SYNTHETIC ANTIBACTERIAL DRUGS SULFONAMIDES TRIMETHOPRIM AND QUINOLONES Thomas M Guenthner Ph D Department of Pharmacology E 418 MSA m c 868 996 2558 tmg uic edu Knowledge Objectives Sulfonamides Know the basic sulfonamide structure and how it relates to PABA Know in a general way the folate synthesis pathway and where it is affected by sulfonamides and trimethoprim Know why they are selectively toxic to microorganisms Know 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 s What 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 sulfonamide When would non absorbable SA s be used Know major uses for bacterial and non bacterial infections Quinolones 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 Sulfonamides sulfamethoxazole sulfisoxazole sulfadiazine sulfadoxine sulfacetamide sulfasalazine Trimethoprim Combinations Cotrimoxazole Sufisoxazole Trimethoprim Cotrimazine Sulfadiazine Trimethoprim Canada only Sulfadoxine Trimethoprim Fansidar Sulfadoxine Pyrimethamine Quinolones nalidixic acid prototype norfloxacin ciprofloxacin 1 Thomas M Guenthner Ph D Department of Pharmacology E 418 MSA m c 868 996 2558 tmg uic edu SYNTHETIC ANTIBACTERIAL DRUGS SULFONAMIDES TRIMETHOPRIM AND QUINOLONES Antibiotics are by definition natural products biosynthesized by microorganisms that are toxic to other species of microorganisms Sulfonamides trimethoprim and quinolones are manmade drugs and are therefore strictly speaking not antibiotics but synthetic antibacterial agents Sulfonamides were the first successful selectively toxic antibacterial drugs Prontosil see below was discovered by Gerhard Domagk in 1936 and used to successfully treat puerperal sepsis childbirth fever in London Prontosil is converted by cellular enzymes to sulfanilamide the prototype of all sulfonamides O O N H2 N N S NH2 S H2 N NH2 OH NH2 H2 N NH2 OH NH2 Prontosil Sulfanilamide Triaminobenzene 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 p Aminobenzoic Acid PABA Pteridine OH PABA and Pteridine H2N H2 C N N N NH H N C N O O Sulfonamides Glutamic Acid CH C H2 C O C CH2 OH H2 C O Dihydropteroate Synthetase O P Folic Acid Dihydropteroic Acid OH N H2N N O O N H CH H2 C O HO H N C H2 C CH O N N Methylenetetrahydrofolic Acid C CH2 OH O C HO O CH3 Tetrahydrofolic Acid Tetrahydrofolic Acid H2 C O Arrows indicate reduced double bonds O P O O O Purines and Pyrimidines H2C OH N N N H CH H2 C N CH2 C H N CH H2 C O C CH2 OH O C HO O N N Methylenetetrahydrofolic Acid Arrow indicates transferable methylene group 2 N N O O HO dTMP H2N N O O NH CH2 Dihydrofolate Reductase N N dUMP H N Dihydrofolic Acid Trimethoprim H OH Sulfonamides prevent synthesis of dihydropteroic acid a folic acid precursor They mimic paraaminobenzoic acid and block dihydropteroate synthetase NH2 NH2 H2N S OH C OH O O Sulfanilamide PABA 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 SULFONAMIDES ABSORPTION Normally given orally or applied topically some soluble salts given parenterally Readily absorbed from GI tract achieving peak blood levels in 30 min except for those designed to remain in intestine see below DISTRIBUTION Highly plasma protein bound will displace other bound drugs and bilirubin Sulfonamides given in late term can induce neonatal jaundice Distributed in total body water readily enter CNS synovial and ocular fluid fetal circulation and milk METABOLISM Primarily by acetylation at free amino group some oxygenation of aromatic ring and or side chain Acetylated metabolites inactive O NH2 HN C CH3 Acetyl CoA O S OH NH2 Sulfanilamide O S OH NH2 N Acetylsulfanilamide 3 ELIMINATION Majority eliminated unchanged Concentrated in urine useful in urinary tract infections older sulfonamides actually formed crystals in tubules and ureter TOXICITY Relatively low CTI relative to most antibiotics toxicity occurs in about 5 of patients 1 Renal toxicity Older sulfonamides crystallized in urine doses of 8 10 grams of drug given daily Risk minimized with advent of newer more soluble forms still prudent to give extra fluids 2 Blood dyscrasias Hemolytic anemia agranulocytosis aplastic anemia thrombocytopenia Immune response to sulfonamide hapten 3 Dermal toxicity rashes pruritus erythema exfoliative dermatitis Stevens Johnson syndrome can be fatal Again probably an immune response 4 Other rare but serious side effects hepatitis drug induced fever 5 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 of sulfonamide to compete with 1 molecule of PABA Resistant cells synthesize PABA at 70x the rate of normal cells PABA from pus can compete with sulfonamides also preformed nucleotides PABA can be produced by hydrolysis of procaine O H2 C C O H 2N H2C CH3 N C H2 CH2 H2O O H 2N H2 C C OH CH3 HO H 2C CH3 N C H2 CH2 CH3 p Aminobenzoic Acid Procaine 2 Bacterial dihydropteroate synthetase is altered so that it no longer is inhibitable by sulfonamides 3 Bacteria utilize salvage pathway which bypasses 1 carbon synthesis of bases Genes for sulfonamide resistance are transferred by R plasmids Generally one resistance phenotype will confer resistance to all sulfonamides Cross resistance to sulfonamides and other drugs also occurs multiple genes on same plasmid 4 H3C O CH3 N 2N N O CH2 NH2 O H3C Trimethoprim TRIMETHOPRIM Introduced in 1969 as a combination with sulfonamides synergizes sulfonamide activity and minimizes bacterial resistance Cotrimoxazole Bactrim Septra 1 part trimethoprim 5 parts sulfamethoxazole Cotrimazine 1 trimethoprim 5
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