1992: Omeprazole and Proton Pump Inhibitors (1992)

Cimetidine and the H2-receptor antagonists had transformed peptic ulcer treatment, but they
suppressed acid incompletely (nocturnal breakthrough) and required continuous therapy because
they did not address the underlying cause in Helicobacter pylori-positive patients.

Omeprazole was developed at Astra AB in Sweden by Pål Lindberg, Lars Brändström, and colleagues.
It belongs to the benzimidazole class and acts as a prodrug: after absorption and diffusion into
the acidic compartment of parietal cells, it undergoes acid-catalysed conversion to sulfenamide,
which irreversibly binds to cysteine residues of H+/K+-ATPase (the proton pump) in the parietal
cell secretory membrane. This irreversible inhibition of the final common pathway of acid secretion
suppresses acid production far more completely and durably than H2 antagonists.

Omeprazole was approved in Europe in 1988 and by the FDA in September 1989 (widely adopted 1992
onwards following broader evidence). Clinical studies demonstrated ~90% healing rates for
duodenal ulcers in 4 weeks, superior to H2 antagonists, and profound efficacy in
gastro-oesophageal reflux disease (GERD), Zollinger-Ellison syndrome, and as part of
Helicobacter pylori eradication regimens (triple therapy).

When omeprazole's original patent expired, AstraZeneca introduced esomeprazole (the S-enantiomer,
Nexium) in 2001, demonstrating that incremental molecular modification could extend commercial
protection. PPIs—extended by lansoprazole, pantoprazole, rabeprazole, and others—became the
most prescribed drug class in the world by the early 2000s. Omeprazole remains on the WHO
Essential Medicines List.