Diuretics + renal pharmacology Flashcards

1
Q

What are the regulatory roles of the kidneys?

A
  • Fluid balance
  • Acid-base balance
  • Electrolyte balance
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Where in the nephron does most of the water and electrolyte reabsorption take place?

A

PCT

(thus is main site of action of diuretics)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is reabsorbed in the ascending and descending limbs of the LoH?

A

Descending limb: water

Ascending limb: solutes (via NKCC2 transporter); impermeable to water as no aquaporin channels on luminal membrane

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

List the main types of drugs acting on the renal tubules

A
  • Carbonic anhydrase inhibitors
  • Osmotic diuretics (mannitol)
  • SGLT2 inhibitors
  • Loop diuretics
  • Thiazides
  • Potassium sparing diuretics
  • Aldosterone antagonists
  • ADH antagonists
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Define the terms; diuretic, natiuretic, aquaretic

A

Diuretic:

Increased production of urine

Natiuretic:

Loss of sodium in urine

Aquaretic:

Loss of water without electrolytes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

For each of the different types of diuretics, list their primary site of action in the nephron

A
  • Carbonic anhydrase inhibitors: PCT
  • Osmotic diuretics: PCT
  • Loop diuretics: ascending limb of LoH
  • Thiazides: DCT
  • K+ sparing diuretics (aldosterone receptor antagonists eg spironolactone): late DCT + early CD
  • ADH antagonists: CD
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Explain the mechanism of action of carbonic anhydrase inhibitors

A
  • Inhibition of CA thus reduced HCO3- and Na+ reabsorption at PCT
  • Reduced HCO3- reabsorption thus less H+ ions to drive Na+/H+ exchanger- thus decreased Na+ reabsorption
  • Enhances Na+ delivery results in K+ loss in the collecting duct; ENaC, due to acidosis as well

Carbonic anhydrase splits carbonic acid into CO2 + H2O

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe the transport of ions through ENaC channels

A

Na+ reabsorbed into tubular cells via ENac

K+ goes other way and is secreted via ENaC into the tubular lumen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Describe and explain the side effects of carbonic anhydrase inhibitors

A

Loss of NaHCO3-

Hypokalaemic metabolic acidosis; hypokalaemia due to upregulation of ENaC + acidosis due to loss of HCO3-

Tolerance developed after 2/3 days

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are carbonic anhydrase inhibitors used for now?

A
  • Glaucoma
  • Mountain sickness
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Why are diuretics that target transporters further upstream not ideal?

A

As the transporters downstream can become upregulated and try to compensate for the actions earlier on in the tubule

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Give an example of an osmotic agent (diuretic) and describe its mechanism of action

A

Mannitol

Draws water to it thus draws water into the tubular lumen via osmosis

Causes an osmotic diuresis

Can have effects along entire tubule, but mostly occurs at PCT due to increased water reabsoption at PCT

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Briefly describe the effects and risks of mannitol (osmotic diuretic)

A
  • Loss of water
  • Reduced intracellular volume
  • Risk of HYPERNATRAEMIA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Are SGLT2 inhibitors a diuretic, natiuretic or aquaretic?

A

Natiuretic; loss of Na+ in urine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Describe the mechanism of action of SGLT2 inhibitors

A
  • Inhibit reabsorption of Na+ and glucose in PCT
  • Increased Na+ and glucose within tubular lumen leads to increased uric acid secretion into lumen
  • Leads to GLUCOSURIA + NATIURESIS

(useful in metabolic syndrome as this is associated with hyperuricaemia)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Explain why SGLT2 inhibitors can be useful in diabetic patients

A
  • Increased NaCl delivery to macula densa in DCT
  • Macula densa thinks there is a high BP
  • Thus causes afferent arteriole constriction
  • Reducing glomerular pressure + hyperfiltration
  • Protective against diabetic nephropathy
17
Q

Give the main clinical effects of SGLT2 inhibitors

A
  • Low plasma glucose levels
  • Reduced body weight
  • Reduced BP
  • Reduced plasma uric acid (beneficial in metabolic syndrome)
  • Reduced glomerular hyperfiltration (useful in DM)
18
Q

Give an example of a loop diuretic

A

Furosemide

19
Q

Describe the mechanism of action of loop diuretics

A
  • Inhibit NKCC2 co-transporter on luminal membrane
  • Normally, K+ back diffusion through ROMK is a driving force for cation reabsorption (Ca2+, Mg2+)- ROMK facilitates Ca2+ + Mg2+ reabsorption
  • Thus, with LD, increased divalent Ca2+ + Mg2+ loss
  • Loss of H+- metabolic alkalosis
  • Enhanced Na+ delivery results in K+ loss in CD (increased stimulation of ENaC channes thus more open)
20
Q

List the main clinical findings of loop diuretics and explain why they can be used to treat hypercalcaemia

A
  • Loss of Na+ and water
  • Hypokalaemic metabolic alkalosis
  • Increased Ca2+ + Mg2+ loss (hypocalcaemia + hypomagnesaemia); thus LD’s can be used for Tx of hypercalcaemia
21
Q

Describe the mechanism of action of thiazide diuretics

A
  • Inhibit Na+/Cl- co-transporter in DCT
  • Low intracellular Na+ facilitates Ca2+ reabsoprtion via NCX on basolateral membrane
  • Enhanced Na+ delivery results in K+ loss in collecting duct (ENaC upregulation)
22
Q

List the main clinical features of thiazide diuretics

A
  • Loss of Na+ and water
  • Hypokalaemic metabolic alkalosis (due to loss of H+ via NHX on luminal membrane)
  • Increased Ca2+ reabsorption- hypercalaemia (opposite to LD’s)
23
Q

Describe how aldosterone acts to increased BP via its action on the nephron

A
  • Increases expression of ENaC on luminal membrane of collecting duct
  • Increases expression of Na+/K+ ATP ase in principal cells of CD
  • Increased Na+ thus water reabsorption
  • Thus increased; effective circulating blood volume, SV, CO, BP
24
Q

Describe the mechanisms of action of spironolactone and amiloride

A
  • Spironolactone: mineralocorticoid/aldosterone receptor antagonist; blocks mineralocorticoid receptor, preventing effects of aldosterone
  • Amiloride: inhibits ENaC channels in CD; counteracting effect of aldosterone
25
Q

Are ADH antagonists natiuretics or aquaretics?

A

Aquaretics; water loss without electrolytes

Diuretic, but not natiuretic

26
Q

Give an example of an ADH antagonist

A

Tolvaptan

27
Q

Describe the mechanism of action of ADH antagonists and name some conditions for which they are used

A
  • Bind to and block V2 receptor (which ADH acts on in CD)
  • Thus, reduced expression of aquaporins on luminal membrane of CD
  • Dilute + large volumes of urine produced

Uses:

Hyponatraemia

APCKD (prevents cyst enlargement)

28
Q

Describe the effect of lithium on ADH and hence diuresis

A

Lithium; Tx for bipolar disorder

Inhibits actions of ADH thus causing diuresis as a side effect

Pt’s polyuric + dehydrated

Diuretic not netiuretic (water loss without electrolytes)

29
Q

Give some clinical features of ADH

A
  • Dilute urine; diuresis
  • Increased free water clearance
  • Raised serum sodium (risk of hypernatraemia)
30
Q

How do alcohol and caffeine lead to diuretic effects?

A

Alcohol:

Inhibits ADH release

Caffeine:

Increases GFR and decreases tubular Na+ reabsorption

31
Q

List some generic adverse drug reactions of diuretics

A
  • Hypovolaemia
  • Hypotension
  • RAAS activation; AKI
  • Electrolyte disturbances; Na+, K+, Mg2+, Ca2+
  • Metabolic abnormalities
  • Anaphylaxis/photosensitivity rash; (rare) allergic reaction; most common with loop diuretics
32
Q

Which types of diuretics are used for hypertension?

A
  • Thiazide diuretics
  • Spironolactone
33
Q

Which types of diuretics are used for heart failure?

A
  • Loop diuretics
  • Spironolactone- non-diuretic benefits; to hold onto K+ lost through action of LD’s
34
Q

Explain the role of secondary hyperaldosteronism in heart failure

A

Body perceives a state of hypovolaemia + hypotension due to reduced CO

Thus, inappropriate activation of RAAS leading to fluid overload – hence requiring diuretics

35
Q

Which types of diuretics are used for decompensated liver disease?

Explain the role of secondary hyperaldosteronism in liver diease

A
  • Spironolactone (1st line)
  • Loop diuretics
  • (Tolvaptan)

Body senses a low effective circulating blood volume due to reduced albumin (synthetic function of liver), leaky vessels

Inappropriate RAAS activation– fluid overload

36
Q

Which types of diuretics are used for nephrotic syndrome?

Explain the role of secondary hyperaldosteronism in nephrotic syndrome

A
  • Loop diuretics (large doses)
  • Thiazides
  • K+ sparing diuretics/potassium supplements

Hypoalbuminaemia due to protein loss in urine, leading to decreased arterial blood volume detected due to decreased intravascular oncotic pressure

37
Q

Why are diuretics needed in chronic kidney disease?

What types of diuretics should you avoid in CKD?

A

Reduced GFR thus increased salt and fluid retention

Avoid K+ sparing diuretics and patients are hyperkalaemic and acidotic anyway

Thus, alkalosis and kalliuretic effects potentially beneficial

38
Q

What type of diuretics tend to be used in chronic kidney disease?

A

Loop diuretics

Due to K+ sparing effect

39
Q

What are Bartter’s, Glitelman’s and Liddle’s syndrome?

A
  • Bartter’s: 100% blockage of NKCC2 co-transporter in ascending limb of LoH; effects like giving pt full dose of loop diuretics
  • Gitelman’s: blockage of Na/Cl co-transporter; effects like full dose of thiazide diuretic
  • Liddle’s: Increased function of ENaC; leads to hypertension

Bartter’s + Gitellamn’s = result from reduced/no function of transporters

Liddle’s syndrome = results from increased function of ENaC