The Clinical Pharmacology of Lidocaine an ... - Circulationcirc.ahajournals.org/content/circulationaha/50/6/1217.full.pdf · The Clinical Pharmacology of Lidocaine ... From the Divisions

The Clinical Pharmacology of Lidocaineas an Antiarrhythymic Drug

By KEN A. COLLINSWORTH, M.D., SUMNER M. KALMAN, M.D.,AND DONALD C. HARRISON, M.D.

SUMMARYThis article reviews current knowledge about lidocaine, with reference to its chemistry, metabolism, elec-

trophysiology, hemodynamic effects, antiarrhythmic uses, pharmacokinetics, and side effects. The criticalimportance of blood levels and their relation to lidocaine's antiarrhythmic and toxic effects is noted, withspecial emphasis given to patients with compromised clearance due to heart failure. On the basis of this in-formation, we present our current approach to the clinical use of lidocaine in the treatment of ventriculararrhythmias, with particular reference to patients with acute myocardial infarction.

Additional Indexing Words:MetabolismAntiarrhythmic actions

ElectrophysiologySide effects

Hemodynamic effectsBlood levels

LIDOCAINE was first synthesized in 1943and was used for many years as a local anes-

thetic agent.' Its first reported use as an antiar-rhythmic drug was in 1950.2 Anesthesiologists sub-sequently adopted lidocaine for treating arrhythmiasoccurring during surgery, and in 1963 its successfuluse in treating arrhythmias occurring during and aftercardiac operations was described.3 Lidocaine has sincebeen used extensively in treating ventriculararrhythmias, and administered intravenously is prob-ably the most widely used agent for the treatment andprevention of cardiac arrhythmias after acute myo-cardial infarction.

Chemistry and Metabolism

The chemical structure of lidocaine is an aromaticgroup, 2,6-xylidine, which is coupled to diethylgly-cine via an amide bond. Lidocaine appears to bemetabolized chiefly by the liver.4 5Studies on hepatictissue homogenates have shown that the microsomalenzyme system is primarily responsible for the hepaticmetabolism of lidocaine.' Its major degradative

From the Divisions of Cardiology and Pharmacology, StanfordUniversity School of Medicine, Stanford, California.

This work was supported in part by NIH grants nos. HL-5709,HL-5866, and 1-PO1-HL-15833-01. Dr. Collinsworth was supportedin part by the Bay Area Heart Research Committee.

Dr. Collinsworth's present address is Department of Medicine,University of California, San Francisco, California 94143.Address for reprints: Donald C. Harrison, M.D., Chief, Car-

diology Division, Stanford University School of Medicine, Stanford,California 94305.

Received April 14, 1973; revision accepted for publication August21, 1974.

Circulation, Volume 50, December 1974

pathway (fig. 1) appears to be conversion to mono-ethylglycinexylidide by oxidative N-de-ethylationfollowed by hydrolysis to 2,6-xylidine.' Evidence ex-ists for a cyclic intermediate in the N-de-ethylation re-action.7 A stable cyclic form, N'-ethyl-2-methyl-N'-(2,6-dimethylphenyl)-4-imidozolidinine, has alsobeen isolated from the urine of humans receiving orallidocaine.7 Further conversion of 2,6-xylidine to 4-hydroxy-2,6-xylidine appears to occur in man, sincethe latter compound excreted in urine over a 24-hourperiod has accounted for over 70% of an orally ad-ministered dose of lidocaine.' A number of otherdegradative pathways produce small amounts of 3-hy-droxylidocaine, 3-hydroxymonoethylglycinexylidide,and glycinexylidide, as well as small amounts of theintermediate compounds in its major metabolic path-way, monoethylglycinexylidide and xylidine.' Hy-droxylation of the aromatic nitrogen also occurs,resulting in the formation of N-hydroxylidocaine andN-hydroxymonoethylglycinexylidide, both of whichhave been identified in the urine of patients given orallidocaine.' Lidocaine is a weak base with a pKa' of7.8510 and up to 10% of lidocaine in unchanged formmay be excreted in the urine, depending on theurinary pH.'.9 Acid urine results in a larger fractionbeing excreted in the urine. Extensive biliary secretionof lidocaine metabolites occurs in rats, but most ofthese metabolites are absorbed in the intestine andthen eliminated via the urine.8 There is no evidencethat biliary secretion and intestinal absorption oflidoDaine metabolites occur in man.9

Electrophysiology

The electrophysiologic effects of lidocaine on1217

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/CH3/ OH 0 C2 H5

N-COCH2-N< C~~~~2H5

OH3N-HYDROXY LIDOCAINE

CH3OHO0 H-N -O-CH2-N

OH3N- HYDROXY- MONOETHYGLYCINEXYLIDIDE

OH30 C2H5

-NHOO-H2N

OH3C2H5

HO CH3/0 C2H5

-NH-0 CH2-N\CH3 0H

3-HYDROXY LIDOCAINE

HO\ OH0

NH O2 N

O3

CH CH30 H

NH-C-OH2- N -NH2C2H5

OH3 CH3

MONOETHYLGLCINEXYLIDIDE

OH3 01 11~~~~/~~~~~~~c1

-N1/1

2,6-XYLIDINE

HO- "~>-NH2

OH34 HYDROXY- 2,6-XYLIDINE

CH3.0

-NH-C-CH2-NH2CH1 211

Ki-el U

OHHC N M53 CH3

N1 ETHYL -2-METHYL-N3 _(2-6-EDMETHYLPHENYL)

-4-IMIDAZOLIDINONE

CH3

GLYCINEXYLIDIDE

c2H5

3-HYDROXY- MONOETHYLXYLDIDIE

Figure 1

Metabolic pathways of lidocaine degradation.

cardiac tissue have been studied extensively. Thoughcontroversy remains, the results of these studies maybe summarized as follows.

Lidocaine causes a slight decrease in automaticity(spontaneous phase 4 depolarization) of pacemakertissue in rabbit atrial tissue in tissue baths at lidocaineconcentrations of 3 and 5 ggml," and in rabbitsinioatrial node at 2.34 gg/Mn1.2 Larger decreases inautomaticity than found in atrial tissue occur incanine Purkinje fibers at extracellular lidocaine con-centrations of 2.34 ptg/M1'2 and 5 gg/mL`' Theselidocaine concentrations are in the range oftherapeutic blood levels (1.4 to 6.0 j.g/ml) in man(discussed below). The diastolic threshold requisite fordepolarization in rabbit atrial tissue is increased at ex-tracellular lidocaine concentrations of 3 and 59ig/ml." In humans, the ventricular diastolicthreshold is either slightly increased' or unchanged14after 1-2 mg/kg intravenous bolus injection. Spon-taneous repetitive discharge after a prematurestimulus is prevented by extracellular lidocaine con-centrations of 5 pg/mI in canine ventricular tissue and10 gg/ml in canine Purkinje tissue."1, 1` Lidocaine in-creases the ventricular fibrillatory threshold in intactrabbit hearts at perfusion concentrations of 1.5-6.2pAg/ml, and in acutely ischemic hearts in dogs, atblood levels of 1.2-5.5 jtg/ml.

The effect of lidocaine on the duration of cardiacaction potential and effective refractory period hasbeen studied."11 13, 16, 17 The action potential durationin canine Purkinje fibers is decreased at extracellularlidocaine concentrations of 2.34 gtg/M1'6' " and 5gtg/Ml."1 Lidocaine also shortens the action potentialduration in ventricular muscle at extracellular concen-trations of 3 ug/in1 in tissue from rabbits" and 2.34p~g/ml in tissue from dogs.'6,1 A more prominenteffect is noted on Purkinje fibers than on ventricularmuscle. '7The effective refractory period is relatively

prolonged compared to the action potential durationin both Purkinje fibers and ventricular muscle.'16Lidocaine's effect on the maximum rate of depolariza-tion and membrane responsiveness has been the sub-ject of controversy."` The reported differences areprobably due to the extracellular potassium concen-trations in the tissue baths at which these two proper-ties are measured.", 16, 18, 19 At physiologic potassiumlevels (5.6 mM), the maximum rate of depolarizationand membrane responsiveness in rabbit ventricularmuscle is decreased by extracellular lidocaine concen-trations of 3 g.g/ml." Hypokalemic solutions (3.0MM), however, cause hyperpolarization of the cellmembrane so that tenfold increases in lidocaine con-centration are needed before depression of membrane


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PHARMACOLOGY OF LIDOCAINE

responsiveness or maximum rate of depolarization oc-curs.1 Conduction velocity in Purkinje fibers inhypokalemic (3.0 mM) bath preparations appears tobe slightly decreased by lidocaine concentrations of5-50,g/ml.l3

Atrioventricular (A-V) node and intraventricularconduction time in man are not significantly changedafter intravenous injections of lidocaine of 1-2mg/kg.20 However, A-V node conduction time is in-creased in dogs given high-dose intravenous injectionsof lidocaine (5-20 mg/kg).21

These electrophysiologic effects cannot be cor-related precisely with lidocaine's antiarrhythmic ac-tions in humans at this time, but can be used tospeculate upon its mode of action in certain specificinstances. Ventricular arrhythmias due to accelerationof ectopic foci may be responsive to lidocaine becauseof its effect on decreasing automaticity by slowing therate of spontaneous phase 4 depolarization. Lidocainehas been shown to abolish the gating function of distalPurkinje tissue by reducing the nonuniformity of ac-tion potential duration in Purkinje tissue, resulting inmore uniform recovery of excitability,'7 and to abolishslowing of conduction in Purkinje tissue.", 17 Re-entrant ventricular arrhythmias may thus be abolishedby lidocaine, due to its effect on action potentialdurations resulting in altered conduction velocity andexcitability.The results reviewed here were obtained mostly

from in vitro animal muscle preparations that werestudied in well-oxygenated baths, in contrast to the invivo situation, where arrhythmias possibly originatefrom ischemic injured myocardium. Anotherdifference would be that in vivo the microcirculationwould be perfused, at least partially, whereas no suchperfusion would exist in vitro. This might change theoxygen availability at different areas in the myocar-dium, and different lidocaine concentrations atdifferent areas in the myocardium might exist in bothinstances. Similar extensive electrophysiologic studieswith lidocaine in vitro in damaged or ischemicmyocardial tissue have not been reported, though arecent report has demonstrated that lidocaine doesaffect differently the electrophysiologic properties ofnormal and ischemic dog Purkinje fibers.22 Thereported differences, in part, may have resulted fromuse of tissues from different animal species and thusreflect species variation in response to lidocaine.Tissue was used from different areas of myocardium,which may also have caused different responses tolidocaine. In addition, different extracellular potas-sium concentrations, which had previously beenshown to alter the electrophysiologic changes inducedby lidocaine in the same tissue,"' 19 were used in theseexperiments. These potassium-related differencesCirculation, Volume 50, December 1974

might have clinical relevance with regard tolidocaine's antiarrhythmic mechanism and efficacy,since they were noted at extracellular potassium con-centrations which occur in many clinical instances,i.e., 3mM and 5.6 mM. A summary of the findings ofelectrophysiologic effects of lidocaine from severalstudies is presented in table 1.

Hemodynamic Effects

The hemodynamic effects of lidocaine have beenstudied in isolated muscle preparations, isolated per-fused hearts, awake and anesthetized animals, animalmodels with acute myocardial infarction, anesthetizedman, and in awake man with acute myocardial infarc-tion.

Lidocaine has been shown to depress the contrac-tility of bath preparations of isolated guinea pig rightventricular muscle.23 In anesthetized dogs, rapid in-travenous injections of lidocaine of 2, 4, and 8 mg/kgresulted in dose-dependent transient decreases of car-diac output, stroke work, arterial pressure, andperipheral vascular resistance.24 Heart rate increasedslightly. Awake dogs showed less marked changes,and when the drug was injected over one minute,negligible depressant effects were seen. Lidocaine hascaused dose-dependent depression of ventricular con-tractility as measured by left ventricular dp/dt inanesthetized dogs when given in i.v. injections of from0.5 to 30 mg/kg.2' Large doses of lidocaine (i.e., 5mg/kg) given as a bolus have produced significanttransient depression of ventricular contractility (leftventricular dp/dt), arterial pressure, heart rate, andcardiac output in anesthetized dogs with experimentalacute myocardial infarction.26 However, when thesame dogs were given a continuous infusion of 200,g/kg/min, minimal circulatory changes developed.When a 2.2 mg/kg i.v. injection was given over one

minute to anesthetized adult human males withoutcardiovascular disease, heart rate did not change, andarterial blood pressure did not decline. In half thepatients, there were actually small increases in thearterial pressure. In awake patients with heart disease,rapid i.v. injections of lidocaine, 1 mg/kg over oneminute27 and 1.5 mg/kg over one-half minute,28caused no significant depression of ventricular func-tion. However, one study has shown, transientminimal depression of ventricular function in half ofthe patients given 100 mg bolus doses.29 The effect ofbolus doses of lidocaine up to 2.0 mg/kg given toanesthetized patients undergoing cardiac surgery hasbeen studied.3 Minimal decreases were seen in rightventricular contractile force as measured by a straingauge attached directly to the right ventricle, and nosignificant changes in arterial pressure or heart ratewere noted.

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Table 1

Electrophysiologic Effects of Lidocaine on Cardiac Muscle

Effect Therapeutic cone. Toxic conc.

Electrical thresholdatria (rabbit) low K low K slightly T

niormal K T normal K TPurkinje fiber (canine) low K -e

Automaticityatria (rabbit) low K low K slightly

inormal K slightly 1 iiormal K slightlyPurkinje fiber (canine) low K i low K

Action potential durationatria (rabbit) low K low K

norrmal K normal Kventricular muscle (rabbit) low K 1 low K I

normal K ilormal K Iventricular muscle (canine) low K or I low K orPurkinje fiber (canine) low K I low K I

Effective refractory periodatria (rabbit) low K low KT

normal K I normal K {ventricular muscle (canine) low K - or low K IPurkinje fiber (canine) low K I low K T

Maximum rate of depolarizatian(phase 0)

atria (rabbit) low K low K Inormal K i normal K i

ventricular muscle (rabbit) low K -* low K Inormal K I normal K

ventricular muscle (canine) low K -- low K 1Purkinje fiber (canine) low K or slightly T low K slightly I or I

Conduction velocityatria (rabbit) low K low K ;

normal K I normal K 4Purkinje fiber (canine) low K 1 or slightly I low K 1

Cone. = concentration; T = inereased = decre

In awake patients with acute myocardial infarction,bolus doses of lidocaine, 1-2 mg/kg30 and 100 mg,31caused no significant depression of cardiac output,heart rate, or arterial pressure. In one patient whoreceived a 5 mg/min continuous infusion of lidocaine,a marked fall of arterial pressure was observed andsinus bradyeardia developed.30 In another study inpatients with acute myocardial infarction, continuousinfusion of lidocaine up to 3 mg/min for up to onehour caused no significant change in left ventricularcontractility, stroke work index, cardiac output,arterial pressure, or heart rate.32

Lidocaine appears to cause no, or minimal, decreasein ventricular contractility, cardiac output, arterialpressure, or heart rate. This generalization wouldseem to apply to normal individuals, patients with car-diac disease, and patients with acute myocardial in-farction. With excessive doses, however, marked

ased; = no change.

depression of cardiac function in patients with acuteinfarction would likely develop. Extrapolating fromdog studies, rapid intravenous bolus injections oflidocaine leading to very high blood levels would bemore likely to cause depression of cardiac functionthan more slowly administered (1-5 min) bolus injec-tions, and it should always be administered in thelatter way in patients with depressed cardiac function.

Antiarrhythmic Actions

Lidocaine administered intravenously has beenhighly effective in terminating ventricular prematurebeats and ventricular tachycardia occurring duringgeneral surgery, during and after cardiac surgery,following acute myocardial infarction, and in thecourse of digitalis intoxication. It has also beensuggested for the prevention and treatment of ven-tricular arrhythmias occurring during cardiac


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catheterization. However, ventricular fibrillation isbest treated by electrical cardioversion, to be followedby lidocaine infusion.The general experience has been that lidocaine has

not been very effective in the treatment of atrialor A-V junctional arrhythmias. In isolated atrial tissue,poor response of ectopic tachycardias to lidocaine hasbeen shown.12

Perhaps the most important use for lidocaine afteracute myocardial infarction is to suppress ventricularpremature beats which often occur in the early postin-farction period. Most cases of ventricular tachycardiaand fibrillation after acute infarction are preceded byventricular premature beats. On the basis of theseobservations, criteria have been developed for thetreatment of ventricular arrhythmias occurring afteracute infarction.32 3 We have recommended suppres-sion of ventricular premature beats when: a) morethan five per minute of unifocal origin occur, b)R-on-T ventricular premature beats are noted, c) mul-tifocal ventricular premature beats occur, d) two ormore ventricular premature beats in a row occur, i.e.,short bursts of ventricular tachycardia.34 In addition,after ventricular tachycardia or fibrillation has beenterminated, lidocaine is administered prophylacticallyfor 24 hours, in an attempt to prevent the recurrenceof ventricular arrhythmias.

Several studies have been carried out to determinethe maintenance dose of intravenous lidocainenecessary to prevent ventricular premature beats. Inone study, it was found that ventricular prematurebeats above a frequency of five per minute were sup-pressed or terminated in 80% of patients by alidocaine blood level of 1.4 to 6.0,g/ml (fig. 2).33 Thislevel was achieved by constant infusion rates of 20-55gg/kg/min (1.4-4.0 mg/min in a 70 kg patient) (fig.3).34 Lower rates are recommended in patients withovert congestive heart failure or liver failure (seebelow.) Under a similar program of treatment, onecoronary care unit reported that occurrence of ven-tricular tachycardia or fibrillation was extremelyrare. 35 Studies have been performed in whichlidocaine was used in standard therapeutic dosesprophylactically after acute myocardial infarction, in arandom manner. 36, 37 In the patients receivinglidocaine, the frequency of ventricular arrhythmias ofall types was clearly lower. However, because sideeffects from lidocaine administration do occur, we donot presently advocate usage of this drug for allpatients after myocardial infarction, but instead preferto administer lidocaine when premonitory signs oflife-threatening cardiac arrhythmias occur.

Pharmacokinetics

The pharmacokinetics of intravenous lidocaineCirculation, Volume 50, December 1974

administration has been studied in normal healthyhumans.38 42 After an intravenous bolus of lidocaine,or after discontinuing a constant infusion, the plasmaconcentration changes describe a biphasic curve thatcan be fitted into two exponential components (fig. 4).There is an early rapid fall in concentration, followedby a later slower decrease in plasma concentration. Anaverage half-life of about 8 min was found in onestudy for the early rapid fall, though considerablevariation was present within the group.38 Anotherreport placed the average value of half-life at 17m.42 The half-life of the later slow decrease inplasma concentration of drug has been reported toaverage 108 minutes38 and 87 minutes41 in normal sub-jects.The two-compartment open model (fig. 5) has been

formulated to explain the biphasic curve observed forthe plasma disappearance of lidocaine.38 41 The first orcentral compartment (CPT 1) includes the in-travascular space, though the calculated volume ofdistribution exceeds plasma volume.38 The second orperipheral compartment (CPT 2) is larger. Whenequilibration is attained for all tissues, the volume ofdistribution exceeds total body water,38 and impliesintracellular concentration of lidocaine. In rats, tissuelidocaine levels in numerous organs are higher thanblood levels, tending to confirm the intracellular con-centration of lidocaine.43

ha

CA

BEFORE LUDOCAINE AFTER LIDOCAINE

R-R iNTERVAL (msec.)

Figure 2

Interval histograms obtained before therapy (left) and duringtreatment (right) with lidocaine, 2 mg/min (32 usg/kg of bodyweight/minute). The abscissa of the interval histogram representsthe R-R interval in milliseconds, and the ordinate the number ofbeats at a given R-R interval. Lidocaine markedly reduced thenumber of premature beats. Total beats in each panel = 160.[Reprinted with permission of Gianelly et al. and New Engl JMed33]

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0.

0

817

6

5

4

32

1

_ ~~~~~~~~~~~/ Sr -~~~~~~~/ 0.-, ,*-

* I . I I ~ ~ ~ ~~II

0 10 1oglKg/min

mg/min 1

20 130 401

2 3

50 160 701 1

4 5

Figure 3

Relation between the rate ofinfusion of lidocaine and the bloodlevel of lidocaine in 39 patientsreceiving a constant infusion. All

levels were measured after at least

two hours of constant infusion in

patients who were not in severe

congestive heart failure or shock.The area enclosed within the rec-

B0 tangle is considered to be the effec-tive therapeutic range. [Reprintedwith permission of Harrison et al.

and Mod Treatm34]

The two phases for the elimination of lidocaine can

be observed best after a steady-state is achieved andinfusion of lidocaine is stopped. The first rapid phaseis due to changes in distribution of lidocaine withinthe two compartments atid hepatic metabolism of thatin the central compartment. The liver extraction ratiofor lidocaine is approximately 70% in individuals withnormal liver function." The second, slower phase ofelimination is dependent at least in part upon theslower net transfer of drug from the larger peripheralcompartment (CPT 2) to the smaller central compart-ment. Thus, the influence of the slow phase ofelimination dominates the calculation of half-life,yielding the value of 87 to 108 min.

Based on the principle that during constant infusionabout five half-life times are required to approachplateau levels of an infused drug,45 and considering a

half-life of 108 min, up to 9 hours would be required

B

0.1

LOGLIDOCAIN E

CONC.

(,ug/mi)

60 120

NORMAL SUBJECTS

180 240

ELIMINATIONFigure 5

Two-compartment open model describing the disposition kinetics

of lidocaine. Drug distributes between compartments one and two

and is eliminated via compartment one. [Reprinted with permissionof Rowland and Thomson and Ann NY Acad Sci38]

MINUTES

Figure 4

A biphasic curve following a single intravenous bolus of 50 mg oflidocaine. A and B are the zero time intercepts of data plotted onsemi-logarithmic paper, while a and ,B are the rapid and slow timeconstants, respectively. The closed circles represent observed data,whereas open circles represent derived data. [Figure reprinted withpermission of Thompson et al. and Am Heart J39]


10r9

Wz

00

-J

0)0

0)

_ ~ ~ ~ ~ aJ si '~

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to reach plateau levels of lidocaine. Higher rates of in-fusion yield higher steady-state levels, but the time toplateau is unchanged. After discontinuing an infusionat a steady-state level, the dominant elimination half-life is approximately two hours.

Attempting to reach therapeutic levels (i.e., 1.4-6.0ug/ml)30,33,34 by using conventional rates of constantinfusion alone (i.e., 20-55 ,ug/kg/min)33 can takeseveral hours, depending on the rate of infusion.Constant infusion technique alone, then, would notacutely provide effective blood levels in life-threatening arrhythmias. Intravenous injections oflidocaine can provide therapeutically effective levelswithin 1 to 2 min, as indicated by clinical observationsof prompt responses of ventricular arrhythmias30 33 34and by determination of plasma levels38 after bolusdoses. However, bolus administration alone is notuseful for managing persistent ventricular arrhyth-mias because lidocaine plasma levels fall rapidlybelow the therapeutic level due to rapid clearancefrom the central compartment, and ventriculararrhythmias have been observed to return within 15 to20 minutes after an injection.30 The practical clinicalapproach is to give a bolus dose at the same time cons-tant infusion is initiated, in order to achieve persistenttherapeutic levels from the onset of administration.34With this approach, it would be expected that an in-itial peak level would be present followed by a rapiddecline to some minimal level, and followed then by aslow rise to plateau concentrations. Using the twocompartment model, it has been computed for anaverage normal individual that a 160 mg lidocaine i.v.injection (2.3 mg/kg in a 70 kg person) simultaneouslygiven at the onset of a 4 mg/min infusion (55,ug/kg/min in a 70 kg person) would produce initialblood levels of 2 to 4 gg/ml, followed by a decline to aminimal level between 1 to 2 ,ug/ml at 20-40 min.4The lidocaine blood level then rises to plateau levelsof 2 to 4 ,ug/ml (fig. 6). Other investigators have com-puted similar results and shown by actualmeasurements in normal individuals that a 100 mg in-jection of lidocaine followed by an infusion of 1mg/min would produce a minimal plasma level of justover 1 gg/ml.38' 40 Using the regimen of constant infu-sion following an initial i.v. injection, it is thus possi-ble to maintain therapeutic lidocaine levels at alltimes after starting the infusion.

Clinical observations demonstrate an increased in-cidence of lidocaine toxicity, primarily manifested bycentral nervous system disturbances in patients withsevere liver disease46 and severe congestive heartfailure.47 Blood levels in excess of 9 utg/ml are fre-quently associated with toxic effects,33 48 though tox-icity has been noted when blood and plasma levelshave been in the 5-9 ,ug/ml range.33 4 In one patientCirculation. Volume 50, December 1974

_JW

W_J

CO.

0_)

z

000_J

5.

4

3

2-

1-

1 2 3 4 5 6 7 8

TIME (hours)Figure 6

Calculated lidocaine plasma level curves where a 4 mg/mininfusion has been combined with a 40 (A), 80 (B), 160 (C), and 320(D) mg rapid intravenous dose. [Reprinted with permission of Boyesand Keenaghan, and Livingstone, Edinburgh79]

with advanced heart failure who was receivinglidocaine at low doses (i.e., 50 mg followed by 1mg/min infusion), near toxic levels of lidocaine weremeasured at 2 hours39 (fig. 7). If the infusion had beencontinued, plateau levels near 12 ,g/ml wouldprobably have been reached. Another patient in car-diogenic shock had lidocaine plasma levels in excess of8.8 ,ug/ml at 24 hours while receiving an infusion ofonly 0.7 mg/min.0

Higher blood levels of lidocaine due to decreased

PLASMA

TIME (min)

Figure 7

Illustration of the difference in plasma level response to infusedlidocaine in a normal subject and a heart failure subject of similarsize. [Reprinted with permission of Thomson et al. and AmHeart J39]

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COLLINSWORTH ET AL.

clearance have been demonstrated by infusinglidocaine and simultaneously measuring cardiac out-put, hepatic clearance of lidocaine, and hepatic bloodflow in patients with stable congestive heart failure."4In this study, lidocaine blood levels varied inverselywith cardiac output, with higher blood levels presentin patients with depressed cardiac output. Hepaticblood flow was linearly related to cardiac output.Higher blood levels correlated well with the degree ofdecreased cardiac output (fig. 8), decreased hepaticblood flow (fig. 9), and decreased lidocaine clearance.These data suggest that the clearance of lidocaine dur-ing steady-state is primarily limited by hepatic bloodflow. Animal studies have also confirmed the correla-tion between decreased cardiac output and hepaticblood flow, resulting in decreased lidocaine clearanceand elevated blood concentrations compared to con-trol animals.51, 52

0

0

0 0 1

111

0

\\.,,

1.41

1.0 1.5 2.0 2.5 3.0 3.5

CARDiAC INDEX (I/min/m2)Figure 8

In a study of lidocaine pharmacokinetics in patientswith advanced liver disease, the steady-state volumeof distribution was increased on the average by a fac-tor of nearly two, the central compartment volume ofdistribution was unchanged, and the plasma clearancewas decreased by almost half, compared to normalsubjects.40 The half-life of the slow phase of elimina-tion was prolonged. As expected, higher than usuallidocaine plasma levels were present during constantinfusion. Changes in plasma protein or tissue affinityfor lidocaine have been suggested as the cause for theincreased volume of distribution.40 Reduced liver en-zyme activity or reduced hepatic blood flow are otherpossible reasons for the decrease in plasma clearance.Care must be used in extrapolating data from com-puter models of distribution to man.However, patients with acute myocardial infarction

often have depressed cardiac output and there may bea redistribution of blood flow away from thesplanchinic bed during the acute phase. Hepatic bloodflow is reduced disproportionately to the reduction inflow elsewhere during the acute stages of infarction,thus causing reduced lidocaine clearance in patientswith acute failure compared with patients withchronic congestive failure. This possibility is sup-ported by the observation that somewhat higher levelsof lidocaine were present in patients shortly afteracute infarction, compared with later stages ofrecovery, when similar rates of infusion were used.'8

a0o

- 2.6

q ex

W 2.2

'-1* >- 1.8 _>. 08

( 1-.

U) 1.4-

40 4.5

The relationship between the arterial lidocaine blood level and thecardiac index in 16 patients is shown. The dotted vertical linerepresents the lowest normal value for cardiac index in our

laboratory of 2.5 L/min/m2. The solid square is the average

lidocaine level and cardiac index for 8 patients with abnormally lowcardiac indices, and the solid triangle the average values for the 8patients with normal cardiac indices. [Reprinted with permission ofStenson et al. and Circulation44]

11

01001.m

0\00

"I~~~ 0

* .

0 250 500 750 1000 1250 1500 1750

ESTIMATED HEPATIC BLOOD FLOW (mi/minIm2)Figure 9

The steady-state arterial lidocaine level related inversely to theestimated hepatic blood flow in ten patients is illustrated. The solidsquare is the average lidocaine level for five patients with hepaticflows of less than 800 ml/min/m2, and the solid triangle is theaverage for five patients with hepatic flows of greater than 800ml/min/m2. [Reprinted with permission of Stenson et al. and Cir-culation44]


3.2

3.0

2.8 L

I-

p-

-11

E 2.6CR

W 2.4z

U 2.20

2.0..

Wj 1.8I-..

I.

l[1.61

F..I. 1 a--- 1- 1 i

1.v 5 1 1 . .-- -.- -1-

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Another study has shown higher than expectedsteady-state plasma levels of lidocaine (i.e., 1.0-2.5,ug/ml) in a group of patients with acute infarctionand congestive heart failure receiving lidocaine in-fusions of 0.7 mg/min.50 The mean plasma half-life inthese patients was prolonged (T-1/2 = 200 min)following cessation of infusion after steady-state levelshad been achieved. The long half-life was in part at-tributed to slow release of lidocaine from peripheraltissues and impaired hepatic clearance, probably dueto diminished perfusion. The plasma clearance oflidocaine was also reduced in these patients40 andwide ranges of values were found for the apparentvolume of distribution. Another group of patients withacute infarction but without severe heart failure havebeen studied in a similar manner.53 In these patients,mean plateau levels of 2.25 ,g/ml were achieved byconstant infusion of lidocaine of 30 ,g/kg/min (i.e.,2.1 mg/min in a 70 kg person). Infusion alone, notpreceded by a bolus dose, had not providedtherapeutic blood levels by 40 minutes. When a 1mg/kg injection preceded the infusion, initialtherapeutic levels of approximately 1.4 ,g/ml wereachieved, followed by a transient drop belowtherapeutic levels. Subsequently, blood levels roseslowly to steady-state between 8 and 12 hours. Afterdiscontinuing the infusion at steady-state levels, aninitial plasma half-life of 120 minutes was found. Alater phase was also present with a half-life of ap-proximately ten hours. Calculations have been madeof expected blood levels in patients with acute infarc-tion, based on data from normal individuals41 and theassumption that the volume of distribution is one-halfof normal in patients with acute infarction.4' 54 An 80mg injection followed by a 2 mg/min infusion wouldbe expected to produce eventual lidocaine bloodlevels between 2 and 4 ,ug/ml, with minimal levels of1 to 2 gg/ml between 20 and 30 minutes. Thesefigures roughly correlate with the data presentedabove during actual clinical testing, though thecalculated blood levels are slightly higher.

Therapeutic Dosage

On the basis of these data reviewed above, and ourown experience, dosage recommendations for the useof lidocaine can be made. In patients with presumednormal cardiac output and normal hepatic functionand blood flow, an initial injection of 2 mg/kgfollowed by a 55 ,ug/kg/min infusion should providetherapeutic lidocaine plasma levels at all times afterthe initial injection. These doses are equivalent to a140 mg dose and approximately 4 mg/min infusion ina 70 kg person. In patients with acute infarction ormoderately reduced cardiac output, an initial injec-Circulation. Volume 50, December 1974

tion of 1.5 mg/kg, followed by 30 ,ug/kg/min infu-sion, is recommended. These doses correspond ap-proximately to a 100 mg dose, followed by a 2 mg/mininfusion in a 70 kg person. Another approach wouldbe to give the two smaller bolus doses of 0.75 mg/kgeach, with the second injection following the first byabout 15 minutes. The drug should always be injectedover several minutes, since very rapid injection mightlead to transiently high plasma levels, with possibletoxic side effects. Slower rates of injection would tendto prevent such high plasma levels, without reductionin antiarrhythmic effectiveness. In patients withmarkedly reduced cardiac output or shock, we recom-mend a dose of no more than 0.75 mg/kg, followed byan infusion of 10-20 ,ug/kg/min. This would corres-pond approximately to a 50 mg injection, followed byan infusion of 0.7 to 1.4 mg/min, in a 70 kg person.Even these doses may be too high in some in-stances.39' 50 In such critically ill cardiac patients inwhom the use of lidocaine is required, monitoring oflidocaine plasma levels, if available, should serve as aguide to the proper dose of lidocaine. Several hoursmust elapse before new constant blood levels are ap-proached when increasing or decreasing the rate of in-fusion. Thus, toxic effects of lidocaine during chronicinfusion might persist for a significant period of timeafter stopping the infusion. One half-life time (ap-proximately 2 hours) is needed for a 50% decrease inthe plasma level, so that significantly decreasedplasma levels with reduction in toxic effects wouldtake more than just a few minutes. If a higher plasmalevel of lidocaine during constant infusion is desired tocontrol an arrhythmia, increasing the rate of ad-ministration from 2 to 3 mg/min would requireseveral hours to reach new steady-state levels. In anycase, significantly increased plasma levels would notdevelop acutely. In such an instance, we recommendan injection of 25 mg or less at the time acutely in-creased plasma levels are required. This can berepeated every 15 to 20 minutes as necessary to con-trol the arrhythmia.

Since the clearance of lidocaine may be reduced inpatients with liver disease, with up to 50% reductionsnoted in some patients with severe cirrhosis,39 40 therecommendation has been made for reduction of infu-sion rates of lidocaine.44 Reduction to one-half therates for normal would seem appropriate. However,individualization of doses should be made based onplasma level determinations, since lidocaine disposi-tion may vary markedly among patients with liver dis-ease.

Patients with chronic renal disease on hemodialysisshow normal pharmacokinetics of lidocaine withregard to half-life times, plasma clearance, andvolume of distribution.40 However, lidocaine

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metabolites are excreted almost entirely in the urine,and some of these metabolites have pharmacologicand possibly toxic effects (see below). Although therehas been no reported additional incidence of toxiceffects during lidocaine administration in patientswith chronic renal failure,34 this may be due to thebrief period of infusion. Lidocaine metabolites wouldprobably accumulate in the plasma during long in-fusions, a collection which might result in toxic effectseven when the plasma levels of lidocaine are notelevated.Though data are not available on this topic,caution is urged in patients with renal disease receiv-ing prolonged infusions of lidocaine.

It is a well-known pharmacologic principle thatplasma levels of certain drugs may be altered by theconcomitant use of another or several other drugs.Patients receiving lidocaine are likely to be receiving anumber of other drugs also, including sedatives,analgesics, inotropic agents, other antiarrhythmicagents and anticoagulants. The effect of such drugs onlidocaine disposition in man has not been determined.However, some information is available from animalstudies. In vitro studies show that phenobarbital in-creases lidocaine metabolism, whereas drugs such asisoniazid and chloramphenicol decrease lidocainemetabolism,55 presumably by altering liver micro-somal enzyme activity. One author has shown that theliver extraction of lidocaine is markedly increased inphenobarbital pretreated dogs,56 probably due toenhanced enzymatic metabolism. A different type ofdrug interaction is illustrated by propranolol,isoproterenol, and glucagon, in which drug-inducedhemodynamic change is the factor that alters anotherdrug's disposition. Propranolol administered to dogsresults in increased lidocaine levels compared to con-trol, by diminishing cardiac output, hepatic bloodflow, and lidocaine clearance.52 In contrast, glucagongiven to dogs and monkeys57 and isoproterenol givento monkeys51 cause increased hepatic blood flow andthereby increased clearance of lidocaine. Whether ornot these animal and in vitro studies apply tolidocaine disposition and plasma levels in humans isspeculative. Clinical studies are needed for elucida-tion of drug interactions with lidocaine in humans.

Lidocaine Blood Levels

With the increasing availability of lidocaine assay,lidocaine therapy can be followed accurately, es-pecially in patients with compromised elimination orin long-term therapy, allowing accurate adjustment oflidocaine infusion rates to achieve the desired plasmalevel and clinical effect. Lidocaine levels are reportedas either blood or plasma levels. Simultaneouslyanalyzed samples show that the value obtained forplasma is about 120% of that obtained for blood, and

the plasma:erythrocyte ratio is approximately 1.34:1,58Until recently, lidocaine levels were reported as thehydrochloride form. Currently, many laboratories arereporting the base form, which is 80% of theequivalent hydrochloride form.

Other Routes of Administration

Intramuscular injection of lidocaine has beensuggested in an attempt to treat arrhythmias inpatients with acute infarction or suspected infarctionwhen they are first seen by a physician outside thehospital.59 Intramuscular injections of 10% lidocainein a 4 mg/kg dose into the deltoid muscle provideblood levels within the therapeutic range of 1.4,g/mlor greater, persisting for 60 to 120 min after initial in-jection in all patients with myocardial infarctiontested (fig. 10).34' 60 Injection into the deltoid muscleprovides higher and more rapid blood60 and plasma65levels than does injection into the gluteal muscle, andthus the former site is recommended. One study hasshown an average reduction of 75% in the number ofventricular premature beats after intramuscularlidocaine injection in patients with acute myocardialinfarction.62 We currently recommend lidocaine, 3 to4 mg/kg intramuscularly, for patients with acute in-farction seen at home by a physician, when prematurebeats are detected and bradyeardia is not present.

Orally administered lidocaine has not been shownto provide effective therapeutic levels (fig. 11).41 63Since lidocaine is metabolized primarily in the liver, itis substantially inactivated by passage through theliver after oral administration. A high incidence ofmild central nervous system side effects has also beenreported after oral administration4' (see below).

3.5 LIDOCAINE 4 mg/kgm

211CD,

20.5

z

0O10 30 60 90 120 180 240TIME POST INJECTION

Figure 10

Blood levels of lidocaine produced by the intramuscular injectionsof 4 mg/kg lidocaine into deltoid muscle of six patients followingacute myocardial infarction [Reprinted with permission of Harrisonet al. and Mod Treatm'4]


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LIDOCAINEPLASMALEVELag/M1

1.b

0.5l

0.2

30 60 90 120 150 ito 210TIE (mi n)Figure 11

Plasma levels of lidocaine following 500 mg of oral doses to subjectsG 0. ( * ) and A.L. (M). Data points represent experimentally deter-mined plasma computer-calculated levels. [Reprinted with permis-sion of Boyes et al. and Clin Pharmacol Ther"']

Lidocaine Resistance

Patients with ventricular arrhythmias resistant tolidocaine have been reported. A study of such patientsreferred to a university hospital has been made.34Some patients in the study were responsive, but onlyto high blood levels greater than 5 ug/ml, and wererefractory to ordinary therapeutic levels (fig. 12).Other patients were considered truly unresponsive tolidocaine, even at elevated blood levels of 10 gg/mland after toxic central nervous system side effectsbegin to appear. (fig. 13). In some of these patientsunresponsive ventricular arrhythmias were due to aparasystolic foci. On the other hand, other patients inthe study were responsive to lidocaine in the usualtherapeutic range, suggesting that lidocaine ad-ministration was inadequate. Also, failure to ad-minister a bolus injection before beginning constantinfusion may result in therapeutically ineffectiveblood levels for several hours, resulting in apparentunresponsiveness.

Side Effects

Serious toxic side effects on the central nervoussystem include focal and grand mal seizures, psy-chosis, and rarely, respiratory arrest.49' 63 Drowsiness,decreased hearing, paresthesias, disorientation, andmuscle twitching may occur, and some patientsbecome acutely disturbed and agitated. The treat-ment of central nervous system side effects includesCirculation, Volume 50, December 1974

E 40

-~4

CJ

t:, 20

(.)z-4

20 09

oto

LJ _i

2 !wc) U51

Q o "

Ji C)_i

urn muS

// 0\ jP

0 \/ NW,J~~~~~~~

30 60 90

minutes120 150

Figure 12

Effect of high dose intravenous infusion of lidocaine on ventricularpremature beats and blood levels is illustrated in this figure. In thetop panel, the number of ventricular premature beats per threeminute block of time are shown for one patient. In the center panel,the dark solid bar represents the period of intermittent infusion oflidocaine, 130 gg/kg/min. In the bottom panel, the blood level oflidocaine achieved during this study is shown. Note that as theblood level of lidocaine was increased with the intermittent infu-sion, the frequency of ventricular premature beats decreased tozero. As the blood level was allowed to fall by stopping the infusion,the number of ventricular premature beats returned to nearly thesame frequency as had been observed in the control period. Thiswas permitted to occur on four separate occasions in this patient, inorder to determine the threshold dose of lidocaine and the thresholdblood level necessary to suppress ventricular premature beats.[Reprinted with permission of Harrison and Alderman and ModTreatm34]

withdrawal of lidocaine and administration ofsedatives. Convulsive disorders respond well to in-travenous barbiturates or diazepam. True allergicreactions to lidocaine are probably extremely rare,64 65though this has been challenged.66The contribution of the metabolic products of

lidocaine degradation to its toxic effects is not clear.The N-dealkylation metabolites, monoethylglycine-xylidide and glycinexylidide may be responsible forcentral nervous system symptoms in some cases.67 Inone patient who was confused and had visualhallucinations, the lidocaine plasma level was in a lowtherapeutic range, while levels of both monoethylgly-cinexylidide and glycinexylidide were considerablyelevated, suggesting an etiologic relationship betweenthe elevated levels of these metabolites and the toxicsymptoms.67 These two metabolites are apparently notpharmacologically inert. Monoethylglycinexylidide

U1' .

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5U)W

6 * * ~~~~~~~~TOXICFfFECTS

z

000

30 80 90 120

TIME IN MINUTESFigure 13

Lack of response of ventricular arrhythmias to high dose lidocaineinfusion. [Reprinted with permission of Harrison and Alderman andMod Treatm341

has been shown to have local anesthetic' and an-

tiarrhythmic68 actions.In addition, monoethylglycinexylidide causes con-

vulsions in animals68' 69 and has approximatelyequivalent convulsive activity compared tolidocaine.69 The convulsive activities of monoethyl-glycinexylidide and lidocaine are additive.69 Glycine-xylidide also has local anesthetic actions.67 Whileglycinexylidide causes death in animals before con-

vulsions are seen, it does potentiate the convulsive ac-

tivities of monoethylglycinexylidide and lidocaine.69Large bolus doses of lidocaine resulting in toxic

levels can produce bradyeardia and hypotension dueto decreased myocardial function.30 Also, the ad-ministration of large doses of lidocaine has beenreported to cause heart block, and second degreeheart block has been reported to be converted to com-plete heart block by lidocaine.4 33' 70 In completeheart block, subsidiary pacemakers may be slowed.'4

Sinus bradyeardias may be further slowed or inducedby lidocaine.34 70 Sinus arrest has been reported in the"sick sinus syndrome" after lidocaine administrationand when used in association with other an-tiarrhythmic drugs.72 Sinus arrest has been induced ina patient with acute anterior infarction in normalsinus rhythm who received large bolus doses oflidocaine, probably resulting in toxic blood levels.73However, in a normally conducting heart with a nor-mal sinus rhythm, therapeutic levels of lidocainecause little or no decrease in A-V conduction20 andminimal cardiac slowing.3 Furthermore, His bundlestudies performed in patients with conduction abnor-malities have shown that increased levels of block in-duced by lidocaine are probably the exception and notthe rule. In patients with first degree heart block andprolonged H-V times, one study has shown no signifi-cant effect of lidocaine on H-V times.74 In anotherstudy,75 patients with prolonged A-H and H-V timesand bilateral bundle branch block were givenlidocaine, without subsequent significant change inA-H or H-V times. In both reports, lidocaine sup-pressed the patients' ventricular premature beats.

These studies would appear to establish thattherapeutic doses of lidocaine may be used safely inpatients with conduction abnormalities. Althoughlidocaine may induce heart block or sinus nodedepression, it probably does so infrequently, andmainly when toxic doses have been given. Either ab-normality should not necessarily be a contraindicationto the cautious use of lidocaine. The failure to sup-press ventricular arrhythmias by withholdinglidocaine may place the patient at greater risk of sub-sequent complications than the risk of inducing heartblock or bradycardia by giving lidocaine. Lidocainemay be safely used in treating ventricular prematurebeats in patients with artificial ventricularpacemakers, without fear of altering pacemaker cap-ture, since the threshold response to artificial pacingdoes not seem to be significantly changed bylidocaine. 14

Acceleration of ventricular response in atrialtachyarrhythmias after lidocaine administration hasbeen reported, presumably due to enhanced A-V con-duction.76 This would seem paradoxical in view ofmost studies which point out either unchanged orslightly diminished A-V conduction by lidocaine.20 Anincrease in the number of ventricular ectopic beats inpatients with acute myocardial infarction has beenreported, using low dose lidocaine infusion.77 In addi-tion, re-entry ventricular beats were increased bylidocaine in animal models of acute infarction in someinstances in one study.78 These reports of paradoxicaleffects of lidocaine would appear to need further con-firmation.

Circulation, Volume 50, Decenmber 1974

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Acknowledgments

Some of the studies cited were carried out in the Coronary CareUnit at Stanford University Hospital with the collaboration of Dr.

Alfred Spivack and the nursing staff, and the cooperation of severalformer cardiac fellows and faculty, who permitted these studies intheir patients. Finally, we have had the excellent editorial assistanceof Mrs. Dorothy McCain in the preparation of this manuscript.

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Circulation, Volume 50. December 1974

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KEN A. COLLINSWORTH, SUMNER M. KALMAN and DONALD C. HARRISONThe Clinical Pharmacology of Lidocaine as an Antiarrhythymic Drug

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1974 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.50.6.1217

1974;50:1217-1230Circulation.

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