55 - Drugs and Kidney Function

Question 1

Four roles of the kidneys

Answer 1

• regulation of water and electrolyte balance
  • endocrine functions
  • excretion of endogenous waste
  • excretion of exogenous compounds

Question 2

*Schematic view of the nephron

Answer 2

EPHRON

Question 3

What happens in the proximal tubule regarding NaCl?

Answer 3

60-70% of water and NaCl reabsorbed.

Organic acids and bases, bicarbonate secreted into lumen.

Question 4

What happens in loop of Henle regarding NaCl?

Answer 4

20-30% of NaCl reabsorbed

Question 5

What happens in distal tubule regarding NaCl?

Answer 5

5-10% of NaCl reabsorbed

Question 6

Where in the nephron does secretion take place?

Answer 6

Proximal tubule

Question 7

Where in the nephron is K+ reabsorbed?

Answer 7

Proximal tubule

Question 8

Where in the nephron is K+ secreted?

Answer 8

Distal tubule, collecting ducts

Question 9

Types of drugs with effects on the kidneys
1)
2)
3)

Answer 9

1) Diuretics
2) Drugs that affect urine pH (EG: sodium bicarbonate to treat aspiring poisoning)
3) Drugs that alter secretion of organic molecules (EG: probenecid inhibits secretion of banned drugs for sport urine tests)

Question 10

Common effect of altering NaCl reabsorption in proximal tubule.

Answer 10

Distal tubule changes NaCl reabsorption to balance out change in proximal tubule.

Question 11

Diuretics

Answer 11

Drugs that increase Na+ and water excretion by decreasing NaCl reabsorption

Question 12

Four classes of diuretics

Answer 12

1) Loop diuretics
2) Thiazide diuretics
3) Potassium-sparing diuretics
4) Osmotic diuretics

Question 13

Most powerful class of diuretics

Answer 13

Loop diuretics

Question 14

Mechanism of loop diuretic action

Answer 14

Act on thick ascending limb in loop of Henle.

Inhibit Na+/K+/2Cl- carrier (transports from lumen into cells).

Question 15

*Normal mechanism of reabsorption in kidneys

Answer 15

NORMAL REABSORPTION

Question 16

Effect of normal Na+/K+/2Cl- cotransporter function

Answer 16

Interstitium becomes hypertonic, so water leaves nehphron to tissues.
Reduces Na+ in distal tubule, which reduces water reabsorption

Question 17

Effect of inhibiting Na+/K+/2Cl- cotransporter

Answer 17

Reduction in hypertonicity of interstitium (reduced water reabsorption)
Increased Na+ in distal tubule (increases osmotic pressure in tubule, reduces water reabsorption)

Question 18

Pharmacokinetics of loop diuretics

Answer 18

Well-absorbed from gut (onset in less than an hour)
Plasma protein-bound. Reaches site of action via secretion
3-6 hour duration

Question 19

Adverse effects of loop diuretics
1)
2)
3)

Answer 19

1) K+ loss from distal tubule
2) H+ excretion (can lead to metabolic alkalosis)
3) Reduced extracellular fluid (in elderly)

Question 20

How do loop diuretics result in hypokalaemia?
1)
2)

Answer 20

1) Increased [Na+] in distal tubule

2) As K+ is cotransported from the lumen with Na+, this increases amount of K+ secreted.

Question 21

Clinical uses of loop diuretics
1) a, b, c, d,
2)

Answer 21

1) salt and water overload in
a) acute pulmonary oedema
b) chronic heart failure
c) ascites (liver cirrhosis)
d) renal failure
2) hypertension (renal impairment)

Question 22

Power of thiazide diuretics

Answer 22

Moderate. Not as powerful as loop diuretics.

Question 23

Mechanism of thiazide diuretic action

Answer 23

Act on the distal convoluted tubule.

Inhibit Na+/Cl- cotransporter.

Question 24

Pharmacokinetics of thiazide diuretics
1)
2)
3)
4)

Answer 24

1) Orally-active
2) Excreted in urine (tubular secretion)
3) Maximum effect is 4-6 hours
4) Duration is 8-12 hours

Question 25

Adverse effects of thiazide diuretics 1) 2)

Answer 25

1) K+ loss from collecting ducts | 2) Increase in plasma uric acid (inhibits tubular secretion of uric acid)

Question 26

Clinical uses of thiazide diuretics 1) 2)

Answer 26

1) Hypertension | 2) Severe resistant oedema (often in combination with loop diuretics)

Question 27

Potassium-sparing diuretics power

Answer 27

Limited diuretic activity

Question 28

Use of potassium-sparing diuretics

Answer 28

Used in combination with K+-losing diuretics to prevent K+ loss

Question 29

Two broad groups of potassium-sparing diuretics

Answer 29

1) Spirolactone - Aldosterone receptor antagonist (prevents aldosterone binding to aldosterone receptor, which binds to DNA). Reduces activation of Na+ channels and stimulates Na+ pump synthesis. 2) Triamterene and amiloride block Na+ channels in collecting tubules and ducts. Inhibits Na+ reabsorption and K+ secretion.

Question 30

Spirolactone pharmacokinetics 1) 2) 3

Answer 30

1) Orally-active 2) Slow onset 3) Short half-life (ten minutes), but metabolite has a long half-life (16 hours). So effect has a long duration.

Question 31

Adverse events of spirolactone

Answer 31

1) Hyperkalaemia (if used alone) | 2) GIT upset

Question 32

Clinical uses of spirolactone 1) 2) 3)

Answer 32

1) Combine with loop or thiazide diuretics 2) Heart failure 3) Hyperaldosteronism

Question 33

``` Osmotic diuretics mechanism 1) 2) 3) 4) ```

Answer 33

1) Pharmacologically-inert (don't interact with receptor) 2) Filtered, not reabsorbed. 3) Reduce passive water reabsorption. 4) Have main effect on water-permeable parts of nephron (proximal tubule, descending limb of loop of Henle, collecting tubules)

Question 34

Clinical uses of osmotic diuretics 1) 2) 3)

Answer 34

1) Elevated intracranial pressure 2) Raised intraocular pressure 3) Prevention of acute renal failure (when GFR is so low that all NaCl and water is reabsorbed)

Question 35

``` Why are the kidneys so susceptible to toxicity? 1) 2) 3) 4) ```

Answer 35

1) Receives 20% of blood supply 2) Substances can be concentrated 3) Kidneys can carry out metabolism 4) Kidneys affected by extrarenal events (EG: increased bp)

Question 36

Hg kidney toxicity 1) 2) 3)

Answer 36

1) Direct toxicity and vasoconstriction 2) Binds to thiol groups in proteins, leading to immune glomerulonephritis (type III hypersensitivity) 3) Damage primarily in proximal tubule (loss of brush-border membranes, mitochondrial changes, apoptosis)

Question 37

Side effects of gentamycin 1) 2) 3)

Answer 37

1) Proteinuria 2) Reduced GFR 3) Altered concentrating ability

Question 38

Which part of the kidney does gentamycin affect?

Answer 38

Apical membrane of proximal tubule

Question 39

``` Mechanism of gentamycin toxicity 1) 2) 3) 4) 5) ```

Answer 39

1) Cationic drug binds anionic phospholipids 2) Altered PIP2 generation 3) This alters intracellular Ca2+ levels 4) Impaired mitochondrial respiration 5) Apoptosis

Question 40

'Vicious cycle' of gentamycin nephrotoxicity

Answer 40

Gentamycin is renally eliminated. | Nephron damage from gentamycin reduces ability to excrete drug.

Question 41

Example of an antineoplastic agent that damages kidneys

Answer 41

Cisplatin

Question 42

Cisplatin 1) 2)

Answer 42

1) Cytotoxic anticancer agent, used for treating prostate tumours 2) Causes dose-limiting nephrotoxicity (proteinuria, increase in blood urea, electrolyte imbalance)

Question 43

Cisplatin mechanism of nephrotoxicity 1) 2) 3)

Answer 43

1) Activated inside cells. 2) Active form forms highly-reactive species, which bind nucleophilic cellular components (EG: thiols in proteins) 3) This occurs in distal tubule and collecting ducts (causes focal tubular necrosis, with glomeruli intact)