Sulfa + Miscs - MCMP Flashcards
What is this?
inactive prontosil
How is inactive prontosil converted into an active metabolite after oral administration?
The azo linkage (N=N) is split which then forms active sulfanilamide.
How is tetrahydrofolic acid formed?
- p-aminobenzoic acid forms a nucleophilic attack on dihydropteroate diphosphate which then creates dihydropteroic acid. This requires dihydropteroate synthase.
- Dihydrofolate synthase attaches a glutamic acid to the dihydropteroic acid which then creates dihydrofolic acid.
- DHFR reduces dihydrofolic acid to tetrafolic acid
Why is tetrahydrofolic acid a critically important metabolite?
It is essential for the production of thymine that is needed for DNA synthesis.
No thymine –> no DNA
What is the mechanism of action of the sulfonamides?
Sulfonamides competitively inhibit incorporation of PABA into the folic acid nucleus by inhibiting dihydropteroate synthase
This prevents the production of folates.
This prevents the production of thymine which then prevents DNA synthesis.
Why are sulfonamides toxic to pathogenic bacteria but not to humans?
- bacteria have to synthesize their own folates which gets inhibited by the sulfonamides
- humans get pre-formed folates from their diet
How can the antibiotic activities of the sulfonamides be reversed?
The metabolic activities of the sulfonamides can be reversed by adding large quantities of PABA to the diet.
Sulfonamides work via competitive inhibition. Outnumbering the sulfonamides with increased levels of PABA decreases the activity of the sulfonamides.
How does the acidity of p-aminobenzoic acid compare to that of sulfanilamide?
- PABA is much more acidic than sulfanilamide.
- The -COOH (carboxyl) makes PABA more acidic.
How does the pKa of the synthetic sulfonamide derivatives impact their potencies?
Decreasing pKa (increasing acidity) enhances potency.
Why does an increase of acidity of the sulfonamide lead to decreased incidence of crystalluria?
The lower pKa enhances water solubility so the sulfonamide will dissolve instead of crystallizing.
What drug is this?
sulfacetamide
What drug is this?
sulfadiazine
What drug is this?
sulfamethoxazole
What drug is this?
sulfasalazine
What is the spectrum of activity of the sulfonamides?
They inhibit GP AND GN bacteria.
Why are the sulfonamides used in combination with other antibiotics?
- Resistance factors are too common for them to be used alone
What are the main clinical uses of the sulfonamides?
- SMX-TMP –> AIDS
- sulfasalazine –> Crohn’s and UC
- sulfadiazine + pyrimethamine –> toxoplasmosis
- How is sulfasalazine metabolized intestinal bacteria?
- What are the biological activities of the metabolites?
- It gets metabolized into mesalamine and sulfapyridine.
- The mesalamine has anti-inflammatory activity.
- The sulfapyridine just causes adverse effects.
What is the mechanism of action of pyrimethamine?
Pyrimethamine is a DHFR inhibitor. This inhibits steps in the biosynthesis of tetrahydrofolic acid.
DHFR = dihydrofolate reductase
What are the mechanisms of resistance to the sulfonamides?
- mutations that cause overproduction of PABA
- Mutations in dihydropteroate synthase that decrease its affinity for sulfonamides
- mutations leading to decreased cell permeability
What are the pharmacokinetic characteristics of the sulfonamides?
Widely distributed and rapidly eliminated
How are sulfonamides metabolized in humans?
- Sulfonamides are metabolized by N-4 N acetylation and in some cases N-1 glucuronidation.
- Metabolites from this have no abx activity.
Human population can be divided into rapid and slow acetylators which impacts metabolism rate.
What drug is this?
Colistin
What is the mechanism of action of colistin?
- Colistin is a cationic detergent that can solubilize bacterial membranes.
- The ammonium cations in colistin displace cations in the bacterial cell membrane and facilitate binding to the anionic lipopolysaccharides in the cell membrane.
What drug is this?
metronidazole
What is the mechanism of action of metronidazole?
partial reduction of the nitro group in anaerobic bacteria leads to a radical anion that degrades bacterial DNA
metronidazole has selective cytotoxicity for anaerobes
What is the main therapeutic use for metronidazole?
Mild to moderate c. diff
What drug is this and what is it’s mechanism of action?
- lefamulin acetate
- Lefamulin selectively binds to the peptidyl transferase center (PTC) of the 50S ribosomal subunit which prevents bacterial protein synthesis
What are the therapeutic uses of lefamulin acetate?
community-acquired bacterial pneumonia
What drug is this and what is its mechanism of action?
- pretomanid
- Pretomanid inhibits mycolic acid biosynthesis and generates nitric oxide.
What are the therapeutic uses of pretomanid?
treatment-resistant tuberculosis
