Aminoglycoside-induced nephrotoxicity occurs predominantly in the proximal tubule due to megalin-mediated endocytosis. The intracellular mechanism of tubular cell death involves:

• A Direct inhibition of 80S ribosome in tubular epithelial cells causing protein synthesis arrest
• B Aminoglycosides displace Ca2+ from membrane phospholipids in tubular cells, causing uncontrolled calcium influx
• C Accumulation in lysosomes causing phospholipidosis, mitochondrial dysfunction, free radical generation, and ultimately apoptosis/necrosis of tubular cells ✓
• D Inhibition of tubular Na+/K+-ATPase causing osmotic swelling and lysis

Explanation

Aminoglycosides (gentamicin, tobramycin, amikacin) are filtered by glomeruli and reabsorbed by proximal tubular cells via megalin (LRP2) receptor-mediated endocytosis. Within lysosomes, they inhibit lysosomal phospholipases (causing phospholipidosis), disrupt mitochondrial function generating reactive oxygen species, and eventually trigger caspase-dependent apoptosis and necrosis. Once-daily dosing reduces nephrotoxicity compared to multiple daily dosing because the megalin receptor saturates transiently (less accumulation), while bactericidal efficacy is preserved (concentration-dependent killing). Monitoring involves trough levels, which reflect tissue accumulation.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.