磺胺类药物及抗菌增效剂-20min.ppt

Antibacterials 磺胺与复方磺胺甲噁唑(Sulfonamides Cotrimoxazole) 北京协和医学院基础学院药理学系 郭 磊 History * 1932: Farben industries patented prontosil azo-dyes Gerhard Domagk proved efficacy in mice awarded Nobel prize in Physiology or Medicine in 1939 Pasteur institute: discovered sulfanilamide as the active component (bioactivation) First Aid Packet carried by U.S. Soldiers in World War II Mechanism of action p-aminobenzoic acid, PABA Sulfonamide base structure H2N COOH ★Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase. Science, 2012; 335 : 1110 Glutamic Acid Dihydrofolic acid 2 ATP Dihydropteridine Dihydropteroic acid Tetrahydrofolic acid Dihydropteroate synthase H2N COOH H2N SO2NH2 Antibacteral spectrum-Broad, bacteriostatic Gram-negative Gram-positive Others Nocardia spp Meningococcus Escherichia coli Streptococcus spp Pneumococcus S. aureus Salmonella Some protozoa Chlamydia trachomatis P. jirovecii T. gondii * nearly complete absorption, never given s.c or i.m A wide, PPB-10-95%, cross placenta BBB, CSF conc = Plasma conc D acetylation, metabolite inactive but toxic. M less soluble in acidic urine, precipitate- crystalluria E Pharmacokinetics Preparations and Clinical Uses Oral absorbable agents Sulfamethoxazole(磺胺甲噁唑) Sulfadiazine (磺胺嘧啶) Sulfadoxine(磺胺多辛) * Oral nonabsorbable agents Sulfasalazine(柳氮磺胺吡啶) Topical agents Sulfacetamide(磺胺醋酰) Mafenide(甲磺米隆) UTI, Parasitic diseases (combined with other antimicrobials)- malaria, toxoplasmosis, PCP ulcerative colitis, enteritis, other IBD Ophthalemic, infections of burn and wound Adverse effects * Crystalluria renal toxicity Hypersensitivity: rashes, stevens-johnson syndrome, drug fever Hemolytic anemia (in G6PD def) Sulfonamides increase the risk of kernicterus in newborns H2N CH2 OCH3 OCH3 OCH3 80 mg trimethoprim Cotrimoxazole (TMP-SMZ) Combination of trimethoprim + sulfamethoxazole H2N SO2NH N CH3 400 mg sulfamethoxazole O p-aminobenzoic acid Dihydrofolic acid Tetrahydrofolic acid Dihydrofolate synthetase Dihydrof