Amiloride

Mechanism

Pharmacological Group

Potassium-sparing diuretic from the pyrazinamide group, selective blocker of sodium channels in the distal nephron.

Mechanism of Action

Amiloride acts directly and selectively blocking the Epithelial Sodium Channel (ENaC) in the luminal membrane of the principal cells in the Cortical Collecting Tubule and the final portion of the TCD:

By blocking the entry of sodium into the principal cell, the negative transepithelial electrical gradient of the lumen is dissipated (which is usually the driving force for potassium to be secreted into the lumen through ROMK channels and hydrogen ions by the proton pumps of the intercalated cells). Therefore, sodium is gently eliminated in the urine while potassium and protons are retained in the body.

Pharmacokinetics

Key Pharmacokinetics

• Bioavailability: 50% orally. It is not metabolized in the liver.
• Excretion: It is eliminated unchanged through the urinary route, 50% by active tubular secretion, and the rest through the fecal route.
• Half-life: 6 to 9 hours.

Indicators and dose

Clinical Indications

• Prevention and treatment of diuretic-induced hypokalemia: Usually formulated in fixed combination with thiazides (hydrochlorothiazide).
• Treatment of Liddle Syndrome: An autosomal dominant genetic disorder characterized by a hyperactive gain-of-function mutation in the ENaC channel (causing severe hypertension and profound hypokalemia). Amiloride is the specific treatment of choice.
• Lithium-induced diabetes insipidus: Blocks the entry of lithium through the ENaC channel into the principal cells of the collecting duct, preventing its intracellular accumulation and subsequent cellular damage that blocks the action of ADH.

Dosage and Settings

• Hypertension / Prevention of Hypokalemia: Start with 5 mg orally per day; It can be increased up to 10 mg daily. Doses up to 20 mg/day are uncommon.
• Liddle syndrome: 5 mg to 15 mg daily.
• Kidney adjustment:
  - CrCl 30-50 mL/min: Reduce the dose by half (50%) and monitor potassium.
  - CrCl < 30 mL/min: Contraindicated.

Security

Contraindications

• Absolute: Hyperkalemia (K+ > 5.5 mEq/L); severe acute or chronic renal failure (CrCl < 30 mL/min); concurrent administration with other potassium-sparing or high-concentration potassium supplements.

Adverse Effects (ADR)

• Very common: Headache, nausea, anorexia, mild diarrhea or constipation.
• Common: Hyperkalemia (particularly in the elderly or patients with underlying diabetic neuropathy), transient hyperchloremic metabolic acidosis.

Interactions

• ACEI / ARA-II / Aldosterone Antagonists: Critical hyperkalemic synergy.
• NSAIDs: High risk of nephrotoxicity and abolition of the natriuretic effect.

Pregnancy and Breastfeeding

Category B. Crosses the placenta in moderate amounts. Not recommended due to the theoretical risk of inducing compensatory uteroplacental hypovolemia.