CSIM2.4: PRINCIPLES OF SELECTIVE TOXICITY
20/01/09
LEARNING OUTCOMES
Classify the major antimicrobial drug groups in terms of their mechanism of action
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Chemotherapy is defined as using chemicals to selectively destroy infectious agents and malignancies
There are two methods of selective targeting of these agents by antimicrobials:
o Selective toxicity – drugs designed to be toxic to pathogens but non-toxic to the host
o Distributional selectivity – broadly toxic drugs that are specifically distributed to targets
Antimicrobial agents such as antibiotics can have two main effects on bacteria:
o Bacteriostatic – prevent or inhibit multiplication
o Bactericidal – actively destroy the organisms
These effects can be achieved through targeting a number of different bacterial cellular processes:
o Cell wall synthesis – penicillins and cephalosporins
o Protein synthesis – tetracycline and chloramphenicol
o DNA replication – ciprofloxacin
o RNA transcription – rifampicin
o Metabolic pathways – sulphonamides
PENICILLINS AND CEPHALOSPORINS
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Penicillins and cephalosporins are bactericidal antibiotics utilising β-lactam structures
o Inhibit transpeptidation reactions crucial to peptidoglycan components of cell wall formation
o Due to protective effect of outer membrane generally not so effective against gram-negatives
o Some bacteria have plasmid-encoded β-lactamases that render them ineffective
Penicillins are more commonly used as broad-spectrum antibiotics to treat most infections
o Relatively large volume of distribution but do not normally penetrate the CSF
o Broad-spectrum but more effective against gram-positives e.g. amoxycillin
o Renal clearance through active tubular secretion with half life of 30 to 80 minutes
o May cause hypersensitivity reactions and mild diarrhoea from disturbance of the gut flora
Cephalosporins are structurally similar to penicillins but are generally reserved for serious infections
o Penetrate the CSF so can be used to treat some bacterial meningitis infections
o More effective against gram-negatives than penicillins e.g. cefuroxime
o Similar clearance and hypersensitivity reactions to penicillins
SULPHONAMIDES
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Sulphonamides are bacteriostatics that inhibit folate synthesis in the production of DNA
o First used in 1933 but rarely feature in modern-day therapeutics
o Many bacteria have developed resistance against them
o Used to treat Pneumocystis carinii (protozoal infection) in immunocompromised patients
o Often prescribed with trimethoprim as an adjunct which targets the same pathway