Anesthesia Pharmacology:  Renal Pharmacology

• Potassium-Sparing Diuretic Agents

  • Introduction:

    • These diuretics inhibit the effects of aldosterone at the cortical collecting tubule and late distal tubule.

  • Mechanisms of action:

    • In the collecting tubule and duct, sodium reabsorption and potassium excretion is regulated by aldosterone.

      • Aldosterone increases potassium secretion by increasing Na/K ATPase activity and sodium and potassium channel activity.

      • Normally, sodium absorption in the collecting tubule results in a lumen-negative electrical force that drives potassium excretion.

      • Aldosterone antagonists interfere with this effect

      • Aldosterone antagonists act similarly with respect to proton movement, accounting for metabolic acidosis associated with aldosterone antagonists.

    • Pharmacologic antagonism at mineralocorticoid receptors ( spironolactone (Aldactone))

    • Inhibition of sodium transport through the luminal membrane (triamterene (Dyrenium), amiloride (Midamor))

    • Some Potassium-Sparing effects occur with nonsteroidal anti-inflammatory drugs, β-blockers, converting enzyme-inhibitors, and angiotensin receptor blockers.

  • Spironolactone (Aldactone):

    • Synthetic steroid: competitive aldosterone antagonist

      • Binds to cytoplasmic mineralocorticoid receptors, preventing receptor complex translocation to the nucleus.

      • Also inhibits formation of active metabolite of aldosterone, by inhibiting 5-alpha reductase activity.

    • Hepatic inactivation

    • Slow onset of action

  • Triamterene (Dyrenium):

    • Renal excretion; hepatic metabolism-- extensive metabolism (short half life)

    • Directly blocks Na entry through sodium-specific channels (apical collecting tubule membrane) -- note that since potassium secretion is coupled to sodium entry, potassium secretion (potassium-sparing) is reduced.

  • Amiloride (Midamor):

    • Excreted unchanged (urine)

    • Directly blocks Na⁺ entry through sodium-specific channels (apical collecting tubule membrane) -- note that since potassium secretion is coupled to sodium entry, potassium secretion (potassium-sparing) is reduced.

  •  Clinical Uses:

    • Mineralocorticoid excess:

      • Conn's syndrome (primary hypersecretion).

      • Ectopic ACTH production (primary hypersecretion).

      • Secondary aldosteronism caused by:

        • Congestive heart failure.

        • Hepatic cirrhosis.

        • Nephrotic syndrome.

        • Conditions that cause renal salt retention with reduced intravascular volume.

          • Other diuretics may further reduce intravascular volume thus worsening secondary aldosteronism.

  •  Toxicity:

    •  Hyperkalemia:

      • Potassium-sparing diuretics can cause significant hyperkalemia

      • Factors that increase the likelihood of hyperkalemia include:

        • Renal disease

        • Presence of agents that reduce renin:

          •  β-blockers

          •  Nonsteroidal anti-inflammatory drugs (NSAIDs)

          •  ACE inhibitors

          •  Angiotensin receptor blockers

      •  Hyperkalemia more likely when potassium-sparing diuretics are used as the only diuretic drug or in the presence of renal insufficiency.

        • Given in combination with thiazides, hypokalemia and metabolic alkalosis associated with thiazide use may be balanced by aldosterone antagonists

        • Since thiazide adverse effects may predominate (hyponatremia, metabolic alkalosis), due to variations in bioavailability, individual dose adjustment of the two drugs may be better.

    • Hyperchloremic Metabolic Acidosis:

      • Acidosis cause by inhibition of proton secretion along with potassium secretion (similar to type IV renal tubular acidosis

    • Gynecomastia:

      •  Endocrine abnormalities associated with synthetic steroids --Spironolactone (Aldactone)

        • Gynecomastia (breast enlargement)

        • Impotence

        • Benign prostatic hyperplasia

    • Acute Renal Failure:

      • Triamterene (Dyrenium) plus indomethacin

    • Kidney Stones:

      • Triamterene (Dyrenium) (poorly soluble) may precipitate in urine, causing renal stones:

    •  Contraindications:

      •  May cause severe (potentially fatal) hyperkalemia

      •  Potassium supplements should be discontinued prior to administration of aldosterone antagonists

      •  Patients with chronic renal insufficiency are at particular risk

      •  Hyperkalemia is also more likely to occur or it if β-blockers or ACE inhibitors are concurrently administered

      •  Impairment of hepatic metabolism of triamterene spironolactone may require dose adjustment