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Y2 LCRS Pharm RI > Diuretics > Flashcards

Diuretics Flashcards

1
Q

What are diuretics?

A

Drugs that act on the renal tubule to promote excretion of H2O

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2
Q

What percentage of filtered fluid is reabsorbed in the proximal tubule?

A

65-70%

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3
Q

How does water move into the epithelial cells from the lumen inthe proximal tubule?

A

Osmosis – it will follow the diffusion of Na+ into the cell

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4
Q

What important protein is present on the basolateral membrane of epithelial cells along most of the tubule and is responsible for maintaining the concentration gradient that allows sodium reabsorption?

A

Na+/K+ ATPase

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5
Q

What other force is present, within the interstitium, that helps draw water in from the tubule?

A

Oncotic pressure – proteins in the blood in the arterioles

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6
Q

Other than through the cell, what other route is there for the movement of ions and water?

A

Paracellular pathway

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7
Q

What is the paraceulluar pathway dependent on?

A

Gap junctions

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8
Q

What two other molecules in the filtrate are reabsorbed in the proximal tubule and are coupled with Na+ reabsorption?

A

Glucose Amino acids

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9
Q

Explain how sodium exchange is linked to carbonic anhydrase?

A

HCO3- and H+ are filtered in the glomerulus They are then converted, by carbonic anhydrase, to H2O and CO2, which freely diffuse into the proximal tubule epithelial cell Inside the epithelial cell, carbonic anhydrase converts the H2O and CO2 to H+ and HCO3- HCO3- is then cotransported with Na+ into the interstitium H+ is exchanged for Na+ at the apical membrane via the Na+/H+ exchanger

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10
Q

How are exogenous agents removed in the kidneys?

A

Drugs are removed by transport proteins that pick up drugs as they pass through the kidneys and transport them into the lumen

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11
Q

Describe the permeability of the loop of Henle to water.

A

The descending limb is freely permeable to water but not to ions The ascending limb is impermeable to water but is permeable to ions

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12
Q

What is the main channel present on the apical membrane of the epithelial cells of the ascending limb of the loop of Henle?

A

Na+/K+/2Cl- cotransporter

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13
Q

What are the channels that are present on the basolateral membrane of the epithelial cells of the ascending limb of the loop of Henle?

A

Na+/K+ ATPase K+/Cl- cotransporte

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14
Q

Describe how the counter-current system is established.

A

The filtrate would travel down the loop of Henle and as it goes up the ascending limb (impermeable to water but permeable to ions), Na+ moves from the tubule to the interstitium thus making the interstitium hypertonic and the tubular fluid hypotonic. Then, more fluid will come down the descending limb (permeable to water) and the hypertonic interstitium will attract water and increase the reabsorption of water from the tubule into the interstitium This will increase the concentration of fluid reaching the ascending tubule where even more Na+ will be reabsorbed and move into the interstitium This occurs repetitively and you end up with a hypertonic interstitium and hypotonic tubular fluid leaving the loop of Henle This hypertonic interstitium is also responsible for increasing water reabsorption in the collecting duct (mediated by vasopressin)

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15
Q

What are the main channels on the apical membrane of epithelial cells of the distal tubule?

A

Na+/Cl- cotransporter Aldosterone dependent sodium channels

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16
Q

Which channels are found on the basolateral membrane of the epithelial cells of the distal tubule?

A

Na+/K+ ATPase K+/Cl- cotransporter

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17
Q

Which aquaporin molecules are found in epithelial cells of the distal tubule?

A

AQP2 – apical membrane AQP3/AQP4 – basolateral membrane

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18
Q

Which vasopressin receptors are present on collecting duct cells?

A

V2 receptors

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19
Q

Describe the effect of aldosterone on collecting duct cells.

A

Aldosterone binds to MR receptors and stimulates the production of Na+ channels and the production of Na+/K+ ATPases

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20
Q

Describe the effect of vasopressin on collecting duct cells.

A

Vasopressin stimulates the production and assembly of AQP2 molecules thus increasing the ability of the collecting duct to reabsorb water

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21
Q

List the five groups of diuretics.

A

Osmotic Diuretics* Carbonic Anhydrase Inhibitors* Loop Diuretics Thiazide Diuretics Potassium Sparing Diuretics *not used clinically to induce diuresis

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22
Q

Give an example of an osmotic diuretic.

A

Mannitol

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23
Q

Describe the mechanism of action of osmotic diuretics.

A

This is a pharmacologically inert chemical that can increase plasma and urine osmolarity It is filtered by the glomerulus but not reabsorbed Increasing the osmolarity of the filtrate means that less water leaves the lumen and is reabsorbed

24
Q

What are osmotic diuretics used for?

A

They are mainly used for their effect in increasing plasma osmolarity –they draw out fluid from cells and tissues (e.g. in oedema)

25
Q

Give an example of a carbonic anhydrase inhibitor

A

Acetazolamide

26
Q

Describe the mechanism of action of carbonic anhydrase inhibitors.

A

Inhibition of carbonic anhydrase reduces HCO3- reabsorption into the blood It also reduces the amount of H+ available within epithelial cells to drive the Na+/H+ exchanger and allow Na+ reabsorption

27
Q

Give an example of a loop diuretic.

A

Frusemide (furosemide)

28
Q

How much fluid loss can loop diuretics cause?

A

15-30%

29
Q

What is the target of loop diuretics?

A

Na+/K+/2Cl- cotransporter

30
Q

Explain how loop diuretics exert their diuretic effect.

A

They block the triple transporter thus reducing the reabsorption of Na+ in the ascending tubule This increases the tubular fluid osmolarity thus reducing water reabsorption from the tubular fluid so the urine fluid volume increases

31
Q

Explain why loop diuretics cause an increase in urinary excretionof Mg2+ and Ca2+.

A

Potassium recycling, under normal conditions, means that there is a certain amount of K+ in the tubular fluid that can maintain the positive lumen potential and drive other positively charged ions (Mg2+ and Ca2+) into the interstitium via the paracellular pathway Loop diuretics cause the loss of potassium recycling meaning that there is insufficient K+ in the lumen to drive the other positive ions through the paracellular pathway so you get increased urinary excretion of Mg2+ and Ca2+

32
Q

Why do loop diuretics cause an increase in K+ loss?

A

Loop diuretics increase the concentration of Na+ in the tubular fluid that is reaching the distal tubule This means that there is increased Na+/K+ exchange is the distal tubule –> increased K+ loss

33
Q

What is the main use of loop diuretics?

A

Oedema

34
Q

What are the unwanted effects of loop diuretics?

A

Hypovolaemia Hypotension Hypokalaemia Metabolic Alkalosis Hyperuricemia

35
Q

Give an example of a thiazide diuretic.

A

Bendrofluazide (bendroflumethiazide)

36
Q

Where do thiazide diuretics act and what do they act on?

A

They act in the distal tubule They bind to the Na+/Cl- cotransporter

37
Q

How much fluid loss can thiazide diuretics cause?

A

5-10% fluid loss

38
Q

What effect do thiazide diuretics have on Mg2+ and Ca2+?

A

Increase in Mg2+ loss Increase Ca2+ reabsorption (unknown mechanism)

39
Q

What are the uses of thiazide diuretics?

A

Hypertension Heart failure Nephrogenic diabetes insipidus Idiopathic hypercalciuria

40
Q

What are the side effects of thiazide diuretics?

A

K+ loss – metabolic alkalosis Inhibits insulin secretion (bad in diabetes mellitus) Hyponatremia Hypovolemia Hyperuricemia

41
Q

What effect do loop diuretics have on renin secretion?

A

Macula densa cells have the same Na+/K+/2Cl- cotransporter that is present in the ascending limb of the loop of Henle and is targeted by loop diuretics This means that loop diuretics prevent the entry of sodium into macula densa cells Detection of low sodium by the macula densa cells stimulates renin secretion

42
Q

Where are macula densa cells found?

A

At the top of the ascending limb of the loop of Henle where the distal convoluted tubule begins The top of the ascending limb comes very close to the afferent arteriole

43
Q

Explain the counter-productive effects of loop and thiazide diuretics on the renin-angiotensin system.

A

Given that they cause a loss of Na+ in the urine, chronic loop and thiazide diuretics will eventually cause reduced Na+ in the blood meaning that less Na+ is filtered in the glomerulus and hence less Na+ will reach the macula densa cells A reduction in the Na+ reaching the macula densa is a stimulus for renin secretion This leads to aldosterone production, which promotes sodium reabsorption (hence counterproductive to the effects we are trying to achieve with diuretics) Therefore plasma volume returns to previous levels after 4-6 weeks

44
Q

What measure can be taken to prevent this ‘tolerance’ to loop diuretics?

A

Give ACE inhibitors with the diuretics

45
Q

What are the two classes of potassium sparing diuretic? Give an example of a drug that falls into each class.

A

Aldosterone receptors antagonist – spironolactone Inhibitors of aldosterone-sensitive sodium channels – amiloride

46
Q

How much fluid loss can potassium-sparing diuretics cause?

A

5%

47
Q

Describe the effects of potassium-sparing diuretics.

A

They reduce sodium reabsorption in the late distal tubule, which leads to increased tubular osmolarity This will result in reduced water reabsorption from the tubular fluid in the collecting duct They also lead to increased H+ retention (because of reduced Na+/H+ exchange)

48
Q

What is the main use of amiloride?

A

It is given with K+ losing diuretics

49
Q

What are the main uses of spironolactone?

A

Hypertension/heart failure Hyperaldosteronism

50
Q

State some unwanted effects of K+ sparing diuretics.

A

Hyperkalaemia – metabolic acidosis Spironolactone (very non-specific action) – gynaecomastia, menstrual irregularities

51
Q

Where does aldosterone act in the kidney tubule?

A

Doesn’t effect the early distal tubule Effects the rest of the distal tubule and the collecting duct.

52
Q

How do diuretics cause hyperuricemia?

A

For diuretics to have their effect they have to get to the tubule lumen Diuretics and uric acid use the same ‘organic anion transporter’ to get from the blood to the tubule lumen Therefore, when diuretic drugs are present they use the organic anion transporter meaning uric acid cant use it Resulting in uric acid build up in the blood.

53
Q

Why are thiazides used rather than other diuretics?

A

The decreased plasma volume effect of diuretics is counteracted 4-6 weeks after beginning treatment due to RAAS adaptation

Thiazides have additional vasodilative effects:

  • Activate eNOS in endothelium –> More NO = vasodilation
  • Ca2+ antagonism
  • Open potassium channels
54
Q

How are diuretics used to treat heart failure?

A

Thiazide/loop used in conjunction with spironolactone

This is because spironolactone inhibits the effects of increased aldosterone levels driven by the RAAS rebound from the loop therapy.

55
Q

Draw the exchanges going on in a proximal tubule cell

A
56
Q

Draw the exchanges going on in a distal tubule cell

A

Y2 LCRS Pharm RI (34 decks)

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