Learning Objective

Describe the mechanism, uses, adverse effects, and drug interactions of loop diuretics, and distinguish them from thiazides in terms of calcium handling.

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Mechanism of Action

Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid) inhibit the Na⁺/K⁺/2Cl⁻ cotransporter (NKCC2) in the thick ascending limb (TAL) → leads to:

• ↓ intracellular K⁺ in the TAL
• ↓ back-diffusion of K⁺ into the lumen
• ↓ lumen-positive potential
• ↓ paracellular reabsorption of Ca²⁺ and Mg²⁺
• ↑ delivery of solute to distal nephron → massive diuresis

Key Outcome: Loops increase Ca²⁺ excretion, unlike thiazides.

Actions of Loop Diuretics on the Thick Ascending Loop (TAL)

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Drugs

• Furosemide
• Torsemide
• Bumetanide
• Ethacrynic acid (non-sulfonamide)

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Sulfonamide Cross-Allergenicity

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Uses

• Acute pulmonary edema
• Congestive heart failure
• Hypertension
• Refractory edemas
• Hypercalcemic states (limited use; promotes Ca²⁺ loss)

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Side Effects

• Sulfonamide hypersensitivity (except ethacrynic acid)
• Hypokalemia + metabolic alkalosis
• Hypocalcemia
• Hypomagnesemia
• Hyperuricemia (competition for OAT secretion)
• Ototoxicity: Worse with ethacrynic acid > furosemide

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Activity

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Drug Interactions

• Aminoglycosides → ↑ ototoxicity
• Lithium → ↓ clearance → lithium toxicity
• Digoxin → ↑ toxicity due to hypokalemia

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Clinical Correlates

Loop vs Thiazide on Calcium

• Loops → ↑ Ca²⁺ excretion (hypocalcemia)
• Thiazides → ↓ Ca²⁺ excretion (hypercalcemia; used in kidney stones)

Thiazides on Smooth Muscle

• Hyperpolarize smooth muscle → vasodilation
• Hyperpolarize β-cells → ↓ insulin release → may cause hyperglycemia

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Activity