Mechanisms and Development of GI Drugs

what are ulcers?

Localized erosion of stomach or duodenum mucosa, can be fatal

what are ulcers caused by?

stress, infection, H.pylori and reaction to NSAIDS, aggrevated by gastric acid

what are common Symptoms of Ulcers

Include abdominal pain, nausea, and bloating.

what is the mechanism in which HCl is produced in the stomach?

- CO2 and water in blood combine to form carbonic acid (H2CO3).

- H2CO3 dissociates and exchanged for Cl-

- HCO3- buffer formed (not needed)

- Cl- ions enter the lumen through channels

- ATP powers excahnge between K+ and H+ ions via a proton pump

- K+ re-enters lumen to maintain electrostatic balance, forming HCl.

what is the therapy for ulcers?

• Medication to lower levels of gastric acid.

• Histamine (H2) antagonists (to bind to H2 receptor and deactivate) and proton pump inhibitors (PPIs), which inhibits the ATPase enzyme

• Antibacterial agents to treat Helicobacter pylori (H. Pylori). Bacteria infect your stomach.

• Herbal remedies

what are the differences between H2 antagonists and PPIs as ulcer therapies?

Both H2 antagonists and PPIs reduce gastric acid but through different mechanisms. H2 antagonists block histamine's action on parietal cells, while PPIs directly inhibit the proton pump responsible for acid secretion.

what is the SKF hypothesis regarding histamine receptors and their relevance to ulcer treatment?

The SKF hypothesis proposed two types of histamine receptors: H1 (responsible for classic histamine effects) and H2 (mediating gastric acid release). This suggested that blocking H2 receptors could treat ulcers without interfering with other histamine functions.

what is the significance of Na-Guanylhistamine in the development of H2 antagonists?

Nα-Guanylhistamine, a partial agonist, demonstrated weaker gastric acid release than histamine but prevented histamine from fully stimulating acid release. This supported the concept of different binding sites on the putative H2 receptor for agonists and antagonists.

how did the understanding of the binding hypothesis lead to the development of Burimamide?

The binding hypothesis proposed separate binding regions on the H2 receptor for agonists and antagonists. By increasing the distance between the imidazole and guanidine groups, researchers aimed to enhance antagonist binding and create a more potent H2 antagonist, leading to Burimamide.

what is the rationale for structural modifications made in the development of Metamide from Burimamide?

The addition of a methyl group to Burimamide, resulting in Metiamide, aimed to reduce basicity and improve imidazole binding. This modification led to a 10-fold increase in potency, but unacceptable side effects prompted further structural changes.

what led to the development of Cimetidine, and what were its advantage and disadvantages compared to Metiamide?

Replacing the thiourea group of Metiamide with a cyanoguanidine moiety yielded Cimetidine, which retained efficacy while improving the side effect profile. Cimetidine became a blockbuster drug but had limitations due to CYP450 enzyme inhibition and drug interactions.

how do PPIs like Omeprazole work to reduce gastric acid secretion?

Proton pump inhibitors like Omeprazole are prodrugs activated in the acidic environment of parietal cell canaliculi. They bind irreversibly to the proton pump enzyme (H+/K+ ATPase), inhibiting acid secretion into the stomach.

what are Parietal Cells?

Cells in stomach lining that secrete gastric acid.

what is Gastric Acid Release stimulated by?

Stimulated by acetylcholine, gastrin, and histamine.

What does H2 antagonist do?

Blocks histamine action at H2 receptors, reducing acid.

what occurs in the proton pump?

- pump protons out of the parietal cells and K+ back in

- requires energy provided by ATP hydrolysis, catalysed by H+/K+ ATPase enzyme, proton pump

- Cl- departs through another channel and HCl is formed in Canaliculus

- K+ exits cells as counter ions for Cl- and are then pumped back in

what is a Proton Pump Inhibitor (PPI)?

Inhibits proton pump, reducing gastric acid secretion. They are prodrugs and are activated by strongly acidic conditions

what is Nα-Guanylhistamine?

Partial agonist reducing gastric acid release from histamine.

Burimamide

Developed from binding hypothesis for stronger H2 antagonism.

what is the SKF Hypothesis??

Proposed H1 and H2 receptor roles in gastric acid release.

what is a Structure-Activity Relationship (SAR)?

Relationship between chemical structure and biological activity.

What is an agonist?

Activates a receptor, producing a biological response.

What is an antagonist?

Blocks receptor action of an agonist.

What is a partial agonist?

Produces submaximal response compared to full agonist.

what is Chelation?

Binding of metal ion forming a ring-like structure.

What are ECL cells?

enterochromaffin-like cells; secrete histamine, which stimulates the secretion of gastric acid from parietal cells