Notes for Pharmacology II practicals MUDr. Alena Máchalová Ph.D., PharmDr. Ondřej Zendulka, Ph.D.; Mgr. Jana Merhautová This study material is exclusively for students of general medicine and stomatology in Pharmacology II course. It contains only basic notes of discussed topics, which should be completed with more details and actual information during practical courses to make a complete material for test or exam studies. Which means that without your own notes from the lesson this presentation IS NOT SUFFICIENT for proper preparation for neither tests in practicals nor the final exam. ANTIBACTERIAL CHEMOTHERAPEUTICS

Classification sulfonamides pyrimidines quinolones (nitro)imidazoles nitrofurans

SULPHONAMIDES structural analog of PABA competitive inhibitor of the enzyme necessary for folic acid synthesis PABA dihydropteorate synthetase dihydrofolic acid dihydrofolate reductase tetrahydrofolic acid (FH 4 ) nucleotides DNA

SULPHONAMIDES broad-spectrum, bacteriostatic I:respiratory and urinary infections, toxoplasmosis, nocardiosis, GIT inflammations, dermatology AE:kidney damage allergic reactions, phototoxicity hematotoxicity hyperbilirubinemia sulfamethoxazole (combination with trimethoprim) sulfadiazine (including Ag + salt, derm.) sulfasalazine (ulcerous colitis) sulfacetamide (ophtal.) sulfathiazole (gyn.)

TRIMETHOPRIM (pyrimidines) Bacteriostatic effect, similar spectrum MoA: dihydrofolatereductase inhibition (bacterias are more sensitive than human cells) I: therapy of uncomplicated urine infections, prostatitis, travelers diarrheas AE: nausea, vomiting, rash Combination with sulfamethoxazole 1:5 = cotrimoxazole I: intestinal infections caused by salmonela, prostatitis, bronchitis, sinusitis, urinary tract infections, pneumonia, gonorrhea, typhus PABA dihydropteorate synthetase dihydrofolic acid dihydrofolate reductase tetrahydrofolate nucleotides DNA

QUINOLONES bactericidal classification: non- fluorinated and fluoroquinolones, generation more modern drugs have broad spectrum MoA: –Inhibition of bacterial DNA gyrase and/or topoizomerase II = inhibition of DNA transcription –Effect depends on concentration, post-antibiotic effect PK: nonabsorbable complexes with food (similar to TTC) I: urinary, respirátory infections, prostatitis etc. AE: (nausea, vomiting, neurotoxicity, cramps, dizziness, headache, painful joints, damage of tendons, fototoxicity CI: gravidity, children (inhibition of cartilage growth)

Quinolones generations Generation Drug I.nalidixic acid, oxolinic acid, pipemidic acid II. norfloxacine, ciprofloxacine, ofloxacine, pefloxacine, lomefloxacine, levofloxacine III. sparfloxacine, gatifloxacine, tosufloxacine, pazufloxacine IV. moxifloxacine, trovafloxacine, gemifloxacine, sitafloxacine

Quinolones of the 1st generation G-, not Pseudomonas Effective concentration only in urine I: Uroinfections E. coli

Quinolones of the 2nd generace G-, some G+, including Pseudomonas I: uroinfections, GIT infections, respiratory infections, infections of the eye (topical administration) fluorinated

Quinolones of the 3rd generation G+ and G-, mycobacteria G+ and G-, anaerobes Reserved chemotherapeutics for severe infections (MRSA is today often resistant!) Quinolones of the 4th generation

(NITRO)IMIDAZOLES MoA: inhibition of DNA replication I: infections caused by anaerobes (vaginal, intestinal, oral), infection caused by Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia (intestinalis), Helicobacter pylori eradication AE: metallic taste in mouth nausea, vomiting, diarrhea CNS disturbance (dizziness, insomnia, depressions) disulfiram reaction Metronidazole Ornidazole Tinidazole

NITROFURANS G+ and G- bacteria, anaerobes, protozoa Therapeutic concentrations only in urine → uroinfections Topically in dermatology, gynekology MoA: binding to DNA, ribosomes, damage of metabolic pathways leading to production of superoxides and other reactive oxygen molecules AE: GIT intolerance, allergy blood count changes (thrombocytopenia, neutropenie, hemolytic anemia) pneumonia, lung fibrosis hepato- and neurotoxicity in long-term therapy Nitrofurantoin Nifuratel – antimycotic Nifuroxazide – intestinal antiseptic