Sulfonamides

General characteristics of Sulfonamides

*Static* -> rely on bodies immune system Broad spectrum: Gram + /Gram - *can have some bad side effects

Which DHFRI do you need to remember?

*Trimethoprim*

Kernicterus

*form of jaundice Sulfonamide given to neonate -> displaces bilirubin from plasma protein -> free bilirubin enters CNS -> CNS depression Recommend: avoid sulfonamides in last month of pregnancy, infants < 2 months

What are the general side effects of all Sulfonamides?

1. Crystalluria 2. Kernicterus 3. Blood Dyscrasias 4. Hypersensitivity 5. Hyperkalemia 6. Drug Interactions

Hypersensitivity What 3 reactions can occur?

1. Erythema Multiforme - asymptomatic macules/papules *slightly less severe 2. Steven-Johnson Syndrome- fever,headache, cough, conjunctivitis followed by bollous eruptions on skin *much more severe 3. Reaction Fever- immune mediated hypersensitivity

What happens once Dihydropteroic Acid is formed?

1. Glutamate is added to Dihydropteroic Acid -> Dihydrofolate (FH2) 2. FH2 is reduced to Tetrahydrofolate (FH4) aka THF

DAPSONE A. Type of Drug B. Classification C. Use

A. Sulfonamide B. Oral Sulfonamide C. Used to treat: Pneumocystis carinii pneumonia, leprosy

SULFISOXIZOLE A. Type of Drug B. Classification C. Use

A. Sulfonamide B. Oral Sulfonamide C. Used with erythromycin for recurrent otitis media

SILVER SULFADIAZINE A. Type of Drug B. Classification C. Uses D. Adverse Reaction

A. Sulfonamide B. Topical Sulfonamide C. Use: 1. For burns to prevent sepsis 2. Silver is toxic to microorganisms D. Sulfa can be absorbed -> caution when applying to large areas

SULFACETAMIDE (Bleph-10) A. Type of Drug B. Classification C. Uses

A. Sulfonamide B. Topical Sulfonamide C. Use: 1. Ulcerative Blepharitis -> eyedrop w/ 10% solution -> treat inflammation of the *eyelid* 2. Bacterial Conjunctivitis

MAFENIDE A. Type of Drug B. Classification C. Uses D. Adverse Reaction

A. Sulfonamide B. Topical Sulfonamide C. Used for Burns D. Inhibits carbonic anhydrase -> Loss of HCO3- (buffer) -> upsets pH balance -> *Metabolic Acidosis*

SULFAMETHOXAZOLE A. Type of Drug B. Classification C. Advantage? D. Use? E. Side Effect?

AKA: Co-trimoxazole A. Sulfonamide B. Oral Sulfonamide C. Can be given with Trimethoprim (DHFRI) -> synergistic effect *inhibits two sequential steps of Folic acid synthesis D. Not system specific -> GI, urinary, resp E. Blood Dyscrasia

Blood Dyscrasia Which drugs to avoid?

Acute hemolytic anemia, aplastic anemia, agranulocytosis rare but can be *fatal* *Avoid topical sulfonamides if pt has history of blood disorder*

Why dont sulfas inhibit human DNA synthesis?

Because we dont create folic acid, we recieve it pre-made from our diet!

What pregnancy rating do sulfonamides have?

Category B: Animal studies: no risk or effects in animals not confirmed in humans

What is the purpose of DHFR? What does a DHFR inhibitor do? What enzyme is inhibited?

DHFR reduces FH2 --> FH4 (THF) *allows for creation of thymidine DHFR inhibitor prevents this reduction by inhibiting: *Dihydrofolate reductase* (DHFR) *cell will not be able to make DNA, cell will die

Sulfonamide: Crystalluria

Drugs can crystallize -> tubular damage Recommend: drink lots of water with oral dosage to minimize risk of nephrotoxicity

What are sulfa drugs often used with? Why?

Generally given with DHFR Inhibitors *allows for synergestic effect and inhibition of second step in folic acid cycle

Main mechanism of Sulfonamides? What synthesis is being inhibited? How?

Inhibit the first step in folic acid synthesis: Enzyme: dihydropteropate synthase Joins *PABA* with *Pteridine* -> Dihydropteroic acid Mechanism: Sulfonamides prevent the function of this enzyme -> cannot join PABA + Pteridine

What interactions can sulfonamides have with other drugs? 1. Warfarin 2. Sulfonylureas

Interacts with warfarin 1. Bumps it off of a plasma protein -> increases the free (active) warfarin in the blood -> increase in blood thinning -> can be fatal 2. Increases hypoglycemia related to oral sulfonylureas due to structural similarity

Dihydropteroic Acid

The immediate precursor to folic acid Formed by PABA joining Pteridine

Why do Sulfas and DHFRI act in synergy?

The two drugs together inhibit sequential steps in the synthesis of folic acid.

Tetrahydrofolate (THF) or (FH4)

Used in one carbon transfers Allows dUMP --> TMP (thymidine monophosphate) *synthesis of thymidine required for DNA synthesis

Hyperkalemia

Usually only occurs due to comorbidity with some other disease

Do sulfonamides cross the placenta?

yes they do -> antibacterial effects as well as unwanted side effects in the fetus