Diuretics Classification Quiz

Diuretics

• Diuretics are medications used to increase the excretion of salt and water by increasing urine output and decreasing extracellular fluid (ECF) volume.
• They induce diuresis in patients.
• Diuretics are classified into several categories.

Classification

• Osmotic diuretics: Examples include mannitol and inulin.
• Carbonic anhydrase inhibitors: Examples include acetazolamide, dorsoloamide, and brinzolamide.
• Loop diuretics: Examples include bumetanide, furosemide, torsemide, and ethacrynic acid.
• Thiazide and Thiazide-like diuretics: Examples include bendroflumethiazide, benzothiazide, hydrochlorothiazide, chlorthalidone, indapamide, and metolazone.
• Potassium-sparing diuretics: These can be further sub-classified into:
  • Agents that antagonize mineralocorticoid receptors, e.g., spironolactone and eplerenone.
  • Inhibitors of sodium ion transport channels in the luminal epithelial membrane, e.g., triamterene and amiloride.
  • Agents that suppress renin or angiotensin II action, e.g., ACE inhibitors like lisinopril, fosinopril, and captopril.
• Angiotensin receptor blockers: Examples include losartan, valsartan, and telmisartan.

Transport Mechanisms/Site of Action

• Understanding the mechanism of action of diuretics requires knowledge of the physiological function of the nephron and its electrolyte transport mechanisms.
• The Bowman's capsule is responsible for filtering the blood.
• Urine formation is a process involving ultra-filtration, secretion, and reabsorption of substances within different sections of the nephron.

Proximal Tubule (PCT)

• The PCT is responsible for the reabsorption of electrolytes such as sodium bicarbonate (85%) and sodium chloride.
• Water reabsorption (60%) in the Proximal Tubules occurs passively to maintain the osmolality of the proximal tubular fluid.
• The proximal tubule initiates NaHCO3- reabsorption via a Na+/H+ exchanger within the luminal membrane.
• This process allows for a one-for-one exchange of sodium ion with a proton (H+) from inside the cell.
• Na+/K+ ATPase in the basolateral membrane of the PCT pumps the reabsorbed sodium ion into the interstitium to maintain low intracellular concentrations. This maintains proper balance.
• Carbonic acid is formed from H+ and HCO3- in the lumen.
• Na2HCO3 dissociation occurs into carbon dioxide (CO2) and water (H2O) via carbonic anhydrase (CA) activity.

Loop of Henle

• The thin limb is involved in water reabsorption via an osmotic gradient within the medullary interstitium.
• Osmotic diuretics further drive water excretion in this segment.
• The thick limb is impermeable to water but absorbs 35% of sodium and chloride via a Na+/K+/2Cl− transporter.
• This transporter is blocked by loop diuretics, inhibiting Cl- ion absorption and increasing excretion of Na+, K+, and Ca2+.
• The luminal positive potential created by this transporter drives the reabsorption of divalent cations (Mg2+ and Ca2+) via the paracellular pathway.

Distal Convoluted Tubule (DCT) and Collecting Tubule (CT)

• The DCT is responsible for absorbing about 10% of sodium and chloride (NaCl).
• It is impermeable to water, causing fluid dilution.
• This transporter is blocked by thiazide diuretics, which inhibits sodium reabsorption, but there is no lumen positive potential for calcium and magnesium reabsorption.
• The CT acts as the major site for potassium secretion and final determination of urinary sodium concentration (5-10% of sodium & chloride are reabsorbed).
• The reabsorption occurs via the Na+/H+ and Na+/K+ exchangers, which are regulated by mineralocorticoids and urinary sodium concentration

RAAS Pathway (Renin-Angiotensin-Aldosterone System)

• RAAS is activated by low plasma sodium concentration and sympathetic stimulation.
• Renin is secreted from the juxtaglomerular apparatus (JGA).
• Renin converts angiotensinogen to angiotensin I, and angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II.
• Angiotensin II is a potent vasoconstrictor and stimulates aldosterone release.
• Aldosterone increases sodium and water reabsorption in the distal convoluted tubule, stimulating sodium-potassium exchange, and increases hydrogen ion secretion in the proximal tubule.

Pharmacology of Specific Agents

• Mannitol: Provides a high intravenous (IV) osmotic diuresis.

  • Mechanism: Filtered by glomeruli, retained in proximal tubules, increasing tubular fluid osmolality, decreasing water reabsorption relative to sodium.
  • Clinical uses: reduce intracranial pressure (ICP) in head injuries and intraocular pressure (IOP) in glaucoma.
  • Adverse effects: dehydration and fluid overload in patients with impaired kidney function.

• Acetazolamide: Inhibits carbonic anhydrase, and reduces the production and reabsorption of bicarbonate from the proximal convoluted tubule (PCT).

  • Clinical Uses: reduce aqueous humor formation, decreasing intraocular pressure (IOP) and used in the treatment of glaucoma.
  • Adverse effects: metabolic acidosis, drowsiness, kidney stone formation, and paresthesia. Contraindicated in patients with liver cirrhosis.

• Loop Diuretics: High ceiling diuretics with rapid and potent diuretic effects, mostly used in treating cardiac failure, pulmonary oedema, acute oliguria or acute renal failure, hypertension and hypercalcemia.

  • Mechanism: act in the thick ascending limb of the loop of Henle, inhibiting the Na+/K+/2Cl− co-transporter, blocking Cl- absorption in the tubular lumen increasing Na+, K+, and Ca2+ excretion, hence increasing excreted urine volume. -Adverse effects: hyperglycemia, allergic reactions, hypokalemia, hypomagnesemia, hypocalcemia, hyperuricemia, and dehydration.

• Thiazide diuretics: Act in the distal convoluted tubule inhibiting the Na+/Cl− co-transporter. These reduce calcium excretion in the urine, also act as weak inhibitors of carbonic anhydrase and increase urinary pH.

  • Clinical uses: Used in the treatment of kidney stones and hypertension. -Adverse effects: hyperuricemia, acute renal failure, hypokalemic alkalosis, hyperglycemia due to glucose intolerance, and hypercholesterolemia.

• Spironolactone: Direct antagonist to aldosterone, inhibiting the synthesis of tubular Na+ channels and Na+/K+ ATPase, involved in Na+, Cl−, and water reabsorption.

  • Clinical uses: used in combination with other antihypertensives, can be used as a replacement for thiazides in patients with hypertension, glucose intolerance, hyperuricemia, and hypokalemia. Also used for treating primary aldosteronism.
  • Adverse Effects: Diarrhea, nausea, vomiting, headaches, confusion, somnolence, and gynecomastia.

• Triamterene & Amiloride: Inhibit sodium transport across sodium channels in the distal convoluted tubule epithelial membrane.

  • Clinical Uses: Weak diuretic action, used in combination with other antihypertensives for treating hypertension.

• ADH/ADH Antagonist (e.g., Desmopressin, Demeclocycline, Lithium carbonate): Anti-diuretic hormone (ADH) antagonists increase urine output. -Mechanism: Desmopressin stimulates V1 and V2 receptors in blood vessels and the kidneys, increasing water reabsorption. -Clinical uses: treatment of neurogenic diabetes insipidus and nocturnal enuresis. Used as an adjunct in hemophilia treatment. -Adverse effects: vasoconstriction, smooth muscle cramps, water intoxication, and hyponatremia. Demeclocycline and Lithium carbonate block ADH action increasing urine volume. Used in the treatment of syndrome of inappropriate ADH secretion (SIADH).

Conclusion

• The presentation highlighted the diverse classes of diuretic agents, their sites of action in the nephron, mechanisms of action, and clinical uses.
• A comprehensive understanding of these agents will be beneficial in clinical practice.