55 - Drugs and Kidney Function Flashcards

1
Q

Four roles of the kidneys

A
  • regulation of water and electrolyte balance
    • endocrine functions
    • excretion of endogenous waste
    • excretion of exogenous compounds
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2
Q

*Schematic view of the nephron

A

EPHRON

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3
Q

What happens in the proximal tubule regarding NaCl?

A

60-70% of water and NaCl reabsorbed.

Organic acids and bases, bicarbonate secreted into lumen.

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4
Q

What happens in loop of Henle regarding NaCl?

A

20-30% of NaCl reabsorbed

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5
Q

What happens in distal tubule regarding NaCl?

A

5-10% of NaCl reabsorbed

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6
Q

Where in the nephron does secretion take place?

A

Proximal tubule

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7
Q

Where in the nephron is K+ reabsorbed?

A

Proximal tubule

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8
Q

Where in the nephron is K+ secreted?

A

Distal tubule, collecting ducts

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9
Q

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

A

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)

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10
Q

Common effect of altering NaCl reabsorption in proximal tubule.

A

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

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11
Q

Diuretics

A

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

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12
Q

Four classes of diuretics

A

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

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13
Q

Most powerful class of diuretics

A

Loop diuretics

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14
Q

Mechanism of loop diuretic action

A

Act on thick ascending limb in loop of Henle.

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

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15
Q

*Normal mechanism of reabsorption in kidneys

A

NORMAL REABSORPTION

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16
Q

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

A

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

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17
Q

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

A

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

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18
Q

Pharmacokinetics of loop diuretics

A

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

19
Q

Adverse effects of loop diuretics
1)
2)
3)

A

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

20
Q

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

A

1) Increased [Na+] in distal tubule

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

21
Q

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

A

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)

22
Q

Power of thiazide diuretics

A

Moderate. Not as powerful as loop diuretics.

23
Q

Mechanism of thiazide diuretic action

A

Act on the distal convoluted tubule.

Inhibit Na+/Cl- cotransporter.

24
Q
Pharmacokinetics of thiazide diuretics
1)
2)
3)
4)
A

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

25
Q

Adverse effects of thiazide diuretics
1)
2)

A

1) K+ loss from collecting ducts

2) Increase in plasma uric acid (inhibits tubular secretion of uric acid)

26
Q

Clinical uses of thiazide diuretics
1)
2)

A

1) Hypertension

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

27
Q

Potassium-sparing diuretics power

A

Limited diuretic activity

28
Q

Use of potassium-sparing diuretics

A

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

29
Q

Two broad groups of potassium-sparing diuretics

A

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.

30
Q

Spirolactone pharmacokinetics
1)
2)
3

A

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.

31
Q

Adverse events of spirolactone

A

1) Hyperkalaemia (if used alone)

2) GIT upset

32
Q

Clinical uses of spirolactone
1)
2)
3)

A

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

33
Q
Osmotic diuretics mechanism 
1)
2)
3)
4)
A

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)

34
Q

Clinical uses of osmotic diuretics
1)
2)
3)

A

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)

35
Q
Why are the kidneys so susceptible to toxicity?
1)
2)
3)
4)
A

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)

36
Q

Hg kidney toxicity
1)
2)
3)

A

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)

37
Q

Side effects of gentamycin
1)
2)
3)

A

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

38
Q

Which part of the kidney does gentamycin affect?

A

Apical membrane of proximal tubule

39
Q
Mechanism of gentamycin toxicity
1)
2)
3)
4)
5)
A

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

40
Q

‘Vicious cycle’ of gentamycin nephrotoxicity

A

Gentamycin is renally eliminated.

Nephron damage from gentamycin reduces ability to excrete drug.

41
Q

Example of an antineoplastic agent that damages kidneys

A

Cisplatin

42
Q

Cisplatin
1)
2)

A

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

43
Q

Cisplatin mechanism of nephrotoxicity
1)
2)
3)

A

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)