Sulfonamide Antimicrobial Agents

Question 1

Sulfanilamide MOA

Answer 1

sulfonamides competitively inhibit dihydropteroate synthase
-incorporation of p-aminobenzoic acid (PABA) into the folic acid nucleus is inhibited competitively by the sulfonamides, which are bioisosteres of PABA
-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.

Question 2

what can Sulfanilamide action be reversed by?

Answer 2

adding large quantities of PABA to the diet

Question 3

difference between Sulfanilamide and PABA

Answer 3

acidity of PABA (pKa 6.5)
sulfanilamide (pKa 10.4)
- PABA is mainly anionic at physiological pH, whereas sulfanilamide is a weak acid (the ratio of anion:acid
is 1:1000 at physiological 7.4).

Question 4

what does adding an electron withdrawing group do to sulfanilamide

Answer 4

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.

Question 5

why do patients need to drink water when taking sulfanilamide

Answer 5

crystallization of the sulfonamide in the urine, resulting in kidney damage
(increase in acidity also decreases the incidence of crystalluria)

Question 6

therapeutic use of sulfanilamides

Answer 6

general inhibit both Gram-(+) and Gram-(–) bacteria, nocardia, Chlamydia trachomatis, and some protozoa and fungi.

Question 7

why are sulfanilamides used in combinations?

Answer 7

resistance factors are too widespread for

these drugs to be used in a single drug therapy

Question 8

inhibiting Dihydrofolate synthase inhibits formation of?

Answer 8

thymine

Question 9

sulfanilamides

Answer 9

Sulfisoxazole has broad spectrum antibiotic activity and is currently the most popular sulfonamide.
-Sulfisoxazole and sulfamethoxazole are mainly used to treat simple urinary tract infections

Question 10

sulfanilamide with antifungals

Answer 10

Trimethoprim inhibits dihydrofolate reductase, so the combination inhibits sequential steps in the biosynthesis
of tetrahydrofolic acid.
-Trimethoprim-sulfamethoxazole, used in AIDS’s patients, with P. jeroveci

Question 11

Gardnerella vaginalis treatment

Answer 11

1:1:1 combination of sulfabenzamide, sulfacetamide, and sulfathiazole

Question 12

sinus and throat infection treatment

Answer 12

Triple sulfas-phenylpropanolamine-pheniramine is also used orally in tablet or suspension

Question 13

Sulfasalazine is a

Answer 13

prodrug

-not absorbed well from the GI tract

Question 14

Sulfasalazine is used to treat

Answer 14

ulcerative colitis and Crohn’s disease

-Bacteria in the GI tract metabolize it to sulfapyridine and 5-aminosalicylic acid, which has antiinflammatory activity

Question 15

sulfanilamides used to treat malaria

Answer 15

Sulfadoxine is a long-acting sulfonamide that is used with pyrimethamine to prevent and treat malaria. Pyrimethamine is an inhibitor of Plasmodium falciparum dihydrofolate reductase.

Question 16

sulfanilamides as toxoplasmosis treatment

Answer 16

combination with pyrimethamine is used for first-line chemotherapy to treat acute toxoplasmosis

Question 17

adverse side effects or sulfanilamides

Answer 17

• All sulfonamides and their derivatives are cross-allergenic
• rash, photosensitivity, and drug fever
• crystalluria and hematopoietic disturbances, including hemolytic or aplastic anemia, granulocytopenia, and thrombocytopenia.

Question 18

syndrome associated with sulfanilamides

Answer 18

Stevens-Johnson syndrome is a rare skin and mucous membrane rash that is potentially fatal

Question 19

resistance

Answer 19

1) Mutations that cause overproduction of PABA
2) Mutations in the target enzyme (dihydropteroate synthase) that decrease its affinity for the sulfonamides
3) Mutations that result in a decrease in cell permeability to the sulfonamides

Question 20

resistance with TMP and SMX

Answer 20

Resistance to trimethoprim is on the rise as indicated by a plasmid-borne copy of the dihydrofolate reductase (DHFR) gene. The DHFR gene often bears a mutation that enables the expressed enzyme to be active in the presence of drug through a decreased binding affinity of trimethoprim. BACTRIM is composed of 400 mg sulfamethoxazole (SMX) and 80 mg trimethoprim (TMP)

Question 21

pharmacokinetics of TMP

Answer 21

TMP is absorbed (85-90%) and distributed more rapidly than sulfonamides and dosages reflect
this fact. Peak plasma levels are 2 µg/mL after 3 hours
-T1/2 is 10-12 hours. This drug
- inactive oxidized metabolites are cleared in the urine.

Question 22

SMX pharmacokinetics

Answer 22

• distributed in the body including the CSF and is also rapidly eliminated
• T1/2 is similar to TMP.

Question 23

difference between SMX and TMP

Answer 23

SMX is not as widely distributed as TMP because of the differences in lipophilicity
-tissue ratio of SMX/TMP is 1:2 to 1:5 indicating the preferential distribution of TMP to tissues
relative to serum

Question 24

Sulfisoxazole half life

Answer 24

Short (6 h)

Prompt (peaks in 1-4 h)

Question 25

Sulfamethizole half life

Answer 25

Short (9 h)

Prompt

Question 26

Sulfadiazine half life

Answer 26

Intermediate (10-17 h)

Slow (peaks in 4-8 h)

Question 27

Sulfamethoxazole half life

Answer 27

Intermediate (10-12 h)

Slow (peaks in 3 h)

Question 28

Sulfapyridine half life

Answer 28

No data Slow

Question 29

Trimethoprim half life

Answer 29

Intermediate (10-12 h)

Prompt

Question 30

metabolism of sulfanilamides

Answer 30

metabolized by N-4 N-acetylation and in some cases N-1

glucuronidation. The metabolites have no antibiotic activity

Question 31

toxic metabolites of sulfanilamides

Answer 31

Hydroxylamine and nitroso