Like para-aminobenzoic acid (PABA), but the acid is replaced with SO₂NH-R. Sulfonamides mimic PABA in the bacterial folic acid synthesis pathway.

[image]

They inhibit folic acid synthesis from PABA, which only occurs in bacteria. Specifically, they competitively inhibit dihydropteroate synthase, which makes dihydropteroic acid from pyridine and PABA.

Bacteriostatic.

Broad spectrum; good activity against both Gram+ and Gram-, but resistance greatly limits use.

1. Overproduction of PABA (main mechanisms): Since sulfonamides are competitive inhibitors of dihydropteroate synthase, bacteria can overproduce PABA to overcome inhibition.

2. Mutation of dihydropteroate synthase conferring low affinity for drug.

3. Destruction of sulfonamides

4. Importation of folate, negating inhibition of synthetic pathway.

Administered orally with good bioavailability (70-100%). Distributed widely to all tissues, including CSF.

Note: Sulfonadmides are not used to treat meningitis because they are bacteriostatic (and due to widespread resistance).

Acetylated in liver.

T_1/2 varies from 4-12hr for different sulfas.

Renally; concentrated in urine, which makes them good UTI antiseptics.

Variation in absorption, t_1/2. Particularly important when combined with other drugs because you need to match dosing interval (e.g. Bactrim = trimethoprim and sulfamethoxazole).

E.g. Sulfamethoxazole is not as well absorbed as sulfisoxazole, but its half life is almost twice as long.

Generally a safe drug.

1. Cystalline aggregates in urinary tract

Note: Primarily with older forms, though patients should always be well-hydrated.

2. Hematopoetic disorders (rare):

-- Acute hemolytic anemia in patients with G6PD deficiency: makes cell susceptible to oxidative damage, and sulfanamides are metabolized to oxidative species.

-- Bone marrow toxicity (agranulocytosis)

3. Hypersensitivity reactions

-- Stevens-Johnson syndrome: life-threatening skin disease (lesions all over body, ulcers on mucus membranes)

-- Skin rash, fever

4. Drug-drug interactions (oral anticoagulants, sulfonylurea hypoglycemic drugs, hydantoin anticonvulsants)

Because crystalline aggregates can form in urine.

Rarely used alone due to resistance. Used in combination with trimethoprim (Bactrim) to treat uncomplicated UTIs, respiratory infections.

Topical preparations are also used for acne, eye infections, and burn wounds.

Sulfonamides potentiate the activity of:

1. Oral anticoagulants (warfarin) - blood becomes too thin

2. Sulfonylurea hypoglycemic drugs (tolbutamide)

3. Hydantoin anticonvulsants (phenytoin)

Just know it mimics folic acid:

[image]

[image]

Like sulfas, broad spectrum: good activity against Gram+ and Gram-.

Prevents reduction of folic acid (dihydrofolate) by inhibitng dyhydrofolate reductase.

Enzyme selectivity: trimethoprim affinity for bacterial (E. coli) dihydrofolate reductase is 50,000 higher than for human enzyme. 

Note: Chemotherapeutic drug methotraxate also targets dihydrofolate reductase, but it's selectivity for bacterial enzyme is only 2X higher than human enzyme selectivity, so it is not safe for use as an antibiotic.

1. Mutation of dihydrofolate reducatase (major)

2. Overproduction of dihydrofolate reductase; drug can't bind all of it.

Administered orally (think about it - it's in Bactrim). Distributed to most body tissues, including CSF.

Bacteriostatic.

Minimal metabolism; t_1/2 = 11hr (like sulfamethoxazole, its Bactrim counterpart)

Excreted renally; acheives high concentrations in urine

They potentiate each others' function (synergy), allowing for lower doses of each drug.

Trimethoprim and sulfamethoxazole (TMP-SMX)

Note: Sulfas and trimethoprim are rarely used alone.

Clinical uses:

1. Uncomplicated UTIs

2. Respiratory tract infections

-- Otitis media in children

-- Prophylaxis of Pneumocystic jiroveci pneumonia in ADIS patients

3. Alternative treatment for Shigella (which is also treated by ciprofloxacin, IV ceftriaxone)