Sulfonamide Antimicrobial Agents

Question 1

Sulfonamide is a pharmacologically active metabolite of …

Answer 1

prontosil

Question 2

Mechanism of action of sulfonamides

Answer 2

Competitively inhibit the incorporation of p-aminobenzoic acid (PABA) into the folic acid nucleus

The sulfonamides inhibit dihydropteroate synthase

(Recall, some bacteria have to make their own folates while mammals can eat preformed folates)

Question 3

Ultimately, inhibiting dihydropteroate synthase inhibits the formation of …

Answer 3

thymine,

which incorporates into DNA

Question 4

Why is sulfanilamide not as active as we would expect at physiologic pH?

Answer 4

its pKa is 10.4, so its anionic at physiologic pH

Question 5

What modification is made to sulfonamide when synthesizing derivates?

Answer 5

Increasing acidity

This is due to the EN of the aromatic substituents as well as resonance stabilization of the anion

Question 6

What are therapeutically used sulfonamides?

Answer 6

Sulfisoxazole
Sulfacentamide
Sulfvenzamide
Sulfamethizole
Sulfamethoxazole
Sulfathiazole
Sulfadizine
Acetyl sulfisoxazole
Sulfasalizine

Question 7

What are the therapeutic uses of sulfonamides?

Answer 7

Inhibit both Gram+ and Gram- bacteria

nocardia, chlamydia, trachomatis, some protozoa and fungi

enteric bacteria such as e. coli, klebsiella, salmonella, shigella, and enterobacter

USUALLY USED IN COMBINATION

SEE NOTES! There is extensive use of these

Question 8

What is currently the most popular sulfonamide?

Answer 8

Sulfisoxazole

Question 9

What combination of drugs is used to treat Pneumocystis jiroveci in AIDS pts?

Answer 9

Trimethoprim-sulfamethoxazole
with Trimethoprim

These inhibit sequential steps in biosynthesis of tetrahydrofolic acid

Question 10

Adverse Reactions to Sulfonamides

Answer 10

Cross-allergenic
—Sulfonamide derivatives in use drugs in other classes as well, so have to be careful

Allergic reactions

• –rash, photosensitivity, and drug fever
• –Stevens-Johnson syndrome

Crystalluria and hematopoietic disturbances, including hemolytic or aplastic anemia, granulocytopenia, and thrombocytopenia.

Anorexia, nausea, vomiting occurs in 1%-2% of patients.

Question 11

What is Steven-Johnson syndrome?

Answer 11

a rare skin and mucous membrane rash that is potentially fatal

Question 12

Sulfonamide Resistance

Answer 12

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 13

Sulfonamide methabolism - TMP (Trimethoprim)

• absorption and distribution
• peak plasma levels
• cleared where?

Answer 13

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 and the T1/2 is 10-12 hours.

This drug and its inactive oxidized metabolites are cleared in the urine.

Question 14

Sulfonamide methabolism - SMX (Sulfamethoxazole)

• distribution
• elimination
• peak serum levels

Answer 14

SMX is widely distributed in the body including the CSF and is also rapidly eliminated.

It reaches peak serum levels of 30-60 μg/mL 3 hours after an oral dose of the combination therapy. The T1/2 is similar to TMP.

Question 15

Differences in distribution of TMP and SMX

Answer 15

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

Question 16

Sulfonamide general metabolism

Answer 16

The sulfonamides are generally 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.