Sulfonamide

Question 1

Sulfa drugs

Answer 1

Contain sulfonamide group (SO2-N)

Question 2

Bacterial Folate Synthesis

Answer 2

Folate required for thymidine/DNA synthesis
Mammalian cells use exogenous folate (diet): can transfer folate across cell membrane
Bacterial cells: no exogenous folate (must synthesize)
Uridine converted to thymidine by thymidylate synthase
Thymidine is necessary to synthesize DNA
THF is necessary for proper function of thymidylate synase (comes from folate)

Question 3

Folate synthesis is a selective target for antibiotics b/c

Answer 3

Bacteria must synthesize folate themselves for thymidine synthesis (necessary for DNA synthesis)Human cells do not have same mechanism: receive folate from diet, which transfers across cell membrane

Question 4

Bacterial Folate Synthesis

Answer 4

1. PABA: Para-Amino-Benzoic-Acid combined with Pteridine by dihydropteroate synthase enzyme to synthesize dihyropteroic acid (which later becomes folate)
2. Dihydropteroic acid is converted to Dihydrofolic Acid and finally Tetrahydrofolate (form of folate necessary for DNA synthesis). Generation of tetrahydrofolate is catalyzed by Dihydrofolate Reductase.

Question 5

Which step of bacterial folate synthesis is inhibited by Sulfonamides?

Answer 5

Dihydropteroate Synthase

Question 6

Which step of bacterial folate synthesis is inhibited by Trimethoprim and Pyrimethamine?

Answer 6

Dihydrofolate Reductase (catalyzes generation of tetrahydrofolate)

Question 7

Trimethroprim and Pyrimethamine are often administered together with a sulfonamide antibiotic for

Answer 7

sequential block of folate synthesis pathway in bacteria.

Question 8

Sulfanomides

Answer 8

Sulfamethoxazole (SMX)
Sulfisoxazole
Sulfadiazine
-Mimics PABA (benzene ring attached to nitrogen group)
-Competitively inhibits dihydropteroate synthesis

Question 9

Bacterial resistance to sulfanomides

Answer 9

Increased PABA
Altered dihydropteroate synthase
Decreased uptake

Question 10

Dapsone

Answer 10

Not a sulfonamide
Competes with PABA for dihydropteroate synthase
Two main uses:
-Mycobacterium leprae (leprosy)
-Pneumocystic jivoreci

Question 11

Sulfanomides

Answer 11

Sulfamethoxazole (SMX)
Sulfisoxazole
Sulfadiazine

Question 12

Sulfanomides are usually administered with

Answer 12

Trimethoprim
-TMP-SMX (Bactrim)
-Sequential block of THF synthesis
Sulfadiazine
-Silver sulfadiazine (cream) for burns
Sulfadiazine and Pyrimethamine
-Sequentially blocks THF synthesis
-Used in toxoplasmosis (HIV)

Question 13

Sulfonamide Toxicity

Answer 13

Hypersensitivity reactions in 3% of patients
Reactions linked to
-Arylamine (NH2) at N4 position
-Nitrogen ring attached to N1 nitrogen
Only sulfonamide antibiotics contain both features

Question 14

Other sulfa drugs

Answer 14

Furosemide (loop diuretic)
Probenicid (gout)
Hydrochlorothiazide (thiazide diuretic)
Acetazolamide (carbonic anhydrase)
Sulfasalazine (IBD)
Sulfonylurea (diabetes)

Question 15

Sulfonamide adverse effects

Answer 15

Same as penicillins

Question 16

Trimethroprim/Pyrimethamine MOA

Answer 16

Inhibit dihydrofolate reductase

Similar to structure of dihydrofolate

Question 17

Trimethroprim/Pyrimethamine Toxicity

Answer 17

Preferentially inhibits bacterial DHF reductase
Some inhibition of human enzyme can occur
Inhibits DNA synthesis of rapidly dividing cells

Question 18

Trimethroprim/Pyrimethamine Toxicity

Answer 18

Bone marrow suppression
-Pancytopenia: Megaloblastic anemia, leukopenia, decreased platelets
Can alleviate with leucovorin (folinic acid)
-Converted to THF
-Does not require dihydrofolate reductase
-Leucovorin rescue

Question 19

Bactrim (TMP-SMX)

Answer 19

Combination is bactericidal
Covers many gram (+) and gram (-)
-Does not cover pseudomonas
-Does not cover B. fragilis (and most anaerobes)
Covers some fungi and parasites

Question 20

Bactrim common uses

Answer 20

UTI (e. coli)

Pneumocystis pneumonia in HIV (Tx/prophylaxis)

Question 21

Can Bactrim (TMP-SMX) be administered in pregnancy?

Answer 21

No
Risk of kernicterus from sulfonamide component
TMP component can disrupt folic acid metabolism

Question 22

What is treatment of choice for Pneumocystis jirovecci

Answer 22

Bactrim (TMP-SMX)
However, hypersensitivity reactions are 6-25 higher in HIV
Alternative therapy needed instead: Dapsone, Pentamidine or Atovaquone (malaria drug)