Pharmacokinetics of Methadone in Adults Undergoing Cardiac Surgery With Extracorporeal Circulation

Introduction:

Pharmacokinetics studies the processes of absorption, distribution, metabolism and excretion of a drug. There are multiple conditions that can affect the expected pharmacokinetic behavior of a drug. In cardiac surgery, for example, most surgeries require stopping the heart. For this, different cardioplegia solutions and an extracorporeal circulation machine (ECC) are used to allow oxygenation and blood circulation to continue to the rest of the body. The establishment of Cardiopulmonary bypass (CPB) involves profound changes that can alter the pharmacokinetics and clinical response to drugs. An adequate knowledge of the magnitude and direction of these changes is therefore necessary for each drug in particular, in order to achieve an optimal dosage at the time of use. In order to optimize postoperative pain management in cardiac surgery, other drugs have been used as an alternative to the usual management of boluses of morphine or fentanyl. Methadone has pharmacokinetic and pharmacodynamic characteristics that make it attractive; however, despite being a relatively old drug, its use in cardiac surgery is relatively recent. To date, few studies have been published with the use of methadone in a single intraoperative bolus scheme, both studies report positive results. However, to date there are no pharmacokinetic or pharmacodynamic studies that provide guidance on how to dose and adjust the dose of methadone in patients undergoing cardiopulmonary bypass in this context.

THEORETICAL FRAMEWORK Pharmacokinetics is the branch of pharmacology that studies the relationship between the dose of a drug and its plasma concentrations, "what the body does to the drug." Pharmacokinetics studies the processes of absorption, distribution, metabolism and excretion of a drug.

Compartment pharmacokinetic models emerge as a way of conceptualizing this study. They describe the organism as a set of compartments where each one represents a part of the biological material in which the drug is supposed to be uniformly distributed and has the same kinetic properties. It is possible to use 1 or more compartments to describe the kinetics of a drug. For the estimation of population parameters, specific study methods are required that allow the most accurate and precise estimation of population parameters, both of fixed effect, as well as of inter and intra-individual random effect. Among the available parametric methods, which assume a known probability distribution, one widely used is the non-linear mixed effects model. Proposed by Sheiner and Beal, it is currently the reference method in pharmacokinetic analysis in large population groups. This method allows estimating inter individual variability without ignoring the large number of limitations present in observational data.

From a clinical perspective, there are multiple conditions that can alter the expected pharmacokinetic behavior of a drug; diseases, for example, can modify the physiological functions of different organs, alter blood flow and alter the metabolism and elimination of some drugs. Another example is the case of cardiac surgery where, for the realization of most of the surgeries it is required to stop the heart. For this, different cardioplegia solutions and an extracorporeal circulation machine (CPB) are used to allow oxygenation and blood circulation to continue to the rest of the body during the surgical procedure. The establishment of CPB involves profound changes that can alter the pharmacokinetics and clinical response to drugs. An adequate knowledge of the magnitude and direction of these changes is therefore necessary for each drug in particular, in order to achieve an optimal dosage at the time of use.