Peptic Ulcer Disease

Dr. Sun - Week 1

Is H. pylori-induced PUD chronic or acute?

Chronic

Is NSAID-induced PUD chronic or acute?

Chronic

Is stress-related mucosal damage chronic or acute?

Acute

Where is the site of damage for H. pylori-induced PUD?

Duodenum > stomach

Where is the site of damage for NSAID-induced PUD?

Stomach > duodenum

Where is the site of damage for stress-related mucosal damage?

Stomach > duodenum

How are symptoms typically presented in H. pylori-induced PUD?

Epigastric pain

How are symptoms typically presented in NSAID-induced PUD?

Often asymptomatic

How are symptoms typically presented in stress-related mucosal damage?

Asymptomatic

What is the depth of the ulcer in H. pylori-induced PUD & stress-related mucosal damage?

Superficial

What is the depth of the ulcer in NSAID-induced PUD?

Deep

How severe is the GI bleeding in H. pylori-induced PUD?

Less severe; single vessel

How severe is the GI bleeding in NSAID-induced PUD?

More severe; single vessel

How severe is the GI bleeding in stress-related mucosal damage?

More severe; superficial mucosal capillaries

What activity do H. pylori have that make them able to survive in the acidic environment of the stomach?

Urease, catalase, and oxidase

How is H. pylori infection transmitted?

Person-to-person via gastro-oral (vomitus) or fecal-oral (diarrhea) contact

How many individuals who have been infected with H. pylori will develop PUD during their lifetime?

10-20%

What are the risk factors for NSAID-induced PUD?

• Previous ulcer or GI bleeding

• Concomitant anticoagulant/antiplatelet, corticosteroid, or other medications that increase bleeding risk

• Older age

• High NSAID doses

• Multiple NSAIDs

• H. pylori infection

What life-threatening complications are associated with chronic PUD?

Upper GI bleeding, perforation, and obstruction

What is considered the most significant risk factor for upper GI bleeding?

NSAID use, especially in older adults

What is the clinical presentation of PUD?

• Epigastric pain

  • Burning/gnawing discomfort in upper middle abdomen

  • May occur at night

  • Symptoms may come and go

• Relationship to food

  • Duodenal ulcer pain may improve after eating, and then return a few hours later

  • Gastric ulcer pain may worsen with food

• Other symptoms

  • N/V

  • Bloating

  • Loss of appetite

  • Weight loss

How is PUD diagnosed?

• Upper endoscopy (measures presence, size and severity)

• H. pylori tests

  • Patients with active PUD and/or past history of PUD w/o documentation of prior cure

  • Endoscopic tests

  • Non-endoscopic tests

    • Urea breath test → H. pylori urease breaks down ingested C-urea

    • Fecal antigen test

    • Serologic tests → detects IgG antibodies to H. pylori in whole blood or finger stick

What is the treatment approach to PUD dependent on?

• Etiology of the ulcer (H. pylori or NSAID)

  • If NSAID-induced, stop taking NSAIDs immediately. If unable to, start PPI to take concurrently with NSAID

• If initial ulcer or recurrent

• Occurrence of complications

What does PUD treatment aim to accomplish?

• Relieve ulcer pain

• Heal the ulcer

• Prevent ulcer recurrence

• Reduce ulcer-related complications (e.g., GI bleeding)

Which drug class is considered most effective for ulcer symptom relief?

PPIs

For H. pylori infections, what combination therapy is recommended?

Antimicrobials + Antisecretory drugs (PPIs or H2RAs)

If a patient must continue taking NSAIDs, but there are at high risk of developing peptic ulcers, what should the next step be?

• Switch to a selective COX-2 inhibitor NSAID

OR

• Prophylactic co-therapy to reduce ulcer risk and related complications

What are the nonpharmacologic therapeutic options for treating PUD?

• Stress reduction

• Smoking cessation

• Avoid foods and beverages that cause dyspepsia or that exacerbate ulcer symptoms (e.g., spicy foods, caffeine, and alcohol)

• Emergent surgery for patients with ulcer-related complications such as bleeding, perforation, or obstruction

What is the first-line regimen for treatment-naive patients with H. pylori infection?

Optimized bismuth quadruple

What drug therapy is included in the first-line H. pylori infection regimen (optimized bismuth quadruple)?

1. Acid Suppressive Therapy → PPI (standard dose) twice daily

2. Antibiotic #1 → Bismuth subcitrate (120-300 mg) or subsalicylate (300 mg) four times daily

3. Antibiotic #2 → Metronidazole 500 mg three or four times daily

4. Antibiotic #3 → Tetracycline 500 mg four times daily

What is the duration of therapy for first-line H. pylori infection regimen (optimized bismuth quadruple)?

10-14 days

What is the recommended regimen for treatment-experienced patients with H. pylori infection?

Rifabutin triple

What drug therapy is included in the H. pylori infection regime for treatment-experienced patients (rifabutin triple)?

As co-formulated capsules called Talicia; 4 capsules three times daily

1. Acid Suppressive Therapy → PPI (Omeprazole 10 mg; standard or double dose) twice daily

2. Antibiotic #1 → Amoxicillin 250 mg (1 g twice or three times daily)

3. Antibiotic #1 → Rifabutin 12.5 mg (150-300 mg/day divided twice or three times daily)

What is the duration of therapy for H. pylori infection regimen in treatment-experienced patients (rifabutin triple)?

14 days

Initial Dose & Usual Range for Omeprazole (Prilosec)

• Initial: 40 mg daily

• Range: 20-40 mg/day

Initial Dose & Usual Range for Lansoprazole (Prevacid)

• Initial: 30 mg daily

• Range: 15-30 mg/day

Initial Dose & Usual Range for Rabeprazole (Aciphex)

• Initial: 20 mg daily

• Range: 20-40 mg/day

Initial Dose & Usual Range for Pantoprazole (Protonix)

• Initial: 40 mg daily

• Range: 40-80 mg/day

Initial Dose & Usual Range for Esomeprazole (Nexium)

• Initial: 40 mg daily

• Range: 20-40 mg/day

Initial Dose & Usual Range for Dexlansoprazole (Dexilant)

• Initial: 30-60 mg daily

• Range: 30-60 mg/day

What PPIs should be adjusted for general hepatic disease?

Omeprazole and Lansoprazole

What PPI should be adjusted for severe hepatic disease?

Pantoprazole

What PPI should be used with caution in severe hepatic disease?

Rabeprazole

What PPI should be limited to 20 mg/day in severe hepatic disease?

Esomeprazole

What PPI should be limited to 30 mg/day in moderate hepatic impairment?

Dexlansoprazole

Which drug therapy is less potent, PPIs or antacids?

Antacids

What drug classes are used as protection layers for PUD?

PCABs, H2RAs, and Mucosal Protectants

Vonoprazan (Voquezna)

PCAB

• 20 mg BID

• Avoid in patients with severe renal or hepatic impairment

Cimetidine (Tagamet)

H2RA

• 300 mg four times daily, 400 mg BID, or 800 mg QHS

• Adjust dose for renal and hepatic impairment

Famotidine (Pepcid)

H2RA

• 20 mg BID, or 40 mg QHS

• Adjust dose for renal impairment

Nizatidine (Axid)

H2RA

• 150 mg BID, or 300 mg QHS

• Adjust dose for renal impairment

Ranitidine (Zantac)

H2RA

• 150 mg BID, or 300 mg QHS

• Adjust dose for renal impairment

Sucralfate (Carafate)

Mucosal Protectant

• 1 g four times daily, or 2 g BID

Misoprostol (Cytotec)

Mucosal Protectant

• 100-200 mcg four times daily

How do uncomplicated NSAID-induced ulcers heal, once the triggering NSAID has stopped?

8-week regimen of an H2RA, PPI, or sucralfate

• PPIs preferred

In patients where the NSAID is continued despite induced ulceration, what should the treatment approach be?

PPI or misoprostol should be initiated

• PPI preferred

• PPI treatment duration should extend to 12 weeks

How can NSAID-related peptic ulcers be prevented?

• Co-therapy of an NSAID with a PPI (most preferred), H2RA, or misoprostol

• Preferential use of a COX-2 selective NSAID

• *Combination of a PPI with a COX-2 selective NSAID — greatest protection against upper GI complications

Misoprostol as prevention of NSAID-related ulcers

Synthetic analog of PG E1 with dual gastroprotective effects by improving mucosal blood flow and stimulating gastric mucosa and bicarbonate secretion

• High rates of nausea, diarrhea, and abdominal cramping have been associated with higher doses — not really preferred for this reason

What type of ulcers that are non-H. pylori and non-NSAID make up 11-44% of peptic ulcer cases?

Idiopathic ulcers

Idiopathic ulcers

• Risk factors: Gastric hypersecretion, gastric outlet obstruction, genetic predisposition, concomitant diseases, and heavy tobacco use

• Treatment: Conventional ulcer healing therapies

  • Maintenance therapy required to prevent complications, due to high rate of recurrent bleeding within 1 year

What patients are candidates for long-term maintenance therapy for ulcer healing?

• High-risk who failed H. pylori eradication

• History of ulcer-related complications

• Frequent recurrences of H. pylori-negative ulcers

• Heavy smokers

• NSAID users

What is considered a refractory ulcer?

Ulcers that persist after 8-12 weeks of standard antisecretory drug treatment

What are the most common causes of refractory ulcers?

• Persistent H. pylori infection

• Use of NSAIDs

What is the treatment approach for patients with refractory ulcers?

• Upper endoscopy (to confirm a nonhealing ulcer)

• Retreat with a double dose of PPI

  • An alternative PPI may be considered

What is the MOA of PPIs?

Irreversibly inhibit gastric H⁺/K⁺-ATPase (proton pump) → acid suppression

• Builds over the first 3-4 days as active pumps are inhibited

• Lasts longer than the plasma half-life because pump inhibition is irreversible

What is the Administration of PPIs?

30-60 minutes before a meal, usually breakfast (most PPIs)

• Must be absorbed systemically and reach proton pumps while they are actively secreting acid

• If BID: before breakfast and dinner

What PPIs are formulated as delayed-release enteric-coated capsules?

Omeprazole, Esomeprazole, Lansoprazole, and Dexlansoprazole

What PPIs are formulated as rapidly disintegrating tablets?

Lansoprazole

What PPIs are formulated as delayed-release enteric-coated tablets?

Rabeprazole, Pantoprazole, and nonprescription Omeprazole

What PPI is formulated as dual delayed-release?

Dexlansoprazole

• Less dependent on meal timing

What PPIs are formulated as immediate-release (oral suspension, oral capsules)?

Omeprazole/sodium bicarbonate

• Controls intragastric pH in the absence of food

What PPIs are formulated as IV?

Esomeprazole and Pantoprazole

Clinical efficacy of PPIs

• Similar in efficacy at equivalent/recommended doses for acid-related disorders

• Dividing the dose can improve 24-hour acid control if unusually high total daily doses are required

• No routine renal dose adjustment, but use caution in severe hepatic impairment

Short-term adverse effects associated with PPIs

• Headache

• Nausea

• Abdominal pain

DDIs with PPis

• ↑ gastric pH → altered absorption

  • Drugs requiring acidic pH = reduced absorption

    • e.g., some HIV and hepatitis C antivirals

    • e.g., ketoconazole and levothyroxine

• CYP2C19 Inhibition

  • Omeprazole and Esomeprazole

• Clopidogrel → CYP2C19 → active metabolite (can’t directly convert)

  • Omeprazole/Esomeprazole inhibit CYP2C19 → potentially ↓ clopidogrel activation and antiplatelet effect

High-yield concerns with long-term use of PPI

• C. diff/enteric infections

• Hypomagnesemia

• Vitamin B12 and iron deficiency

• Fracture risk

• Altered gut microbiome

What are the most commonly used H2RAs for treatment of PUD?

Famotidine, Cimetidine, and Nizatidine

What is the MOA of H2RAs?

Block histamine H2 receptors on gastric parietal cells

• ↓ gastric acid secretion, particularly nocturnal acid secretion

• Less potent acid suppression than PPIs

What are some key clinical points regarding H2RAs?

• Given at bedtime because of their effect on nocturnal acid secretion

• Tachyphylaxis to acid suppression can develop over time

• Renally eliminated → reduce dose in moderate-to-severe renal impairment

What adverse effects are associated with H2RAs?

Generally well tolerated

• Possible reversible thrombocytopenia

• Use caution about effects/accumulation in renal impairment

Which H2RA has the most drug interactions due to its inhibition of multiple CYP450 enzymes?

Cimetidine

What drugs do Cimetidine interact with?

• Warfarin

• Phenytoin

• Theophylline

• Clopidogrel

What is the MOA of Sucralfate?

Aluminum salt of sucrose sulfate — forms protective barrier over the ulcer, protecting it from acid and pepsin

• Heals ulcers but is not commonly used for PUD today

Why isn’t Sucralfate commonly used?

• Multiple daily doses → 1 g four times daily or 2 g twice daily

• Large tablets

• Complicated administration

• Many absorption-related drug interactions — give interacting drugs at least 2 hours before taking sucralfate

What adverse effects are associated with Sucralfate?

• Constipation — most common

• Aluminum accumulation (in severe renal impairment/dialysis)

• Long-term use → possible hypophosphatemia

What is an important clinical pearl regarding administration of PPIs?

Before meals

What is an important clinical pearl regarding administration of H2RAs?

Often bedtime

What is an important clinical pearl regarding administration of Sucralfate?

Separate from other drugs (by at least 2 hours)

What is a key concern with taking PPIs?

Long-term effects/interactions

What is a key concern with taking H2RAs?

Renal dosing; tolerance

What is a key concern with taking Sucralfate?

Drug interactions; constipation

Classic drug interaction pearl with PPI use

Omeprazole-Clopidogrel

Classic drug interaction pearl with H2RA use

Cimetidine-CYP450

Classic drug interaction pearl with Sucralfate use

Fluoroquinolone binding

What is the main action of PPIs?

Blocks proton pump

What is the main action of H2RAs?

Blocks H2 receptor

What is the main action of Sucralfate?

Protects ulcer surface

What is the MOA of Misoprostol?

Synthetic PGE₁ analogue

• ↓ gastric acid secretion

• ↑ mucosal protection

What is the main indication of Misoprostol?

Prevention of NSAID-induced gastric ulcers (especially in high-risk patients)

What are the major adverse effects of Misoprostol?

• Diarrhea — dose-dependent and most common

• May also cause abdominal cramping and nausea

• Taking with food may reduce GI effects