Sulfonamide Antimicrobials Flashcards
The first drug discovered to be effective against bacterial infections
Prostosil
What type of drug is Prostosil?
Prodrug
Prostosil is converted to…
p-aminobenzenesulfonamide
What p-aminobenzenesulfonamide (Sulfanilamide) used to treat?
Vaginal Candida albicans
What is PABA?
p-aminobenzoic acid
PABA is incorporated into ______ in the process of making _____
Folic Acid Nucleus
Thymine (DNA)
Step in thymine synthesis inhibited by Sulfonamides?
How?
Incorporation of PABA
Inhibition of Dihydropteroate Synthase
Why don’t sulfonamides mess up human DNA synthesis?
Mamallian cells primarily utilize folates in the diet
Bacteria have to make their own
Type of inhibition seen in sulfonamides?
Competitive
Aside from inhibition of Dihydropteroate Synthase, how might sulfonamides act as antimicrobials
Some strains of bacteria use sulfonamides as a substrate, but the product is not capable of undergoing the next reaction
How do you reverse sulfonamides?
Add in large quantities of PABA
Difference in the acidity of PABA ad sulfanilamide
PABA - 6.5
Sulfonalimide - 10.4
Difference in the structure of PABA and sulfanilamide
PABA – ends with COOH
Sulfanilamide – SO2NR2
PABA is mainly ________ at physiologic pH
Sulfanilamide is mainly ___________
PABA – Anionic
Sulfanilamide – a Weak Acid
How did early work reveal that sulfonamide derivatives could be made more potent
By attaching electron-withdrawing heteroaromatic rings
This acidified the sulfonamide nitrogen
Why does attaching the aromatic ring to a sulfonamide derivative cause it to become more acidic?
Electronegativity of the aromatic substituients
Resonance stabilization of the anion
Side effects influences by increasing the acidity of Sulfanilamines?
Decreased incidence of crystalluria
which is sulfonamide crystallization in the urine resulting in kidney damage
Name the 9 clinically used sulfonamides
Sulfisoxazole Sulfimethizole Sulfacetamide Sulfmethoxazole Sulfabenzamide Sulfathiazole Sulfadiazine Acetyl Sulfisoxazole Sulfasalizine
Clinical targets of sulfonamides?
G+ and G-
Nocardia, Chlamydia
Some protazoa and fungi
Enteric bacteria
Why are sulfonamides usually used in combinations?
Too many resistance factors for these drugs
Most common sulfonamide combination therapy
Trimthoprim-Sulfamethoxazone
Bactrim
What is Bactrim
Trimethoprim (80mg) -Sulfamethoxazole (400mg)
What does trimethoprim do?
Inhibits dihydrofolate reductase
How to trimathoprim and sulfamethoxazole complement one another?
The combination inhibits two sequential steps in the biosynthesis of tetrahydrofolic acid
Trimethoprim-sulfamethoxazole is a common treatment for…
AIDS patients with Penumocystis jiroveci
The most popular sulfonamide?
Sulfisoxazole
Sulfisoxazole and sulfamethoxazole are mainly used for…
UTIs
Combination of Sulfa drugs used to treat Gardnerella vaginalis
Sulfabenzamide
Sulfacetamide
Sulfathiazole
Triple Sulfas
Why take a triple sulfas-phenylpropanolamine-pheniramine?
Used orally or in suspension form
Treat sinus and throat infections
What is sulfasalazine?
A prodrug with poor GI absorption
Bacteria in the GI tract metabolize sulfasalazine into…
Sulfapyridine and 5-aminosalicyclic acid (an anti-inflammatory)
What is Sulfasalazine used to treat?
Ulcerative Colitis
Crohn’s Disease
Problem with directly administering Salicyclates?
Irritation to the gastric mucosa
What is sulfadoxine? What is it used to treat?
A long-acting sulfonamide used with pyrimethamine to prevent and treat malaria
What does pyrimethamine do?
It is an inhibitor of falciparum hihydrofolate reductase
Name for the combination of sulfadoxine and pyrimethamine?
Fansidar
What is sulfadiazine used to treat?
Used w/ pyrimethamine as first line chemo to treat acute Toxoplasmosis
Adverse reaction of all sulfonamides and their derivatives
Cross-Allergenic
Crystalluria
Hematopoetic disturbances
Examples of sulfonamide derivatives
Carbonic anhydrase inhibitors
Thiazides
Furosemide
Sulfonylurea hypoglycemic agents
Ways a sulfonamide allergic reaction may present
Rash, Photosensitivity, Drug Fever
Stevens-Johnson syndrome
Rarely, anorexia, nausea, vomiting
What is Stevens-Johnson syndrome?
A rare sulfa drug allergic response resulting in a potentially fatal skin and MM rash
Hematopoetic disturbances associate with sulfa drugs
Hemolytic or aplastic anemia
Granulocytopenia
Thrombocytopenia
Three mechanisms for sulfonamide resistance…
- Mutations causing PABA overproduction
- Mutations in the dihydroperoate synthase that decrease affinity
- Mutations that decrease cell permeability to sulfonamides
Resistance to trimethoprim is indicated by…
DHFR gene
What does the DHFR gene do?
Enables the expressed enzyme to be active in the presence of drug through a decreased binding affinity of trimethoprim
Why is trimethoprim so much of a smaller component of bactrim?
TMP is absorbed at (85-90%) and distributed much faster than sulfonamides
How is trimethoprim cleared
The drug and its oxidized metabolites are cleared in the urine
Sulfamethoxalone (SMX) distribution through body
Widely distributed (including CSF) Rapidly eliminated
Half life of TMP and SMX
about 10-12 hours
TMP or SMX, who is more widely distributed
TMP (because its more lipophilic)
Preferential distribution of tmp to tissues
How are sulfonamides metabolized?
N-4 acetylation and sometimes N-1 glucaronidation
