Anti-arrhythmic effects of lidocaine metabolites

Burney, Robert G.; DiFazio, Cosmo A.; Peach, Michael J.; Petrie, Kent; Silvester, M. J.

doi:10.1016/0002-8703(74)90287-7

Cited by 64 publications

(18 citation statements)

References 6 publications

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“…In addition, the kinetics of recovery from MEGX block was prolonged somewhat by acidosis, which may promote suppression of arrhythmia in ischemic myocardium. GX was reported one-fourth as potent as lidocaine in a model of ventricular arrhythmia (Tenthorey et al, 1981), but failed to suppress ouabain-toxic atrial arrhythmias (Burney et al, 1974). The present study suggests that its antiarrhythmic action probably is minimal at clinically observed blood levels in patients with ischemic ventricular arrhythmias, since V max block at the onset of diastole was less than onesixth that seen with lidocaine, and recovery from block was not delayed by acidosis.…”

Section: Discussionmentioning

confidence: 48%

“…Previous experimental studies suggest that this MEGX concentration would produce some antiarrhythmic effect. MEGX was reported to have about one-third the equimolar potency of lidocaine for antifibrillatory action in chloroform-exposed mice, one-half the potency for premature ventricular contraction suppression in dogs after coronary ligation, full potency for suppression of ouabain-toxic atrial arrhythmias in guinea pigs, and one-fourth the potency for block of frog sciatic nerve (Ehrenberg, 1948;Smith and Duce, 1971;Burney et al, 1974). In comparison, we found that the level of V max block immediately after action potential repolarization was one-third of the block with lidocaine at 30 tiu concentration, similar to the reported potency ratios for nerve block and suppression of ventricular arrythmia.…”

Section: Discussionmentioning

confidence: 99%

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

Broughton¹,

Grant²,

Starmer³

et al. 1984

Circulation Research

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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)

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

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

Broughton¹,

Grant²,

Starmer³

et al. 1984

Circulation Research

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“…The anti-convulsant activity of MEGX is unknown, although its convulsant potency has been evaluated in animal models where it was shown to be comparable to that of lidocaine [4]. The antiarrhythmic activity of MEGX has been determined in an animal model by Burney et al [5] who found it to be approximately 80% as potent an anti-arrhythmic agent as lidocaine [5]. The cardiac toxicity potency of MEGX is unknown.…”

Section: Discussionmentioning

confidence: 99%

Development of an optimal lidocaine infusion strategy for neonatal seizures

et al. 2006

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“…The contribution of MEGX plasma concentrations in the development of toxicity as reported earlier (Strong & Atkinson, 1972;Strong et al, 1973;Halkin et al, 1975) has been supported in this investigation. This finding suggests that analytical techniques intended to aid lignocaine therapy by plasma level monitoring should include measurement of MEGX, a pharmacologically (Burney, Di Fazio, Peach, Petrie & Silvester, 1974) and toxicologically (Blumer et al, 1973) active metabolite, as well as the parent drug.…”

Section: Discussionmentioning

confidence: 99%

Lignocaine kinetics in cardiac patients and aged subjects.

Nation¹,

Triggs²,

Selig³

1977

Brit J Clinical Pharma

158

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1 The pharmacokinetics following long term intravenous infusion of lignocaine to cardiac patients have been examined. 2 Plasma levels and half‐lives of lignocaine and monoethylglycinexylidide (MEGX) showed wide inter‐patient variability. 3 Toxicity reactions to therapy were associated with elevated lignocaine and/or MEGX plasma levels. 4 In a separate study the effect of age on the pharmacokinetics of lignocaine was examined using bolus doses (50 mg) of the drug to young and aged subjects. 5 Elderly subjects had significantly longer half‐lives for lignocaine compared to younger individuals although no change in plasma clearance occurred. 6 The drug appeared to distribute differently in the aged as reflected by significantly increased apparent volumes of distribution. 7 The 24 h urinary recovery of the major metabolite (total 4‐hydroxyxylidine) showed a significant reduction in the elderly when compared to the young. 8 The clinical significance of these studies with respect to lignocaine therapy has been discussed.

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Anti-arrhythmic effects of lidocaine metabolites

Cited by 64 publications

References 6 publications

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

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

Development of an optimal lidocaine infusion strategy for neonatal seizures

Lignocaine kinetics in cardiac patients and aged subjects.

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