Pharm 21 - Diuretics Flashcards
Where is the Na/K ATPase found?
K in, Na out
On the basal membrane of the kidney cell (proximal tubule)
Drives Na out of the cell to ensure a conc gr for Na to diffuse into the cell via the tubular/apical side - ensures maximal Na reabsorption
What are diuretics
Drugs acting on the renal tubule to promote excretion of Na, Cl and H2O.
What does the oncotic pressure in the interstitium do?
It draws water from the PCT into the capillaries - oncotic pressure exerted by the proteins in blood
What other route of transmission of ions is there in the proximal tubule cell?
Paracellular pathway - dependent on gap junctions - PCT cells have large gap junctions
Glucose and amino acid reabsorption is coupled with?
Sodium reabsorption - specifically the Na+/H+ antiporter
Explain how sodium exchange is linked with carbonic anhydrase
- After being filtered by the glomerulus, HCO3- and H+ converted to H2O + CO2 by membrane bound carbonic anhydrase (apical/tubular side)
- CO2 + H2O freely diffuse into the cell, where cytoplasmic carbonic anhydrase converts it back into HCO3- and H+
- HC03- reabsorbed into capillaries via Na+/HCO3- cotransporter (basal side)
- H+ used for the Na+/H+ anti porter
What other important thing does the kidney excrete?
Exogenous agents - kidney has a lot of transport proteins that pick up the drug (often by recognising polar conjugate groups)
The PCT absorbs upto how much filtrate?
70%
What happens in the descending Loh
Freely permeable to water - so water moves from tubule (isotonic) through the descending limb cell into the interstitium (hypertonic due to plasma proteins)
The ascending Loh is the first part of the kidney that is not….
Freely permeable to water
Explain what happens in the ascending Loh cell?
- Na+/K+/2Cl- absorbed on the tubular/apical side via Na+/K+/2Cl- transporter
- On the basolateral membrane, Na+/K+ ATPase and K+/Cl- cotransporter move these electrolytes from epithelial cell into interstitium
(3. Small paracellular pathway also present)
What is the importance of the countercurrent system?
Ensuring we retain as much fluid as possible (by having a very concentrated interstitium which enables more water reabsorption from CD)
Capillaries pass in the opposite direction to the flow of fluid - hence “counter current”
Where is aldosterone produced?
Adrenal glands
What happens in the early DCT?
Any Na left in tubules absorbed via Na+/Cl- cotransporter (apical side)
What happens in the late DCT
Aldosterone and mineralocorticoids become more important in up regulating Na+/K+ ATPase and Na+ channels
Which 2 molecules are important in mediating CD function?
Aldosterone (binds to mineralocorticoid receptors) and Vasopressin (synthesise/assemble AQP2 for water reabsorption following Na)
2 ways how diuretics work
- Inhibit reabsorption of Na and Cl (i.e. increase excretion)
- Increase osmolarity of tubular fluid (i.e. decrease osmotic gradient across epithelia)
What are the 5 main classes of diuretics and give an example of each
- Osmotic diuretics - e.g. mannitol (acts throughout tubule)
- Carbonic anhydrase inhibitors - e.g. acetazolamide (acts mainly in PCT)
- Loop diuretics - e.g. frusemide (furosemide)
- Thiazides - e.g. bendrofluazide bendroflumethiazide)
- K+ sparing drugs (e.g. amiloride, spironolactone)
Osmotic diuretics (Eg mannitol) work how?
By raising osmolarity of plasma and kidney filtrate (but is pharmacologically inert)
How do carbonic anhydrase inhibitors work?
- Decreases Na+/H+ exchange
2. So more Na+ in tubule, so more water in tubule also
Where do loop diuretics act?
On the ascending Loh
What do loop diuretics target?
The triple Na+/K+/2Cl- transporter
How do loop diuretics work
- By targeting the triple Na/K/2Cl transporter, less Na reabsorbed = more Na retained in lumen
- Remove K+ recycling - so less positive lumen potential - so less drive for other positive ions to interstitium via paracellular pathway - so tend so lose other positive ions in urine (e.g. Ca/Mg)
Loop diuretics are the most powerful diuretics. How much fluid loss can they cause?
15% - 30%
How do loop diuretics mean less water is reabsorbed from CD?
Increases tubular fluid osmolarity = decreases osmolarity of medullary interstitium (as less sodium reabsorbed)= less H2O reabsorbed in CD
How can loop diuretics cause hypokalaemia?
- Less Na reabsorbed at ALOH, so more passes on to DCT
2. Kidney desperately tries to reabsorb Na, but has to sacrifice K+ due to Na+/K+ ATPase
Which 2 classes of diuretics can cause hypokalaemia?
- Loop diuretics
2. Thiazides
How do thiazide diuretics work?
Acts on (early) DCT
- Binds to Na/Cl co transporter on apical side and blocks it
- Increased tubular fluid osmolarity = less H2O reabsorption in CD
How do thiazides impact Mg and Ca reabsorption?
Increased Mg LOSS and increased Ca REABSORPTION
How much fluid loss can thiazide diuretics cause?
5-10%
Which cells in the kidney release Renin?
Macula densa cells (by detecting the amount of Na reaching it)
Why can it be a problem to administer thiazides/loop diuretics long term?
- Chronic diuretic use = less Na in blood = less Na filtered = less Na reaching macula densa
- This causes renin secretion
- Renin stimulates Na+ reabsorption
- Now there are 2 competing systems (RAAS / diuretics)
- Consequently, ACEi sometimes coadminstered w diuretics
(Loop diuretics are worse as they block the same protein present on Macula densa that absorbs Na)
Frusemide is a?
Loop diuretic
Bendrofluazide is a?
Thiazide
Which are the least powerful diuretic agents?
K sparing diuretics
Act on late DCT and CD
What are the 2 classes of K sparing drugs?
- Aldosterone receptor antagonists (e.g. Spironolactone)
2. Inhibitors of aldosterone-sensitive Na channels (e.g. Amiloride)
How much fluid loss can a K sparing diuretic yield?
5%
Why can K sparing diuretics cause increased H+ retention?
Less Na+/H+ exchange
What are side effects of Loop diuretics
- Hypovolemia
- Metabolic alkalosis
- Hyperuricemia
- Hypokalaemia
- Hyponatremia
What are side effects of thiazides
- Hypovolemia
- Metabolic alkalosis
- Hyperuricemia
- Hypokalaemia
- Hyponatremia
What are side effects of K+ sparing diuretics
- Hyperkalemia (as less Na+/K+ exchange)
Why is metabolic alkalosis a side effect?
Cl- loss
What is hyperuricemia and how does it happen
Diuretic must go from blood side to apical membrane on tubular side. So it must be transported from basolateral side to apical side. Basally, it is transported by a transporter thet also transports uric acid, so competing w uric acid means uric acid is retained.
Diuretics are used to treat hypertension. What is first line treatment diuretic?
Thiazides - “salt sensitive” hypertension
Why thiazides over loop diuretics?
Initially loop diuretics are better (for a month or so) - due to their diuretic properties
HOWEVER, thiazides chronically have vasodilatory effects, which decreases TPR.
How do thiazides have a vasodilatory effect
- Activates eNOS
- Ca channel antagonism
- Opening of K channel inducing hyperpolarisation
Loop diuretics are given in? Why?
Heart failure
Acute reduction in congestion as decreases Na load by 30%
However chronic use associated w resistance due to RAS activation
Now sometimes given w K sparing diuretics - helps prevent resistance of loop diuretics
