Sulfonamide Antimicrobials

Question 1

The first drug discovered to be effective against bacterial infections

Answer 1

Prostosil

Question 2

What type of drug is Prostosil?

Answer 2

Prodrug

Question 3

Prostosil is converted to…

Answer 3

p-aminobenzenesulfonamide

Question 4

What p-aminobenzenesulfonamide (Sulfanilamide) used to treat?

Answer 4

Vaginal Candida albicans

Question 5

What is PABA?

Answer 5

p-aminobenzoic acid

Question 6

PABA is incorporated into ______ in the process of making _____

Answer 6

Folic Acid Nucleus

Thymine (DNA)

Question 7

Step in thymine synthesis inhibited by Sulfonamides?

How?

Answer 7

Incorporation of PABA

Inhibition of Dihydropteroate Synthase

Question 8

Why don’t sulfonamides mess up human DNA synthesis?

Answer 8

Mamallian cells primarily utilize folates in the diet

Bacteria have to make their own

Question 9

Type of inhibition seen in sulfonamides?

Answer 9

Competitive

Question 10

Aside from inhibition of Dihydropteroate Synthase, how might sulfonamides act as antimicrobials

Answer 10

Some strains of bacteria use sulfonamides as a substrate, but the product is not capable of undergoing the next reaction

Question 11

How do you reverse sulfonamides?

Answer 11

Add in large quantities of PABA

Question 12

Difference in the acidity of PABA ad sulfanilamide

Answer 12

PABA - 6.5

Sulfonalimide - 10.4

Question 13

Difference in the structure of PABA and sulfanilamide

Answer 13

PABA – ends with COOH

Sulfanilamide – SO2NR2

Question 14

PABA is mainly ________ at physiologic pH

Sulfanilamide is mainly ___________

Answer 14

PABA – Anionic

Sulfanilamide – a Weak Acid

Question 15

How did early work reveal that sulfonamide derivatives could be made more potent

Answer 15

By attaching electron-withdrawing heteroaromatic rings

This acidified the sulfonamide nitrogen

Question 16

Why does attaching the aromatic ring to a sulfonamide derivative cause it to become more acidic?

Answer 16

Electronegativity of the aromatic substituients

Resonance stabilization of the anion

Question 17

Side effects influences by increasing the acidity of Sulfanilamines?

Answer 17

Decreased incidence of crystalluria

which is sulfonamide crystallization in the urine resulting in kidney damage

Question 18

Name the 9 clinically used sulfonamides

Answer 18

Sulfisoxazole
Sulfimethizole
Sulfacetamide
Sulfmethoxazole
Sulfabenzamide
Sulfathiazole
Sulfadiazine
Acetyl Sulfisoxazole
Sulfasalizine

Question 19

Clinical targets of sulfonamides?

Answer 19

G+ and G-
Nocardia, Chlamydia
Some protazoa and fungi
Enteric bacteria

Question 20

Why are sulfonamides usually used in combinations?

Answer 20

Too many resistance factors for these drugs

Question 21

Most common sulfonamide combination therapy

Answer 21

Trimthoprim-Sulfamethoxazone

Bactrim

Question 22

What is Bactrim

Answer 22

Trimethoprim (80mg) -Sulfamethoxazole (400mg)

Question 23

What does trimethoprim do?

Answer 23

Inhibits dihydrofolate reductase

Question 24

How to trimathoprim and sulfamethoxazole complement one another?

Answer 24

The combination inhibits two sequential steps in the biosynthesis of tetrahydrofolic acid

Question 25

Trimethoprim-sulfamethoxazole is a common treatment for...

Answer 25

AIDS patients with Penumocystis jiroveci

Question 26

The most popular sulfonamide?

Answer 26

Sulfisoxazole

Question 27

Sulfisoxazole and sulfamethoxazole are mainly used for...

Answer 27

UTIs

Question 28

Combination of Sulfa drugs used to treat Gardnerella vaginalis

Answer 28

Sulfabenzamide Sulfacetamide Sulfathiazole Triple Sulfas

Question 29

Why take a triple sulfas-phenylpropanolamine-pheniramine?

Answer 29

Used orally or in suspension form | Treat sinus and throat infections

Question 30

What is sulfasalazine?

Answer 30

A prodrug with poor GI absorption

Question 31

Bacteria in the GI tract metabolize sulfasalazine into...

Answer 31

Sulfapyridine and 5-aminosalicyclic acid (an anti-inflammatory)

Question 32

What is Sulfasalazine used to treat?

Answer 32

Ulcerative Colitis | Crohn's Disease

Question 33

Problem with directly administering Salicyclates?

Answer 33

Irritation to the gastric mucosa

Question 34

What is sulfadoxine? What is it used to treat?

Answer 34

A long-acting sulfonamide used with pyrimethamine to prevent and treat malaria

Question 35

What does pyrimethamine do?

Answer 35

It is an inhibitor of falciparum hihydrofolate reductase

Question 36

Name for the combination of sulfadoxine and pyrimethamine?

Answer 36

Fansidar

Question 37

What is sulfadiazine used to treat?

Answer 37

Used w/ pyrimethamine as first line chemo to treat acute Toxoplasmosis

Question 38

Adverse reaction of all sulfonamides and their derivatives

Answer 38

Cross-Allergenic Crystalluria Hematopoetic disturbances

Question 39

Examples of sulfonamide derivatives

Answer 39

Carbonic anhydrase inhibitors Thiazides Furosemide Sulfonylurea hypoglycemic agents

Question 40

Ways a sulfonamide allergic reaction may present

Answer 40

Rash, Photosensitivity, Drug Fever Stevens-Johnson syndrome Rarely, anorexia, nausea, vomiting

Question 41

What is Stevens-Johnson syndrome?

Answer 41

A rare sulfa drug allergic response resulting in a potentially fatal skin and MM rash

Question 42

Hematopoetic disturbances associate with sulfa drugs

Answer 42

Hemolytic or aplastic anemia Granulocytopenia Thrombocytopenia

Question 43

Three mechanisms for sulfonamide resistance...

Answer 43

1. Mutations causing PABA overproduction 2. Mutations in the dihydroperoate synthase that decrease affinity 3. Mutations that decrease cell permeability to sulfonamides

Question 44

Resistance to trimethoprim is indicated by...

Answer 44

DHFR gene

Question 45

What does the DHFR gene do?

Answer 45

Enables the expressed enzyme to be active in the presence of drug through a decreased binding affinity of trimethoprim

Question 46

Why is trimethoprim so much of a smaller component of bactrim?

Answer 46

TMP is absorbed at (85-90%) and distributed much faster than sulfonamides

Question 47

How is trimethoprim cleared

Answer 47

The drug and its oxidized metabolites are cleared in the urine

Question 48

Sulfamethoxalone (SMX) distribution through body

Answer 48

``` Widely distributed (including CSF) Rapidly eliminated ```

Question 49

Half life of TMP and SMX

Answer 49

about 10-12 hours

Question 50

TMP or SMX, who is more widely distributed

Answer 50

TMP (because its more lipophilic) | Preferential distribution of tmp to tissues

Question 51

How are sulfonamides metabolized?

Answer 51

N-4 acetylation and sometimes N-1 glucaronidation