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Y2 - PHARM > Diuretics > Flashcards

Diuretics Flashcards

1
Q

What are diuretics?

A

Drugs that act on the renal tubule to promote excretion of Na+, Cl- and 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

1) How does water move into the epithelial cells from the lumen in the proximal tubule?
2) What other force is present, within the interstitium, that helps draw water in from the tubule?

A

1)

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

2)

  • Constant oncotic pressure between the blood and the PCT because the glomerulus filters the blood but cannot filter out the protein, this remains in the blood and sets up this osmotic gradient as it attracts lots of water back to the blood
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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
  • So this pumps out Na+ out of the epithelial cell into the blood in order to feed it into the blood as a form of reabsorption
  • This Na+ efflux also maintains this concentration gradient set up in regards there being a lower concentration of sodium in the epithelial cells and high concentration in the lumen of the PCT in order to facilitate the movement of sodium into the epithelial cell
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5
Q

Other than through the cell (transcellular pathway), what other route is there for the movement of ions and water at the PCT and what is this route dependent on?

A
  • Paracellular pathway - i.e. through the gap junctions that are in between the epithelial cells of the PCT
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6
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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7
Q

Explain the actions of carbonic annhydrase, various transporters and the transport of bicarbonate and hydrogen at the PCT and mention also how this is linked to sodium reabsorption here

A
  • HCO3- and H+ are converted by carbonic annhydrase on the apical membrane of the epithelial cells in the PCT into H2O and CO2 which can freely diffuse across the membrane (as you’ve gone from polar to non-polar)
  • Carbonic annhydrase also converts the H2O and CO2 now within the cell back into HCO3- and H+
  • The now intracellular H+ is useful as its exchanged at an antiporter on the apical surface of the epithelial cell membrane with Na+ (so H+ is effluxed and Na+ is influxed to the cell)
  • Glucose and Amino acids transport is also coupled to this transporter in order for influx to the epithelial cell
  • HCO3- is then symported at the basolateral membrane with Na+ into the blood to complete the way in which this whole thing is coupled to Na+ reabsorption
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8
Q

How are exogenous agents such as drugs 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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9
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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10
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 (symporter)
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11
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- cotransporter
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12
Q

Summarise the movement of ions across the ascending loop of Henle, mentioning the transporters involved here for transcellular movement, and mention another type of movement

A
  • There is a sodium / potassium / chloride symporter on the apical membrane of the epithelial cells of the ascending loop of Henle so these all enter the cell
  • There is a Na+ / K+ ATPase on the basolateral membrane so Na+ is exported into the blood for reabsorption and there is K+ is imported into the epithelial cell in exchange
  • There is a K+ / Cl- symporter on the basolateral membrane also which exports the K+ and Cl- together out into the blood for reabsorption
  • There is also paracellular movement of some ions such as Cl- but this is a minor phenomenon within the ALOH
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13
Q

Describe how the counter-current system is established and then say what the point of it all is

A
  • The descending loop is permeable to water and impermeable to Na+
  • The filtrate travels down the loop of Henle and meanwhile, Na+ moves from the ascending limb 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 which leaves the descending limb as it is water permeable, making the tubular fluid more concentrated
  • By increasing the concentration of the tubular fluid, even more Na+ will be reabsorbed and move into the interstitium. Remember, the ascending limb is impermeable to water so this prevents the destruction of this concentration set-up
  • This occurs repetitively and you end up with a very hypertonic interstitium and hypotonic tubular fluid leaving the loop of Henle
  • AKA the point is you’re trying to make the interstitium as concentrated as possible so by the time you get to the collecting duct, you’ll get lots of water reabsorption by osmosis as mediated by VP
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14
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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15
Q

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

A
  • Na+/K+ ATPase
  • K+/Cl- cotransporter (symporter which effluxes them both into the blood - reabsorption)
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16
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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17
Q

Which vasopressin receptors are present on collecting duct cells?

A
  • V2 receptors
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18
Q

Describe the effect of aldosterone on collecting duct cells

A
  • Aldosterone stimulates the production of Na+ channels on the apical membrane and the production of Na+/K+ ATPases
  • Thereby greatly increasing the reabsorption of Na+
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19
Q

Describe the effect of vasopressin on collecting duct cells

A
  • Vasopressin stimulates the production and assembly of AQP2 molecules on the apical membrane, thus increasing the ability of the collecting duct to reabsorb water
20
Q

List the five groups of diuretic

A
  1. Osmotic Diuretics
  2. Carbonic Anhydrase Inhibitors
  3. Loop Diuretics
  4. Thiazide Diuretics
  5. Potassium Sparing Diuretics
21
Q

Give an example of an osmotic diuretic

A

Mannitol

22
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
23
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)
24
Q

Give an example of a carbonic anhydrase inhibitor

A
  • Acetazolamide
25
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
  • Less Na+ reabsorption means less water reabsorption so more water in the urine to be excreted
26
Q

Give an example of a loop diuretic

A
  • Frusemide (furosemide)
27
Q

What is the target of loop diuretics?

A
  • Na+/K+/2Cl- cotransporter on the ascending limb of the loop of Henle
28
Q

Explain how loop diuretics exert their diuretic effect

A
  • They block the triple transporter (Na+ / K+ / Cl- symporter) 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
29
Q

Explain why loop diuretics cause an increase in urinary excretion of 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+ instead
30
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 - hypokalaemia
31
Q

What is the main use of loop diuretics?

A
  • Reducing oedema
32
Q

What are the unwanted effects of loop diuretics?

A
  • Hypovolaemia
  • Hypotension
  • Hypokalaemia
  • Metabolic Alkalosis
33
Q

Give an example of a thiazide diuretic

A
  • Bendrofluazide (bendroflumethiazide)
34
Q

Ho do thiazide diuretics work, where do they act and what do they act on?

A
  • They act in the distal tubule
  • They bind to and inhibit the Na+/Cl- cotransporter
  • Thereby reducing reabsorption of these ions and threreby reducing water reabsorption
35
Q

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

A
  • Increase in Mg2+ and Ca2+ reabsorption (unknown mechanism)
36
Q

What are the uses of thiazide diuretics?

A
  • Hypertension
  • Heart failure
  • Nephrogenic diabetes insipidus
  • Idiopathic hypercalciuria
37
Q

What are the unwanted effects of thiazide diuretics?

A
  • K+ loss – metabolic alkalosis
  • Inhibits insulin secretion (bad in diabetes mellitus)
38
Q

What effect do loop diuretics have on the macula densa cells?

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
39
Q

Where are macula densa cells found?

A
  • At the top of the ascending limb of the loop of Henle
  • The top of the ascending limb comes very close to the afferent arteriole
40
Q

1) Explain the counter-productive effects of loop and thiazide diuretics on the renin-angiotensin system and why this is more severe with loop diuretics than with thiazide diuretics
2) What measure can be taken to prevent this from happening?

A

1)

  • Given that they cause a loss of Na+ in the urine, 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
  • Loop diuretics have this effect even more because they directly inhibit the Na+ / K+ / Cl+ which is also found on the macula densa cells in the DCT as well as on the PCT (PCT being the intended target), thereby reducing further the entry of sodium to 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)

2)

  • Give ACE inhibitors with the diuretics
41
Q

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

A
  1. Aldosterone receptors antagonist – spironolactone
  2. Inhibitors of aldosterone-sensitive sodium channels – amiloride
  • Basically both of them inhibit the actions of aldosterone but in different ways
42
Q

Why do potassium-sparing diuretics not have much effect on fluid loss i.e. weak diuretic effect?

A
  • Because they act on the late DCT and CD mainly where there is a low [Na+] already so will not have much effect as they won’t be able to manipulate the sodium as much
43
Q

Describe the effects of potassium-sparing diuretics

A
  • They reduce sodium reabsorption in the late DCT, 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)
44
Q

What is the main use of amiloride?

A
  • It is given with K+ losing diuretics
45
Q

What are the main uses of spironolactone?

A
  • Hypertension/heart failure
  • Hyperaldosteronism
46
Q

State some unwanted effects of K+ sparing diuretics

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

Y2 - PHARM (27 decks)

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