Diuretics Flashcards
What are diuretics?
Drugs that act on the renal tubule to promote excretion of Na+, Cl- + 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 in the proximal tubule?
Osmosis: follows 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 draws water towards blood
Other than transcellularly, what other route is there for the movement of ions and water?
Paracellular pathway
What is the paracellular pathway dependent on?
Gap junctions
What 2 molecules in the filtrate are reabsorbed in the proximal tubule coupled with Na+ reabsorption? Which protein allows this movement?
Glucose
Amino acids
Sodium-Hydrogen exchanger protein
Explain how sodium exchange is linked to carbonic anhydrase?
HCO3- + H+ are filtered in the glomerulus
Carbonic anhydrase converts them to H2O + CO2, which freely diffuse into the proximal tubule epithelial cell
Inside the epithelial cell, carbonic anhydrase converts them back to H+ + HCO3-
HCO3- is 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 + transport them into the lumen
Describe the permeability of the loop of Henle to water.
Descending limb is freely permeable to water but not to ions
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 channels are present on the basolateral membrane of the epithelial cells of the ascending limb of the loop of Henle?
Na+/K+ ATPase
K+/Cl- cotransporter
Describe how the counter-current system is established.
Filtrate travels down the LOH + as it goes up the ascending limb, Na+ moves from the tubule to the interstitium thus making the interstitium hypertonic + tubular fluid hypotonic.
Then, more fluid comes down the descending limb (permeable to water) + the hypertonic interstitium attracts water + increases reabsorption of water from the tubule into the interstitium
This increases the conc. of fluid reaching the ascending tubule where even more Na+ will be reabsorbed + move into the interstitium
This occurs repetitively, resulting in a hypertonic interstitium + hypotonic tubular fluid leaving the LOH
Hypertonic interstitium is also responsible for increasing water reabsorption in the CD (mediated by vasopressin)
What are the main channels on the apical membrane of epithelial cells of the distal tubule?
Na+/Cl- cotransporter
Aldosterone dependent sodium channels
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?
AQP2: apical membrane
AQP3/AQP4: basolateral membrane
Which vasopressin receptors are present on collecting duct cells?
V2 receptors
Describe the effect of aldosterone on collecting duct cells.
Aldosterone stimulates production of Na+ channels + Na+/K+ ATPases
Describe the effect of vasopressin on collecting duct cells.
Vasopressin stimulates production + assembly of AQP2 molecules thus increasing the ability of the CD 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.
Increases plasma + urine osmolarity
Filtered by the glomerulus but not reabsorbed
Increasing osmolarity of filtrate means less water leaves the lumen + is reabsorbed
What are osmotic diuretics used for?
Mainly used for their effect in increasing plasma osmolarity –they draw out fluid from cells + tissues (e.g. in oedema)
Give an example of a carbonic anhydrase inhibitor
Acetazolamide
Give an example of a loop diuretic.
Frusemide (furosemide)
How much fluid loss can loop diuretics cause?
15-30%
What is the target of loop diuretics?
Na+/K+/2Cl- cotransporter in ascending limb of LOH
Explain how loop diuretics exert their diuretic effect.
Block the triple transporter thus reducing reabsorption of Na+ in the ascending limb
This increases tubular fluid osmolarity thus reducing water reabsorption so urine fluid volume increases
Explain why loop diuretics cause an increase in urinary excretion of Mg2+ and Ca2+.
K+ recycling, in normal conditions, means a certain amount of K+ in the tubular fluid maintains the positive lumen potential + drive other positively charged ions (Mg2+ + Ca2+) into the interstitium via the paracellular pathway
Loop diuretics cause loss of K+ recycling meaning 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+ + 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
So there is increased Na+/K+ exchange in distal tubule –> increased K+ loss
What are the main uses of loop diuretics?
Oedema + Heart failure
What are 6 unwanted effects of loop diuretics?
Hypovolaemia Hypotension Hypokalaemia Metabolic Alkalosis Hyperuricemia Hyponatremia
Give an example of a thiazide diuretic.
Bendrofluazide
Where do thiazide diuretics act and what do they act on?
Act in the distal tubule
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+ + Ca2+ reabsorption
unknown mechanism
What are the main uses of thiazide diuretics?
Hypertension
Heart failure
What are 6 unwanted effects of thiazide diuretics?
Hypovolaemia Hypotension Hypokalaemia Metabolic Alkalosis (increased Na+/K+ exchange causes increased K+ loss) Hyperuricemia Hyponatremia
What effect do loop diuretics have on the macula densa cells?
Macula densa cells have the same Na+/K+/2Cl- cotransporter that is present in the ascending limb of the LOH + is targeted by loop diuretics
This means loop diuretics prevent the entry of Na+ into macula densa cells, thus stimulating renin secretion
Where are macula densa cells found?
At the top of the ascending limb of the LOH
where it comes very close to the afferent arteriole
Explain the counter-productive effects of loop and thiazide diuretics on the renin-angiotensin system.
They cause loss of Na+ in the urine, so cause reduced Na+ in the blood meaning less Na+ is filtered in the glomerulus + hence less Na+ reaches the macula densa cells
Also reduce blood volume + pressure
Both reduction in Na+ reaching the macula densa + reduced renal perfusion pressure are stimuli for renin secretion
This leads to aldosterone production, which promotes Na+ reabsorption (hence counterproductive to the desired diuretic effects)
What measure can be taken to prevent the actions of unwanted activation of RAAS when using diuretics?
Give ACE inhibitors 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 effects of potassium-sparing diuretics.
Reduce Na+ reabsorption in the late distal tubule, which leads to increased tubular osmolarity
Results in reduced water reabsorption from the tubular fluid in the CD
Also lead to increased H+ retention (because of reduced Na+/H+ exchange)
What is the main use of amiloride?
Given with K+ losing diuretics
What is the main use of spironolactone?
Hypertension/ heart failure (alongside loop diuretic)
State an unwanted effect of K+ sparing diuretics.
Hyperkalaemia: metabolic acidosis (due to less Na+/K+ exchange)
By what mechanisms of action can diuretics work?
Inhibit reabsorption of Na+ + Cl- (increase excretion)
Increase osmolarity of tubular fluid (decrease osmotic gradient across epithelia)
How do thiazides exert their diuretic effect?
Inhibit Na+ + Cl- reabsorption in early distal tubule
Increase tubular fluid osmolarity, decreasing water reabsorption in the CD
Why can diuretics cause hyperuricemia?
Diuretics + uric acid use the same transport protein to access tubular cells, thus presence of diuretics means there is competition for transporters
