C4 Interactions between therapeutics and biological targets Flashcards
Three problems caused by dyspepsia?
Too much acid
Acid in the wrong place (reflux)
Damage of protective lining (H.pylori, NSAID use)
What are the therapeutics and biological targets of the following... Antacids H2RAs NSAIDs PPIs
Antacids/alginates (direct physiochemical mechanism)
H2RA (GPCR)
NSAIDs (enzyme, intracellular target)
Proton Pump Inhibitors (transmembrane transport cysteine residue)
What happens in an H2 receptor when agonist binds?
Loop formed so G alpha subunit cannot bind
Note : normally a G alpha unit joins nwith GDP attached and then GDP –> GTP leads to cAMP
Three ways that enzymes act as therapeutic targets?
1 Inhibition by reversible binding in the active site (competitive inhibition)
2 Covalent modification
3 Inhibition at a site distant from the active site (Allosteric inhibition)
What is carbonic anhydrase (CA II) ?
required fro secretion of HCl by parietal cells
Metalloprotein : Zn2+ ion in the active site
Catalyses : CO2 + H2O —->(eqm) HCO3- + H+
What two enzymes do NSAIDs target?
COX 1 and COX 2
Describe COX-1 and what inhibition by NSAIDs results in
Constitutive ; inhibition causes adverse drug reactions because prostaglandin formation reduced
COX - 1 responsible for prostaglandin formation from arachidonic acid
Describe COX-2 and what inhibition by NSAIDs results in
Inducible; enzyme induced results in pain so inhibition is desirable because prevents pain
How do NSAIDs prevent COX 1 and 2?
Prevent the binding of arachidonic acid
Which two residues are key targets of NSAIDs?
Ser - 350
Arg - 120
Journey of a Proton Pump Inhibitor…
Stomach (pH 1 to 2), protected by enteric coating, remains as prodrug
Duodenum (pH 6 to 6.5) uncharged, easily absorbed
Blood (pH 7.4) uncharged, systemic circulation
Parietal Cells (pH
Why does it take time before PPIs are fully active?
Proton pump in cytoplasmic vesicles are not targeted by PPIs
Recycling of proton pumps from cytoplasmic vesicle to apical membrane required for full inhibition of vitually all/most proton pumps (up to three days)
What is the role of gastric acid in stomach?
Antibacterial
Facilitate action peptidase
Physical function of stomach remains intact
Does inhibition of proton pump affect digestion?
Proteolytic enzymes secreted by pancreas apparently compensate for loss of gastric acid and pepsin activity
More susceptible to food poisoning
