Diuretics Flashcards
What are diuretics?
Drugs that act on the renal tubule to promote excretion of Na+, Cl- and H2O
What percentage of filtered fluid is reabsorbed in the proximal tubule?
65-70%
How does water move into the epithelial cells from the lumen inthe proximal tubule?
Osmosis – it will follow the diffusion of Na+ into the cell
What important protein is present on the basolateral membrane of epithelial cells along most of the tubule and is responsible for maintaining the concentration gradient that allows sodium reabsorption?
Na+/K+ ATPase
What other force is present, within the interstitium, that helps draw water in from the tubule?
Oncotic pressure – proteins in the blood in the arterioles
Other than through the cell, what other route is there for the movement of ions and water?
Paracellular pathway
What two other molecules in the filtrate are reabsorbed in the proximal tubule and are coupled with Na+ reabsorption?
Glucose
Amino acids
Explain how sodium exchange is linked to carbonic anhydrase?
HCO3- and H+ are filtered in the glomerulus
They are then converted, by carbonic anhydrase, to H2O and CO2, which freely diffuse into the proximal tubule epithelial cell
Inside the epithelial cell, carbonic anhydrase converts the H2O and CO2 to H+ and
HCO3-
HCO3- is then cotransported with Na+ into the interstitium
H+ is exchanged for Na+ at the apical membrane via the Na+/H+ exchanger
How are exogenous agents removed in the kidneys?
Drugs are removed by transport proteins that pick up drugs as they pass through the kidneys and transport them into the lumen
Describe the permeability of the loop of Henle to water.
The descending limb is freely permeable to water but not to ions
The ascending limb is impermeable to water but is permeable to ions
What is the main channel present on the apical membrane of the epithelial cells of the ascending limb of the loop of Henle?
Na+/K+/2Cl- cotransporter
What are the channels that are present on the basolateral membrane of the epithelial cells of the ascending limb of the loop of Henle?
Na+/K+ ATPase (present throughout the nephron)
K+/Cl- cotransporter
Describe how the counter-current system is established.
The filtrate would travel down the loop of Henle and as it goes up the ascending limb (impermeable to water but permeable to ions), Na+ moves from the tubule to the interstitium thus making the interstitium hypertonic and the tubular fluid hypotonic.
Then, more fluid will come down the descending limb (permeable to water) and the hypertonic interstitium will attract water and increase the reabsorption of water from the tubule into the interstitium
This will increase the concentration of fluid reaching the ascending tubule where even more Na+ will be reabsorbed and move into the interstitium
This occurs repetitively and you end up with a hypertonic interstitium and hypotonic tubular fluid leaving the loop of Henle
This hypertonic interstitium is also responsible for increasing water reabsorption in the collecting duct (mediated by vasopressin)
What are the main channels on the apical membrane of epithelial cells of the distal tubule?
Early DCT:
Na+/Cl- cotransporter
from late DCT onwards, it will ALSO have:
Aldosterone dependent sodium channels
AQP2 (via ADH binding to V2 receptors)
Which channels are found on the basolateral membrane of the epithelial cells of the distal tubule?
Na+/K+ ATPase
K+/Cl- cotransporter
Which aquaporin molecules are found in epithelial cells of the distal tubule (late DCT and collecting duct)?
AQP2 – apical membrane
AQP3/AQP4 – basolateral membrane
Which vasopressin receptors are present on collecting duct cells and late DCT?
V2 receptors
Describe the effect of aldosterone on collecting duct cells (and late DCT).
Aldosterone stimulates the production of Na+ channels on apical side (facing lumen) and the production of more Na+/K+ ATPases
Describe the effect of vasopressin on collecting duct cells.
Vasopressin stimulates the production and assembly of AQP2 molecules thus increasing the ability of the collecting duct to reabsorb water
List the five groups of diuretics.
Osmotic Diuretics Carbonic Anhydrase Inhibitors Loop Diuretics Thiazide Diuretics Potassium Sparing Diuretics
Give an example of an osmotic diuretic.
Mannitol
Describe the mechanism of action of osmotic diuretics.
This is a pharmacologically inert chemical that can increase plasma and urine osmolarity
It is filtered by the glomerulus but not reabsorbed
Increasing the osmolarity of the filtrate means that less water leaves the lumen and is therefore excreted
What are osmotic diuretics used for?
They are mainly used for their effect in increasing plasma osmolarity –they draw out fluid from cells and tissues (e.g. in oedema)
Give an example of a carbonic anhydrase inhibitor
Acetazolamide
Describe the mechanism of action of carbonic anhydrase inhibitors.
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 so less Na reabsorption so less water reabsorption
Give an example of a loop diuretic.
Frusemide (furosemide)
How much fluid loss can loop diuretics cause?
15-20%
What is the target of loop diuretics?
Na+/K+/2Cl- cotransporter
Explain how loop diuretics exert their diuretic effect.
They block the triple transporter thus reducing the reabsorption of Na+ in the ascending tubule
This increases the tubular fluid osmolarity thus reducing water reabsorption from the tubular fluid so the urine fluid volume increases
Explain why loop diuretics cause an increase in urinary excretion of Mg2+ and Ca2+.
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
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+
Why do loop diuretics cause an increase in K+ loss?
Loop diuretics increase the concentration of Na+ in the tubular fluid that is reaching the distal tubule
The kidney will increase the activity of Na/K atpase on basolateral membrane in order to reabsorb all this Na. This increases K+ loss
What is the main use of loop diuretics?
Oedema
What are the unwanted effects of loop diuretics?
Hypovolaemia + Hypotension
Hypokalaemia
Hyponatraemia
Metabolic Alkalosis
Give an example of a thiazide diuretic.
Bendrofluazide (bendroflumethiazide)
Where do thiazide diuretics act and what do they act on?
They act in the distal tubule
They bind to the Na+/Cl- cotransporter
How much fluid loss can thiazide diuretics cause?
5-10% fluid loss
What effect do thiazide diuretics have on Mg2+ and Ca2+?
Increase in Mg2+ and Ca2+ reabsorption (unknown mechanism)
NB this is opposite to Loop diuretics which cause more excretion of these two ions
What are the uses of thiazide diuretics?
Hypertension
Heart failure
Nephrogenic diabetes insipidus
Idiopathic hypercalciuria
What are the unwanted effects of thiazide diuretics?
Hypovolaemia + hypotension) Hyponatremia Hypokalaemia (More sodium so increased Na/K+ atpase activity) Metabolic alkalosis Hyperuricemia
Same as loop diuretic + hyperuricemia
What effect do loop diuretics + thiazides have on the macula densa cells?
Macula densa cells stimulate renin release when they detect low tubular Na. Thiazide and loop both work by reducing Na reabsorption. Overtime, blood Na drops and so tubular fluid Na also drops. This triggers macula densa to stimulate renin release from juxtaglomerular cells. This is why Thiazide and loop diuretics patients get a rebound RAAS activation overtime.
Also, Loop diuretics block the triple transporter which is also present on the macula densa cells and so this has a direct instant effect because macula densa cells instantly realises ‘where is the sodium gone’ and so will start triggering renin release
Where are macula densa cells found?
At the top of the ascending limb of the loop of Henle
The top of the ascending limb comes very close to the afferent arteriole
Why would one pick thiazides over other diuretics, despite its rebound RAAS effect?
Chronic use of thiazides = vasodilating properties= Reduced TPR (unknown mechanism)
What measure can be taken to prevent this from happening?
Give ACE inhibitors or K+ sparing diuretics to block the effects of the rebound RAAS with the diuretics
What are the two classes of potassium sparing diuretic? Give an example of a drug that falls into each class.
Aldosterone receptors antagonist – spironolactone
Inhibitors of aldosterone-sensitive sodium channels – amiloride
How much fluid loss can potassium-sparing diuretics cause?
5%
Describe the MOA of potassium-sparing diuretics.
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
State some unwanted effects of K+ sparing diuretics.
Hyperkalaemia
H+ retention
loss of which ion can lead to metabolic alkalosis?
Cl- loss is associated with MA
Hence Loop diuretics and Thiazides are both associated with MA (inhibit triple transporter or Na/Cl- cotransporter)
How do diuretics cause hyperuricemia
Most diuretics act on apical membrane transporters and they access the apical membrane by entering the cell via the organic anion transporter. This transporter is used for uric acid excretion too and so they compete against each other
