PPIs Flashcards
What is a prodrug?
a drug that requires biological priming before becoming therapeutically active
What are the disadvantages of using omeprazole?
has the potential to inhibit CYP2C19
- can affect the metabolism of other drugs
= e.g. clopidogrel is not activated from its prodrug
interferes with calcium absorption
- increased risk of hip fractures and osteoporosis
hypomagnesia
vitamin B12 absorption is affected
increased risk of developing community acquired pneumonia (CAP) and C.difficile
- reduced acidity of the stomach means bacteria can grow
What are the functional groups in omeprazole?
electron rich pyridine (has EDGs)
- is the most basic
= is protonated first
sulfoxide
electron rich benzimidazole (has EDGs)
- is less basic
= is protonated second, is the rate determining step
the methylene group connecting pyridine to the sulfoxide and benzimidazole allows them to be close enough for cyclisation to occur easily
the methoxy groups in the pyridine and benzimidazole groups are electron donating
- makes the rings more electron rich
What are the different PPIs and their defining groups?
omeprazole
- has methoxy groups on pyridine and benzimidazole which are e donating groups
- has methyl groups on either side of the methoxy group on the pyridine which are e donating groups
lansoprazole
- has a trifluoroethoxy group on the pyridine which allows greater rotation and more e donating into the ring
- has no substituents on the benzimidazole
pantoprazole
- has 2 methoxy groups on the pyridine ring allowing more rotation of the para group and greater e donating
- has 2 fluorine groups attached to the methoxy on the benzimidazole group which are e withdrawing causing slower prodrug activation due to slower protonation
rabeprazole
- has a methoxypropoxy e donating group para to the O group on the pyridine ring which makes the ring more basic and nucleophilic leading to faster prodrug activation
- has no substituents on the benzimidazole ring
What is the difference between the R and S enantiomers of omeprazole? Which is superior and why?
S enantiomer
- highest priority group is the pyridine while lowest priority group is the lone pair
- has slower metabolism therefore is the superior enantiomer
R enantiomer
- highest priority group is the lone pair and lowest priority group is the pyridine
- is metabolised faster so is less favoured
How does omeprazole enter the stomach parietal cells? Why can it not leave?
omeprazole from the bloodstream cross the cell membrane to enter the parietal cells
- is unprotonated
= neutral and lipophilic
once it enters, the pyridine ring is readily protonated via the free protons from the H+/K+ ATPase pump
- is too polar to cross back so omeprazole concentrates in the parietal cell
How does pka of the benzimidazole ring affect prodrug activation?
the higher the pka of the benzimidazole, the faster protonation occurs
the more basic the benzimidazole ring, the faster protonation occurs
Why does omeprazole only reversibly inhibit the proton pump?
omeprazole has a high pka meaning it is protonated quickly resulting in rapid prodrug activation
- methoxy group is e donating leading to faster protonation (ring is more basic)
this means it only reach the thiol of cystein 813 instead of cysteine 822 which is deeper in the pump and would cause irreversible inhibition
- inhibition is reversed by glutathione
How can irreversible inhibition of the proton pump occur?
the active drug must reach deep into the proton pump until it reaches the thiol of cysteine 822
- prodrug activation cannot be too rapid
How is acid secretion restored/inhibition reversed?
formation of new proton pumps
reactivation of the inhibited proton pumps by glutathione
- glutathione reduces the disulphide linkage which joins the drug and the enzyme (disulphide reduction)
Why does pantoprazole cause irreversible inhibition? How is it designed for longer activity?
pantoprazole has a lower pka
- is a weaker base
- protonation is slower resulting in slower prodrug activation
= means it can reach deeper into the enzyme and inhibit the thiol of cysteine 822
lower pka
- fluorines attached the the benzimidazole rings are e withdrawing making the ring less e rich leading to slower activation
Why does it take a week to achieve maximum acid suppression?
only a few proton pumps are active at a time
- only the active pumps are inhibited
must inhibit the pumps within their 1-1.5 hr half life
most pumps will activate over a period of 6hrs
pumps are always being synthesised
- especially at night
inhibited pumps are regenerated by glutathione
What are the advantages to me too drugs?
therapeutic choice
- each drug has its own metabolic pathway
= depends on their metabolism rates
all except rabeprazole are oxidised by CYP2C19
- individuals with less active variants of CYP2C19 expressed with have higher serum levels of PPIs than expected
What is the metabolism of omeprazole?
CYP2C19
- benzylic oxidation
= pyridine ring
CYP3A4
- sulfoxide is oxidised to sulfone
What is the metabolism of pantoprazole?
CYP2C19
- para-methoxy demethylation
Sulphotransferase
- sulfation = of the demethylated methoxy which is now hydroxy
CYP3A4
- sulfoxide to sulfone
