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*Y2 LCRS Pharmacology* > Diuretics > Flashcards

Diuretics Flashcards

1
Q

What are Diuretics?

A

Drugs that act on the renal tubule to promote the excretion of Na+. Cl- and H20

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2
Q

Summerise the reabsorption that occurs in the Proximal Convoluted Tubule:

A

Lots of water, Sodium and Bicarbonate are reabsorbed in the PCT mainly by:

Oncotic pressure
Na/K ATPase pumps
Na/HCO3 Contransporters
in the basal membrane

Also reuptake of Exogenous agents

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3
Q

What occurs in the descending limb of the loop of Henle?

A

Freely Permeable to water - Water moves from lumen into interstiutium

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4
Q

What occurs is the ascending loop of Henle?

A

Not permeable to water

Na+/K+/2Cl- transporter uptakes these ions into the cells

Basally, Na+/K+ ATPase and K+/Cl- Cotransporter move them into interstitium maintaining the concentration gradient allowing absorption from the lumen into the cell

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5
Q

What is the purpose of the Loop of Henle and the counter-current flow?

A

To keep the interstitium hypertonic

Decrease the osmolarity of the fluid in the ascending limb

Allow for reabsorption and retention of water in the descending limb and collecting ducts by maintaining a large concentration gradient

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6
Q

What occurs in the early distal convoluted tubule?

A

Any remaining sodium is reabsorbed by Na+/Cl- transporters apically

(this will ensure the tubule fluid has a low osmolarity for reabsorption of water)

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7
Q

What happens in the late distal tubule?

A

Aldosterone and Aquaporins become to be more important here

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8
Q

What is aldosterone, and what effect does it have in the nephron?

How does it work?

A

Mineralocorticoid Steroid

Binds to the Mineralocorticoid receptors (MR) in the cells of the Late DCT and Collecting duct

Via the nucleus it increases the production of both:

  • Na+ channels in the apical membrane
  • Na+/K+ ATPase in the basolateral membrane

Responsible for maintaining sodium reabsorption and its concentration gradient

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9
Q

What hormone is responsible for water retention in the Collecting duct?

How does it work?

A

Vasopressin

It increases the transcription and insertion of Aquaporin 2 molecules into the basal membrane that allow the water in the tubule to follow the sodium

Also causes insertion of AQP 3/4 into the basolateral membrane

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10
Q

How do most Diuretics work?

A

Inhibit the reabsorption of Sodium and Chlorine ions which leads to a decreased osmotic gradient across the epithelia

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11
Q

What are the Five main classes of Diuretics?

Give an example for each:

A

Osmotic Diuretics - Mannitol

Carbonic Anhydrase Inhibitors - Acetazolamide

Loop Diuretics - Fursemide

Thiazide Diuretics - Bendrofluazide

Potassium-sparing Diuretics - Spironolactone

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12
Q

Where does each class of Diuretic act?

A
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13
Q

What is Mannitol?
What is it used for?
Where does it act?
How does it work?

A

Osmotic Diuretic

Not directly used as diuretic; used to raise plasma osmolarity to draw out fluid from cells and tissues (Oedema)

Will have the same effect throughout the nephron

Pharmacologically inert - works like excess glucose in DM causing polyuria - Increases the osmolarity of plasma and kidney filtrate
Less water will leave the lumen due to decreased osmotic gradient

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14
Q

What is Acetazolamide?

What does it do?
How does it work?
Where does it act?
Why is it not used much?

A

Carbonic Anhydrase Inhibitor

Prevents Carbonic Anhydrase from converting CO2 + H20 to H+ and HCO3- in the cells of the PCT

Therefore there will be less H+ to be exchanged with Na+ at the apical membrane - Less sodium is absorbed - Less water is reabsorbed

The kidney is good at compensating and as this drug acts early in the kidneys, they have a long time to compensate for it and thus it is not very effective and isn’t used much clinically

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15
Q

What is Furosemide?

Where does it act?
How does it work?

A

Loop Diuretic - works on the ascending limb of the Loop of Henle

Targets the Na+/K+/2Cl- triple transporter - greatly impairs sodium reabsorption in the ascending loop

Decrease in osmolarity of medullary interstitium - less water reuptake in loop and CDs

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16
Q

What are all of the effects of Furosemide?

A
  • Less Na+ and Cl- reabsorption
  • Less water reabsorption
  • Less reabsorption of Ca+ and Mg2+ due to loss of K+ recycling
  • Loss of K+ - due to more Na+ getting to the DCT and being antiported with K+ which remains in the lumen
17
Q

How effective is Furosemide?

What increase in water loss does it cause?

A

Very stronk

Can cause 15-30% fluid loss
(normally 1-2% fluid is lost in urine)

18
Q

What is Potassium recycling?

How is it affected by Furosemide?

A

Normally K+ is reabsorbed by the triple transporter

It then diffuses back out of the cell into the lumen

This creates a Positive lumen potential which drives the movement of positive ions (Na,Ca,Mg) across the paracellular pathway into the interstitium

Furosemide blocks this recycling and therefore positive ions are lost in urine

19
Q

What is Bendroflumethiazide?

Where does it act?
How does it work?

A

Thiazide Diuretic

Early DCT

Binds to the Na/Cl Cotransporter

Prevents Na+ uptake and therefore reduces the osmotic gradient

20
Q

Why do Thiazides have less of an effect than Loop Diuretics?

A

They work in the PCT vs the Loop and only about 5-10% of water reabsorption occurs there

21
Q

What are the effects of Thiazides on other ion concentrations?

A

Causes K+ loss as there is more Na+ present in the late PCT so the Na+/K+ exchanger has more Na to exchange

Also causes an increase in Mg2+ loss and Ca2+ reabsorption, but no one knows why..

22
Q

Summerise the problem with long term use of Loop and Thiazide diuretics:

A

They increase Na+ excretion
Less Na+ in blood
Less Na+ filtered in nephron
Less Na+ to enter macula densa cells

Decrease in Na+ in MD is a stimulus for Renin Secretion in order to reabsorb Na+

This activates the RAAS which negates the effects of the diuretics

23
Q

What is the solution to the Diuretic Renin problem?

A

Coadminister ACE inhibitors

24
Q

What is Spironolactone?

Where does it act?
How does it work?
How much fluid loss does it cause?

A

Aldosterone Receptor Antagonist - Potassium Sparing Diuretic

Inhibits Mineralocorticoid receptors in the Collecting duct

Prevents the effects of aldosterone by preventing it from causing insertion of Na+ channels in the Apical membrane and Na+/K+ ATPase in the basal membrane

Less Na reabsorption leads to 5% fluid loss

25
Q

What is Amiloride?

How does it work?

A

Potassium Sparing Diuretic

Blocks the Na+ channel inserted in the apical membrane by Aldosterone

26
Q

Why are they called ‘Potassium-sparing’?

A

Other diuretics cause an increase in the [Na+] reaching the collecting duct, which leads to increased Na+/K+ exchange in CD cells resulting in more lost K+

These only reduce the Na uptake in the collecting duct so has no effect on K+

27
Q

What are the effects of Spironolactone on ion levels?

A

Inhibits Na+ reabsorption
Inhibits concomitant K+ secretion

Causes H+ retention (reduced Na+/H+ exchange)

Loss of Uric Acid

28
Q

List the possible side effects of Thiazides and Loop diuretics:

A

Hypovolemia

Hyponatremia

Hypokalemia

Metabolic Alkalosis

Hyperuricaemia

(Loop has stonger side effects)

29
Q

What are the side effects of Carbonic Anhydrase inhibitors?

A

Metabolic Acidosis due to HCO3- loss

30
Q

What are the side effects of Potassium-sparing diuretics?

A

Hyperkalemia

Spironolactone isn’t very specific in targeting receptors - can cause gynaecomastia, menstrual disorders and testicular atrophy

31
Q

How do Thiazides and Loop diuretics cause Hyperuricaemia?

A

They use the Organic Anion Transporter (OAT) to enter cells in the nephron

This is normally used by Uric Acid
Drug can compete with Uric acid and prevent as much being excreted from the blood, so it builds up

32
Q

What’s the first-line treatment for HPT?

A

Thiazides

(Salt sensitive)

Thiazides > calcium channel blockers > ACEi – for treating high SBP

33
Q

What is the response to Thiazides over time?

A

First 4-6 weeks: Reduction in BP due to decreased Blood Volume

After: Plasma volume restored due to tolerance

Chronic: Reduction of TPR due to – activation of eNOS, Ca2+-channel antagonism and opening of KCa-channels.

Leads to: NO production, less calcium influx and hyperpolarisation.

*Y2 LCRS Pharmacology* (20 decks)

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