Selective Toxicity Mechanisms

Question 1

What do drugs that kill bacteria target?

Answer 1

differences in:

• ribosomes
• membranes
• cell walls
• enzymes
• DNA

Question 2

Ribosomes are targeted by which drugs?

Answer 2

tetracyclines, aminoglycosides

Question 3

Membranes are targeted by which drugs?

Answer 3

polyene antibiotics

Question 4

Cell walls are targeted by which drugs?

Answer 4

penicillins, cephalosporins, vancomycin

Question 5

Enzymes are targeted by which drugs?

Answer 5

sulphonamides, trimethoprim

Question 6

DNA is targeted by which drugs?

Answer 6

quinolones, rifampicin

Question 7

What is the mechanism of sulfonamide in bacterial DNA toxicity?

Answer 7

• 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

Question 8

What is the mechanism of trimethoprim in bacterial DNA toxicity?

Answer 8

• 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

Question 9

Co-trimoxazole

Answer 9

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

Question 10

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

Answer 10

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

Question 11

cytotoxic anti-cancer agents target cells that are

Answer 11

actively dividing/growing

Question 12

Methotrexate

Answer 12

• 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

Question 13

What is the mechanism of cancer cell toxicity by methotrexate?

Answer 13

• 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

Question 14

What are the adverse effects of methotrexate?

Answer 14

• 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

Question 15

How is glucose reabsorbed in the proximal tubule?

Answer 15

• 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

Question 16

Why is the renal medulla especially sensitive to hypoxic damage?

Answer 16

• 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

Question 17

What is a ‘triple-whammy?’

Answer 17

• 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

Question 18

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

Answer 18

• 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!

Question 19

How is paraquat activated?

Answer 19

• electron transport (NADPH) or photosynthesis

Question 20

What is the danger of paraquat?

Answer 20

• 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