Question

Write down the Strategies to make drugs more resistant to hydrolysis and metabolism with an emphasis on lidocaine.

Answer 1

There are several strategies that are taken to make the drug more resistant to hydrolysis and metabolism.

1.

Steric shields: some functional group have more susceptibility to enzymatic and chemical degradation than the others. Such as amides and esters are much more affordable to the hydrolysis than the other compounds like oximes and carbamates. Introducing steric shields in these drugs will increase the stability. Introduction of steric shield will block the hydrolysis of peptide links.

2.

Isosteric or bioisostere replacement: the replacement of more reactive ester to the less reactive amide is usually done in this strategy. Such as, the methyl group on the phenyl ring will impose the steric shielding whereas replacing the ester (procaine) to a less reactive amide (lidocaine) slows the enzymatic reaction of hydrolysis.