Pharmacokinetics of Local Anaesthetics in Infants and Children

Abstract

Amide local anaesthetics used for regional anaesthesia in paediatric patients are potent sodium channel blockers with marked stereospecificity, which consistently influences their action, especially their toxic action on the heart. At toxic concentrations, they induce severe arrhythmias with the potential for cardiac arrest. These agents are all bound to serum proteins, mainly to alpha(1)-acid glycoprotein (AAG), but also to human serum albumin. Protein binding ranges from 65% (lidocaine) to more than 95% (bupivacaine, ropivacaine). Because AAG is a major acute phase protein, its concentration rapidly increases when inflammatory processes develop, particularly during the postoperative period. Neonates and infants have a lower AAG concentration in serum as compared with adults; therefore, their free fraction of local anaesthetics is increased accordingly. This has important clinical implications since, at least at steady state, the toxic effects of local anaesthetics are directly related to the free (unbound) drug concentration. After injection into the epidural space, absorption into the bloodstream follows a biphasic process. The buffering properties of the epidural space are important and prevent a rapid rise in concentration. In infants and children, the epidural space seems to protect patients in a similar manner. Moreover, it has been observed that the peak plasma concentration (C(max)) of ropivacaine is delayed in infants and children when compared with adults. The time to C(max) decreases from 90-120 minutes in infants aged less than 6 months to 30 minutes in children aged more than 8 years. This delay in C(max) may also be related to the lower clearance observed in younger patients. Local anaesthetics are metabolised by cytochrome P450 (CYP). The main CYP isoforms involved are CYP3A4 for lidocaine and bupivacaine and CYP1A2 for ropivacaine. CYP3A4 is not mature at birth but is partly replaced by CYP3A7. The intrinsic clearance of bupivacaine is only one-third of that in adults at 1 month of age, and two-thirds at 6 months. CYP1A2 is not fully mature before the age of 3 years. Indeed, the clearance of ropivacaine does not reach its maximum before the age of 5 years. However, at birth this clearance is not as low as expected, and ropivacaine may be used even in younger patients.

Effects of bupivacaine, levobupivacaine and ropivacaine on myocardial relaxation

“…Papillary muscles must be studied at this temperature because it is difficult to maintain stability of mechanical parameters at 37°C and at low frequency, because high-stimulation frequency induces core hypoxia. 43 Lastly, following in vivo administration (for example after unintended intravascular injection) a large proportion of LAAs can bind to α 1 -acid glycoprotein and albumin, 44 and thus the concentrations of 8 µg·mL -1 (3.10 -5 M, bupivacaine) which results in myocardial toxicity, would rarely be achieved clinically. 6 However, cardiac contractile depression might be observed in clinical practice as it has been observed with blood concentrations of ropivacaine as high as 17.44 mg·L -1 (6.10 -5 M).…”

Does hyaluronic acid decrease the apoptotic effect of bupivacaine?

“…[17] Physiologically around 95% of bupivacaine and analogs bind to proteins, while the remaining 5% exert clinical effects. [18] Following joint surgeries, most of the macro-molecules including hyaluronic acid within the joint are washed out. As a consequence, tissue would be exposed to a toxic Cell culture studies cannot represent in vivo environments.…”

Evaluation of high-performance liquid chromatography and mass spectrometry method for pharmacokinetic study of local anesthetic ropivacaine in plasma

“…We further examined the specificity of this method for the measurement of blood ropivacaine in rabbits. Since the amount of an unbound drug influences its pharmacological effect, knowledge of the unbound fraction may have significant pharmacodynamic implications (11). Ropivacaine is mainly bound to α 1 -acid glycoprotein in plasma protein (9).…”