Diuretics and the Nephron

To revise the nephron transport processes in the proximal tubule:

Sodium-Potassium ATPase Pump: Located on the blood side of the cell, this pump actively transports sodium out of the cell and potassium into the cell, maintaining a low intracellular sodium concentration and a high intracellular potassium concentration.
Sodium Reabsorption: The low intracellular sodium concentration drives the reabsorption of sodium from the lumen into the cell.
Organic Anion Transporters: Sodium reabsorption is coupled with the transport of organic anions such as phosphate, glucose, and amino acids.
Sodium-Hydrogen Ion Exchange: Sodium is reabsorbed in exchange for hydrogen ions, which are secreted into the lumen.
Bicarbonate Reabsorption: Bicarbonate in the lumen combines with hydrogen ions to form $H<em>2CO</em>3$ , which is then converted to water and carbon dioxide by carbonic anhydrase. Water and carbon dioxide diffuse into the cell, where they are converted back to bicarbonate, which is then reabsorbed.
Paracellular Transport: Sodium and water are reabsorbed between cells via paracellular transport.

Mechanism of Action: Acetazolamide inhibits carbonic anhydrase, reducing the availability of hydrogen ions for the sodium-hydrogen ion exchange pump. This leads to decreased sodium reabsorption.
Limited Diuretic Effect: Acetazolamide has minimal diuretic properties because it only blocks one of the sodium reabsorption mechanisms in the proximal tubule, and sodium can be reabsorbed in other nephron segments.
Side Effects:
- Metabolic Acidosis: Due to the inhibition of hydrogen ion excretion and bicarbonate reabsorption.
- Hypokalemia: Due to downstream effects in the nephron.
Other Uses:
- Glaucoma
- Altitude sickness
- Metabolic alkalosis
- Alkalization of urine

Mechanism of Action: SGLT2 inhibitors block the sodium-dependent glucose transporter 2, which is responsible for reabsorbing glucose in the proximal tubule.
Glucose and Sodium Reabsorption: These inhibitors reduce glucose reabsorption, leading to increased glucose excretion in the urine and a small diuretic effect due to decreased sodium reabsorption.
Primary Use: Oral hypoglycemic agents, not primarily used as diuretics.

Sodium-Potassium ATPase Pump: Maintains low intracellular sodium concentration.
Triple Cotransporter: Reabsorbs sodium, two chlorides, and potassium from the lumen into the cell.
Potassium Recycling: Potassium is recycled out of the cell to drive the triple cotransporter.
Paracellular Transport of Calcium and Magnesium: A positive charge in the lumen, generated by potassium recycling, drives the reabsorption of calcium and magnesium.

Mechanism of Action: Loop diuretics inhibit the triple cotransporter in the loop of Henle, blocking the reabsorption of sodium, chloride, and potassium.
Side Effects:
- Hypokalemia: Due to increased sodium delivery to the distal nephron, leading to increased potassium secretion.
- Metabolic Alkalosis: Due to increased sodium delivery to the distal nephron, leading to increased hydrogen ion secretion.
- Increased uric acid and gout.
- Hypocalcemia, Hypomagnesemia, Hypercalciuria, Hypermagnesuria: Due to the disruption of calcium and magnesium reabsorption in the loop of Henle.
Common uses:
- Fluid overload (heart failure, nephrotic syndrome, kidney failure).

A genetic disorder that mimics the effects of loop diuretics by disrupting the function of the triple cotransporter or related proteins in the loop of Henle.

Sodium-Potassium ATPase Pump: Maintains low intracellular sodium concentration.
Sodium-Chloride Cotransporter: Reabsorbs sodium and chloride from the lumen into the cell.

Mechanism of Action: Thiazide diuretics inhibit the sodium-chloride cotransporter in the distal convoluted tubule, blocking the reabsorption of sodium and chloride.
Side Effects:
- Hypokalemia and metabolic alkalosis (same reasons as loop diuretics).
- Low levels of calcium and magnesium within the urine: Increase calcium reabsorption and reduce the amount of calcium that's within the urine.
- Hyponatremia due to impaired ability to maximally dilute urine.
Common Uses:
- Add-on to loop diuretics.
- Hypertension.
Types of Thiazide Diuretics:
- Chlorothiazide
- Indapamide
- Chlorthalidone (contains a sulphur moiety)
Side Effects: Increased uric acid and gout.
Gittleman Syndrome: Genetic abnormality similar to thiazide diuretics. Can be distinguished from Bartter syndrome (loop diuretics) by looking at urinary calcium levels.

Principal Cells:
- Sodium-Potassium ATPase Pump.
- Epithelial Sodium Channel (ENaC): Allows sodium to enter the cell.
- Potassium secretion.
Intercalated Cells:
- Hydrogen ion secretion.
Regulation: All transport processes are under the control of aldosterone.

Amiloride: Blocks the ENaC receptor, preventing sodium reabsorption.
Aldactone: Blocks aldosterone, inhibiting all transport processes in the distal collecting duct.
Side Effects: Hyperkalemia and metabolic acidosis (opposite of loop and thiazide diuretics).
Combination with Other Diuretics:
Potassium-sparing diuretics (amiloride or aldactone) can be combined with loop or thiazide diuretics to improve diuretic effect and minimize side effects (hypokalemia and metabolic alkalosis).
Aldactone blocks the effects of aldosterone, which is activated by the renin-angiotensin system in response to loop and thiazide diuretics.
Used as antihypertensives
Aldactone is used in patients with primary hyperaldosteronism to block the effects of excess aldosterone.
Patients on Aldactone or Omiluride might also be on other agents that can increase their potassium, or might have some chronic kidney disease that can increase their potassium.