Selective toxicity

Chemotherapy

• use of drugs to eradicate pathogenic organisms or neoplastic cells

• based on principle of selective toxicity

• includes

• antimicrobial drugs, antibacterial, antiparasitic drugs, antineoplastic

Chemotherapy

• implies that a drug can influence one kind of living cell without affecting others even if they are in close proximity

• expressed by a drugs therapeutic index or ratio

• least toxicity to the host when they target unique differences

• most toxicity to host when they target common pathway

• works by finding vulnerable targets in micro-organisms that dont exist in eukaryotic cells

Selective toxicity

• indication of how selective the drug is in producing the desired effects

• prefer a high index

• as provides a general indication of the margin of safety of a drug

• measured by the ratio of the toxic dose/therapeutic dose

therapeutic index or ratio

• due to differences in absorption or biotransformation of the toxic substances

• e.g. tetracyclines inhibit protein synthesis in bacteria cells

• selectivity depends on accumulation of tetracyclines in bacterial cells

• bacteria uses active transport to uptake the drug and accumulates, this uptake is not in humans

• e.g. grisofulvin - antifungal - used to injure funghi in the keratinised cells such as microsporum - inhibits fungal mitosis and is deposited in keratin precursor cells, thus when they differentiate, drug is tightly bound and persists in the keratin - providing resistance to fungal invasion - 12 weeks

differences in distribution

• differences in the way in which essential metabolites are built up

• e.g. synthesis of folate - found in bacteria which allows DNA production and not humans, as lack dihydropterotate thus needed in diet,

• sulfonamides compete with PABA for dihydropteroate synthetase

differences in comparative biochemistry

• functionally identical in the host and parasite but structurally different

• dihydrofolate exists in both mammals and bacterial cells but is structurally different in terms of molecular weight, reaction kinetics, electrophoretic mobility, co-enzyme specificity, inhibitor response

analagous enzymes

• substances produced by an microorganism that in low concentrations will inhibit the growth or reproduction or will kill other organisms

• they differ based on physical, chemical, pharmacological, mOA, antimicrobial spectra

antibiotics

• funghi - penicillin, griseofulvin

• bacteria - bacitracin, polymyxin, gentamicin

• actinomycetes - streptomycin, chloramphenicol, tetracycline, erythromycin, vancomycin

sources of antibiotics

• chemical structure - beta lactams, tetracylines

• mechanism of action - nucleic acid synthesis, cell wall synthesis, folate synthesis, cell membrane disrupters

• bactericidal/bacteriostatic

• spectrum of activity - broad or narrow

antibiotic classification

• kills sensitive organisms so that the number of viable organisms falls rapidly after exposure to the drug

• penicillin

bactericidal

• inhibit the growth of bacteria, number of bacteria stays constant but does not kill it

• tetracycline

bacteriostatic

• active against a wide range of different microbes

• gram + and neg bacteria

• can include chlamydia, protozoa

• tetracycline

broad spectrum antibiotics

• active against relatively few pathogens

• nystatin - candida

• polymyxins - gram bacilli

• benzylpenicillin - gram + bacteria

narrow spectrum antibiotics

• Selectively toxic with minimal effects on the host.

• Easy to tolerate without complex drug regimen (long plasma half-life ie once a day

dosing)

• Bactericidal rather that bacteriostatic.

• Narrow spectrum rather than broad.

• Low costs (for producer and for consumer).

• Activity remains stable in storage and transport (shelf-life).

• Suitable bioavailability: must reach necessary concentrations in tissues or body sites (nails, prostate etc).

• Oral and parenteral dosage forms

• No interference with other drugs

characteristic of an ideal antibiotic