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Year 2 - Pharm Lectures 11+ > Diuretics > Flashcards

Diuretics Flashcards

1
Q

Explain the main points about the PCT in the kidneys

A

Sodium is taken up and co-transports the H2O
• 65-70% of Na+ reabsorbed.

There are lots of basal Na+/K+-ATPases to retain the sodium gradient

Oncotic pressure is assisted by the movement of:
• proteins & sodium

Carbonic anhydrase on inside the lumen ensures that bicarbonate is broken down
• to allow CO2 and H2O to pass into the cell
• HCO3- can be reabsorbed
• H+ can be used to drive the Na+/H+ exchanger (at apical membrane)
• (onenote!!)

Many drugs are exported OUT of the PCT into the lumen

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2
Q

Explain the main points about the LoH in the kindeys

A

Descending limb
– only H2O reabsorption via AQA molecules

Ascending limb:
– Impermeable to water for countercurrent flow
– Triple transporter (Na, Cl, K) re-absorbs ions
 Na+ is also reabsorbed para-cellularly
 This generates the hypertonic interstitium

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3
Q

Explain the Countercurrent Effect of the Kidneys

A
  1. Loop is filled with isotonic fluid
  2. Na+ is pumped OUT of the ascending limb into the interstitium
    • fluid in ascending limb decreases in osmolarity
  3. Concentrated interstitium pulls water IN to it from descending limb
    • fluid in descending limb increases in osmolarity
  4. More fluid flows into the tubule and shifts the descending limb fluid into the ascending limb
  5. Na+ is pumped again OUT of the ascending limb into the interstitium
    • ascending limb fluid decrease in osmolarity
  6. Na+ is pumped again out of the ascending limb into the interstitium. Ascending limb fluid decrease in osmolarity.
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4
Q

Explain the main points about the EARLY DCT in the kidneys

A

Mediated by the Na+/Cl—co-transporter
• draws more ions into the interstitium

Impermeable to free water reabsorption
• mediated mainly by selective AQA2 channels under VP control (much more common in late DCT than early though)

NO gap junctions so not permeable to free re-uptake.

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5
Q

Explain the main points about the LATE DCT & Collecting Duct in the kidneys

A

Aldosterone induces Na+-channel production

VP induces AQA2 synthesis dependant on blood osmolarity
• AQA3/4 constitutively expressed on basal membrane

Impermeable to free water re-uptake
• osmolarity increases as you pass deeper into the medulla so any free absorption would ruin the gradient as water would pass back into the tubular fluid

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6
Q

What are the 2 ways diuretics can work?

A
  1. INHIBITING the reabsorption of Na+ & Cl-
    • raising excretion
  2. Increasing the osmolarity of the tubular fluid
    • decrease osmotic gradient (i.e. osmotic diuretics)
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7
Q

What are the 5 main classes of diuretics?

A
  1. Osmotic diuretics
  2. Carbonic anhydrase inhibitors
  3. Loop diuretics
  4. Thiazides
  5. Potassium-sparing diuretics
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8
Q

Which diuretics are used clinically used?

A

ONLY
• loop diuretics
• thiazides
• K+-sparing

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9
Q

How do Osmotic Diuretics work?

A

Reduce water re-uptake at any part of the nephron that enables water re-absorption
• i.e. PCT, LoH & CD

Pharmacologically inert and is NOT reabsorbed after being filtered

Only action is to DECREASE the osmotic gradient by RAISING the osmolarity of the tubular fluid –> reduce water reabsorption
• interferes with the countercurrent flow.

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10
Q

What are osmotic diuretics normally used?

A

NOT as a diuretic

Used to raise PLASMA OSMOLARITY to fraw out fluid from cells & tissues
• e.g. in oedema

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11
Q

Example of a osmotic diuretic drug?

A

Mannitol

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12
Q

How do Carbonic Anhydrase diuretics work?

A

Acts at the PCT

By inhibiting the carbonic anhydrase, acetazolamide can:
• Increase HCO3- in the tubular fluid
• Increase the pH of the cell as LESS H+ ions are made from CO2 and H2O and so…
• Less Na+ is taken back up by the Na+/H+-anti-porter

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13
Q

What effect does Carbonic Anhydrase therefore have on the reabsorption of Na+ and H20

A

Action on Na+ reabsorption
• inhibit Na+ and HCO3- reabsorption in PCT

Action on H2O reabsorption
• increase tubular fluid osmolarity –> decrease water reabsorption

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14
Q

What other effect can carbonic anhydrase inhibitors have and when can this cause an issue?

A

Increase delivery of HCO3- to DCT
AND
increase K+ loss

  • This is bad for patients taking Digoxin
  • 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

Example of a Carbonic Anhydrase Inhibitor drug?

A

Acetazolamide

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16
Q

How do Loop Diuretics work?

A

Acts on the ascending limb of the LoH

Loop diuretics are strong diuretics
– 15-30%

Inhibit the triple transporter:
• impacts the countercurrent effect (less H20 reabsorption in CD)

Results in:
• K+ and Na+ loss
as well as
• loss of Ca2+ and Mg2+

17
Q

How does Loop Diuretics cause the loss of Ca2+ & Mg2+

A

There is a small leak of K+ into the tubule from the cell physiologically
• furosemide inhibits this –> less positive luminal pressure –> less paracellular transport of ions

• Mg2+ and Ca2+ ion loss due to loss of K+ recycling

18
Q

Example of a Loop Diuretic Drug?

A

Frusemide

19
Q

How do Thiazides work?

A

Act on the early DCT

Inhibit the Na+/Cl- co-transporter.
• not as strong as loop diuretics – 5-10%

Results in:
• K+ and Mg2+ loss and
• Ca2+ re-absorption (via an unknown mechanism)

Na+ may not be lost but exchanged in the late DCT with potassium so K is lost but not Na?

20
Q

What other effect do Thiazides have?

A

Increase Na+ delivery to DT

• increase K+ loss (as increase in Na+/k+ exchange)

21
Q

Example of a thiazide drug?

A

Bendroflumethiazide

22
Q

What is an problem that BOTH thiazides & loop diuretics have?

A

Release of RENIN from macula densa cells

23
Q

Explain the problem with BOTH thiazides & loop diuretics

A

Macula densa cell that detects the tubular [Na+] in the late ascending thick limb of the LoH

What effect would diuretics have on renin secretion?
• decreased Na+ load in the tubule will INCREASE renin secretion
• to promote Na+ reabsorption

Therefore diuretics would promote renin secretion

These effects result in resistance to chronic use diuretics!

24
Q

What diuretic would have the greatest effect on renin secretion?

A

LOOP DIURETICS

as they retain MORE Na+ in the tubule

25
Q

What is the final issue that BOTH thiazides and loop diuretics lead to and how is it tackled?

A

These effects result in resistance to chronic use diuretics!

So very common to administer ACE Inhibitors with diuretics

26
Q

How do K+-sparing diuretics work?

A

Spironolactone
– aldosterone receptor agonist

Amiloride
– aldosterone-sensitive Na+ channel inhibitor

These are not very powerful diuretics – 5%
• inhibit sodium reabsorption in the early DCT

Also cause decreased reabsorption of Na+ in the DCT and increased H+ retention
- due to effects of decreased Na+/H+ exchange

27
Q

Classes of K+ sparing drugs?

A

Spironolactone
– aldosterone receptor agonist

Amiloride
– aldosterone-sensitive Na+ channel inhibitor

28
Q

Common SEs seen with the use of diuretics?

A

Hypovolaemia
– loop diuretics
– thiazides

Hyponatraemia
– loop diuretics
– thiazides

Hypokalaemia
– loop diuretics
– thiazides

Metabolic alkalosis
– loop diuretics
– thiazides

Hyperuricaemia
– loop diuretics
– thiazides
– Loop diuretics have a more powerful effect of all

Hyperkalaemia
– K+-sparing diuretics

Metabolic acidosis
– carbonic anhydrase inhibitors

29
Q

Exampl the Hyperuricaemia SE seen with the use of diruetics

A

Diuretic drugs use the OAT to transport into the tubule from the drug and thus can compete with uric acid in the blood

This can lead to a greater blood concentration of uric acid

OAT = Organic Anion Transporter

30
Q

Why are other diuretics NOT K+-sparing?

A

Other diuretics cause an INCREASE in [Na+] reaching the CD
• leads to increased Na+/K+ exchange in the CD
• results in lots of K+ being LOST in the urine

31
Q

Explain the clinical use of diuretics in hypertension

A

Thiazides are the 1st line treatment in many countries
• Thiazides are especially useful in salt-sensitive hypertension

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

32
Q

Explain the response seen in patients with hypertension when given thiazides

A

Due to DECREASE in BV

Initial (4-6 weeks)
– reduction of BP due to reduction of blood volume

After 4-6 weeks
– plasma volume restored due to tolerance

Chronic thiazides
– 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.

33
Q

Explain the clinical effects of diuretics use in HF and oedema?

A

Loop diuretics

Acute reduction in congestion
o but will increase renin secretion –> cardiac remodelling

Chronic use is associated with resistance & RAS activation
o additional use of K+ sparing diuretics is used to try to stop the rebound activation of RAS

Year 2 - Pharm Lectures 11+ (23 decks)

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