Selective Toxicity Mechanisms Flashcards Preview

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Flashcards in Selective Toxicity Mechanisms Deck (20)
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1
Q

What do drugs that kill bacteria target?

A

differences in:

  • ribosomes
  • membranes
  • cell walls
  • enzymes
  • DNA
2
Q

Ribosomes are targeted by which drugs?

A

tetracyclines, aminoglycosides

3
Q

Membranes are targeted by which drugs?

A

polyene antibiotics

4
Q

Cell walls are targeted by which drugs?

A

penicillins, cephalosporins, vancomycin

5
Q

Enzymes are targeted by which drugs?

A

sulphonamides, trimethoprim

6
Q

DNA is targeted by which drugs?

A

quinolones, rifampicin

7
Q

What is the mechanism of sulfonamide in bacterial DNA toxicity?

A
  • Sulfonamide structure resembles PABA, an important precursor to folic acid which is essential precursor of DNA
  • PABA is converted to folate by dihdropteroate synthase
    • sulfonamide binds to the synthase and inhibits it
    • no folate = no DNA synthesis
    • tf inhibits growth and is bacteriostatic
8
Q

What is the mechanism of trimethoprim in bacterial DNA toxicity?

A
  • Once PABA is converted to folate, the folate is converted to tetrahydrofolate by dihydrofolate reductase
  • trimeothoprim inhibits the reductase, preventing synthesis of DNA
    • tf is also bacteriostatic
  • better side effect profile than sulfonamide (less toxic to mitochondria)
  • 1st line drug in UTIs because it is cleared into urine in its active form
9
Q

Co-trimoxazole

A
  • sulfonamide + trimethoprim
  • bacteriostatic by halting DNA synthesis
  • synergistic evidence in vitro, questionable in vivo
10
Q

What are the targets for cellular toxicity of anti-cancer drugs?

A
  • uncontrolled division
    • failure to differentiate
    • failure to apoptose
    • failure to senesce
    • failure of growth suppressors
    • faulty growth signalling
    • fulsome blood supply
11
Q

cytotoxic anti-cancer agents target cells that are

A

actively dividing/growing

12
Q

Methotrexate

A
  • cytotoxic anti-cancer drug (high doses)
  • cytotoxic immunosuppressant (lower doses eg rheumatoid arthritis, psoriasis)
  • inhibits purine synthesis
    • inhibits human dihydrofolate reductase (not bacteria)
  • resembles folic acid in structure (important precursor in DNA synthesis)
  • teratogenic, can be used to terminate ectopic pregnancies
13
Q

What is the mechanism of cancer cell toxicity by methotrexate?

A
  • in humans methotrexate inhibits dihdrofolate reductase from converting folate to tetrahydrofolate
    • this is similar to the action of trimethoprim on the bacterial isoform of the enzyme
  • this prevents synthesis of thymidylate etc. required for DNA synthesis
  • here, folate is dietary (so PABA conversion to folate is less essential)
  • vaguely selective against cancer cells because it is cytotoxic
    • ie targets cells that are actively dividing, like cancer cells
    • can affect our cells that are constantly dividing:
      • eg RBCs and WBCs in bone marrow (hence immunosuppressant action); growth of endometrium in females is inhibited (hence teratogenic); causes GIT side effects and disorders
14
Q

What are the adverse effects of methotrexate?

A
  • vaguely selective against cancer cells because it is cytotoxic
    • ​​ie targets cells that are actively dividing, like cancer cells
    • tf can also affect our cells that are constantly dividing:
      • ​RBCs and WBCs in bone marrow (hence immunosuppressant action)
      • growth of endometrium in females is inhibited (hence teratogenic)
      • causes GIT side effects and disorders
15
Q

How is glucose reabsorbed in the proximal tubule?

A
  • pumped in from the lumen with Na and amino acids
  • pumped out on the interstitial side via Na/glucose and Na/amino acid cotransporters that are driven by the Na/K-ATPase
  • tf glucose reabsorption is metabolically expensive
16
Q

Why is the renal medulla especially sensitive to hypoxic damage?

A
  • the countercurrent exchange setup that allows the kidney to concentrate urine allows for O2 to travel from the arteries to the veins
  • this makes the medulla relatively hypoxic compared to the cortex
  • tf it is more sensitive to hypoxic damage
  • variable with pathophysiology
17
Q

What is a ‘triple-whammy?’

A
  • the combination of a diuretic and an ACE inhibitor (or AT1 receptor antagonist/ARB) used to treat hypertension plus an NSAID
    • can lead to acute renal failure
18
Q

What is the mechanism of renal failure due to a triple-whammy?

A
  • when medullary hypoxia starts to damage the kidney, renal cells produce prostaglandins as a ‘last-resort’ mechanism of getting more O2
    • PGs cause vasodilation and increase renal blood flow without increasing glomerular filtration (renal workload)
  • NSAIDs block the renal cells from producing PGs
    • in combination with the intentional lowered BP and renal perfusion by the anti-hypertensive diuretic & ACE inhibitor
    • and the AT1 antagonist/ARB causing constriction of the efferent arteriole to reduce blood flow (to increase GFR)
    • can lead to hypoxic damage, especially in those who are dehydrated or have pre-existing renal failure (elderly)
      • tf hydration is first intervention!
19
Q

How is paraquat activated?

A
  • electron transport (NADPH) or photosynthesis
20
Q

What is the danger of paraquat?

A
  • activated by reduction to a radical form
  • radical oxidises other molecules, makes ROS (O2-, H2O2)
    • destroy cell membranes, proteins, DNA
  • it is selectively toxic local to site of administration
    • can be deadly if sprayed on or swallowed by mammals
    • accumulates in lung epithelial cells
      • some subclasses actively pump it into their cytoplasm
    • tf high doses kill indiscriminantly, lower doses selectively kill lung tissue only