Sulfa & Sulfonamide Drugs: Action, Resistance, Pharmacokinetics, Adverse Reactions, Quizzes of Pharmacology

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Sulfa drugs -Mechanism of action

sulfa substitutes for PABA which bacteria use to make folic acid sulfa drugs are analogs of PABA sulfa inhibits dihydropteroate synthase in bacteria TERM 2

Sulfa drugs -Activity

DEFINITION 2 poor against anarobes good for a wide range of organisms gram neg and pos norcardia Chlamydia some enteric (E. coli and klebsiella, salmonella, shigella,enterobacter) TERM 3

Sulfa drugs - Resistance

DEFINITION 3 mutations in the bacteria that cause (a) increased synthesis of PABA (b) produce the synthesizing enzyme for folic acid that has reduced affinity for sulfa drugs (c) reduced permeability in cell wall to sulfa drugs TERM 4

Sulfa Drugs - Pharmacokinetics

DEFINITION 4 (a) oral absorbable (b) oral nonabsorable (c) topical TERM 5

Sulfa Drugs - ADRs

DEFINITION 5 (a) allergy (b) Stevens Johnson syndrome (rare, < 1%)

Sulfa Drugs - Combination to prevent

resistance

(a) trimethoprim inhibit bacterial dihydrofolic acid reductase TERM 7

Sulfa Drugs - Drug Actions

DEFINITION 7 (a) bacteriostatic all sulfa drugs except combination (b) bactericidal combination with trimethoprim TERM 8

Sulfonamide -Structure / Source

DEFINITION 8 Prontosil biotransformed in the liver to sulfonamide Prontosil is a prodrug converted in vivo to sulfonamide The para-NH2 is essential for antibiotic activity. Most sulfa drugs made from substitutions in the sulfur portion of the molecule. TERM 9

Sulfonamide - Mechanism of Action

DEFINITION 9 Bacteria have unique synthetic pathway used to produce folic required for DNA synthesis. Synthesis starts with p-amino benzoic acid (PABA). In bacteria (not mammals) folic acid is synthesized from PABA Sulfa substitutes for PABA and blocks folic acid synthesis. Folic acid loss results in impaired DNA synthesis. Bacteriostatic. TERM 10

Sulfonamide - Pharmacokinetics

DEFINITION 10 F = 70 -100 % following po dose Peak Cp levels in 2 - 6 h post po dose Drug distributes into most tissues including brain and CSF. Major biotransformation is through acetylation. Most metabolites are inactive

Sulfonamide - ADRs

Crystal formation (precipitation) in urinary tract. Drink large amounts of water, keep urine alkaline. sulfisoxazole. Hemolytic anemia found in G6PD deficiency. Sulfadiazine incidence is 0.05%. Agranulocytosis following sulfadiazine, 0.1% Aplastic anemia (suppression of bone marrow) rare, Hypersensitivity dermatitis (rashes), fever, pruritus. sulfisoxazole incidence 2% TERM 12

Sulfonamide - Clinical uses

DEFINITION 12 Urinary tract infections, sulfisoxazole Nocardiosis (Norcardia, soil bacterium) pneumonia, 6 months po sulfasoxazole. Toxoplasmosis, pyrimethamine + sulfadiazine combination. Broad Spectrum: Both Gram Pos/Neg including E. coli, Klebsiella, Salmonella, Enterobacter TERM 13

Sulfonamide - Mechanism of resistance

DEFINITION 13 Gene mutation at the chromosome level Through random mutations Lower the binding affinity of the dihydropteroate synthase for sulfa drug Develop an active transport in the cell wall to remove sulfa drug Develop an alternate pathway for synthesis of folic acid Increase the synthesis of PABA to overcome block by Sulfa. Resistant Staph produce 70x more PABA compared to non- resistant Staph TERM 14

Trimethoprim

DEFINITION 14 Specific inhibitor of bacterial dihydrofolate reductase Combined with sulfamethoxazole TMP:SMZ ratio 1:20 in blood to provide improved efficacy. TMP is 20x more active against most bacteria compared to SMZ. Target for TMP is second enzyme in folic acid pathway. TERM 15

TMP:SMZ Combination

DEFINITION 15 Bacteria synthesize Folic acid, its vitamin in humans. Humans do not have enzyme target of SMZ. Bacteria can not absorb Folic acid from patient tissue fluids (EXCEPT Enterococci). TMP target, dihydrofolate reductase is found in humans but TMP has 10 000 greater affinity for bacterial enzyme compared to human enzyme

Trimethoprim/Sulfamethoxazole

Also called cotrimoxazole. Mostly used for urinary tract infections but high distribution into tissues after po dosing makes it useful for lower extremity infections. Bacteriostatic against all organisms tested. Good for staph and MRSA Used to treat Pneumocystis pneumonia in AIDS patients. Allergic reactions possible from mild rash to Stevens-Johnson Syndrome (systemic skin disease)Hemolytic anemia in patients with G6PD deficiency TERM 17

Sulfisoxazole

DEFINITION 17 oral used only for lower UTI infections TERM 18

Sulfadiazine

DEFINITION 18 oral first line of therapy for toxoplasmosis when combined with pyrimethamine TERM 19

Trimethoprim

DEFINITION 19 oral used only for lower UTI infections may be safely prescribed to patients with sulfonamide allergy TERM 20

Pyrimethamine

DEFINITION 20 oral first line therapy for toxoplasmosis when combined with sulfadiazine coadminister with leucovorin to limit bone marrow toxicity

Pyrimethamine-sulfadoxine

oral second line malaria treatment