Proton Pump Inhibitors (PPIs)

Definition:
Þ Proton Pump Inhibitors (PPIs) are a group of drugs that suppress gastric acid secretion
by irreversibly inhibiting the H⁺/K⁺ ATPase (proton pump) located on the apical
membrane of gastric parietal cells.

Why are they powerful?

• They block the final common
pathway of acid secretion.

• Irreversible binding → effect

lasts until new pumps are
synthesized.

• Results in strong, long-

lasting suppression of gastric
acid.

1
 Mechanism of Action (MoA)
1. PPIs are prodrugs → become active in acidic environment of parietal cells' canaliculi.

2. Converted to sulfenamide, which binds covalently to sulfhydryl groups of the H⁺/K⁺ ATPase.

3. This irreversible inhibition leads to:

Þ ↓ Acid secretion (basal + meal-induced)

Þ ↑ Gastric pH
Þ ↓ Pepsin activity (pH-dependent)

‫ ﺗﻌﺎل وﯾﺎي اذﻛﺮك ﺑﯿﮭﺎ ﺗﺪﻟﻞ اﻧﺖ ﻋﻤﻲ‬parietal cells' canaliculi ‫اﻧﺖ ﻛـ ﺻﯿﺪﻻﻧﻲ ﯾﺠﻮز ﻧﺎﺳﻲ اﻟـ‬

🔬 Parietal Cells and Canaliculi

Parietal cells (also known as oxyntic cells) are specialized cells in the lining of the stomach
responsible for secreting hydrochloric acid (HCl).

Inside these cells, you’ll find intricate structures called canaliculi — small, deep invaginations or
channels of the apical membrane.

2
🔹 Function of Canaliculi:
1. Increased Surface Area

Þ Canaliculi drastically increase the surface area of the cell's apical membrane.
Þ This is important to maximize the number of proton pumps (H⁺/K⁺ ATPase) embedded
in the membrane.

2. Site of Acid Secretion

Þ The H⁺/K⁺ ATPase pumps are located on the canaliculi membranes.

Þ These pumps exchange intracellular H⁺ ions for extracellular K⁺ ions, releasing H⁺ into
the stomach lumen and creating a highly acidic environment (pH ~1–2).

3. Activation of Proton Pump Inhibitors (PPIs)

Þ PPIs are activated in the acidic canaliculi and bind irreversibly to the proton pumps.
Þ This blocks acid secretion until new pumps are synthesized.

4. Physiological Role

Þ The acid secreted into the stomach is essential for:

§ Digestion of food (especially proteins)
§ Activation of pepsinogen → pepsin
§ Killing ingested pathogens

🧠 Clinical NOTE :

• PPIs (e.g. omeprazole) target these canaliculi specifically.

• They are prodrugs that become activated in the acidic environment of the canaliculi, then
bind covalently to the H⁺/K⁺ ATPase, inhibiting acid secretion effectively.

3
4
5
 Clinical Uses
💊 Clinical Uses of PPIs (Proton Pump Inhibitors)

1. Gastroesophageal Reflux Disease (GERD)

• Relief of heartburn, regurgitation, and esophagitis

• Promotes healing of erosive esophagitis

2. Peptic Ulcer Disease (PUD)

• Treatment of gastric and duodenal ulcers

• Promotes ulcer healing by reducing acid

3. H. pylori Eradication Therapy

• Part of triple or quadruple therapy

• Enhances antibiotic effectiveness by increasing gastric pH

4. NSAID-Induced Ulcers

• Treatment and prevention of ulcers caused by nonsteroidal anti-inflammatory drugs

• Especially used in long-term NSAID users

5. Zollinger-Ellison Syndrome

• Treats hypersecretory conditions caused by gastrin-secreting tumors

• Requires high-dose, long-term PPI use

6. Stress Ulcer Prophylaxis (ICU Patients)

• Prevents stress-related mucosal damage in critically ill patients

7. Functional Dyspepsia

• Reduces upper abdominal discomfort not explained by ulcers or reflux

8. Barrett’s Esophagus

• Reduces acid exposure to prevent progression to dysplasia or adenocarcinoma

6
 💊 Proton Pump Inhibitor (PPI) Drugs

1. Omeprazole

• Brand: Losec®, Prilosec®

• Notes: First PPI developed, widely used

2. Esomeprazole

• Brand: Nexium®
• Notes: S-isomer of omeprazole, improved bioavailability

3. Lansoprazole

• Brand: Prevacid®, Lanzor®

• Notes: Fast onset, ODT (orally disintegrating tablets) available

4. Dexlansoprazole

• Brand: Dexilant®
• Notes: Dual delayed-release, food-independent

5. Pantoprazole

• Brand: Protonix®, Controloc®

• Notes: Less CYP interaction, available in IV form

6. Rabeprazole

• Brand: AcipHex®, Pariet®

• Notes: Rapid action, acid-stable

7. Ilaprazole

• Brand: Noltec® (mainly in Asia)

• Notes: Newer PPI, long-acting

7
8
9
 💊 Omeprazole (Brand Name: Prilosec® / Losec®)

🔹 Drug Class:
Þ Proton Pump Inhibitor (PPI)
🔹 Mechanism of Action:

Þ Irreversibly inhibits H⁺/K⁺ ATPase (proton pump) in gastric parietal cells

Þ Suppresses both basal and stimulated gastric acid secretion
Þ Requires activation in acidic environment → acts at parietal cell canaliculi

📋 Clinical Uses:

1. GERD (Gastroesophageal Reflux Disease)

• Reduces heartburn and esophageal inflammation

2. Peptic Ulcer Disease (PUD)

• Heals gastric and duodenal ulcers

3. H. pylori Eradication Therapy

• Combined with antibiotics in triple therapy

4. NSAID-Induced Ulcers

• Treats and prevents ulcers caused by NSAIDs

5. Zollinger-Ellison Syndrome

• High-dose omeprazole to manage acid hypersecretion

6. Functional Dyspepsia

• Reduces upper abdominal discomfort

10
⏱ Dosage & Administration:

• Typical dose:

▫ 20–40 mg once daily

▫ Taken 30–60 minutes before meals (usually breakfast)

• Formulations:

▫ Delayed-release capsules
▫ Oral suspension (Zegerid® with sodium bicarbonate)
▫ Available OTC in some countries

⚠ Side Effects:

Common:

• Headache
• Nausea
• Diarrhea
• Abdominal pain

Long-term use risks:

• Vitamin B12 deficiency
• Hypomagnesemia
• Osteoporosis/fracture risk
• C. difficile infection

🔄 Drug Interactions:

• Inhibits CYP2C19 → may affect metabolism of:

• Clopidogrel (↓ effectiveness)
• Diazepam, warfarin, phenytoin

11
 ⚠ Omeprazole & Clopidogrel Interaction

🔹 Clopidogrel:

• An antiplatelet drug used to prevent blood clots (e.g. in heart attack, stroke, stents)
• It is a prodrug → must be activated in the liver by the enzyme CYP2C19
• Clopidogrel (inactive) --[CYP2C19]--> Active drug

🔹 Omeprazole:

• A Proton Pump Inhibitor (PPI) that inhibits CYP2C19

• This enzyme is essential for activating clopidogrel

❗ What Happens?

➡ When Omeprazole inhibits CYP2C19

➡ Clopidogrel is not fully activated
➡ Reduced antiplatelet effect
➡ Higher risk of cardiovascular events (like heart attacks or stent thrombosis)

📌 Clinical Advice:

• Avoid using Omeprazole with Clopidogrel if possible

• Prefer Pantoprazole or Rabeprazole (less CYP2C19 inhibition)
• If acid suppression is needed, choose a PPI with minimal CYP interaction

12
 Esomeprazole (Nexium)
💊 Esomeprazole (Brand Name: Nexium®)

🔹 Drug Class:
Proton Pump Inhibitor (PPI)

🔹 Type:
• S-isomer of Omeprazole
• Developed to improve absorption and efficacy

⚙ Mechanism of Action:

• Irreversibly inhibits H⁺/K⁺ ATPase in gastric parietal cells

• ↓ ↓ Gastric acid secretion (both basal and stimulated)
• Requires activation in the acidic canaliculi of parietal cells

📋 Clinical Uses:

1. GERD (Gastroesophageal Reflux Disease)

▫ Healing of erosive esophagitis
▫ Long-term management of GERD symptoms
2. Peptic Ulcer Disease (PUD)
▫ Heals gastric and duodenal ulcers
3. H. pylori Eradication
▫ Part of triple therapy (esomeprazole + antibiotics)
4. NSAID-Induced Ulcers
▫ Prevents and treats ulcers caused by NSAIDs
5. Zollinger-Ellison Syndrome
▫ High doses may be used to control acid hypersecretion
6. Prevention of rebleeding in upper GI bleeding
▫ IV esomeprazole used post-endoscopy

▫ Oral dose should be taken 30–60 min before meals

13
⚠ Side Effects:

Common:
• Headache
• Nausea
• Abdominal pain
• Flatulence

Long-term risks:
• ↓ Vitamin B12
• ↓ Magnesium
• ↑ Fracture risk (osteoporosis)
• ↑ Risk of C. difficile infection

🔄 Drug Interactions:

• CYP2C19 metabolism (less than omeprazole but still relevant)

• May slightly reduce effect of clopidogrel, but less than omeprazole
• May affect absorption of pH-dependent drugs (e.g. ketoconazole, iron)

✅ Why Esomeprazole over Omeprazole?

• Better bioavailability
• More consistent acid suppression
• Once-daily dosing effective in most patients
• Less variability between patients in drug metabolism

14
 Pantoprazole (Protonix)
• Drug Name (Generic): Pantoprazole

• Brand Names: Protonix, Somac, Pantoloc

• Drug Class: Proton Pump Inhibitor (PPI)

🔹 PPIs are the strongest acid-suppressing medications.

🔹 Pantoprazole is used to treat acid-related disorders of the stomach and esophagus.

Mechanism of Action
• Site of Action: Parietal cells in the stomach lining

• Target: H⁺/K⁺ ATPase enzyme (also called the proton pump)

• Action:
Þ Pantoprazole binds irreversibly to the proton pump.
Þ This blocks the final step in gastric acid secretion.
Þ Leads to long-lasting suppression of stomach acid production.
📌 It works best when taken before meals, because the proton pumps are most active then.

15
Þ Clinical Uses (Indications)
1. Gastroesophageal Reflux Disease (GERD)
o To relieve symptoms like heartburn and regurgitation.
2. Peptic Ulcer Disease (PUD)
o Healing gastric and duodenal ulcers caused by acid or H. pylori.
3. Erosive Esophagitis
o Healing damage caused by acid reflux.
4. Zollinger-Ellison Syndrome
o A rare condition with excess gastrin, causing extreme acid production.
5. Stress Ulcer Prophylaxis
o For critically ill patients in ICU to prevent ulcers due to stress.

🟡 Dosage & Administration

🔸 Adult Dose (Oral):

• 20 mg or 40 mg once daily
• Dose depends on condition and severity

🔸 IV Form (Injection):

• 40 mg IV once daily
• Used if patient cannot take oral meds (e.g., NPO patients)

📌 Timing:

• Take 30 to 60 minutes before meals, preferably breakfast

• Do not crush or chew delayed-release tablets

Onset & Duration

• Onset of Action: About 2.5 hours
• Peak Effect: Within a few days of daily use
• Duration: Suppresses acid for 24 hours or more

🧠 Since it binds irreversibly, acid production recovers only after new pumps are
synthesized.

16
Common Side Effects
• Headache
• Diarrhea or constipation
• Nausea, flatulence
• Abdominal discomfort

Usually mild and temporary.

🟡 Long-term Side Effects (Chronic Use)

1. Vitamin B12 deficiency

• Due to reduced absorption with low acid
2. Magnesium deficiency (hypomagnesemia)
• May cause muscle cramps, arrhythmias
3. Osteoporosis & fractures
• Especially hip, wrist, spine fractures with long use
4. Increased risk of infections:
• Clostridium difficile (C. diff) diarrhea
• Pneumonia

🟡 Drug Interactions

• Clopidogrel:
• Pantoprazole may slightly reduce its activation, but less than omeprazole
• Drugs needing acid for absorption:
• e.g., Ketoconazole, iron salts → ↓ absorption
• Methotrexate (high dose):
• ↑ Methotrexate toxicity

🟡 Contraindications & Precautions

• Absolute contraindication:
• Allergy to pantoprazole or other PPIs
• Use with caution:
• In patients with liver disease
• If symptoms persist >2 months, investigate for malignancy

17
18
Use in Special :
👶 Pediatrics:

• Approved for children ≥5 years (for GERD)

🤰 Pregnancy:

• FDA Category B → Safe when clearly needed

🤱 Lactation:

• Enters breast milk in small amounts → use with caution

👴 Elderly:

• Use lowest effective dose to avoid long-term risks

🟡 Patient Counseling Points

✅ Take the medication before meals, same time daily

✅ Swallow whole, don’t chew or crush
✅ Don’t stop suddenly after long-term use → rebound acid
✅ Report signs of:

• Persistent diarrhea
• Muscle cramps
• Fatigue
• Bone pain

19
 Lansoprazole (Prevacid)
🟢 General NOTE:

• Generic Name: Lansoprazole

• Brand Name: Prevacid
• Drug Class: Proton Pump Inhibitor (PPI)

🔸 Used to treat acid-related disorders in the stomach and upper GI tract.

🟢 Mechanism of Action

• Lansoprazole binds irreversibly to the H⁺/K⁺ ATPase enzyme in gastric parietal cells.
• This blocks the final step in the production of gastric acid.
• Result: Long-lasting reduction in both basal and stimulated acid secretion.

📌 Works best when taken 30–60 minutes before meals.

🟢 Clinical Uses (Indications)

1. Gastroesophageal Reflux Disease (GERD)

2. Peptic Ulcer Disease (PUD) – gastric and duodenal ulcers
3. Erosive Esophagitis
4. Zollinger-Ellison Syndrome
5. NSAID-induced ulcer prevention
6. Helicobacter pylori eradication (as part of triple therapy)

20
🟢 Dosage & Administration

✅ Adults:

• GERD: 15–30 mg once daily

• PUD: 15–30 mg once daily for 4–8 weeks
• H. pylori eradication:
• Triple therapy: Lansoprazole + Amoxicillin + Clarithromycin for 10–14 days

✅ Pediatrics:

• Approved in children >1 year (GERD): 15 mg daily

🕓 Timing:

• Take before meals, preferably before breakfast

🟢 Formulations

• Delayed-release capsules
• Orally disintegrating tablets (ODT)
• Suspension granules (for oral solution)

💡 ODT useful for patients who can’t swallow pills.

🟢 Onset & Duration

• Onset: ~1.5–2 hours

• Peak acid suppression: ~4 days of daily use
• Duration of action: Up to 24 hours or longer

21
Side Effects

🟡 Common:

• Headache
• Nausea
• Diarrhea or constipation
• Abdominal pain

🔴 Serious (Long-term use):

• Vitamin B12 deficiency

• Hypomagnesemia
• Increased risk of osteoporotic fractures
• C. difficile infection
• Interstitial nephritis (rare)

🟢 Contraindications

• Hypersensitivity to lansoprazole or other PPIs

• Caution with hepatic impairment

📌 Prolonged use without clear indication should be avoided.

🟢 Use in Special Populations

👶 Children:

• Approved for certain conditions above age 1 year

🤰 Pregnancy:

• FDA Category B → generally safe

🤱 Breastfeeding:

• Excreted in small amounts; use with caution

👴 Elderly:

• Use lowest effective dose, especially long-term

22
NOTE:

✅ Take before meals, at the same time daily

✅ Do not crush or chew capsules or ODTs
✅ Inform doctor if used more than 8 weeks
✅ Monitor for long-term side effects (bone pain, muscle cramps, fatigue)

Drug Interactions
• ↓ Absorption of drugs needing acidic pH:
• e.g., ketoconazole, itraconazole, iron
• Clopidogrel: Less interaction than omeprazole, but caution advised
• Warfarin: Monitor INR if used long-term

23
 Rabeprazole (AcipHex)
🔵 General NOTE:

• Generic Name: Rabeprazole

• Brand Name: AcipHex
• Drug Class: Proton Pump Inhibitor (PPI)

🔹 Used to treat acid-related disorders like GERD, ulcers, and more.

🔵 Mechanism of Action

• Rabeprazole irreversibly inhibits the H⁺/K⁺ ATPase enzyme (proton pump) on gastric
parietal cells.
• This blocks the final step of acid production, leading to a significant and prolonged
reduction in gastric acidity.

🕐 Begins acting faster than other PPIs in some studies.

🔵 Clinical Uses (Indications)

1. Gastroesophageal Reflux Disease (GERD)

2. Duodenal & Gastric Ulcers
3. Zollinger-Ellison Syndrome (ZES)
4. Erosive Esophagitis
5. Helicobacter pylori eradication
Þ As part of triple therapy with amoxicillin + clarithromycin
6. NSAID-associated ulcer prevention

24
Dosage & Administration
✅ Adults:

• GERD / Ulcers: 20 mg once daily

• H. pylori Triple Therapy:
Þ Rabeprazole 20 mg + Amoxicillin 1000 mg + Clarithromycin 500 mg, all twice daily for
7–14 days

✅ Pediatrics:

• Approved for use in children ≥12 years (GERD)

🕓 Timing:

• Best taken before meals, usually in the morning

🔵 Formulations

• Delayed-release tablets (enteric coated)

• Sprinkle capsules (for children in some markets)

📌 Tablets should not be crushed or chewed.

🔵 Onset & Duration

• Onset: 1–2 hours

• Peak inhibition: Within 3–4 days of daily use
• Duration: ~24 hours
• Note: May have slightly faster onset compared to omeprazole

25
Side Effects
🟡 Common:

• Headache
• Diarrhea
• Nausea
• Abdominal pain
• Flatulence

🔴 Long-term Risks:

• Vitamin B12 deficiency

• Hypomagnesemia
• Bone fractures (hip, wrist, spine)
• C. difficile infection
• Rare: Interstitial nephritis

🔵 Drug Interactions

• Drugs needing acidic pH:

• e.g., iron, ketoconazole → ↓ absorption
• Clopidogrel:
• Rabeprazole has minimal effect on its metabolism (safer than omeprazole)
• Methotrexate:
• High-dose methotrexate levels may ↑

🔵 Contraindications & Warnings

• Hypersensitivity to rabeprazole or other PPIs

• Use cautiously in long-term therapy
• Evaluate for gastric malignancy if symptoms persist despite treatment

26
Use in Special Populations

👶 Children:

• Approved for children ≥12 years for GERD

🤰 Pregnancy:

• Category B → Generally safe

🤱 Breastfeeding:

• Use with caution; limited data

👵 Elderly:

• Monitor for long-term complications (fractures, B12 deficiency)

🔵 NOTE:

✅ Take before meals, same time daily

✅ Do not chew or crush the tablet
✅ Report signs of:

• Persistent diarrhea
• Muscle spasms or fatigue (low magnesium)
• Bone pain

✅ Don’t stop suddenly after long-term use → Rebound acid hypersecretion

27
28