

P450 system (CYP2C19 and CYP3A4)P450 system (CYP2C19 and CYP3A4) Sulfated metabolites are excreted in the Sulfated metabolites are excreted in the

urine or fecesurine or feces Hepatic disease reduces the clearance of Hepatic disease reduces the clearance of

lansoprazole--reduce doselansoprazole--reduce dose

Metabolized by hepatic CYPsMetabolized by hepatic CYPs

Common PPI Side EffectsCommon PPI Side Effects

Headache (2.9-6.9%) Headache (2.9-6.9%) vs.vs. Placebo (2.5-6.3%)Placebo (2.5-6.3%) Diarrhea (3%)Diarrhea (3%) vs.vs. Placebo (3.1%)Placebo (3.1%) Abdominal pain (2.4-5.2%) Abdominal pain (2.4-5.2%) vs.vs. Placebo (3.1-Placebo (3.1-

3.3%)3.3%) Constipation (1.1-1.5%)Constipation (1.1-1.5%) vs. Placebo (0-0.8%)vs. Placebo (0-0.8%)

B12 malabsorption reported with omeprazoleB12 malabsorption reported with omeprazole

Drug-Drug InteractionsDrug-Drug Interactions

Warfarin (potentiated)Warfarin (potentiated)– EsomeprazoleEsomeprazole– LansoprazoleLansoprazole– OmeprazoleOmeprazole– RabeprazoleRabeprazole

Diazepam (potentiated)Diazepam (potentiated)– EsomeprazoleEsomeprazole– OmeprazoleOmeprazole

2. Histamine H2. Histamine H22-Receptor -Receptor Antagonists (HAntagonists (H22RAs)RAs)

HH22RAsRAs

Reversibly compete with histamine for binding Reversibly compete with histamine for binding to Hto H22 receptors on the basolateral membrane receptors on the basolateral membrane

of parietal cellsof parietal cells Less potent than PPIs but still suppress acid Less potent than PPIs but still suppress acid

by 70% over 24 hrsby 70% over 24 hrs Predominantly inhibit basal acid suppression Predominantly inhibit basal acid suppression

(nocturnal)(nocturnal) Available OTCAvailable OTC

Available HAvailable H22RAsRAs

Cimetidine (Tagamet)Cimetidine (Tagamet) Ranitidine (Zantac)Ranitidine (Zantac) Famotidine (Pepcid) (iv)Famotidine (Pepcid) (iv) Nizatidine (Axid)Nizatidine (Axid)

**All exist in generic form**All exist in generic form

PharmacokineticsPharmacokinetics

Rapidly absorbed after oral administrationRapidly absorbed after oral administration Serum concentrations peak in 1-3 hrSerum concentrations peak in 1-3 hr Therapeutic levels maintained up to 12 hrs (Bid dose)Therapeutic levels maintained up to 12 hrs (Bid dose) Small percentage is protein boundSmall percentage is protein bound 10% to 35 % metabolized by the liver10% to 35 % metabolized by the liver Drugs and metabolites primarily excreted by kidneys Drugs and metabolites primarily excreted by kidneys

(**reduce doses in renal disease)(**reduce doses in renal disease) Development of tolerance (3 days)Development of tolerance (3 days) Rebound response upon discontinuationRebound response upon discontinuation

Common HCommon H22RA Side EffectsRA Side Effects

All less than 3%All less than 3%– DiarrheaDiarrhea– HeadacheHeadache– DrowsinessDrowsiness– FatigueFatigue– Muscular painMuscular pain– ConstipationConstipation

Much less commonMuch less common– Confusion, delirium in the elderlyConfusion, delirium in the elderly– Associated with thrombocytopeniaAssociated with thrombocytopenia– Cimetidine anti-androgen effectsCimetidine anti-androgen effects

Drug-Drug InteractionsDrug-Drug Interactions

Avoided by not using cimetidineAvoided by not using cimetidine– Cimetidine inhibits CYPsCimetidine inhibits CYPs

Pregnancy Category BPregnancy Category B

3. Prostaglandin Analogs: 3. Prostaglandin Analogs: MisoprostolMisoprostol

Protective Effects of Protective Effects of ProstaglandinsProstaglandins

PGEPGE22 and PGI and PGI2 2 synthesized by gastric mucosasynthesized by gastric mucosa Acid-reducing effectsAcid-reducing effects

– Bind to EPBind to EP33 receptors on parietal cells receptors on parietal cells– Decrease acid productionDecrease acid production

Cytoprotective effectsCytoprotective effects– Stimulation of mucin and bicarbonateStimulation of mucin and bicarbonate– Increase mucosal blood flowIncrease mucosal blood flow

Contrast with NSAIDS which diminish prostaglandin Contrast with NSAIDS which diminish prostaglandin formation by inhibition of cycloxygenase and lead to formation by inhibition of cycloxygenase and lead to ulcer formationulcer formation

Misoprostol: CytotecMisoprostol: Cytotec

Synthetic analog of PGESynthetic analog of PGE11

– Enhanced potencyEnhanced potency– Increased oral bioavailabilityIncreased oral bioavailability

Inhibit basal acid secretion (85-95%)Inhibit basal acid secretion (85-95%) Inhibit stimulated acid secretion (75-85%)Inhibit stimulated acid secretion (75-85%)

Misoprostol StructureMisoprostol Structure

PGEPGE11MisoprostolMisoprostol

PharmacokineticsPharmacokinetics

Rapidly absorbed Rapidly absorbed Rapidly de-esterfied to misoprostol acid--Rapidly de-esterfied to misoprostol acid--

the active metabolitethe active metabolite Therapeutic effect peaks at 60-90 minutesTherapeutic effect peaks at 60-90 minutes Lasts 3 hours (qid dose required)Lasts 3 hours (qid dose required) Free acid excreted mainly in urineFree acid excreted mainly in urine

Side EffectsSide Effects

Diarrhea ± abdominal cramps as high as 30%Diarrhea ± abdominal cramps as high as 30% Begins within 2 weeks and often resolves Begins within 2 weeks and often resolves

spontaneously in 1 weekspontaneously in 1 week Can exacerbate inflammatory bowel diseaseCan exacerbate inflammatory bowel disease Contraindicated during pregnancy (Cat x)Contraindicated during pregnancy (Cat x)

4. Sucralfate: Carafate4. Sucralfate: Carafate

SucralfateSucralfate

Sulfated polysaccharideSulfated polysaccharide Acid activatedAcid activated Administered on an empty stomach 1 hr before mealsAdministered on an empty stomach 1 hr before meals Undergoes cross-linking to produce a thick, viscous Undergoes cross-linking to produce a thick, viscous

polymer that adheres to epithelial cells and ulcer polymer that adheres to epithelial cells and ulcer craters for up to 6 hrscraters for up to 6 hrs

Stimulates local prostaglandin synthesisStimulates local prostaglandin synthesis Binds bile acidsBinds bile acids

SucralfateSucralfate

Common Side EffectsCommon Side Effects

Constipation (2%)Constipation (2%) Aluminum toxicityAluminum toxicity Avoid in renal failureAvoid in renal failure May impair absorption of other drugsMay impair absorption of other drugs Thought to be safe during pregnancy (Cat B)Thought to be safe during pregnancy (Cat B)

5. Antacids5. Antacids

AntacidsAntacids

Sodium bicarbonateSodium bicarbonate CaCO3CaCO3 MgMg2+2+ hydroxides hydroxides AlAl3+3+ hydroxide hydroxide

AntacidsAntacids

Given orally 1-3 hrs after meals and bedtimeGiven orally 1-3 hrs after meals and bedtime Single dose provides 120mEq neutralizing Single dose provides 120mEq neutralizing

capacity--equivalent to one dose of an Hcapacity--equivalent to one dose of an H22RARA MgMg+2+2 based preparations increase motility based preparations increase motility

– DiarrheaDiarrhea AlAl+3+3 based preparations relax smooth muscle based preparations relax smooth muscle

– ConstipationConstipation CaCa+2+2 based preparations release CO2 based preparations release CO2

– Belching, nausea, distension, and flatulence.Belching, nausea, distension, and flatulence.

Common Side EffectsCommon Side Effects

Aluminum toxicity with renal diseaseAluminum toxicity with renal disease– Osteoporosis, enchephalopathy, myopathyOsteoporosis, enchephalopathy, myopathy

HypercalcemiaHypercalcemia– Phosphate retentionPhosphate retention– Calcium precipitation in the kidneyCalcium precipitation in the kidney

Impair absorption of some drugsImpair absorption of some drugs– Take 2 hrs before or after other drugsTake 2 hrs before or after other drugs

Specific Treatments of Acid-Specific Treatments of Acid-Peptic DisordersPeptic Disorders

Treatment of GERDTreatment of GERD

GoalsGoals– Resolution of symptoms (NERD)Resolution of symptoms (NERD)– Healing of esophagitis (pathologic GERD)Healing of esophagitis (pathologic GERD)

Healing rates Healing rates

Drug Drug 4wks4wks 8wks8wks PPI’s PPI’s 80%80% 90%90% HH22RA’sRA’s 50%50% 75%75%

GERD Therapy GERD Therapy (uncomplicated)(uncomplicated)

Empiric treatment with PPI or HEmpiric treatment with PPI or H22RARA Consider “step-up” therapyConsider “step-up” therapy EGD EGD

– Onset older than 40 yoaOnset older than 40 yoa– Symptoms greater than 10 yearsSymptoms greater than 10 years– Not better with a PPINot better with a PPI– Alarm symptoms such as dysphagia, weight Alarm symptoms such as dysphagia, weight

loss, melenaloss, melena When stable, “step-down” therapyWhen stable, “step-down” therapy

Peptic Ulcer Disease (PUD)Peptic Ulcer Disease (PUD)

Imbalance between mucosal defense factors and Imbalance between mucosal defense factors and aggravating factors (acid and pepsin)aggravating factors (acid and pepsin)

Worldwide prevalence 10%Worldwide prevalence 10% 80-90% of ulcers related to H. pylori infection or 80-90% of ulcers related to H. pylori infection or

chronic NSAID usechronic NSAID use– Impaired production of somatostatin by D cellsImpaired production of somatostatin by D cells

– Reduction of cytoprotective prostaglandins (PGEReduction of cytoprotective prostaglandins (PGE22

and PGIand PGI22))

Healing Rates of PUDHealing Rates of PUD

PPI’sPPI’s 80-90 %80-90 % H2RA’s, MisoprostolH2RA’s, Misoprostol 60-75%60-75%

Invtravenous PPI is clearly the preferred Invtravenous PPI is clearly the preferred therapy in patients with acute bleeding therapy in patients with acute bleeding ulcersulcers

H. Pylori Treatment H. Pylori Treatment Reduces PUD RecurrenceReduces PUD Recurrence

• 10-20% vs. 55-70% (untreated)10-20% vs. 55-70% (untreated)• ““Triple Therapy”Triple Therapy”• PPI BID• Clarithromycin BID• Amoxicillin or Metronidazole

NSAID Ulcer ProphylaxisNSAID Ulcer Prophylaxis

Chronic NSAID users have a 2-4% risk of Chronic NSAID users have a 2-4% risk of developing symptomatic PUDdeveloping symptomatic PUD

PPIs are more superior to HPPIs are more superior to H22RA’s and RA’s and

misoprostol in preventing PUD recurrencemisoprostol in preventing PUD recurrence– Gastric ulcers 5-13% vs. 10-16%Gastric ulcers 5-13% vs. 10-16%– Duodenal ulcers 0.5-3% vs. 4-10%Duodenal ulcers 0.5-3% vs. 4-10%

Heartburn in PregnancyHeartburn in Pregnancy LES decreases 33-50% during 2nd LES decreases 33-50% during 2nd

and 3rd trimesters--progesterone and 3rd trimesters--progesterone mediatedmediated

EGD if needed (intractable EGD if needed (intractable symptoms)symptoms)

TherapyTherapy1.1. Lifestyle modificationsLifestyle modifications2.2. AntacidsAntacids3.3. Sucralfate (Cat B)Sucralfate (Cat B)4.4. H2RA (Cat B)H2RA (Cat B)5.5. PPI (Cat B) except omeprazole PPI (Cat B) except omeprazole

(Cat C)(Cat C)