Aminoglycosides cellular toxicity

Figure 9.2. Mechanisms of aminoglycoside toxicity. This schematic representation summarizes the principles of aminoglycoside toxicity discussed in the text. Treatment with the drugs leads to the formation of reactive oxygen species through a redox-active complex with iron and unsaturated fatty acid or by triggering superoxide production by way of NADPH oxidase. An excess of reactive oxygen species, not balanced by intracellular antioxidant systems, will cause an oxidative imbalance potentially severe enough to initiate cell death pathways. Augmenting cellular defenses by antioxidant therapy can reverse the imbalance and restore homeostasis to protect the cell.

High serum levels of certain antibiotics may cause toxicity by affecting cellular processes in the host directly. For example, aminoglycosides can cause ototoxicity by interfering with membrane function in the hair cells of the organ of Corti. 

Tubular cell toxicity This involves the cellular transport systems mentioned previously and is thus dose dependent to a degree. Examples of tubular cell toxins include aminoglycosides, calcineurin inhibitors, amphotericin, antiviral agents, cisplatin, methotrexate, contrast agents and cocaine. 

Several reports have mentioned the possibilities of toxicity stemming from other pathways. For example, inhibition of protein synthesis may lead to undesirable cellular events that lead to toxicity. Aminoglycosides have also been shown to inhibit Klenow DNA polymerase as well as poly(A)-specific... 

Reportedly, SDD of aminoglycosides results in less accumulation in renal cells because the reabsorption of aminoglycoside is saturation dependent (30,31). Animal studies have shown that SDD allows a longer period when there is no additional drug exposure with reduced aminoglycoside burden for cellular processing (26), there is theoretically less inherent toxicity. 

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