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Fundamental Properties of Local Anesthetics. II. Measured Octanol

Buffer Partition Coefficients and pK_a Values of Clinically Used Drugs

Anesthesia Research Laboratories, Brigham & Womens Hospital, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.

Abstract

Because local anesthetic molecules interact with ion channel proteins embedded in membranes to effect impulse blockade, and because their clinical potency often depends on both vascular absorption and distribution into the tissue surrounding the site of deposition, the ability to partition into these various compartments is an important determinant of local anesthetic action. Therefore, the hydrophobic nature of local anesthetics used clinically was characterized by the octanol:bufer partition coefficients of their charged (P⁺) and neutral (P⁰) species. This was accomplished by previously described optical methods in which direct spectrophotometric measurement of both the pH-dependent distribution coefficient (Q) and of the ionization permit calculation of the pK_a and partition coefficients. The rates of alkaline hydrolysis of ester-linked molecules also were measured to assess potential interference of such hydrolysis with the physicochemical assays. Results indicate that the hydrophobicity of a local anesthetic is increased by manipulation of the molecular structure at three sites: (a) the aromatic ring; (b) the intermediate linking group; and (c) the tertiary amine. P⁰ for the agents studied was 10³-10⁵ times greater than P⁺. Although there is no systematic relationship between hydrophobicity and pK_a, the latter is greater with ester-linked (pK_a = 8.59–9.30) than with amide-linked (pK_a = 7.92–8.21) local anesthetics. All of the charged species, with the exception of bupivacaine, selectively partition into the aqueous environment (P⁺ < 1.0). The temperature dependence of partitioning of the local anesthetics, measured at 25 and 36°C, indicates an entropy-driven hydrophobic uptake. Solutions bufered with bicarbonate and including 5% CO₂ showed the same local anesthetic partitioning as that of CO₂-free solutions, suggesting that potentiation of impulse blockade by CO₂ is not due to increased membrane uptake. Correlations of physicochemical properties of local anesthetics with potencies on isolated nerve confirm that the more potent local anesthetics have greater octanol:buffer partition coefficients, and that the ester-linked local anesthetics are more potent than their amide-linked counterparts having the same hydrophobicities. The correlations of structure with potency also suggest that the extracellular protonated species may contribute to impulse blockade.

Key Words: ANESTHETICS, LOCAL-partition coefficients • SOLUBILITY, PARTITION COEFFICIENTS-local anesthetics

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