Pharmacology 20 - Diuretics Flashcards
Describe the normal function of the proximal tubule cell
- Sodium and water diffuse into the cells
- At the basal membrane, sodium and potassium ions are exchanged (sodium into the blood) - ensures there is always a concentration gradient
- No protein in the tubule, but protein in the blood. Generates oncotic pressure and draws water from lumen into the blood (using aquaporins and paracellularly)
- Sodium hydrogen exchange at the apical membrane (hydrogen into lumen, sodium into cell)
- Glucose and amino acids cross with sodium
- Carbonic anhydrase converts bicarbonate and hydrogen ions into carbon dioxide and water which can cross the membrane and be converted back to carbonic anhydrase
- Bicarbonate ions enter blood via sodium channel exchanger
- Exogenous agents excreted into urine
- Most of the sodium and water is reabsorbed there
Describe the normal function of the loop of Henle
- Sodium leaves ascending limb and enters the medullary interstitium, causing fluid in the ascending limb to decrease in osmolarity (uses sodium/ chloride/ potassium channel at apical membrane, sodium potassium exchanger and potassium chloride symporter at the interstitium). Paracellular diffusion of sodium also.
- Descending limb permeable to water, so more concentrated medullary interstitium draws water from the descending limb, causing the fluid in the descending limb to increase in osmolarity
- More fluid enters and forces fluid from descending to ascending limb. This fluid has increased osmolarity
- Countercurrent effect
Describe permeability of the loop of Henle
- Descending limb is permeable to water
- Ascending limb is impermeable to water, permeable to sodium, potassium and chloride
Describe normal physiology of the distal tubule
- Early tubule there is sodium chloride cotransport into the cell, sodium potassium ATPase at the interstitium and potassium chloride symporter
- Late tubule is aldosterone sensitive so has sodium ion channels
- Also actions of aquaporins increasing cell permeability to water
- Tight junctions - water cannot move easily without aquaporins
Describe normal physiology of the collecting duct
- High osmolarity of the interstitium leads to water reabsorption from the collecting duct and concentration of urine, using aquaporins
- Countercurrent effect
How do diuretics work?
- Inhibit reabsorption of sodium and calcium (increase excretion)
- Increase osmolarity of tubular fluid (decrease osmotic gradient across the epithelia)
List the five main classes of diuretics and give an example
- Osmotic diuretics (eg. mannitol)
- Carbonic anhydrase inhibitors (eg. acetazolamine)
- Loop diuretics (eg. frusemide)
- Thiazides (eg. bendrofluazide)
- Potassium sparing diuretics (amiloride, spironolactone)
Where do osmotic diuretics act?
- Proximal tubule, loop of Henle and collecting duct.
- Increase osmolarity of the tubular fluid, impairing ability of water to leave
Where do carbonic anhydrase inhibitors act?
Proximal tubule
Where do loop diuretics act?
Ascending loop of henle
Where do thiazides act?
Distal tubule
Where do potassium sparing diuretics act?
Collecting duct and late distal tubule
Describe mechanism of action of loop diuretics
- Frusemide inhibits sodium, potassium and chloride cotransporter in the ascending limb (decreasing sodium and chloride reabsorption)
- Increases tubular fluid osmolarity, decreases osmolarity of medullary interstitium and therefore decreases water reabsorption in the collecting duct
- Increases sodium delivery to distal tubule and therefore increases potassium loss (in common with thiazides)
- Loss of potassium recycling (potassium from the lumen driving passive diffusion of ions via paracellular route, resulting in increased loss of calcium and magnesium)
- Interferes with the countercurrent effect, loss of 15-30% water
Describe mechanism of action of thiazide diuretics
- Inhibit sodium and chloride reabsorption in the early distal tubule 5-10% (block sodium-chloride cotransport protein)
- Increases tubular fluid osmolarity and decreases water reabsorption in the collecting duct
- Increase sodium delivery to distal tubule and potassium loss
- Increases magnesium loss and calcium reabsorption
How do diuretics affect renin secretion?
- Thiazine and loop diuretics decrease sodium load
- Particular problem is loop diuretics, as they block sodium entry to the macula densa cells
- Diuretics cause sodium loss and water loss long term, which causes renin release from macula densa cell
What are the classes of potassium sparing drugs?
- Aldosterone receptor antagonists (spironolactone)
- Inhibitors of aldosterone-sensitive sodium channels (amiloride)
Describe action of spironolactine
- Normally aldosterone increases sodium potassium ATPase at basal membrane and sodium ion channels at the apical membrane
- Spironolactone blocks these effects, therefore decreasing sodium channels and potassium ATPase
Describe action of amiloride
Blocks the sodium channels at the apical membrane of the distal tubule cell
List actions of potassium sparing diuretics
- Inhibit sodium reabsorption in early distal tubule
- Increase tubular fluid osmolarity and decrease water reabsorption in the collecting duct
- Decrease reabsorption of sodium to distal tubule and increase hydrogen retention
- Weakest diuretics - 5%
List the common side effects of diuretics
Loop diuretics and thiazides
- Hypovolemia
- Hypokalemia
- Hyponatremia
- Metabolic alkalosis (due to chloride ion loss)
- Hyperuricemia
Potassium sparing diuretics
- Hyperkalaemia due to sodium/ potassium exchange
How does hyperuricemia occur?
- Uric acid uses the same transporter as the diuretics
- This transporter is on the basal membrane, and excretes the diuretic and uric acid into the lumen
- This allows the diuretic to get to the apical membrane (their site of action)
- Therefore uric acid and the diuretic are competing for the transporter and less uric acid is extreted.
List clinical uses of diuretics
- Thiazides first line treatment in hypertension (over 55 or Afro-Caribbean) - bring volume down
- Treatment of heart failure and oedema
Why are thiazides used in hypertension treatment?
- Initial response due to decreased plasma volume, over time the plasma volume is respored
- Over time, decreased TPR as there is activation of eNOS, calcium channel antagonism and opening of Kca channel (smooth muscle hyperpolarisation)
How are diuretics used in treatment of heart failure and oedema?
- Loop diuretics decrease sodium and water retention, decreasing blood pressure and decreasing ventricular filling pressures
- Reduces the amount of blood in the system to reduce oedema, by loss of sodium and fluid
- However, they also increase renin secretion so chronic use is associated with resistance, so there is additional use of potassium sparing diuretics, which reduces the sodium potassium change later in the kidney and reduces sodium and water retention greater, reducing risk of death
