Week 11: Diuretics and Renal Function Flashcards
What are diuretics?
diuretics are agents that act on the tubules to inhibit the reabsorption of sodium chloride, resulting in the increased excretion of these ions (which cause increased excretion of water)
What are some conditions which diuretics are used for?
- Edema
- Edema with sodium overload (cardiac, renal or hepatic disease)
- Edema without sodium overload (acute pulmonary edema following MI) - Hypertension
- Increased blood pressure is caused by increased blood pressure
- We can thus decrease ECF volume with diuretics - Hypercalcemia
- A number of diuretics influence the reabsorption of calcium - Idiopathic hypercalciuria
- Is a condition where there is increased loss of calcium
- Thus, to reduce loss of calcium - Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
- This will cause excess water levels
- Thus, aquaretics can be used - Nephrogenic diabetes insipidus
- Despite already being polyuria, diuretics can be used to reduce the water flow that goes out beyond the collecting duct
What are the 2 types of diuretics and the subclasses of diuretics?
Direct: Loop, thiazide and potassium sparing diuretics
Indirect: Osmotic diuresis, carbonic anhydrase inhibitors
Where do loop diuretics act on in the nephron?
Thick ascending limb of loop of henle, Hence why it is so potent
What is the mechanism of action of loop diuretics and how it causes metabolic alkalosis
- Loop diuretics bind to the chloride binding site on the Sodium-Potassium-2-Chloride symporters that are present in the thick ascending limb
- This transporter is inhibited, and as it usually accounts for roughly 25% of sodium reabsorption, inactivation of the transporter causes extensive sodium excretion
- As they are not reabsorbed, more solutes are delivered to the distal tubule, where the increased osmotic pressure further reduces water reabsorption
The increased sodium in distal tubule causes increased exchange for potassium (excretion of potassium) (VIA ENaCs
- The hypokalaemic state this causes then causes increased exchange by the hydrogen-potassium ATPase (as body has low K+ therefore wants to reabsorb it) causing a metabolic alkalosis
How do loop diuretics decrease calcium reabsorption /increase calcium excretion?
- This is caused by the effect of the diuretics on the transepithelial voltage
- Normally, the action of the sodium-potassium-2-chloride symporter forces potassium out of the cell into the lumen which creates a positive transepithelial voltage
- This provides a driving force for the calcium to move into the blood via paracellular pathways
- When the sodium-potassium-2-chloride symporter is blocked by loop diuretics, this positive transepithelial voltage is abolished, and thus the driving force for calcium reabsorption is taken away
- This causes decreased calcium reabsorption and increased calcium excretion
What is the most frequently used diuretic for antihypertension?
Thiazide diuretics
Explain the mechanism of action for thiazide diuretics and how it can cause metabolic alkalosis
- Thiazide diuretics are a sodium-chloride symporter inhibitors in the DCT by binding to the Chloride site (luminal side)
- This decreases the co-transportation of sodium and chloride into the epithelial tubular cell
- This causes 10% of the normal sodium reabsorption to be inhibited, taking the solutes to the distal parts of the tubule
- When it reaches the principal cells, some is reabsorbed (through aldosterone) whilst most still occurs
- The increased sodium content increases this reabsorption, which causes increased potassium to come out (VIA ENaCS), then the hydrogen-potassium ATPase is also then triggered pumping more hydrogen excretion and potassium reabsorption
- This hydrogen exchange also happens through sodium-hydrogen exchange
- This causes loss of hydrogen ions, facilitating metabolic alkalosis
Which diuretic is used to treat hypercalciuria
Thiazide diuretic
How do thiazide diuretics increase calcium reabsorption
- Thiazide diuretics inhibit sodium reabsorption into the cell
- This causes decreased sodium concentration in the cell
- As a result, the sodium-calcium exchanger on the basolateral side increases sodium entry into the cell
- This conversely increases calcium transport into the ECF creating a concentration gradient
- Calcium reabsorption is then increased on the apical surface
Where do potassium sparing diuretics act on in the nephron?
Collecting duct upong principal cells
Where do thiazide diuretics act on in the nephron?
Early Distal Convoluted tubule
What are the mechanism of action of potassium sparing diuretics?
- Aldosterone antagonists
- These work by competitively blocking the binding sites for aldosterone
- This inhibits the sodium reabsorption action of aldosterone, which will decrease potassium secretion
- This acts within the cell as it is a steroid hormone (it is the only form of diuretic that doesn’t act on the luminal side e.g. spironolactone) - Drugs that block sodium channels
- These block sodium channels on the luminal side of the membrane in the collecting duct (e.g. ENaCs)
- Therefore, there is less sodium available for transport across the basolateral membrane, so less potassium excretion (and indirectly hydrogen secretion)
- These diuretics can be prescribed in combination with thiazides and loop diuretics to prevent hypokalaemia
Do potassium sparing diuretics cause metabolic acidosis or alkalosis and why?
Inhibition of sodium reabsorption therefore will get increase K in cells. This means you will get decrease of the K/H+ exchanger in ENaCs which results in less hydrogen excretion.
What are the target sites for osmotic diuretics and what do they do?
- The sight of action of these osmotic diuretics are those regions which are freely permeable to water, the proximal convoluted tubule, descending limb of loop of Henle and collecting duct (in the presence of ADH)
Increase water excretion as that hold onto water in the lumbinal membrane
What is the target site for carbonic anhydrase inhibitors
- This drug works at the proximal convoluted tubule
Explain the mechanism of action for carbonic anhydrase inhibitors? and does it cause metabolic alkalosis or acidosis?
- The first is it inactivates the carbonic anhydrase present on the luminal membrane of the PCT which is used in the reabsorption of the bicarbonate. As there is less reabsorption there is increased excretion
- The next is by inactivating the carbonic anhydrase present with in the tubular cell. This inhibits the secretion of hydrogen, which will reduce sodium reabsorption through the sodium-hydrogen exchanger
- So as a result of this carbonic anhydrase inhibitor, bicarbonate reabsorption will be less, hydrogen secretion will be less causing reduced sodium reabsorption causing an increase secretion of all solutes mentioned
- This causes metabolic acidosis
What are aquaretics and what do they do?
- Is a class of drug that promotes the excretion of water without electrolyte loss
- These are ADH receptor antagonists which causes the principal cells within the collecting duct to reduce the expression of aquaporin 2
- The actual mechanism of actions of these aquaretics is as follows;
- Blocks V2 receptors producing free water diuresis as ADH is blocked downregulating the formation of aquaporin 2
- It acts on the principal cell collecting ducts
- As a result of their action, the urine cannot be concentrated and dilute urine is excreted
What must you take into consideration when looking at the GFR for someone who potentially may have kidney disease?
- It is important to note however, that GFR must decline substantially before there will be an increase in plasma creatine concentration that is detected clinically
- That is, a 50% loss of functioning nephrons will only reduce GFR by 25% (as the remaining nephrons will compensate)
- So even though there is a sign, it is not nearly clear enough in the early phases of kidney disease
