Inhibition of Metabolism- Folic acid antagonists

Question 1

The Sulphonamides:

Answer 1

In Vitro and In vivo experiments showed different results. The active component is Sulphanilamide.

Question 2

Sulphanilamide:

Answer 2

Sulphanilamides are analogue of p-amino benzoic acid (PABA)- basic building block in synthesis of folic acid in bacteria.
most bacteria synthesise folate.
tetrahydrofolic acid is required for nucleic acid and amino acid synthesis. Depletion of THF inhibits DNA + RNA synthesis.

Question 3

Tetrahydrofolic acid biosynthetic pathway in Bacteria and how it is inhibited.

Answer 3

Sulphonamides compete with PABA for active site dihydropteroate synthetase.
This causes a decline in folic acid which in turn causes a decrease in synthesis of purines and pyrimidines. This causes cessation of growth or cell death.

Question 4

Mode of action of sulphonamides:

Answer 4

Sulphonamides are structural and competitive analogues of PABA, but increased concs of PABA can overcome inhibition of DHF. Some sulphonamides may also be substrates substrates for DHPS.
formation of analogues of reduced forms of pteoric acid may inhibit subsequent steps (false synthesis)

Question 5

Spectrum of activity and use of sulphonamides:

Answer 5

broad spectrum
mostly bacteriostatic and slow to act
Use on its own has declined.
Sulphadiazine is used for protection of close contacts in meningococcal meningitis.
Also, this is used in conjunction with pyrimethamine to treat toxoplasmosis.
Topical silver sulphadiazine used to treat patients with serious burns to prevent and treat infections on the wound.

Question 6

2,4-diaminopyrimidines

Uses

Answer 6

Mainly for UTIs
trimetrexate is an antipneumocystis agent
Methotrexate is antineoplastic agent
They can also be antimalarials

Trimethoprim:
competitively inhibits bacterial dihydrofolate reductase (DHFR) which usually catalyses reduction of DHF to THF in bacteria, protozoans and vertebrates.
It has higher affinity for bacterial DHFR than the corresponding verterbrate enzyme.

Question 7

Sulphonamides & Trimethoprim used in combination:

Background
spectrum of use
Pharmacology
Adverse effects

Answer 7

Both are bacteriostatic; together they are synergistic and bactericidal. Causes sequential blockade of folic acid metabolism.
Used vs many aerobic G- + G+, pneumocystis and several protozoans.
RTIs include streptococcus pneumoniae
UTI: E.coli, proteus mirabilis
GIT pathogens: salmonella Typhi
They are paired together because of similar absorptive and pharmocokinetic properties.
Good oral absorption
serum half-lives of around 10hrs
Both distributed to most tissue including CSF
Ratio must be about 1:20 TMP:SMX
Generally well tolerated but with some GI side effects
hypersensitivity reactions in 3-5% of cases.
Rare severe or fatal effects- aplastic anaemia, toxic epridermal necrolysis