Antacids, H2 Antagonists, and PPIs Overview

Acidity of gastric juice

Gastric juice has a pH of less than 1, with proton concentration as high as 0.15 mol/L (150,000 nmol/L), compared to normal cell concentration of 40 nmol/L.

Main sites for pharmaceutical manipulation of gastric acid production

1) Antacids 2) H2 receptor antagonists 3) Proton pump inhibitors 4) Antimicrobial agents

Role of carbonic anhydrase in acid production

Carbonic anhydrase catalyzes the reaction between CO2 and water to form carbonic acid, which is part of the acid secretion process.

Main mechanism of action for antacids

Antacids are alkaline substances that quickly neutralize acid in the stomach.

Common chemical compounds used as antacids

Sodium bicarbonate, calcium carbonate, aluminum salts, and magnesium salts.

Forms in which antacids are available

Gums, lozenges, tablets, powders, and liquids.

Main limitation of antacids

They don't solve the underlying problem of acid secretion; they only neutralize existing acid.

Structure of histamine

Histamine contains an imidazole ring (a heterocyclic aromatic ring with two nitrogen atoms) connected to an aliphatic amine side chain. The imidazole ring is crucial for receptor binding.

pKa values for histamine

Histamine has two pKa values: 5.7 (from the imidazole) and 9.8 (from the aliphatic amine). These determine the protonation states at physiological pH.

Tautomerism in histamine

Histamine can exist in tele or pros tautomers (depending on which nitrogen in the imidazole ring has the hydrogen). Only the tele tautomer (H on the tele nitrogen) permits binding with the H2 receptor.

Conformers of histamine in solution

Both trans and gauche conformers exist in solution. The trans conformer is believed to bind to both H1 and H2 receptors.

Burimamide

The first H2 blocker developed, but it had limited oral bioavailability.

Metiamide

Caused a decrease in white blood cells (granulocytopenia) in some patients, making them prone to infections; this side effect was associated with the thiourea moiety.

Cimetidine

Has an extra methyl group, sulfur atom, and a cyano group (C≡N) which reduces the basicity of the guanidine group.

Ranitidine

Has a furan ring (instead of imidazole), a sulfur atom, and guanidine with a nitro group; it's 4-10 times more potent than cimetidine.

Famotidine

Has a thiazole ring, sulfur atom, and a sulfonamide group; it's 40-60 times more potent than cimetidine.

Ranitidine Withdrawal

Withdrawn from the market in 2019 due to an impurity (NDMA) produced during synthesis, not due to the drug's toxicity itself.

CMN 131

The lead compound for PPIs but had severe acute toxicity associated with its thioamide group.

Omeprazole

Contains a pyridine ring, methylsulfinyl linker, and benzimidazole; these structural elements provide the balance between potency and stability.

PPIs Accumulation

PPIs are weak bases that accumulate in the acidic compartment of parietal cells and become protonated; they only become active in the low pH environment of the stomach.

PPIs Mechanism of Action

PPIs are prodrugs that transform in acidic conditions into an active sulfenamide form, which reacts with thiol groups in the H+/K+ ATPase enzyme, forming a disulfide bond that irreversibly inactivates the enzyme.

Esomeprazole

The S-chiral version of omeprazole (which is a mix of both isomers); produces higher plasma concentrations because it undergoes less metabolism by CYP 2C19.

H2 Blockers vs PPIs

H2 blockers compete with histamine for binding to H2 receptors, preventing histamine-stimulated acid secretion; PPIs irreversibly inhibit the H+/K+ ATPase pump directly, blocking the final step of acid production regardless of stimulus.

PPIs Specificity Factors

PPIs' specificity comes from: 1) Being weak bases that concentrate in acidic canaliculi, 2) Forming permanent cations that cannot escape the canaliculi, 3) Converting to active species at low pH near the target enzyme, and 4) Being inactive at neutral pH.