1SYNTHETIC ANTIBACTERIAL DRUGS:SULFONAMIDES, TRIMETHOPRIM AND QUINOLONESThomas M. Guenthner, Ph.D.Department of PharmacologyE-418 MSA, m.c. [email protected] Objectives:Sulfonamides:Know the basic sulfonamide structure and how it relates to PABAKnow in a general way the folate synthesis pathway, and where it is affected by sulfonamides andtrimethoprimKnow why they are selectively toxic to microorganismsKnow important factors of disposition, i.e. : rapid absorption, high degree of plasma protein binding,metabolism by acetylation, renal elimination.Know major toxicities and side effects (especially hematological and dermatological)How do bacteria become resistant?Compare mechanism of action of trimethoprim to that of SA'sWhat combinations are used?Why is this an effective combination?Know the major differences between short acting vs. long acting SA’s (disposition, toxicity)Know names of 4 major short acting and 1 long acting sulfonamideWhen would non-absorbable SA's be used?Know major uses for bacterial and non-bacterial infectionsQuinolones (oxacin drugs)What is their common structural feature?How do they work?Why are they selectively toxic?What side effects are known?What is their general clinical usefulness?Important Drugs:Sulfonamidessulfamethoxazolesulfisoxazolesulfadiazinesulfadoxine sulfacetamidesulfasalazineTrimethoprimCombinationsCotrimoxazole (Sufisoxazole + Trimethoprim)Cotrimazine (Sulfadiazine + Trimethoprim) (Canada only)Sulfadoxine + TrimethoprimFansidar (Sulfadoxine + Pyrimethamine)Quinolonesnalidixic acid (prototype)norfloxacinciprofloxacin2NH2NH2NH2NNNH2NH2SOHNH2OProntosilSulfanilamideTriaminobenzeneNH2SOHNH2OOHOCH2ONNOOCH3POOOOHOCH2ONNOOPOOOHdUMPdTMPN,N-MethylenetetrahydrofolicAcidPABA and PteridineDihydropteroic AcidDihydrofolic AcidDihydropteroate SynthetaseTetrahydrofolic AcidDihydrofolate ReductasePurines and PyrimidinesSulfonamidesTrimethoprimNN NNNH2OHCH2NHCONHCHCH2CCH2COHOHOOPteridinep-Aminobenzoic Acid Glutamic Acid(PABA)Folic AcidTetrahydrofolic Acid(Arrows indicate reduced double bonds)NN NHCH2CHNHNH2OHCH2NHCONHCHCH2CCH2COHOOHON,N-Methylenetetrahydrofolic Acid(Arrow indicates transferable methylene group)NN NHCH2CHNNH2OHCH2NCONHCHCH2CCH2COHOOHOCH2Thomas 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.3NH2SNH2OOHNH2COOHSulfanilamidePABASulfanilamideSO OHNH2NH2SO OHNHNH2COCH3Acetyl CoAN-AcetylsulfanilamideSulfonamides 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 inactive4CNH2OCH2CH2NCH2CH3OCH2CH3CNH2OOHH2OProcainep-Aminobenzoic AcidOHCH2CH2NCH2CH2CH3CH3ELIMINATIONMajority 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)5NNCH2OOOCH3CH3CH3NH2N2TrimethoprimTRIMETHOPRIM -- 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
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