Diuretics and Their Mechanisms of Action

Diuretics and Their Mechanisms of Action

• Diuretics increase urine output and often solute excretion, mainly sodium and chloride.
• A primary mechanism involves decreasing renal tubular sodium reabsorption, leading to natriuresis (increased sodium excretion) and diuresis (increased water excretion).
• Water excretion increase due to sodium remaining in tubules, creating osmotic pressure preventing water reabsorption
• Many diuretics influence the excretion of other solutes (potassium, chloride, magnesium, calcium) which are co-influenced by sodium reabsorption.
• Diuretics are commonly used to reduce extracellular fluid volume in edema and hypertension.
• Initial diuretic effect on renal output is substantial (up to 20-fold increase in a few minutes), but chronic effects are mitigated by compensatory mechanisms.
• These compensatory responses (reducing arterial pressure, GFR, increasing renin/Ang II), eventually equalize sodium intake and excretion.
• Different diuretics target specific regions of the nephron.

Osmotic Diuretics

• Osmotic diuretics, like mannitol, urea, and sucrose, increase tubular fluid osmolarity by being filtered but poorly reabsorbed.
• This increased osmolarity reduces water reabsorption from tubules.
• High blood glucose levels (diabetes) can lead to osmotic diuresis when glucose exceeds the tubule’s reabsorption capacity.
• Elevated blood glucose above 250 mg/dl results in excess glucose in the tubules, causing osmotic diuresis and polyuria.
• Polyuria is countered by polydipsia (increased fluid intake) due to dehydration and high extracellular fluid osmolarity.

Loop Diuretics

• Loop diuretics (furosemide, ethacrynic acid, bumetanide) block the Na+-K+-2Cl- co-transporter in the thick ascending loop of Henle.
• This inhibits reabsorption, thus increasing urinary output of sodium, chloride, potassium, and water.
• Loop diuretics hinder the countercurrent multiplier system, reducing renal medullary osmolarity.
• This impairs the ability to dilute or concentrate urine as the concentration of the medullary interstitial fluid decreases
• Acutely, loop diuretics might increase urine output by twenty-five times (as much as 20%-30% of the glomerular filtrate).

Thiazide Diuretics

• Thiazide diuretics (chlorothiazide, hydrochlorothiazide) block the Na+-Cl- co-transporter in the early distal tubule.
• This leads to lesser sodium and water excretion if compared to loop diuretics, but they are useful in other conditions when loop diuretics might be contraindicated.
• Maximum effect of thiazides is about 5%-10% of glomerular filtrate; this can cause some of the normally reabsorbed sodium into the distal tubule, to end up in the urine.

Carbonic Anhydrase Inhibitors

• Carbonic anhydrase inhibitors (acetazolamide) block carbonic anhydrase in the proximal tubule.
• Inhibition reduces bicarbonate (HCO3-) reabsorption, affecting sodium reabsorption as well.
• This can contribute significantly (osmotically) to diuresis.
• Noteable disadvantage is a possible elevation in acidity.

Mineralocorticoid Receptor Antagonists

• Mineralocorticoid receptor antagonists (spironolactone, eplerenone) block aldosterone (receptors) in collecting tubules, reducing sodium reabsorption and increasing potassium excretion.
• These drugs are "potassium-sparing" diuretics because they prevent potassium loss.
• Excessive potassium can gather in extracellular fluids, which might be harmful in certain conditions.

Sodium Channel Blockers

• Sodium channel blockers (amiloride, triamterene). inhibit sodium reabsorption and potassium secretion in collecting tubules, similar to mineralocorticoid receptor antagonists.
• These diuretics are also potassium-sparing, as previously mentioned, mainly blocking Na+ entry to the collecting tubule cells' luminal membranes.
• By causing a reduced entry of sodium into the cells, it blocks Na+-K+ ATPase activity, consequently reducing potassium excretion.