Chemotherapeutic Agents

1
Chemotherapeutic Agents

• Antibiotics
• Synthetic Drugs

2
History

• Ancient remedies
• ________ in egyptian times
• Quinine
• Ehrlich
• Salvarsan
• Domagk
• Dyes led to discovery of sulfa drugs
• Fleming
• ________________ mold

3
Properties of Antimicrobial Agents

• Selective Toxicity

4
Spectrum of Activity

• Narrow

• Broad

5
Drug Mechanisms of Action

• Inhibition of Cell Wall Synthesis
• Bacterial peptidoglycan
• Bacterial mycolic acid
• Fungal ß-glucans
• Disruption of Cell Membrane Function
• Bacterial membrane proteins - polymyxins
• Fungal ergosterol

6
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

7
Side Effects

• Toxicity
• Accumulation in kidneys
• Liver metabolism
• Allergy
• Disruption of Microflora

8
Resistance to Drugs

• Chromosomal mutations
• Plasmid borne resistance genes

9
Mechanisms of Drug Resistance

• Mutations in Target molecules
• Ribosome alterations
• Alterations in membrane permeability
• Transport pumps exclude drugs
• Enzyme development
• Penicillinases (ß lactamase)

10
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

11
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. ß lactamase effects

12
Limiting Drug Resistance

• Effective Drug Concentrations
• Simultaneous Drug Administration
• Synergism
• Antagonism
• Restricting Drug Prescriptions

13
Determining Microbial Sensitivities

• Disk Diffusion Method
• Dilution Method

14
Ideal Antimicrobial Attributes

• Solubility
• Selective toxicity
• Stable toxicity level
• Allergenicity

• Tissue stability
• Resistance Acquisition
• Shelf Life
• Cost

15
Antibacterials Cell Wall Target

• Penicillins
• Natural
• Semisynthetic
• Many Gram ves but Staphylococcus is mostly
  resistant
• Safe, but allergies in 1-5 of adults

16
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

17
Antibacterials Cell Membrane Target

• Polymyxins
• Topical use only
• Injure bacterial plasma membrane
• Used for Pseudomonas dermatitis

18
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)
• Legionnaires disease
• Bacteriostatic, may be used with other drugs
• Low toxicity

19
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 travellers diarrhea, anthrax

20
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

21
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

22
Antifungals

• Flucytosine
• Nucleoside analog
• Tolnaftate/ Terbinafine (Lamisil)
• Topicals, unclear mech. of action
• Superficial and cutaneous mycoses

23
Antivirals

• Nucleotide analogs
• Ribavirin anti-influenza, anti-herpes
• Zidovudine (AZT) anti-HIV
• Acyclovir anti-herpes

24
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

25
Antiprotozoan Drugs

• Quinine/derivatives
• Malaria
• Metronidazole
• Trichomonas/Giardia
• Pyrimethamine
• Toxoplasmosis
• Suramin
• Trypanosoma

26
Antihelminthic Drugs

• Niclosamide
• Tapeworms
• Affect CHO synthesis in worms
• Mebendazole
• Roundworms
• Blocks glucose uptake
• Piperazine
• Neurotoxin
• Pinworms and Ascaris
• Can cause convulsions in children