Pharm 21 - Diuretics Flashcards Preview

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Flashcards in Pharm 21 - Diuretics Deck (47)
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1
Q

Where is the Na/K ATPase found?

K in, Na out

A

On the basal membrane of the kidney cell (proximal tubule)

Drives Na out of the cell to ensure a conc gr for Na to diffuse into the cell via the tubular/apical side - ensures maximal Na reabsorption

2
Q

What are diuretics

A

Drugs acting on the renal tubule to promote excretion of Na, Cl and H2O.

3
Q

What does the oncotic pressure in the interstitium do?

A

It draws water from the PCT into the capillaries - oncotic pressure exerted by the proteins in blood

4
Q

What other route of transmission of ions is there in the proximal tubule cell?

A

Paracellular pathway - dependent on gap junctions - PCT cells have large gap junctions

5
Q

Glucose and amino acid reabsorption is coupled with?

A

Sodium reabsorption - specifically the Na+/H+ antiporter

6
Q

Explain how sodium exchange is linked with carbonic anhydrase

A
  1. After being filtered by the glomerulus, HCO3- and H+ converted to H2O + CO2 by membrane bound carbonic anhydrase (apical/tubular side)
  2. CO2 + H2O freely diffuse into the cell, where cytoplasmic carbonic anhydrase converts it back into HCO3- and H+
  3. HC03- reabsorbed into capillaries via Na+/HCO3- cotransporter (basal side)
  4. H+ used for the Na+/H+ anti porter
7
Q

What other important thing does the kidney excrete?

A

Exogenous agents - kidney has a lot of transport proteins that pick up the drug (often by recognising polar conjugate groups)

8
Q

The PCT absorbs upto how much filtrate?

A

70%

9
Q

What happens in the descending Loh

A

Freely permeable to water - so water moves from tubule (isotonic) through the descending limb cell into the interstitium (hypertonic due to plasma proteins)

10
Q

The ascending Loh is the first part of the kidney that is not….

A

Freely permeable to water

11
Q

Explain what happens in the ascending Loh cell?

A
  1. Na+/K+/2Cl- absorbed on the tubular/apical side via Na+/K+/2Cl- transporter
  2. On the basolateral membrane, Na+/K+ ATPase and K+/Cl- cotransporter move these electrolytes from epithelial cell into interstitium

(3. Small paracellular pathway also present)

12
Q

What is the importance of the countercurrent system?

A

Ensuring we retain as much fluid as possible (by having a very concentrated interstitium which enables more water reabsorption from CD)

Capillaries pass in the opposite direction to the flow of fluid - hence “counter current”

13
Q

Where is aldosterone produced?

A

Adrenal glands

14
Q

What happens in the early DCT?

A

Any Na left in tubules absorbed via Na+/Cl- cotransporter (apical side)

15
Q

What happens in the late DCT

A

Aldosterone and mineralocorticoids become more important in up regulating Na+/K+ ATPase and Na+ channels

16
Q

Which 2 molecules are important in mediating CD function?

A

Aldosterone (binds to mineralocorticoid receptors) and Vasopressin (synthesise/assemble AQP2 for water reabsorption following Na)

17
Q

2 ways how diuretics work

A
  1. Inhibit reabsorption of Na and Cl (i.e. increase excretion)
  2. Increase osmolarity of tubular fluid (i.e. decrease osmotic gradient across epithelia)
18
Q

What are the 5 main classes of diuretics and give an example of each

A
  1. Osmotic diuretics - e.g. mannitol (acts throughout tubule)
  2. Carbonic anhydrase inhibitors - e.g. acetazolamide (acts mainly in PCT)
  3. Loop diuretics - e.g. frusemide (furosemide)
  4. Thiazides - e.g. bendrofluazide bendroflumethiazide)
  5. K+ sparing drugs (e.g. amiloride, spironolactone)
19
Q

Osmotic diuretics (Eg mannitol) work how?

A

By raising osmolarity of plasma and kidney filtrate (but is pharmacologically inert)

20
Q

How do carbonic anhydrase inhibitors work?

A
  1. Decreases Na+/H+ exchange

2. So more Na+ in tubule, so more water in tubule also

21
Q

Where do loop diuretics act?

A

On the ascending Loh

22
Q

What do loop diuretics target?

A

The triple Na+/K+/2Cl- transporter

23
Q

How do loop diuretics work

A
  1. By targeting the triple Na/K/2Cl transporter, less Na reabsorbed = more Na retained in lumen
  2. Remove K+ recycling - so less positive lumen potential - so less drive for other positive ions to interstitium via paracellular pathway - so tend so lose other positive ions in urine (e.g. Ca/Mg)
24
Q

Loop diuretics are the most powerful diuretics. How much fluid loss can they cause?

A

15% - 30%

25
Q

How do loop diuretics mean less water is reabsorbed from CD?

A

Increases tubular fluid osmolarity = decreases osmolarity of medullary interstitium (as less sodium reabsorbed)= less H2O reabsorbed in CD

26
Q

How can loop diuretics cause hypokalaemia?

A
  1. Less Na reabsorbed at ALOH, so more passes on to DCT

2. Kidney desperately tries to reabsorb Na, but has to sacrifice K+ due to Na+/K+ ATPase

27
Q

Which 2 classes of diuretics can cause hypokalaemia?

A
  1. Loop diuretics

2. Thiazides

28
Q

How do thiazide diuretics work?

A

Acts on (early) DCT

  1. Binds to Na/Cl co transporter on apical side and blocks it
  2. Increased tubular fluid osmolarity = less H2O reabsorption in CD
29
Q

How do thiazides impact Mg and Ca reabsorption?

A

Increased Mg LOSS and increased Ca REABSORPTION

30
Q

How much fluid loss can thiazide diuretics cause?

A

5-10%

31
Q

Which cells in the kidney release Renin?

A

Macula densa cells (by detecting the amount of Na reaching it)

32
Q

Why can it be a problem to administer thiazides/loop diuretics long term?

A
  1. Chronic diuretic use = less Na in blood = less Na filtered = less Na reaching macula densa
  2. This causes renin secretion
  3. Renin stimulates Na+ reabsorption
  4. Now there are 2 competing systems (RAAS / diuretics)
  5. Consequently, ACEi sometimes coadminstered w diuretics

(Loop diuretics are worse as they block the same protein present on Macula densa that absorbs Na)

33
Q

Frusemide is a?

A

Loop diuretic

34
Q

Bendrofluazide is a?

A

Thiazide

35
Q

Which are the least powerful diuretic agents?

A

K sparing diuretics

Act on late DCT and CD

36
Q

What are the 2 classes of K sparing drugs?

A
  1. Aldosterone receptor antagonists (e.g. Spironolactone)

2. Inhibitors of aldosterone-sensitive Na channels (e.g. Amiloride)

37
Q

How much fluid loss can a K sparing diuretic yield?

A

5%

38
Q

Why can K sparing diuretics cause increased H+ retention?

A

Less Na+/H+ exchange

39
Q

What are side effects of Loop diuretics

A
  1. Hypovolemia
  2. Metabolic alkalosis
  3. Hyperuricemia
  4. Hypokalaemia
  5. Hyponatremia
40
Q

What are side effects of thiazides

A
  1. Hypovolemia
  2. Metabolic alkalosis
  3. Hyperuricemia
  4. Hypokalaemia
  5. Hyponatremia
41
Q

What are side effects of K+ sparing diuretics

A
  1. Hyperkalemia (as less Na+/K+ exchange)
42
Q

Why is metabolic alkalosis a side effect?

A

Cl- loss

43
Q

What is hyperuricemia and how does it happen

A

Diuretic must go from blood side to apical membrane on tubular side. So it must be transported from basolateral side to apical side. Basally, it is transported by a transporter thet also transports uric acid, so competing w uric acid means uric acid is retained.

44
Q

Diuretics are used to treat hypertension. What is first line treatment diuretic?

A

Thiazides - “salt sensitive” hypertension

45
Q

Why thiazides over loop diuretics?

A

Initially loop diuretics are better (for a month or so) - due to their diuretic properties

HOWEVER, thiazides chronically have vasodilatory effects, which decreases TPR.

46
Q

How do thiazides have a vasodilatory effect

A
  1. Activates eNOS
  2. Ca channel antagonism
  3. Opening of K channel inducing hyperpolarisation
47
Q

Loop diuretics are given in? Why?

A

Heart failure

Acute reduction in congestion as decreases Na load by 30%

However chronic use associated w resistance due to RAS activation

Now sometimes given w K sparing diuretics - helps prevent resistance of loop diuretics

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