Diuretics and Nephron Anatomy.NinjaN

Diuretics

• Diuretics are medications increasing sodium, chloride, and water excretion in urine.
• This process, diuresis, targets specific nephron sections.

Anatomy and Physiology of the Nephron

• The nephron has sections filtering/reabsorbing substances.
• Proximal convoluted tubule (PCT) reabsorbs 65% sodium and water.
• Descending loop of Henle primarily reabsorbs water.
• Ascending loop of Henle reabsorbs 25% sodium and some water.
• Distal convoluted tubule (DCT), early and late, reabsorb sodium (5% each), close to 100% overall reabsorption.
• Late DCT sodium reabsorption depends on aldosterone, produced by adrenal cortex.
• Aldosterone promotes sodium and water reabsorption, while antidiuretic hormone (ADH) primarily promotes water reabsorption.

Sites of Diuretic Action

Proximal Convoluted Tubule (PCT)

• Carbonic anhydrase inhibitors (CAIs) like acetazolamide act on PCT.
• CAIs inhibit carbonic anhydrase, disrupting bicarbonate reabsorption, indirectly affecting sodium and water.

Ascending Limb of the Loop of Henle

• Loop diuretics (furosemide, torsemide, bumetanide, ethacrynic acid) are potent.
• Inhibit sodium-potassium-2-chloride (NKCC2) co-transporter, increasing sodium, chloride, and water excretion.
• Also inhibit calcium and magnesium absorption, increasing their excretion.

Early Distal Convoluted Tubule (DCT)

• Thiazide diuretics (e.g., hydrochlorothiazide) inhibit the sodium-chloride co-transporter in early DCT.
• This lowers sodium and chloride reabsorption.
• Thiazides indirectly increase calcium reabsorption due to a sodium-calcium exchange mechanism. This leads to less calcium excretion.

Late Distal Convoluted Tubule (DCT)

• Potassium-sparing diuretics (spironolactone, amiloride) target late DCT.
• Drugs inhibit sodium reabsorption mechanism at this site.
• Potassium-sparing diuretics are classified as aldosterone antagonists and ENaC blockers.
• Aldosterone antagonists block aldosterone receptor, preventing sodium channel synthesis, sodium-potassium pumps and potassium channels.
• ENaC blockers prevent sodium entry into principal cells by blocking ENaC. Both types reduce sodium and water reabsorption with minimal potassium loss.

Osmotic Diuretics

• Osmotic diuretics (mannitol, urea) increase blood osmolarity.
• Mannitol, a filtered molecule, creates an osmotic gradient pulling water from extravascular spaces (e.g., brain tissue), causing aquaresis.
• Used to lower intraocular and intracranial pressure.

Pharmacodynamic and Pharmacokinetic Considerations of Diuretics

• Diuretics show dose-response relationships, with a threshold and ceiling dose.

Indications for Diuretics

• Used for fluid diuresis, managing heart failure, chronic kidney disease, acute kidney injury, hypertension, and edema.
• Acetazolamide treats altitude sickness, high-altitude pulmonary edema, corrects metabolic alkalosis, reduces intraocular pressure, and lowers intracranial pressure.

Adverse Effects of Diuretics

• Osmotic diuretics can cause hypovolemia, hypotension, hypernatremia (if kidney function ok), and exacerbation of hypervolemia (pulmonary edema, hyponatremia) in renal insufficiency.
• CAIs can cause metabolic acidosis, influencing intraocular and intracranial pressure.
• Loop diuretics lead to hypokalemia, ototoxicity (tinnitus, hearing loss), and inhibit calcium and magnesium reabsorption.
• Thiazide diuretics cause hypokalemia and hypomagnesemia, and increase blood calcium levels.
• Potassium-sparing diuretics cause hyperkalemia.

Loop Diuretic Dosage and Response

• Loop diuretics' dosage is adjusted based on patient response until the ceiling dose is reached.
• Bumetanide has the highest potency, needing the lowest dose. Torsemide is next, followed by furosemide, requiring the highest dose. Potency varies.
• Furosemide's bioavailability is about 50% (oral dose needs doubling). Bumetanide and torsemide have over 80% bioavailability.
• Loop diuretics are historically used to treat hypercalcemia by inhibiting sodium, chloride and potassium reabsorption.

Loop Diuretics

• The most potent diuretics, these drugs block NKCC in the loop of Henle.
• Inhibit NKCC2, causing sodium, chloride, and water loss.
• Bumetanide and torsemide have high bioavailability approaching 100%.
• Furosemide has 50% bioavailability, so the oral dose must be doubled to match its IV effect.
• Loop diuretics cause more water loss than sodium loss, potentially resulting in hypernatremia and can be used to treat hyperkalemia.
• Adverse effects include: hypernatremia, hypovolemia, hypocalcemia, hypomagnesemia, hypokalemia, metabolic alkalosis, hyperuricemia, hyperglycemia, and ototoxicity.

Thiazide Diuretics

• Thiazide diuretics block sodium chloride transporters (NCC) in the early DCT.
• Thiazides do not induce calcium excretion; they promote calcium reabsorption (potential hypercalcemia).
• They can cause vasodilation, lowering systemic vascular resistance and blood pressure.
• Treatment choice for hypertension and hypercalciuria (reduced risk of kidney stones, benefit for osteoporosis).
• Adverse effects include hyponatremia, hypercalcemia, hypomagnesemia, hypokalemia, metabolic alkalosis, hyperuricemia, hyperglycemia, and hyperlipidemia.

Potassium-Sparing Diuretics

• Act in later DCT segments, categorized into aldosterone blockers and ENaC blockers.
• Aldosterone blockers (spironolactone, eplerenone) inhibit aldosterone to prevent sodium reabsorption and potassium excretion.
• ENaC blockers (amiloride, triamterene) directly block ENaC.
• Treatment choices for hyperaldosteronism (Conn's syndrome). Useful for hypertension and CHF (preventing potassium loss), improving overall mortality with aldosterone blockers and can treat nephrogenic diabetes insipidus.
• Adverse effects include hyperkalemia, metabolic acidosis, gynecomastia, erectile dysfunction, amenorrhea, and menstrual irregularities (likely aldosterone blocker-related).

Carbonic Anhydrase Inhibitors

• Block carbonic anhydrase, inhibiting bicarbonate reabsorption.
• Used to treat altitude sickness, high-altitude pulmonary edema, glaucoma, and idiopathic intracranial hypertension.
• Can be an adjunct to diuretic therapy to combat metabolic alkalosis.
• Adverse effects include metabolic acidosis, risk of kidney stones, hyperammonemia, and mild hypokalemia.

Diuretic Regimen for Fluid Overload

• Loop diuretics are often first-line for fluid overload due to potency.
• If loop diuretic response is inadequate, a thiazide may be added to combat potential hypernatremia.
• To counteract potential hypokalemia and metabolic alkalosis arising from loop and thiazide use, a potassium-sparing diuretic can be added. A CAI can also be used to combat alkalosis and to enhance efficacy.

Diuretic Therapy in Cirrhosis-Related Edema

• Aldosterone blockers (spironolactone) are often the first choice for cirrhosis-related ascites, hepatomegaly, and peripheral edema.
• Aldosterone blockers reduce sodium and water retention.
• Loop diuretics might be added for further enhanced sodium and water excretion.
• Other supportive therapies are paracentesis and albumin administration.

Summary of Diuretic Treatment and Key Points

• Diuretics are important for managing fluid overload in various conditions (CHF, CKD, AKI, fluid overload, ascites).
• Start with potent diuretics, adjusting the regimen based on response and adverse effects.
• Monitor electrolytes (especially potassium), being mindful of diuretic adverse effects; monitor elderly and patients with pre-existing conditions for hypovolemia.
• Consult a healthcare specialist/doctor for personalized advice.