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Reversal of the Electrocardiographic Effects of Cocaine by Lidocaine. Part 2. Concentration‐Effect Relationships
Author(s) -
Grawe Jeffrey J.,
Hariman Robert J.,
Winecoff Allison P.,
Fischer James H.,
Bauman Jerry L.
Publication year - 1994
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/j.1875-9114.1994.tb04163.x
Subject(s) - lidocaine , qrs complex , anesthesia , repolarization , local anesthetic , antiarrhythmic agent , medicine , chemistry , electrophysiology , heart disease
Ventricular arrhythmias due to cocaine may be related to its ability to slow ventricular conduction or prolong repolarization. We previously showed that lidocaine reversed QRS prolongation due to cocaine. The purposes of these experiments were to characterize cocaines concentration‐effect relationship on both ventricular conduction and repolarization, and to determine the effects of lidocaine on these relationships. The effects of lidocaine on cocaine‐induced electrocardiographic changes were studied in 20 isolated, Tyrode‐perfused guinea pig hearts. Variables at cocaine concentrations ranging from 3–195 μM were measured and repeated in the presence of a fixed concentration of lidocaine 30 μM. Using nonlinear regression analysis, the sigmoid E max and simple E max models were fit to cocaine concentration versus percentage change in QRS plots. Measures of best fit indicated that this relationship was best described by the sigmoid E max model. Compared with cocaine alone, the curve for cocaine with lidocaine showed a greater EC50 (concentration at 50% of maximum effect) (59 vs 100 pM) but similar E max (371 vs 367%), consistent with competition. Similar values were obtained from the linear transformation of the data. Cocaine concentration versus percentage change in the JT C interval showed a biphasic effect: concentrations below 65 μM prolonged JT C , but those above 65 μM had no effect or decreased JT C . In contrast to changes in QRS, addition of lidocaine increased the effects of cocaine on JT C : area under the concentration‐effect curve for cocaine alone was 720 versus 859 μM% for cocaine with lidocaine. Lidocaine reverses cocaine‐induced slowed ventricular conduction through competition for binding, but it appeared to increase cocaine‐induced prolongation of repolarization. These findings can be explained by the different effects on sodium and potassium currents depending on cocaine concentration, and may have important implications regarding mechanisms and therapy of cocaine‐induced arrhythmias.