Diuretics Flashcards
What percentage of sodium is reabsorbed?
60-70% in the convoluted tubule
What are the features of the PCT that allows reabsorption of sodium an water?
- lots of basal Na+/K+-ATPases to retain the sodium gradient
- Oncotic pressure is assisted by the movement of proteins and sodium
- Carbonic anhydrase on inside the lumen ensures that bicarbonate is broken down to allow CO2 and H2O to pass into the cell
What happens in the descending loop of Henle?
only H2O reabsorption via AQA molecules
What happens in the ascending loop of Henle?
Impermeable to water – for countercurrent flow
Triple transporter (Na, Cl, K) re-absorbs ions - Na+ is also reabsorbed para-cellularly -> generates the hypertonic interstitium
How is the countercurrent effect generated?
- 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 into 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
What happens in the early DCT?
Draws more ions into the interstitium -mediated by the Na+/Cl—co-transporter
Impermeable to free water reabsorption
(no gap junctions), mediated mainly by selective AQA2 channels under VP control (much more common in late DCT than early though).
What happens in the late DCT (collecting duct)?
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
How do diuretic work?
by:
- Inhibiting the reabsorption of Na+ and 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? Give examples of each
- Osmotic diuretic e.g mannitol
- Carbonic anhydrase inhibitors e.g acetazolamide
- Loop diuretics e.g furosemide (frusemide)
- Thiazides e.g bendroflumethiazide (bendrofluazide)
- Potassium-sparing diuretics e.g miloride, spironolactone
- only last three used clinically
How do osmotic diuretics work?
Reduce water re-uptake at any part (PCT, LoH, CD) of the nephron that enables water re-absorption
Only action is to decrease the osmotic gradient by raising the osmolarity of the tubular fluid -> reduce water reabsorption
- Interferes with the countercurrent flow
Are osmotic diuretics reabsorbed?
Pharmacologically inert and not reabsorbed after being filtered.
How do carbonic anhydrase inhibitors work?
- Acts at the PCT.
By inhibiting the carbonic anhydrase, acetazolamide can:
- Increase bicarbonate in the tubular fluid
- Increase the pH of the cell as LESS H+ ions are made from CO2 and H2O -> Less Na+ is taken back up by the Na+/H+-anti-porter
What is the effect of carbonic anhydrase inhibitors on sodium reabsorption?
inhibit Na+ and HCO3- reabsorption in PCT
What is the effect of carbonic anhydrase inhibitors on water reabsorption?
increase tubular fluid osmolarity -> decrease water reabsorption
What are other effects of carbonic anhydrase?
increase delivery of HCO3- to DCT and increase K+ loss
- This is bad for patients taking Digoxin!
Why are carbonic anhydrase inhibitors not used clinically?
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
How do loop diuretics work?
Acts on the ascending limb of the LoH
Inhibit the triple transporter -> Impacts the countercurrent effect -> Results in K+ and Na+ loss as well as loss of Ca2+ and Mg2+
There is a small leak of potassium into the tubule from the cell physiologically and furosemide inhibits this -> less positive luminal pressure -> less paracellular transport of ions
Mg2+ and Ca2+ ion loss due to loss of K+ recycling
How do thiazides work?
Act on the early DCT
Inhibit the Na+/Cl—co-transporter -> Results in K+ and Mg2+ loss and Ca2+ re-absorption (via an unknown mechanism)
What effect would diuretics have on renin secretion?
Decreased sodium load in the tubule will increase renin secretion to promote sodium reabsorption therefore diuretics would promote renin secretion
What diuretic would have the greatest effect on renin secretion?
loop diuretics - retain more sodium in tubule
What is a problem with thiazides and loop diuretics?
resistance to chronic use diuretics
How do potassium sparing diuretics work?
Spironolactone – aldosterone receptor agonist
Amiloride – aldosterone-sensitive Na+ channel inhibitor
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
What are the side effects of diuretics?
Loop diuretics and thiazides: - Hypovolaemia - Hyponatraemia - Hypokalaemia - Metabolic alkalosis Hyperuricaemia
- Loop diuretics have a more powerful effect of all
K+-sparing diuretics:
- Hyperkalaemia
carbonic anhydrase inhibitors:
- Metabolic acidosis
How do diuretics cause hyperuricaemia?
Diuretic drugs use the OAT to transport into the tubule from the drug and thus can compete with uric acid in the blood -> can lead to a greater blood concentration of uric acid
What are thiazides used for clinically?
1st line treatment in many countries for hypertension
- especially useful in salt-sensitive hypertension
Thiazides > calcium channel blockers > ACEi – for treating high SBP
Describe the response to thiazides
- 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
What are loop diuretics used for clinically?
heart failure and oedema
acute reduction in congestion
- But will increase renin secretion -> cardiac remodelling
What is chronic use of loop diuretics associated with? How is this accommodated for?
resistance and RAS activation
- Additional use of K+ sparing diuretics is used to try to stop the rebound activation of RAS
