95 - Selective Toxicity of Drugs Flashcards
Examples of selectivity
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Species-level toxicity
Cell-level selectivity
Organ-level selectivity
Examples of antimicrobials against bacterial ribosomes
Tetracyclines, aminoglycosides
Sulfonamides
Target bacterial folic acid metabolism.
Resembles para-amino benzoic acid (part of folic acid)
Bacterial folate metabolism
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PABA (para-amino benzoic acid) converted to folate.
Folate converted to tetrahydrofolate.
Tetrahydrofolate converted to precursors to nucleotides.
Example of syndergy between antimicrobials
Sulfonamides (inhibit PABA -> folate), trimethoprim (inhibit folate -> tetrahydrofolate)
Example of synergy between antimicrobials
Sulfonamides (inhibit PABA -> folate), trimethoprim (inhibit folate -> tetrahydrofolate)
Enzyme that sulfonamides interfere with
Dihyropteroate synthase
Enzyme that trimethoprim interferes with
Dihyrofolate reductase
What does methotrexate resemble?
Folic acid
Effects of methotrexate
Inhibits purine synthesis.
Inhibits DTMP synthesis.
Anti-cancer agent.
Human folic acid metabolism
Folate to tetrahydrofolate (through dihydrofolate reductase)
Tetrahydrofolate to precursors of nucleotides (EG: thymidylate).
What does methotrexate inhibit?
Dihydrofolate reductase.
Functions of methotrexate
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✦ Inhibits human dihydrofolate reductase
(inactive in bacteria)
✦ Cytotoxic anticancer agent (large doses)
✦ Cytotoxic immunosuppressant (lower doses,
rheumatoid arthritis)
Functions of methotrexate
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✦ Inhibits human dihydrofolate reductase
(inactive in bacteria)
✦ Cytotoxic anticancer agent (large doses)
✦ Cytotoxic immunosuppressant (lower doses,
rheumatoid arthritis)
Risk of methotrexate
Known teratogen
When is methotrexate prescribed in pregnant women?
To terminate an ectopic pregnancy (can abort)
How often is methotrexate taken?
Once per week (high risk of overdose, overdose is nasty)
*Kidney ion transfer
KIDNEY ION
*Kidney ion transfer
KIDNEY ION
Active driver of ion transport in the kidneys
Na/K ATPase
Active driver of ion transport in the kidneys
Na/K ATPase
How is renal architecture unconventional?
Transfer of oxygen from arteries to veins via countercurrent exchange
Why are the testicular arteries arranged in an unconventional manner?
Countercurrent exchange of testosterone.
Reduces the amount of testosterone released into the body, so that it is easier to regulate.
How is most testosterone released into the body
Through the lymphatics, bound to albumin proteins.
Test released into the venous blood is mostly transferred to the arterial blood, back to the testes (via countercurrent exchange)
Outcome of renal unconventional blood supply
Relative hypoxia in the kidneys.
Not absolute hypoxia (as kidneys function normally), but is at a risk of hypoxia.
Countercurrent exchange of kidneys
Arteries of one nephron are beside the veins of an adjacent nephron.
What can lead to kidney damage?
Conditions leading to low renal perfusion (kidneys already in a state of relative hypoxia)
Triple whammy
Combination of a diuretic and an ACE
inhibitor (or AT1 receptor antagonist) is
effective treatment for hypertension.
Add in NSAID leads to acute renal failure.
Why can NSAID lead to renal failure?
Prostaglandin-mediated vasodilation preserves renal blood flow when diuretic and ACE-I are administered.
Safe hypertension treatment
Diuretic + ACE inhibitor.
Safe hypertension treatment
Diuretic + ACE inhibitor.
Danger with diuretic and ACE inhibitor hypertension treatment
Patients can self-prescribe NSAID, which leads to renal failure when co-administered with ACEI and diuretic
Example of a nephrotoxic antibiotic
Gentamycin
Class of antimicrobial that gentamycin is
Aminoglycoside
Side effects of gentamycin
Nephrotoxic, ototoxic (leads to deafness, vertigo)
Advised length of gentamycin treatment
No more than 48 hours.
Once per day (one bolus)
Advised length of gentamycin treatment
No more than 48 hours.
Once per day (one bolus)
How is gentamycin excreted?
Entirely through kidneys
Why might gentamycin be ototoxic?
Selectively taken up by hair cells in the ear.
Gets into the fluid area of the cochlea (slow clearance area).
Not known how it gets into hair cells
Why is gentamycin administered once per day?
Equally effective if administered once per day.
Less toxic to ear, kidney.
Need to get through trough period, where gentamycin enters cochlea, leaks out slowly.
Patients who are at higher risk of ototoxicity with gentamycin treatment
Those exposed to continuous loud sound during treatment, those with tinnitus.
Paraquat
Herbicide.
Paraquat
Herbicide.
How does paraquat work?
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Activated into a radical form by getting electrons from electron transport chains.
Radical form oxidises anything it can tough, makes ROS.
Destroys cell membranes, DNA, proteins, etc.
What activates paraquat in a plant?
e- in chloroplasts
How does paraquat get activated in mammalian cells?
Accepts electrons from NADPH.
Effect of paraquat on mammals
Activated by accepting e- from NADPH.
Accumulates in lung epithelial cells via active transport.
Effect of paraquat on mammals
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Activated by accepting e- from NADPH.
Accumulates in lung epithelial cells via active transport.
Effect of paraquat on mammals
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Activated by accepting e- from NADPH.
Accumulates in lung epithelial cells via active transport.
Lung epithelium exposed to very high concentrations
Dose difference of paraquat for mammals
Low dose selectively kills lung epithelial cells.
High doses destroy tissues systemically.
Dose difference of paraquat for mammals
Low dose selectively kills lung epithelial cells.
High doses destroy tissues systemically.
