H2 antagonists and PPIs

Question 1

what is peptic ulcer and its causes?

Answer 1

erosion of mucosal surface
exposed surface by stomach acid

causes - stress, alcohol, H pylori, NSAIDs

Question 2

describe gastric acid secretion?

Answer 2

gastric acid secretion - active transport

CO2 + H20 - carbonic acid
carbonic acid catalysed by carbonic anhydrase - results in H+ and HCO3- ions

HCO3- are actively secreted out into basal side of parietal cell - exchanged with chloride ions

H+ ions are exchanged with K+ ions using the H+/K+ ATPase pump at the apical side

H+ ions and Cl- ions combine to make acid

Question 3

list the stomach cells?

Answer 3

chief cells
parietal cells
mucus secreting cells
hormone secreting cells - gastrin

Question 4

how can parietal cells be pharmacologically manipulated?

Answer 4

antacids - alkaline substances chemically neutralise acids in stomach

H2 antagonists - inhibit histamine

PPIs - inhibit pump - inhibit acid secretion

antimicrobials - destroy any bacteria that may cause ulcers

Question 5

briefly describe the chemistry of antacids?

Question 6

briefly describe the chemistry of histamine?

Answer 6

at physiological pH - it is protonated at primary amine

the tele tautomer (H in the tele N) - allows binding to receptor

tautomerism - imp for H2 interaction not H1

Question 7

describe the development of H2 antagonists?

Answer 7

guanidine - 1st analogue synthesised to mimic histamine - acted as an agonist instead of antagonist as pKa was very high so amine was always protonated

thiourea - replaced C=N group with C=S and alkyl chain (EDG) which reduced pKa
- produced effective H2 antagonists

metamide - extra methyl and sulphur group, increased chain length,

cimetidine was developed after it was found out how to reduce guanidine pKa by adding CN or NO2 as the R group

ranitidine- 4-10x more potent than cimetidine, longer duration of action, less CYP inhibition, tertiary amines allow formation of salts
- however ranitidine was discontinued after it was found to produce an impurity = NDMA had risk factor to cancer

famotidine - 40-60x more potent than cimetidine

Question 8

describe the development of PPIs?

Answer 8

bunch of PPIs were produced - led to omeprazole being produced

omeprazole - contains pyridine and benzimidazole ring and sulphur
- weak base accumulates in acidic compartment
- substituents were added to pyridine ring - to obtain pKa that maximised accumulation in parietal cells

Question 9

describe the MOA of PPIs?

Answer 9

sulfenamide - key reactive species - intermediate that has a S-N bond

thiol group on proton pump reacts with other sulphur - causes a disulphide adduct
- causes S-N bond to break

covalent bond formed b/w pump and omeprazole - inactivates pump, doesn’t release H+ ions, no acid secretion