Interaction of aminoglycoside antibiotics and lithium at the neuromuscular junctions

Lithium in the form of the carbonate or citrate salts has been used by Cade in 1949 for the treatment of affective disorders. Lithium is known to reduce the supply of inositol, the key substrate for the phosphoinositide cascade, by inhibiting some of the enzymes which hydrolyse the inositol phosphates. On the other hand aminoglycoside antibiotics are used extensively in the treatment of life-threatening infections despite their three important toxicities on kidney, ear and neuromuscular junctions. It has been suggested that aminoglycoside antibiotics inhibit the signal-transduction pathway by interaction with the inositol polyphospholipids, thereby inhibiting the production of second messenger molecules. In 1977 two case reports described prolonged neuromuscular blockades, one following succinylcholine and the other after pancuronium in patients receiving lithium therapy. The following investigation was undertaken to determine whether lithium interferes with aminoglycoside antibiotics (gentamycin and amikacin) at the neuromuscular junctions. The neuromuscular blocking effect of aminoglycoside antibiotics were tested in the isolated phrenic nerve-hemidiaphragm preparation of the rat. The IC50 of gentamycin and amikacin were 1.75 and 5.27 mmol.l-1 respectively. Thereafter sodium chloride of the media was partially replaced by lithium chloride and the effect of gentamycin (1.75 mmol.l-1) and amikacin (5.27 mmol.l-1) were studied in this media. Incubation of the preparation by 0.5, 1.5 and 5.0 mmol.l-1 lithium 30 min before the use of antibiotics reduced the neuromuscular blocking effect of gentamycin and amikacin significantly. It appears that the prevention of the antibiotic-induced neuromuscular blockade by lithium observed in this study may be due to the changes of release of acetylcholine at the neuromuscular junctions.