Sulphanomides

Question 1

Why can sulphonamides be used without fear of disrupting metabolism in humans?

Answer 1

a. Tetrahydrofolate is a vitamin required for nucleotide synthesis. Sulphonamides block tetrahydrofolate synthesis in bacteria. Dihydropteroate synthetase is not present in humans. Tetrahydrofolate is needed by both, but it is made from folic acid (obtained from the diet) in humans.

Question 2

Which enzymes do sulphonamides inhibit? Do humans have a similar enzyme?

Answer 2

a. Dihydropteroate

b. Folic acid

Question 3

What was protonsil ?

Answer 3

a. Red dye, pro drug metabolized to active sulphonamide with antibacterial activity in vivo

Question 4

Draw the structure of a typical sulphonamide. What needs to be varied to have an effect on dosage?

Answer 4

a. H2N-Benzene-SOO-NHR2

b. R2 is varied and determined blood levels.

Question 5

Draw the structure of a typical sulphonamide. What is the function of R2?

Answer 5

b. Affects plasma protein binding
c. Determines blood levels and lifetime of the drug
d. Affects solubility

Question 6

Draw structures to show how sulphonamide metabolised

Answer 6

me-C=O-HN-Benezene-etc..

Question 7

What risk did Japanese and Chinese populations have while using the earlier versions of sulphonamides?

Answer 7

a. In water system
b. Sulphonamides are metabolised in humans by N-acetylation
c. N-Acetylation increases hydrophobic character
d. Reduces aqueous solubility
e. May lead to toxic side effects

Question 8

How were sulphonamides improved so that Japanese or Chinese populations could safely take them?

Answer 8

a. Thiazole ring is replaced with a pyrimidine ring
b. Pyrimidine ring is more electron withdrawing
c. Sulphonamide NH proton is more acidic and ionisable
d. Sulphadiazine and its metabolite are more water soluble
e. Reduced toxicity

Question 9

What is the mechanism of sulphonamide action? Please also draw the structures of PABA and sulphonamides.

Answer 9

a. Target Dihydropteroate synthetase - bacterial enzyme by mimicking enzyme substrate - para-aminobenzoic acid (PABA)
b. PABA: H2N-Benzene-CO2H
c. Sulph: R1HN-Benzene-S=OO-NHR2

Question 10

List the reasons for sulphonamide resistance as discussed in class

Answer 10

a. More PABA synthesized
b. Decreased membrane permeability to sulphonamide
c. Decreased KM for sulphonamide