Sulfonamides Flashcards
Be able to describe how the inactive prontosil can be converted to an active antibiotic after oral administration.
a) Prontosil is a prodrug of the active sulfonamide, p-aminobenzenesulfonamide.
b) Prontosil is reduced by intestinal bacteria and generates sulfanilamide (active).
Be able to explain how tetrahydrofolic acid is formed, and why it is a critically important metabolite.
a) Dihydropteroate diphosphate –> dihydropteroate synthase –> forms dihydropteroic acid –> dihydrofolate synthase –> forms dihydrofolic acid –> DHFR –> forms tetrahydrofolic acid
b) Important because thymine is necessary for making DNA.
Be able to describe the mechanism of action of the sulfonamides.
a) Incorporation of p-aminobenzoic acid (PABA) into the folic acid nucleus is inhibited competitively by the sulfonamides, which are bioisosteres of PABA. Sulfonamide inhibits dihydropteroate synthase.
b) The structure of sulfanilamide resembles that of PABA – inhibits incorporation of PABA into folic acid nucleus.
Be able to explain why the sulfonamides are toxic to pathogenic bacteria but not to humans.
a) Since mammalian cells utilize preformed folates in the diet and some bacterial cells are required to make their own folic acid, the sulfonamides have selective toxicity for bacterial cells as opposed to mammalian cells.
Be able to describe how the antibiotic activities of the sulfonamides can be reversed.
a) The antibiotic activity of sulfonamides can be reversed by adding large quantities of PABA to the diet.
Be able to describe how the acidity of p-aminobenzoic acid compares with that of sulfanilamide.
a) PABA is mainly anionic at physiological pH, whereas sulfanilamide is a weak acid (ratio of anion:acid is 1:1000 at physiological 7.4). 1000x as much sulfanilamide compared to PABA.
Be able to describe the relationship between the pKa of synthetic sulfonamide derivatives and their potencies.
a) PABA has a pKa of 4.9, and sulfanilamide has a pKa of 10.4.
Be able to explain how aromatic substituents on the sulfonamide nitrogen can increase acidity.
a) The attachment of electron-withdrawing heteroaromatic rings acidified the sulfonamide nitrogen and enhanced the potency. Increase in acidity is due to the electronegativity of the aromatic substituent as well as resonance stabilization of the anion.
Be able to describe how an increase in the acidities of the sulfonamides can lead to a decrease in the incidence of crystalluria.
a) Increase in acidity also decreases the incidence of crystalluria (crystallization of the sulfonamide in the urine, resulting in kidney damage). Still recommended to drink lots of water to avoid crystalluria.
Be able to characterize the antibiotic spectrum of the sulfonamides.
a) Inhibit both gram(+) and gram(-) bacteria, and some protozoa and fungi. Enteric bacteria such as E. coli, klebsiella, salmonella, shigella, and Enterobacter, are inhibited.
Be able to explain why the sulfonamides are used in combination with other antibiotics.
a) To get more potency and inhibit formation of resistance. The resistance factors are too widespread for these drugs to be used in a single drug therapy.
b) Antifungal activity of trimethoprim-sulfamethoxazole important for treatment of AIDs-infected pts that have developed infections caused by pneumocystis jirovecii. Trimethoprim inhibits dihydrofolate reductase, so the combo inhibits sequential steps in the biosynthesis of tetrahydrofolic acid.
Be able to list the main clinical uses of the sulfonamides.
a) Sulfasalazine is used to treat ulcerative colitis and Crohn’s disease.
b) Sulfadiazine in combo with pyrimethamine is used for 1st line chemo to treat acute toxoplasmosis.
Be able to describe how sulfasalazine is metabolized by intestinal bacteria, and characterize the biological activities of the metabolites.
a) Sulfasalazine is a prodrug that’s not absorbed well from GI tract. Bacteria in GI tract metabolize it to sulfapyridine and 5-aminosalicyclic acid which has anti-inflammatory activity.
b) Direct administration of 5-aminosalicylic acid is irritating to the gastric mucosa.
Be able to describe the mechanism of action of pyrimethamine, and its therapeutic uses when combined with certain sulfonamides.
a) Pyrimethamine is a DHFR inhibitor, preventing formation of tetrahydrofolic acid.
Be able to describe the main bacterial resistance mechanisms to sulfonamides.
a) Mutations that cause overproduction of PABA.
b) Mutations in the target enzyme (dihydropteroate synthase) that decrease its affinity for the sulfonamides.
c) Mutations that result in a decrease in cell permeability to the sulfonamides.
Be able to characterize the pharmacokinetics of the main sulfonamides.
a) TMP is absorbed and distributed more rapidly than sulfonamides. It is cleared in the urine.
b) SMX is widely distributed in the body including the CSF and is also rapidly eliminated. SMX is not as widely distributed as TMP because of the differences in lipophilicity.
Be able to specify how the sulfonamides are metabolized in humans.
a) Metabolized by N-4 N-acetylation and in some cases N-1 glucuronidation. The metabolites have NO antibiotic activity. Hydroxylamine and nitroso metabolites are toxic.
b) Human population can be divided into rapid and slow acetylators. This affects rate of metabolism of sulfonamides in humans.
Be able to recognize the structure of colistin and describe its mechanism of action.
a) Polycation that has lipophilic regions, so the overall structure resembles that of a cationic detergent that is able to solubilize bacterial membranes. The ammonium cations are able to displace cations in the bacterial cell membrane (Mg++ and Ca++) and facilitates binding of the antibiotic to anionic lipopolysaccharides in the cell membrane.
Be able to recognize the structure of metronidazole and describe its main therapeutic use and mechanism of action.
a) Useful for treatment of anaerobic bacteria and protozoa. DRUG of CHOICE for treatment of 1st episodes of mild-moderate C. diff infections.
b) MOA: partial reduction of the nitro group in anaerobic bacteria leads to a radical anion that degrades bacterial DNA.
Be able to recognize the structures of Lefamulin acetate and pretomanid and describe their mechanisms of action and therapeutic uses.
a) Lefamulin acetate:
i) Uses: community-acquired bacterial pneumonia
ii) MOA: selective binding to the peptidyl transferase center of the 50S ribosomal subunit to prevent bacterial protein synthesis.
b) Pretomanid:
i) Uses: treatment-resistant tuberculosis
ii) MOA: inhibits mycolic acid biosynthesis through an unknown mechanism, and poisons respiration (mitochondria) through generation of nitric oxide.
