Selective Toxicity Flashcards
3 principles of selective toxicity?
- Differences between the biochemistry of host tissues and infectious agents
- Differences between normal and cancer cells (e.g., at the level of metabolic pathways between normal and tumouric cells or invading species)
- Often there is a high degree of discrimination [ratio of therapeutic to toxic effects is/(must be) wide]
Describe the peptidoglycan bacterial cell wall and what each portion consists of
Sugars and aas: semi-rigid, tight-knit molecular complex; enables lysis resistance
Polysaccharide portion: NAG and NAM
Protein portion: short aa chains that link polysac layers juntos to form cross bridges by NAM
Explain how lipopolysacs are a major component of gram negative bacteria and what they are made of
LPS: major component of Gram –ve bacteria; regulates structural integrity, protects from chemical injury
Has a lipid and a polysaccharide portion:
Lipid A (endotoxin) in lipid portion triggers fever and shock
Describe the action of transpeptidase
Which drug targets transpeptidase?
Transpeptidase cross-links the peptides coming off NAM
Connects each row of sugars and peptidog layer w its adjacent row/layer→ tight-knit molecular complex
Penicillin inhibits transpeptidation, which activates autolytic enzymes, killing the bacteria
Describe the moa of Aminoglycosides and give 2 examples
Aminoglycosides, e.g. streptomycin, gentamicin
Relate the theraputic index with chemotherapy
Therapeutic index = 1 (means that the conc that causes toxicity is = conc that causes cancer cell death)
The therapeutic index should be wide, not narrow
All dividing cells affected → huge side effects
Draw out the pathway of folate synthesis
Describe the moa of methotrexate as an anti tumour agent
Does it also affect normal human cells?
Binds strongly to dihydrofolate reductase. This inhibits tetrahydrofolic acid synthesis
Methotrexate=folic acid analogue, but acts a false building block
So it inhibits nucleotide synthesis, prevents cancer cell division
Human cells also need FA, but use diet FA-> less affected by methotrexate at therapeutic doses
Describe the moa of sulphonamides
Bacteria source PABA extracellularly to make folic acid
Sulphonamides mimic and thus inhibit PABA, block it from binding to pteridine residue–> can’t make FA
Sulfonamide folate complex (pseudofolate) kills bacteria
Give 3 examples of sulphonamides
(prontosil, sulphamethoxazole, dapsone)
Describe the moa of zidovudine against HIV
Zidovudine (ZDV): thymidine analogue which lacks OH
Prodrug is phosphorylated to active ZDVTP
This binds HIV reverse transcriptase bc of higher affinity than endogenous thymine
ZDVTP incorporated into growing DNA strand and terminates synthesis due to there being Azido (N3 grp) instead of OH
Hay chain termination, new cells don’t get infected
Give an example of when antifolates can target protozoal infections
Include a drug example
Antifolates in malaria treatment target v late stage of asexual repro
Slow-acting, so don’t give in critical sitch (time is of essence)
Eg proguanil has intrinsic antimalarial activity – ability to evoke a max. response after binding to a receptor
Describe the mechanism of action of proguanil
Converted into active triazine metabolite (cycloquanil)
This inhibits DHFR and thymidylate synthase of sensitive parasites
Folate co-factors and DNA synthesis inhibited
Affects primary liver and asexual RBC stages= this is before symptoms start so is important in prophylaxis
Kills acute P. vivax malaria, but no effects on latent P.vivax ( (hypnozoites)
Gametocytes unaffected; but fertilised gametes in the gut of the mosquito do not develop
Give examples, indications and moa of antifungal agents
Amphotericin B (lipophilic): broad-spectrum, for serious systemic infections.
Amphotericin B interacts hydrophobically w ergosterol in fungal cell membrane and forms pores in it
Creates transmembrane channel, electrolytes leak out
Selectively toxic – humans have cholesterol, not ergosterol
Nystatin: thrush (oral and vaginal)
