Pharmacokinetics and pharmacodynamics of medullar agents: a. Local anaesthetics

Abstract

In considering the pharmacokinetics of local anaesthetics, both the systemic absorption and systemic disposition are of importance. Systemic absorption of local anaesthetics limits the duration of nerve block and is of concern in view of systemic toxicity. Initial absorption rates are higher after epidural than after subarachnoid injection, whereas the slower, secondary absorption rates are similar. Amide-type local anaesthetics undergo extensive tissue distribution. Volumes of distribution vary from approximately 60 to nearly 200 litres. Elimination occurs almost exclusively by biotransformation. Amide-type agents are predominantly metabolized in the liver. Total body clearances vary from 0.6 to 2.4 litres/min. Ester-type agents are hydrolysed in the liver and in blood, ensuring very fast elimination. Blood or plasma concentrations after single epidural injections vary with the local anaesthetic and the dose. Addition of adrenaline to local anaesthetic solutions reduces the peak plasma concentrations. Long-term continuous epidural infusions for postoperative pain relief may result in significant accumulation, reflecting increases in plasma protein binding. Plasma concentrations after subarachnoid administration are very low, so the risk of systemic toxicity is very small. The main factors determining the onset, quality and duration of epidural neural blockade are the local anaesthetic employed and its physicochemical properties. Onset in the caudad segments is usually faster, and spread of analgesia is higher in older patients. Addition of adrenaline prolongs the duration. Ongoing clinical studies show that ropivacaine is an effective long-acting local anaesthetic when given epidurally. Bupivacaine has frequently been used, either as a glucose-free or hyperbaric solution, for spinal anaesthesia. Glucose-free bupivacaine solutions provide long-lasting motor blockade, but appear to provide an unpredictable spread of analgesia. Advancing age has been shown to be associated with a prolonged duration of analgesia with glucose-free bupivacaine solutions and a greater spread of analgesia with hyperbaric bupivacaine solutions.