Local anesthetics: injection route alters relative toxicity of bupivacaine

Site of injection affects the toxicity of local anesthetics, perhaps because differences in tissue binding, vascular uptake, and hepatic clearance affect drug disposition. Three local anesthetics with different physical and pharmacologic properties were given intraperitoneally or subcutaneously to mice assay median convulsant (CD50) and median lethal (LD50) doses. The toxicity of bupivacaine, a long-acting, tightly tissue-bound local anesthetic agent was increased only 30% to 40%, whereas the toxicities of lidocaine and chloroprocaine were increased 300% to 400%, by giving the drugs intraperitoneally rather than subcutaneously. Because of this, bupivacaine appeared to be 13 times more toxic than chloroprocaine when subcutaneously, but only 4.5 times more toxic relative to chloroprocaine when assayed intraperitoneally. We conclude that a drug's therapeutic index (ratio of potency to toxicity) relative to a standard drug is affected considerably by route of extravascular administration.