Lipid solubility modulates pH potentiation of local anesthetic block of Vmax reactivation in guinea pig myocardium.

Abstract

SUMMARY. Current theories envision recovery from local anesthetic block of sodium channels via slow hydrophilic and fast hydrophobic paths. Extracellular pH reduction which increases cationic/neutral anesthetic form should especially prolong recovery kinetics of highly lipid soluble compounds that could readily exit via the hydrophobic pathway at normal extracellular pH. To test this hypothesis, we compared the effects of three related compounds with similar pKa on the time course of V max reactivation in guinea pig papillary muscle at pH<, 7.4 and 6.95. The compounds were lidocaine and its two desethylation products, monoethylglycinexylidide and glycinexylidide. Judged from the octanol:water partition coefficient, lidocaine was the most lipid soluble (log partition coefficient 2.39 ± 0.10), followed by monoethylglycinexylidide (log partition coefficient 1.32 ± 0.09) and glycinexylidide was the least lipid soluble (log partition coefficient 0.41 ± 0.09). At 30 MM and pHo 7.4, the potency order for W mix depression at zero diastolic interval was lidocaine (53 ± 6%), monoethylglycinexylidide (17 ± 3%), and then glycinexylidide (7.8 ± 1.9%). The decay of V^ block appeared monoexponential, and the time constant of recovery was dose independent. Most important is the fact that there were significant differences in the r r increase with extracellular pH reduction (P < 0.05; Scheffe contrasts). The increase was greatest with lidocaine [73 ± 28% (mean ± SD)], less with monoethylglycinexylidide (42 ± 15%), and least with glycinexylidide (13 ± 17%). The simplest interpretation of the differences in extracellular pHdependence of recovery kinetics was that recovery from block due to the neutral form of these ionizable local anesthetics depended on lipid solubility, whereas recovery from block due to the protonated form depended on molecular weight. (Circ Res 55: 513-523, 1984)

Cardiac-Specific External Paths for Lidocaine, Defined by Isoform-Specific Residues, Accelerate Recovery From Use-Dependent Block

“…This is consistent with the expectation that the P-loop mutation C373Y alters a hydrophilic path. This interpretation fits well the theoretical framework proposed by Broughton et al 17 The role of the hydrophilic path was clear for the P-loop-induced path, but less clear for the D4S6 path. The two paths seemed to be affected differently by pH change, and they are additive, leading us to suggest that the paths are separate, with the D4S6 path being through the protein itself.…”

“…17 When the data in Table 2 for hH1a clones were fit into the equation, charged and neutral were calculated to be 394 and 64.9 ms, respectively, in good agreement with those obtained by Broughton et al 17 using isolated myocytes at two pH points (pH 6.9 and 7.4), despite different experimental conditions and methods; charged and neutral were 476 and 43 ms, respectively. Interestingly, a similar treatment for h-C373Y yielded charged and neutral of 704 and 68.6 ms, respectively ( Figure 3B and Table 4).…”

“…We show that these isoform-specific residues influence the lidocaine recovery kinetics and define cardiac-specific external paths for lidocaine. The data are fit into a mathematical model 17 to separate the recovery-time constants for charged and neutral lidocaine molecules. From this result, we propose a model that suggests the impact of the external path on the drug kinetics.…”

Antiarrhythmic drug action. Blockade of the inward sodium current.

“…The hypothesis predicts that increases in r t would be especially prominent with highly lipid-soluble drugs which can exit the channel through the hydrophobic membrane phase. The demonstration by Broughton et al (1984) confirms the prediction that the increase in r r at low pH by lidocaine and its two desethyl metabolites correlates with their lipid solubility. The slowing of the recovery of Vmix during acidosis observed in most of these studies would enhance the blocking action of antiarrhythmic drugs during acidosis.…”

Effect of lidocaine in acute ischemic situations: A computer modelling study

“…The substantial fall in external pH during myocardial ischemia changes the kinetics of drug binding to the Na + channel and may explain the more depressant effect of these drugs during myocardial ischemia [6]. A study has found that the kinetics of recovery from lidocaine were increased and slowed when the extracellular pH was reduced [7,8].…”