Abstract
Local anesthetics are one of the most widely used drug classes in clinical practice. Like many other biological molecules, their properties are altered depending on their protonation status, which is dependent on the pH of the environment. We studied the transport energetics of seven local anesthetics from the extracellular fluid across the biological membrane to the axoplasm in order to understand the effect of pH value on their efficacy and other pharmaco-dynamic properties. In this we applied three different methods of solvent reaction field in conjunction with quantum chemical calculations to reproduce experimental values of n-octanol/water partition coefficients for both neutral and protonated forms. Only the SMD method of Cramer and Truhlar was able to reproduce experimental partition coefficient values. The results are discussed in terms of the function of local anesthetics under physiological conditions and in the case of local acidosis.
Highlights
Local anesthetics are a class of compounds originally developed from cocaine to expand its use as a numbing agent, while diminishing its unwanted side effects
Ester linked local anesthetics share the same attributes with amide-linked ones
We demonstrated that local anesthetics flow from the compartment with a higher pH value to the compartment with a lower pH value since protonated local anesthetics have a more favorable solvation energy than their neutral counterparts
Summary
Local anesthetics are a class of compounds originally developed from cocaine to expand its use as a numbing agent, while diminishing its unwanted side effects (e.g. disturbances in heart rhythm and heart attacks, neurological effects). Broadening the therapeutic window, reducing the toxicity and fine-tuning the pharmacodynamic properties of local anesthetics are a few of the key goals that can be achieved by furthering research into the physiochemical characteristics of local anesthetics
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