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Pharmacology Year 2 > Diuretics > Flashcards

Diuretics Flashcards

1
Q

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

A

65-70%

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2
Q

How does water move into the epithelial cells from the lumen (and then into the interstitium) in the proximal tubule?

A

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

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3
Q

What important protein is present on the basal 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
(i.e. Na+ into interstitium and K+ back into cell => Na+ conc. gradient between lumen and cell so that Na+ can diffuse across apical membrane)

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4
Q

What force is present (other than that provided by Na+ reabsorption), 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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5
Q

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

A

Paracellular pathway

Gap junctions

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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? Specifically, what exchange protein are they coupled with?

A

Glucose
Amino acids

Na+/H+ exchanger

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7
Q

Explain how sodium exchange is linked to carbonic anhydrase? Hence, describe how HCO3- (bicarbonate) ions are absorbed.

A
  • HCO3- and H+ are filtered at the glomerulus
  • Carbonic anhydrase converts them into H2O and CO2, which freely diffuse into the proximal tubule epithelial cell
  • Inside the epithelial cell, carbonic anhydrase converts the H2O and CO2 back into H+ and HCO3-

HCO3- is then cotransported with Na+ into the interstitium (at the basal membrane).
H+ is then driven back into the lumen in exchange for Na+ at the apical membrane via the Na+/H+ exchanger

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8
Q

How may exogenous agents be removed in the kidneys?

A

Drugs are removed by transport proteins that pick up drugs as they pass through the interstitium 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

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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11
Q

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

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

A

Apical (facing lumen):
Na+/K+/2Cl- cotransporter

Basal (facing interstitium):
Na+/K+ ATPase
K+/Cl- cotransporter

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12
Q

Describe how the counter-current system of the loop of Henle is established.

A

Ascending limb is impermeable to water => Na+ leaves the ascending limb and enters medullary interstitium => Fluid in ascending limb decreases in osmolarity (decreases in concentration).

Descending limb is permeable to water => the more concentrated medullary interstitium draws water from the permeable descending limb => Fluid in descending limb increases in osmolarity (increases in concentration)

More fluid enters (the descending limb) and forces fluid from descending to ascending limb (remember from above that this fluid is increased in osmolarity) => as this fluid is now in the ascending limb, more Na+ leaves to enter the interstitium, concentrating it further.

Cycle continues.

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13
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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14
Q

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

Hence state what molecules are reabsorbed here?

A

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

Na+, Cl- and H2O

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15
Q

Which aquaporin molecules are found in which membranes of the epithelial cells of the distal tubule? Why are they important?

A

AQP2 – apical membrane
AQP3/AQP4 – basal membrane

H2O isn’t able to get into the interstitium via paracellular pathway or transcellular (via Na+) - only APQs allow H2O transport.

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16
Q

Which vasopressin receptors are present on collecting duct cells?

A

V2 receptors

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17
Q

Describe the effect of aldosterone on collecting duct cells (i.e. what channels/transporters it stimulates and the result of this)

A

Aldosterone (via MR) stimulates the production of Na+ channels and the production of Na+/K+ ATPases therefore facilitating Na+ reabsorption and hence H2O reabsorption.

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18
Q

List the five groups of diuretics.

A 
Osmotic Diuretics
Carbonic Anhydrase Inhibitors
Loop Diuretics
Thiazide Diuretics
Potassium Sparing Diuretics
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19
Q

Give an example of an osmotic diuretic.

A

Mannitol

20
Q

What kind of chemical is an osmotic diuretic, and describe its mechanism of action in the kidneys?
Describe another use (the main use) of an osmotic diuretic.

A

This is a pharmacologically inert chemical that is filtered by the glomerulus but not reabsorbed => it increases urine osmolarity so that less water leaves the lumen and is reabsorbed.

Mainly used for their effect in increasing plasma osmolarity as they draw out fluid from cells and tissues (e.g. in oedema)

21
Q

Give an example of a carbonic anhydrase inhibitor

A

Acetazolamide

22
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

23
Q

Give an example of a loop diuretic.

A

Frusemide (or furosemide)

24
Q

How much fluid loss can loop diuretics cause?

A

15-30%

25
Q

What cotransporter do loop diuretics block?

Hence, explain how loop diuretics exert their diuretic effect.

A

Na+/K+/2Cl- cotransporter (in the ascending limb)

=> They reduce the reabsorption of Na+ (and Cl-) in the ascending tubule
=> This increases the tubular fluid osmolarity and decreases medullary interstitum osmolarity.
=> decreased H2O reabsorption in the collecting duct (and descending limb).

26
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; note that K+ after being transported by the triple transporter will leak a little back into lumen.

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+

27
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

28
Q

What is the main use of loop diuretics?

A

Treating oedema

29
Q

What are the 4 unwanted effects of loop diuretics?

A 
Hypovolaemia
Hypotension
Hypokalaemia
Metabolic Alkalosis
Hyperuricemia
30
Q

Give an example of a thiazide diuretic.

A

Bendrofluazide (or bendroflumethiazide)

31
Q

Where do thiazide diuretics act and what do they bind to and inhibit?
State the result of this?

A

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

Inhibit Na+ and Cl- reabsorption in early distil tubule
=> increased tubular fluid osmolarity => decreased H2O reabsorption in the collecting duct.

32
Q

What percentage loss of Na+ and Cl- can thiazides cause?

A

5-10%

33
Q

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

A

Increased Mg2+ loss and increased Ca2+ reabsorption (unknown mechanism)

34
Q

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

A

Increased delivery of Na+ to distal tubule => increased in K+ loss

35
Q

What are the uses of thiazide diuretics?

A

Hypertension
Heart failure
Nephrogenic diabetes insipidus
Idiopathic hypercalciuria

36
Q

What are the side effects of thiazide diuretics?

A 
Metabolic alkalosis (Cl- loss)
Hypovolaemia
Hyperuricemia
Hyponatremia
Hypokalemia
37
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

38
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, 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)

39
Q

What measure can be taken to prevent this from happening?

A

Give ACE inhibitors with the diuretics

40
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

41
Q

How much fluid loss can potassium-sparing diuretics cause?

A

5%

42
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)

43
Q

What is the main use of amiloride?

A

It is given with K+ losing diuretics

44
Q

What are the main uses of spironolactone?

A

Hypertension/heart failure

Hyperaldosteronism

45
Q

State some unwanted effects of K+ sparing diuretics.

A

Hyperkalaemia

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

46
Q

Explain why diuretics cause hyperuricaemia?

A

Diuretic and uric acid are both too big to be filtered at the glomerulus, however a transport protein at the basal membrane will ‘pick-up’ either of them up from the interstitium and drive them into the lumen for excretion.
This is good for the diuretic as it is now able to bind to its targets on the apical membrane, but as uric acid has to compete with diuretic for the same transporter, less of it will be excreted => more in the plasma.

Pharmacology Year 2 (32 decks)

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