Diuretics Flashcards
Explain the main points about the PCT in the kidneys
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
Explain the main points about the LoH in the kindeys
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
Explain the Countercurrent Effect of the Kidneys
- Loop is filled with isotonic fluid
- Na+ is pumped OUT of the ascending limb into the interstitium
• fluid in ascending limb decreases in osmolarity - Concentrated interstitium pulls water IN to it from descending limb
• fluid in descending limb increases in osmolarity - More fluid flows into the tubule and shifts the descending limb fluid into the ascending limb
- Na+ is pumped again OUT of the ascending limb into the interstitium
• ascending limb fluid decrease in osmolarity - Na+ is pumped again out of the ascending limb into the interstitium. Ascending limb fluid decrease in osmolarity.
Explain the main points about the EARLY DCT in the kidneys
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.
Explain the main points about the LATE DCT & Collecting Duct in the kidneys
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
What are the 2 ways diuretics can work?
- INHIBITING the reabsorption of Na+ & Cl-
• raising excretion - Increasing the osmolarity of the tubular fluid
• decrease osmotic gradient (i.e. osmotic diuretics)
What are the 5 main classes of diuretics?
- Osmotic diuretics
- Carbonic anhydrase inhibitors
- Loop diuretics
- Thiazides
- Potassium-sparing diuretics
Which diuretics are used clinically used?
ONLY
• loop diuretics
• thiazides
• K+-sparing
How do Osmotic Diuretics work?
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.
What are osmotic diuretics normally used?
NOT as a diuretic
Used to raise PLASMA OSMOLARITY to fraw out fluid from cells & tissues
• e.g. in oedema
Example of a osmotic diuretic drug?
Mannitol
How do Carbonic Anhydrase diuretics work?
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
What effect does Carbonic Anhydrase therefore have on the reabsorption of Na+ and H20
Action on Na+ reabsorption
• inhibit Na+ and HCO3- reabsorption in PCT
Action on H2O reabsorption
• increase tubular fluid osmolarity –> decrease water reabsorption
What other effect can carbonic anhydrase inhibitors have and when can this cause an issue?
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
Example of a Carbonic Anhydrase Inhibitor drug?
Acetazolamide
How do Loop Diuretics work?
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+
How does Loop Diuretics cause the loss of Ca2+ & Mg2+
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
Example of a Loop Diuretic Drug?
Frusemide
How do Thiazides work?
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?
What other effect do Thiazides have?
Increase Na+ delivery to DT
• increase K+ loss (as increase in Na+/k+ exchange)
Example of a thiazide drug?
Bendroflumethiazide
What is an problem that BOTH thiazides & loop diuretics have?
Release of RENIN from macula densa cells
Explain the problem with BOTH thiazides & loop diuretics
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!
What diuretic would have the greatest effect on renin secretion?
LOOP DIURETICS
as they retain MORE Na+ in the tubule
What is the final issue that BOTH thiazides and loop diuretics lead to and how is it tackled?
These effects result in resistance to chronic use diuretics!
So very common to administer ACE Inhibitors with diuretics
How do K+-sparing diuretics work?
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
Classes of K+ sparing drugs?
Spironolactone
– aldosterone receptor agonist
Amiloride
– aldosterone-sensitive Na+ channel inhibitor
Common SEs seen with the use of diuretics?
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
Exampl the Hyperuricaemia SE seen with the use of diruetics
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
Why are other diuretics NOT K+-sparing?
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
Explain the clinical use of diuretics in hypertension
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
Explain the response seen in patients with hypertension when given thiazides
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.
Explain the clinical effects of diuretics use in HF and oedema?
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
