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