Transcript Document
Chemotherapeutic Agents Antibiotics Synthetic Drugs 1 History Ancient remedies – ________ in egyptian times – Quinine Ehrlich – Salvarsan Domagk – Dyes led to discovery of sulfa drugs Fleming – ________________ mold 2 Properties of Antimicrobial Agents Selective Toxicity 3 Spectrum of Activity Narrow Broad 4 Drug Mechanisms of Action Inhibition of Cell Wall Synthesis – Bacterial peptidoglycan – Bacterial mycolic acid – Fungal β-glucans Disruption of Cell Membrane Function – Bacterial membrane proteins - polymyxins – Fungal ergosterol 5 Drug Mechanisms of Action Inhibition of Protein Synthesis – 70S vs 80S protein synthesis (bacteria) Inhibition of Nucleic Acid Synthesis – Unique bacterial or viral enzymes may be affected Antimetabolites – Essential biochemical pathways are blocked, mostly bacteria, e.g. Folate synthesis inhibition by sulfa drugs 6 Side Effects Toxicity – Accumulation in kidneys – Liver metabolism Allergy Disruption of Microflora 7 Resistance to Drugs Chromosomal mutations Plasmid borne resistance genes 8 Mechanisms of Drug Resistance Mutations in Target molecules – Ribosome alterations Alterations in membrane permeability – Transport pumps exclude drugs Enzyme development – Penicillinases (β lactamase) 9 Mechanisms of Drug Resistance Enzyme Activity Changes – PABA binding much greater than sulfa drug binding Alterations in Anabolic Pathways – Uptake of folic acid rather than synthesis 10 Generations of Drugs First/Second/Third Line Drugs – Used as evolving resistances limit the usefulness of original drugs Cross Resistance – Similar drugs are all broken down by the resistant microbe, e.g. β lactamase effects 11 Limiting Drug Resistance Effective Drug Concentrations Simultaneous Drug Administration • Synergism • Antagonism Restricting Drug Prescriptions 12 Determining Microbial Sensitivities Disk Diffusion Method Dilution Method 13 Ideal Antimicrobial Attributes Solubility Tissue stability Selective toxicity Resistance Acquisition Stable toxicity level Shelf Life Allergenicity Cost 14 Antibacterials — Cell Wall Target Penicillins – Natural – Semisynthetic – Many Gram +ve’s but Staphylococcus is mostly resistant – Safe, but allergies in 15% of adults 15 Antibacterials — Cell Wall Target Cephalosporins – Work similarly to penicillins – Safe but more expensive Carbapenems – Work like penicillins, more stable – Broader spectrum – Still effective against Staphylococcus 16 Antibacterials — Cell Membrane Target Polymyxins – Topical use only – Injure bacterial plasma membrane – Used for Pseudomonas dermatitis 17 Antibacterials — Protein Synthesis Inhibition Aminoglycosides (*mycin) – Streptomycin original • Toxicity, deafness • Chromosomal mutation causing resistance Tetracyclines (Aureomycin) – Soluble – Good for obligate intracellulars – Cause tooth discoloration in children / fetal bone malformations Chloramphenicol – Tocicity makes it a drug of last choice in U.S.A. Macrolides (Erythromycin) – Legionnaire’s disease – Bacteriostatic, may be used with other drugs – Low toxicity 18 Antibacterials — Nucleic Acid Synthesis Inhibition Rifampin – Blocks RNA transcription – Red colored, v. soluble – Used against M. tuberculosis, N. meningitidis – Many negative interactions with other meds. Quinolones – Inhibit DNA gyrase – Used in traveller’s diarrhea, anthrax 19 Antibacterials — Antimetabolites Sulfonamides – Block folate synthesis Isoniazid – Interferes with vitamin B conversions Ethambutol – Similar to Isoniazid, often used together Nitrofurans – Interfere with KREbs cycle/ETC – Used in UTIs – Veterinary topical agent 20 Antifungals Imidazoles (Clotrimazole) – – – – Disrupt ergosterol synthesis Some cross-reactivity with cholesterols Mostly for cutaneous and superficial conditions Ketoconazole – safe for oral administration Polyenes (Amphotericin B) – Ergosterol targeted – Systemic infections only, severe side effects Griseofulvin – Impairs mitotic spindle formation – Oral admin, for cutaneous and superficial mycoses 21 Antifungals Flucytosine – Nucleoside analog Tolnaftate/ Terbinafine (Lamisil) – Topicals, unclear mech. of action – Superficial and cutaneous mycoses 22 Antivirals Nucleotide analogs – Ribavirin anti-influenza, anti-herpes – Zidovudine (AZT) anti-HIV – Acyclovir anti-herpes 23 Antivirals Amantidine/Rimantidine – Prevents Influenza A virus penetration – Ataxia/insomnia in many elderly Interferons – Promote release of antiviral proteins in uninfected cells Immunoenhancers – T lymphocyte stimulators 24 Antiprotozoan Drugs Quinine/derivatives – Malaria Metronidazole – Trichomonas/Giardia Pyrimethamine – Toxoplasmosis Suramin – Trypanosoma 25 Antihelminthic Drugs Niclosamide – Tapeworms – Affect CHO synthesis in worms Mebendazole – Roundworms – Blocks glucose uptake Piperazine – Neurotoxin – Pinworms and Ascaris – Can cause convulsions in children 26