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PH6.1 | PH6.1 | Acid Peptic Disease Pharmacotherapy — SDL Guide — SDL Guide (Part 2)

Proton Pump Inhibitors — Pharmacology and Clinical Use

Proton pump inhibitors are the cornerstone of pharmacotherapy for most acid peptic conditions and represent the largest-selling drug class globally. Their superiority over H2RAs is rooted in a unique mechanism: they block the final common effector of acid secretion irreversibly, regardless of which stimulus (histamine, acetylcholine, or gastrin) activated the parietal cell.

Mechanism: PPIs are prodrugs (weak bases, pKa ~4.0). After oral absorption, they are carried in the bloodstream (inactive at neutral pH) to the acidic secretory canaliculus of the active parietal cell, where the low pH (pH ~1) converts them to the active sulphenamide form. This active compound forms a covalent, irreversible disulphide bond with cysteine residues (typically Cys813 and Cys892) on the α-subunit of H⁺/K⁺-ATPase, permanently inactivating that pump molecule. Acid secretion from that parietal cell is abolished until the cell synthesises new pump molecules — a process requiring 18–24 hours. This is why:
(a) PPIs must be taken 30–60 minutes before a meal (when proton pumps are being recruited to active secretory canaliculi); taking them fasting reduces efficacy.
(b) Acid suppression builds over 3–5 days (not all pumps are inactivated on day 1).
(c) Twice-daily dosing is superior to once-daily for severe GERD or ZES.

Pharmacokinetics: All PPIs are absorbed orally (enteric-coated formulations protect from gastric acid before absorption), metabolised hepatically by CYP2C19 (and CYP3A4). Genetic polymorphism in CYP2C19 creates poor metabolisers (higher plasma levels, longer duration) and ultra-rapid metabolisers (lower efficacy). Rabeprazole is less dependent on CYP2C19 (non-enzymatic conversion), making it more predictable across genotypes. Half-lives are short (~1–2 hours) but pharmacodynamic duration extends to 24–36 hours due to irreversible pump binding. Esomeprazole (S-isomer of omeprazole) achieves higher bioavailability with less first-pass metabolism.

Adverse drug reactions:
- Short-term (common, generally mild): headache, diarrhoea, nausea, flatulence, abdominal pain.
- Long-term (clinically significant — risk increases with duration):
- Hypomagnesaemia (refractory to oral supplementation; requires PPI cessation in severe cases)
- Increased risk of Clostridioides difficile infection (acid suppression reduces colonisation resistance)
- Reduced absorption of iron, calcium, vitamin B₁₂ (calcium carbonate requires acid for dissolution; B₁₂ requires acid/pepsin for cleaving from food proteins)
- Possible increased fracture risk (long-term, likely via calcium malabsorption)
- Rebound acid hypersecretion on abrupt discontinuation after prolonged use
- Drug interaction with clopidogrel: omeprazole and esomeprazole are potent CYP2C19 inhibitors → reduce conversion of clopidogrel prodrug to active thienopyridine → potentially reduced antiplatelet effect. Pantoprazole or rabeprazole preferred in clopidogrel-treated patients.
- Drug interaction with methotrexate: PPIs reduce methotrexate tubular secretion → toxicity risk at high doses.

Clinical uses: PUD (first-line for healing; superior to H2RAs); GERD (first-line for erosive GERD, step-down therapy); ZES (high-dose PPI, 40–120 mg/day); H. pylori eradication regimens (provide the acid-suppressive base); NSAID-induced ulcer treatment and prevention (co-prescribing).

H₂-Receptor Antagonists and Antacids

H₂-receptor antagonists were the first highly effective antisecretory agents and transformed peptic ulcer management before the PPI era. Before PPIs became available in the late 1980s, H2RAs such as cimetidine and ranitidine were the drugs of choice for peptic ulcer disease and GERD, and their introduction represented a genuine therapeutic revolution. Understanding their mechanism clarifies both their appropriate remaining uses — on-demand symptom relief, ICU stress-ulcer prophylaxis — and their limitations compared to PPIs, including the critical difference between reversible receptor antagonism and irreversible enzyme inhibition. Recognising that ranitidine was globally withdrawn in 2020 is equally important for safe contemporary prescribing.

Mechanism of H2RAs: They are reversible, competitive antagonists at the histamine H₂ receptor on the parietal cell basolateral membrane. By blocking histamine — the dominant physiological stimulant (it also potentiates gastrin and ACh signals) — H2RAs reduce both basal and stimulated acid secretion. Importantly, because they compete reversibly (unlike the covalent PPIs), their effect is overcome by large enough agonist concentrations, and tolerance (tachyphylaxis) develops within days to weeks of regular use (due to upregulation of H₂ receptors and possible compensatory hypergastrinaemia).

Individual agents:
- Famotidine (current prototype): 40 mg daily equivalent; the preferred H2RA in clinical practice today; no significant CYP450 inhibition; renal excretion (dose-reduce in renal failure).
- Cimetidine (first H2RA, historical importance): less potent; notable for broad CYP450 enzyme inhibition (CYP1A2, 2C9, 2C19, 2D6, 3A4) → interactions with warfarin, phenytoin, theophylline, lidocaine, propranolol; antiandrogenic (binds androgen receptor) → gynaecomastia, impotence in men with high doses; rarely used today.
- Ranitidine: withdrawn globally in 2020 (NDMA contamination risk — NDMA is a probable human carcinogen). Do not prescribe.
- Nizatidine: similar profile to famotidine; largely replaced by PPIs.

Pharmacokinetics: H2RAs are well absorbed orally, partially metabolised hepatically (cimetidine) or primarily excreted renally (famotidine, nizatidine); all penetrate the CNS to a small degree (cimetidine most — occasional mental confusion in elderly at high doses). Short duration (6–10 hours) necessitates twice-daily dosing for 24-hour control.

Clinical uses: Relief of mild-to-moderate symptoms; on-demand use; prevention of stress ulcers in ICU patients (often famotidine IV); short-term relief while establishing PPI therapy.

Antacids neutralise existing gastric acid chemically, providing rapid (within minutes) but short-lived (30–60 min fasting, 2–3 hours post-meal) symptom relief. They do not suppress acid secretion.
- Magnesium hydroxide: rapid-acting, laxative effect (Mg²⁺ osmotic) — do not use in renal failure (Mg²⁺ accumulation).
- Aluminium hydroxide: slower-acting, constipating; binds phosphate (used therapeutically in hyperphosphataemia of renal failure); may adsorb other drugs — space dosing by 2 hours.
- Calcium carbonate: rapid-acting; risk of milk-alkali syndrome with overuse; rebound acid secretion.
- Combinations (Mg(OH)₂ + Al(OH)₃): balance laxative/constipating effects.
- Sodium bicarbonate: rapid but transient; gas and belching; should not be used long-term (systemic alkalosis, sodium load in hypertensives, rebound acid).

Mucosal Protectants

Mucosal-protecting agents act on the defensive side of the aggressive/defensive balance. They are not substitutes for acid suppression in healing established ulcers, but serve as important adjuncts or as the preferred agents in specific contexts such as NSAID-induced ulcer prevention and H. pylori eradication.

Sucralfate is an aluminium salt of sucrose octasulphate. In the acidic pH of the stomach, it polymerises into a sticky, viscous paste that selectively adheres to exposed mucosal proteins at the ulcer base, forming a physical protective barrier that lasts 6 hours. It also stimulates mucus, bicarbonate, and prostaglandin secretion, and has some local trophic effects on mucosal regeneration. Sucralfate does not significantly inhibit acid secretion. Because it requires an acidic environment for activation, it should not be combined with antacids or PPIs (acid suppression impairs its polymerisation). It adsorbs other drugs — administer at least 2 hours apart from fluoroquinolones, phenytoin, digoxin, and warfarin. Generally well-tolerated; main adverse effect is constipation (released Al³⁺). Renal-failure patients accumulate aluminium — avoid in severe renal impairment.

Bismuth compounds (bismuth subcitrate = colloidal bismuth subcitrate/De-Nol; bismuth subsalicylate = Pepto-Bismol) have direct bactericidal activity against H. pylori — they coat the organism, disrupt the outer membrane, and inhibit urease, phospholipase, and protease. They also stimulate mucus secretion and prostaglandin production. Bismuth is not a first-line ulcer-healing drug in isolation, but it is essential in bismuth-based quadruple therapy for H. pylori eradication (PPI + bismuth + tetracycline + metronidazole × 10–14 days), used as second-line or in clarithromycin-resistant regions. Key adverse effects: blackening of stool and tongue (bismuth sulphide — reassure the patient); encephalopathy with high-dose systemic absorption (rare with standard courses); salicylate-related effects from subsalicylate formulations (avoid in aspirin-sensitive patients and children — Reye's syndrome risk with subsalicylate).

Misoprostol is a synthetic prostaglandin E₁ (PGE₁) analogue. It acts on EP1/EP3 receptors on parietal cells (reducing cAMP → decreased acid secretion) and on EP1/EP2 receptors on mucosal cells (stimulating mucus and bicarbonate secretion, increasing mucosal blood flow — the 'cytoprotective' effect). Its primary clinical role today is prevention of NSAID-induced gastric ulcers in high-risk patients (>65 years, history of PUD, concurrent corticosteroids or anticoagulants). It is also used as a medical abortifacient (in combination with mifepristone) and for cervical ripening — both indications exploiting its uterotonic effects. Critical contraindication: misoprostol is absolutely contraindicated in pregnancy (it causes uterine contractions → risk of abortion, premature delivery, or fetal harm). Other adverse effects: diarrhoea, abdominal cramps (prostaglandin effect on intestinal smooth muscle — dose-limiting), nausea, uterine cramping.