Page 1Page 2Page 3Page 4Page 5Page 6Page 71Thomas M. Guenthner, Ph.D.Department of PharmacologyE-418 MSA, m.c. [email protected] ANTIBACTERIAL DRUGS:SULFONAMIDES, TRIMETHOPRIM AND QUINOLONESAntibiotics are, by definition, natural products biosynthesized by microorganisms that are toxicto other species of microorganisms. Sulfonamides, trimethoprim and quinolones are man-made drugs and are therefore, strictly speaking, not antibiotics, but synthetic antibacterialagents.Sulfonamides were the first successful selectively toxic antibacterial drugs. Prontosil (seebelow) was discovered by Gerhard Domagk in 1936, and used to successfully treat puerperalsepsis (childbirth fever) in London. Prontosil is converted by cellular enzymes to sulfanilamide,the prototype of all sulfonamides.MECHANISM OF SULFONAMIDE TOXICITY:Sulfonamides interfere with bacterial folic acid synthesis. Folic acid is a 1-carbon donor,required for the de novo biosynthesis of purines and pyrimidines.2Sulfonamides prevent synthesis of dihydropteroic acid, a folic acid precursor. They mimic para-aminobenzoic acid and block dihydropteroate synthetase.Sulfonamides are bacteriostatic drugs; they stop DNA synthesis and prevent cell division.SELECTIVE TOXICITY:Sulfonamides are selectively toxic to bacteria because folate synthesis is obligatory in bacteria;eukaryots obtain folate preformed in the diet. DISPOSITION OF SULFONAMIDESABSORPTIONNormally given orally or applied topically; some soluble salts given parenterallyReadily absorbed from GI tract, achieving peak blood levels in 30 min, except for thosedesigned to remain in intestine (see below)DISTRIBUTIONHighly plasma protein bound; will displace other bound drugs and bilirubin. Sulfonamides givenin late term can induce neonatal jaundiceDistributed in total body water, readily enter CNS, synovial and ocular fluid, fetal circulation andmilkMETABOLISM Primarily by acetylation at free amino group; some oxygenation of aromatic ring and/or sidechain.Acetylated metabolites inactive3ELIMINATIONMajority eliminated unchangedConcentrated in urine; useful in urinary tract infections; older sulfonamides actually formedcrystals in tubules and ureterTOXICITYRelatively low CTI (relative to most antibiotics); toxicity occurs in about 5% of patients1) Renal toxicity -- Older sulfonamides crystallized in urine (doses of 8-10 grams of drug givendaily)Risk minimized with advent of newer, more soluble forms; still prudent to give extrafluids2) Blood dyscrasias -- Hemolytic anemia, agranulocytosis, aplastic anemia, thrombocytopeniaImmune response to sulfonamide hapten?3) Dermal toxicity -- rashes, pruritus, erythema, exfoliative dermatitis (Stevens-Johnsonsyndrome can be fatal)Again probably an immune response4) Other rare but serious side effects -- hepatitis, drug-induced fever5) Less serious side effects -- headache, gi discomfort (nausea, loss of appetite)BACTERIAL RESISTANCE: Bacteria become resistant to sulfonamides by:1) Synthesizing large amounts of PABA. It takes 5,000 to 25,000 molecules ofsulfonamide to compete with 1 molecule of PABA. Resistant cells synthesize PABA at70x the rate of normal cells.- PABA from pus can compete with sulfonamides (also preformed nucleotides)- PABA can be produced by hydrolysis of procaine2) Bacterial dihydropteroate synthetase is altered so that it no longer is inhibitable bysulfonamides3) Bacteria utilize "salvage pathway" which bypasses 1-carbon synthesis of basesGenes for sulfonamide resistance are transferred by R-plasmids. Generally, one resistancephenotype will confer resistance to all sulfonamides. Cross-resistance to sulfonamides andother drugs also occurs (multiple genes on same plasmid)4TRIMETHOPRIM -- Introduced in 1969 as a combination with sulfonamides; synergizessulfonamide activity and minimizes bacterial resistanceCotrimoxazole (Bactrim, Septra): 1 part trimethoprim/5 parts sulfamethoxazoleCotrimazine: 1 trimethoprim/ 5 sulfadiazineBlocks bacterial dihydrofolate reductase (similar to methotrexate); acts at a different step of thesame folate synthetase pathway inhibited by sulfonamides100,000x higher affinity for bacterial than mammalian enzymeNot only provides synergy with sulfonamides, but because 2 compounds act at different pointson same pathway, chances of resistance developing are a geometric product (much smaller)Synergy apparent in treatment of non-bacterial respiratory infections, but not absolute; foruncomplicated UTI, trimethoprim alone is just as effective as combination.INDIVIDUAL SULFONAMIDES:Historically classified as short-acting, long-acting and non-absorbed, according to their rates ofabsorption and distribution. All structurally similar, except for substituents on N1 nitrogen; substitution of N4 nitrogenterminates activity (acetylation site)5 Sulfisoxazole, Sulfamethoxazole, Sulfadiazine: short acting sulfonamides; rapidly absorbedand excreted3 most commonly prescribed sulfonamides, last 2 in combination with trimethoprim.Sulfadimethoxine: Long-acting sulfonamide (poorly excreted); quite toxic but useful inprotozoal infections, especially in AIDS patientsSilver salt of Sulfadiazine, topical use in burns.Sulfacetamide, topical use in eye, due to low irritation.Poorly absorbed sulfonamides: e.g. Phthalylsulfathiazole; used to sterilize the gut prior tobowel surgery (aminoglycosides preferred). Non-absorbed, gut flora cleave N4 group.Dapsone: Antileprosy drug. Not a sulfonamide in strict sense, but a related compound(sulfone) with same mechanism of actionCLINICAL USES OF SULFONAMIDESLimited due to resistance problems, but addition of trimethoprim has greatly extended theirusefulness.6Useful against most (non-resistant) Gram+ and many Gram- bacteriaCommonly used (normally as cotrimoxazole) in lower urinary tract infections, particularly due toE. Coli, and prostatitis; trimethoprim alone also used; quinolones are replacing them as drug ofchoice.Once commonly used in bacterial dysentery due to shigella and salmonella; resistance limiteduse, but became useful again as combination with trimethoprimSometimes used in meningococcal infections; other antibiotics preferred.Topical sulfonamides used in eye (conjunctivitis) and prophylactically for burnsProtozoal infections; very important role for sulfonamides and trimethoprim, since theseinfections respond poorly to antibiotics- Chlamydia, nocardia, toxoplasma- chloroquine resistant plasmodium falciparum- Pneumocystis carinii in immune
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