8
Pharmacology, electrophysiology, and pharmacokinetics of mexiletine Mexiletine is a class I antiarrhythmic agent that is active after both oral and intravenous administration and similar in structure and activity to lidocaine. It decreases phase 0 maximal rate of depolarization (vmax) by fast sodium channel blockade. The marked rate dependence of \imax depression may explain mexiletine’s lack of effect on normal conduction and its efficacy against ventricular tachyarrhythmias. Mexiletine significantly decreases the relative refractory period in His-Purkinje fibers without changing the sinus rate or atrioventricular and His-Purkinje conduction times. Action potential duration is usually shortened. Mexiletine may aggravate preexisting impairment of impulse generation and conduction. Uptake and distribution of mexiletine are rapid, systemic bioavailability is about 90%, and tissue distribution is extensive. Mexiletine is primarily metabolized in the liver; 10% to 15% is excreted unchanged in the urine. Elimination half-life is g to 11 hours after intravenous or oral administration. Mlcrosomal enzyme induction shortens mexiletine’s elimination half-life, whereas hepatic disease and acute myocardial infarction prolong it. Renal disease has little effect, although hemodialysis increases mexiletine clearance. Plasma concentrations from 0.75 to 2.0 mg/L are usually associated with a desirable therapeutic response. (AM HEART J 107:1058, 1984.) R. L. Woosley, M.D., Ph.D., T. Wang, M.D., W. Stone, M.D., L. Siddoway, M.D., K. Thompson, M.D., H. J. Duff, M.D., I. Cerskus, Ph.D., and D. Roden, M.D. Nashville, Tenn. Mexiletine was first synthesized in an attempt to modify the structure of the anorectic agent phen- metrazine and thereby reduce side effects in the central nervous system.’ The result was an agent with anticonvulsant activity. Later, when other antiepileptic agents were found to exhibit antiar- rhythmic activity, mexiletine was found to be effec- tive in suppressing experimentally induced ventric- ular arrhythmias in several animal models.2 Mexiletine is a structural analog of two other antiarrhythmic agents, lidocaine and tocainide. Although mexiletine remains an investigational drug in North America, it has been in clinical use in Europe and England since 1976. ELECTROPHYSIOLOGY AND PHARMACOLOGY Mexiletine is similar to lidocaine in chemical structure (Fig. l), electrophysiologic effects on From the Departments of Medicine and Pharmacology, Vanderbilt Univer- sity School of Medicine. Supported by grants from Boehringer Ingelheim, Ltd., and by U.S. Public Health Service Grants 5MOl RR-95, GM 31304, and GM07569. Dr. Roden is a recipient of the Clinician-Scientist Award of the American Heart Association. Reprint requests: R. L. Woo&y, M.D., Ph.D., Division of Clinical Pharma- cology, Vanderbilt University School of Medicine, Nashville, TN 37232. nerves and myocardial membranes, and experimen- tal and clinical spectrum of antiarrhythmic activity. Nonetheless, enough differences exist so that mexi- letine cannot simply be considered an oralIy active lidocaine. Mexiletine’s efficacy in controlling ventricular arrhythmias in animal models is well established. In dogs, at a plasma concentration of 3 mg/L, it abolished ventricular tachycardia after ligation of a coronary artery in 60% of the animals, and at a plasma concentration of 5.3 mg/L it accomplished the same in 100% of the animals.2~3 In ouabain- induced arrhythmias in dogs, at a plasma concentra- tion of 1 mg/L, mexiletine abolished ventricular ectopic beats3 while at plasma concentrations of 1 to 2 mg/L it restored the low fibrillation threshold of the ischemic ventricle to control levels after electri- cally induced fibrillation. Similar effects were seen in the anesthetized rat.4 The threshold current required to cause ventricular fibrillation in normal, nonischemic myocardium was increased 100% by intravenous mexiletine.3s4 Pretreatment with mexi- letine did not prevent induction of arrhythmias by ouabain in the guinea pig. However, during induced ventricular fibrillation, a concentration of 3.3 mg/L was sufficient to restore sinus rhythm.5 The electrophysiologic effects presumably re-

Pharmacology, electrophysiology, and pharmacokinetics of mexiletine

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Page 1: Pharmacology, electrophysiology, and pharmacokinetics of mexiletine

Pharmacology, electrophysiology, and pharmacokinetics of mexiletine

Mexiletine is a class I antiarrhythmic agent that is active after both oral and intravenous administration and similar in structure and activity to lidocaine. It decreases phase 0 maximal rate of depolarization (vmax) by fast sodium channel blockade. The marked rate dependence of \imax depression may explain mexiletine’s lack of effect on normal conduction and its efficacy against ventricular tachyarrhythmias. Mexiletine significantly decreases the relative refractory period in His-Purkinje fibers without changing the sinus rate or atrioventricular and His-Purkinje conduction times. Action potential duration is usually shortened. Mexiletine may aggravate preexisting impairment of impulse generation and conduction. Uptake and distribution of mexiletine are rapid, systemic bioavailability is about 90%, and tissue distribution is extensive. Mexiletine is primarily metabolized in the liver; 10% to 15% is excreted unchanged in the urine. Elimination half-life is g to 11 hours after intravenous or oral administration. Mlcrosomal enzyme induction shortens mexiletine’s elimination half-life, whereas hepatic disease and acute myocardial infarction prolong it. Renal disease has little effect, although hemodialysis increases mexiletine clearance. Plasma concentrations from 0.75 to 2.0 mg/L are usually associated with a desirable therapeutic response. (AM HEART J 107:1058, 1984.)

R. L. Woosley, M.D., Ph.D., T. Wang, M.D., W. Stone, M.D., L. Siddoway, M.D., K. Thompson, M.D., H. J. Duff, M.D., I. Cerskus, Ph.D., and D. Roden, M.D. Nashville, Tenn.

Mexiletine was first synthesized in an attempt to modify the structure of the anorectic agent phen- metrazine and thereby reduce side effects in the central nervous system.’ The result was an agent with anticonvulsant activity. Later, when other antiepileptic agents were found to exhibit antiar- rhythmic activity, mexiletine was found to be effec- tive in suppressing experimentally induced ventric- ular arrhythmias in several animal models.2

Mexiletine is a structural analog of two other antiarrhythmic agents, lidocaine and tocainide. Although mexiletine remains an investigational drug in North America, it has been in clinical use in Europe and England since 1976.

ELECTROPHYSIOLOGY AND PHARMACOLOGY

Mexiletine is similar to lidocaine in chemical structure (Fig. l), electrophysiologic effects on

From the Departments of Medicine and Pharmacology, Vanderbilt Univer- sity School of Medicine.

Supported by grants from Boehringer Ingelheim, Ltd., and by U.S. Public Health Service Grants 5MOl RR-95, GM 31304, and GM07569.

Dr. Roden is a recipient of the Clinician-Scientist Award of the American Heart Association.

Reprint requests: R. L. Woo&y, M.D., Ph.D., Division of Clinical Pharma- cology, Vanderbilt University School of Medicine, Nashville, TN 37232.

nerves and myocardial membranes, and experimen- tal and clinical spectrum of antiarrhythmic activity. Nonetheless, enough differences exist so that mexi- letine cannot simply be considered an oralIy active lidocaine.

Mexiletine’s efficacy in controlling ventricular arrhythmias in animal models is well established. In dogs, at a plasma concentration of 3 mg/L, it abolished ventricular tachycardia after ligation of a coronary artery in 60% of the animals, and at a plasma concentration of 5.3 mg/L it accomplished the same in 100% of the animals.2~3 In ouabain- induced arrhythmias in dogs, at a plasma concentra- tion of 1 mg/L, mexiletine abolished ventricular ectopic beats3 while at plasma concentrations of 1 to 2 mg/L it restored the low fibrillation threshold of the ischemic ventricle to control levels after electri- cally induced fibrillation. Similar effects were seen in the anesthetized rat.4 The threshold current required to cause ventricular fibrillation in normal, nonischemic myocardium was increased 100% by intravenous mexiletine.3s4 Pretreatment with mexi- letine did not prevent induction of arrhythmias by ouabain in the guinea pig. However, during induced ventricular fibrillation, a concentration of 3.3 mg/L was sufficient to restore sinus rhythm.5

The electrophysiologic effects presumably re-

Page 2: Pharmacology, electrophysiology, and pharmacokinetics of mexiletine

Volume 107 Number 5, Part 2 Mexiletine pharmacology 1059

Similarities Exist In: 1 .Chemical Structure CONTROL 1x1Cf7M

CH3

LIDOCAINE NHhH3 - N:c”;;;

'CH3 1x1Cf6M 5~10-~1111

CH3

MEXILETINE

CH3

Fig. 1. Chemical structures of lidocaine and mexiletine. 1x10-'M 1~10-~M

sponsible for mexiletine’s antiarrhythmic activity vary in different tissues and different experimental conditions. Mexiletine blocks the fast sodium chan- nel, reducing phase 0 maximal upstroke velocity (Vmax). Thus it is considered a class I antiarrhyth- mic agent.6z 7 In isolated rabbit myocardial fiber preparations, mexiletine decreases conduction velocity and prolongs the effective refractory period (ERP) with little or no change in action potential duration (APD).5 In isolated Purkinje fibers of the dog, a decrease in APD was observed, accompanied by a somewhat shortened ERPB (Fig. 2), but the ratio of ERP to APD was consistently increased-an effect that may account for antiarrhythmic activity. The decrease in APD was uniform throughout the conducting tissue. Other work, however, has sug- gested that mexiletine, like lidocaine, may preferen- tially shorten APD where it is longest, resulting in a greater homogeneity of APD throughout the distal conduction system.7

In sheep Purkinje fibers stimulated at a constant rate, mexiletine decreased phase 0 overshoot and Vmax and shortened APD.g The APD effect was evident at concentrations lower than those that affected phase 0 parameters. Mexiletine also decreased the spontaneous firing rate induced by hypokalemia or isoproterenol, by shifting the threshold voltage to a less negative value. Ouabain- induced delayed afterdepolarizations were also sup- pressed. Like lidocaine, mexiletine at low concentra- tion (<3 mg/L) had a greater effect on premature action potentials or on those elicited at fast stimula- tion rates. This suggests that the reactivation of the sodium channel, rather than the sodium conduc- tance, is affected.g

Campbelllo recently explored the kinetics of the depression of $max in the guinea pig ventricle. Mexiletine, disopyramide, and encainide all exhib- ited a rate dependence in their depression of Vmax,

--k- -t- *, L .&

Fig. 2. Electrophysiologic effects of mexiletine in iso- lated Purkinje fibers of the dog. The upper trace in each panel represents zero potential and the lower, the differ- ential signal of the upstroke velocity of phase 0 (dV/dL,,). A concentration-dependent depression of dV/dt,,,,, and the abbreviation of the APD are demonstrated. (Re- printed with permission from Yamaguchi et a1.8)

but marked differences were apparent in kinetics of onset and recovery of the effects. Depression of frmax progressively increased with increasing fre- quency of stimulation. However, mexiletine was an order of magnitude faster in responding to a rate change than the other two class I agents. Campbell suggested that this may be due to mexiletine’s comparatively smaller molecular size, which might allow it greater movement to and from a sodium channel receptor site. Data for mexiletine were similar to those for lidocaine and tocainide, also compounds of molecular weight lower than most class I antiarrhythmics. This marked rate depen- dence of mexiletine’s effects on Vmax might explain its particular efficacy in suppressing fast (>185 bpm) rather than “slow” ventricular tachycardias.

Experimental conditions are an important factor in determining the electrophysiologic effects of mex- iletine. Under normal conditions, the APD and absolute refractory period of canine Purkinje fibers were shortened in a dose-dependent manner.” Changes in APD were seen at concentrations lower than those required to elicit changes in phase 0 depolarization. g, l1 Under hypoxic conditions, the electrophysiologic effects of mexiletine were exag- gerated; some effects seen only at potentially toxic concentrations under normal conditions were evi- dent at “therapeutic” levels under hypoxia. Frame et a1.12 demonstrated a modest rate-dependent block

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1060 Woosley et al. may, 1884

Amarlcsn Haart Journal

Table I. Effects of combined therapy with mexiletine and quinidine in 17 patients

Quinidine Quinidine and mexiletine Mexiletine

Maximum dosage (mg/day)

Suppression of VEDs (“0 ) Ventricular tachycardia Side effects

Diarrhea Nausea Tremor/nervousness Other

1042 k 362 824 k 298 (Q) 950 t 202 800 f 239 (M)

59 i 16 85.9 k 26 62.5 t 25 11117 l/17 10117

11117 l/l7 o/17 o/17 l/l7 7117 o/17 l/l7 7117 3117 o/17 o/17

Abbreviation: VEDs = ventricular ectopic depolarizations Data reproduced with permission from Duff et al.ls

Table II. Electrophysiologic actions of mexiletine (M) and quinidine (Q) in isolated rabbit heart

VERP (msec) mAPD (msec) CT (msec) VERPImAPD

Low Q (0.5 mmol/L) Low M (2.3 mmol/L) Low Q plus low M High Q (15 mmol/L) High M (37 mmol/L)

3+2 14 k 8 0.6 r 1.0 -1 f 3 2k3 3k6 -1 + 1 o-1-3

29 + 12* 2 * 14 0.8 + 1 8 k 3* 40 f 21* 56 + 6* 19 + 16t 4 It 3* 19 rf: 8* 12 r 5 12 f 3* 3 k 2t

*p < 0.01. tp < 0.05. Increase from baseline, ?r: + SE. Abbreviation: mAPD = monophasic action potential duration. Data reproduced with permission from Duff et al.‘*

of Vmax at normal potassium concentration that was enhanced at high potassium concentrations. These results suggest that mexiletine would have minimal effects on the normal heart, but would be clinically useful in suppressing fast responses during ischemia and after myocardial infarction. Mexiletine has no significant effect on slow, calcium-dependent channels, nor does it affect autonomic activity.13

In an electrophysiologic study in man, mexiletine had little effect on atrial refractoriness, consistent with its lack of effect in atria1 fibrillation or flutter. Mexiletine produced a significant decrease in the relative refractory period of His-Purkinje fibers and the atrioventricular (AV) node, but no significant changes in the sinus rate or AV or His-Purkinje conduction times.14 In contrast, Roos et all5 found that the ERP of the AV node was not consistently altered, while the functional refractory period increased in most patients. Mexiletine increased AV nodal conduction time at paced atria1 rates.

The depressant effect of the drug was more pronounced in patients with preexisting impairment of impulse generation and conduction. When His- Purkinje conduction was impaired by disease, mexi- letine consistently lengthened the H-V interval, suggesting that it is likely to produce AV block in patients with underlying conduction distur-

bances.*5s l6 Severe bradycardia and abnormal pro- longation of the sinus node recovery time have been found in patients with sick sinus syndrome.15 Con- flicting results in the electrophysiologic data may be due to differing and perhaps even inadequate mexi- letine concentrations at receptor sitesI

Since mexiletine has a relatively low therapeutic index, its use in low doses with other antiarrhythmic agents is of special interest. We evaluated the efficacy of mexiletine and quinidine in combination in 21 patients with frequent ventricular extrasys- toles and recurrent ventricular tachycardia who were unresponsive to, or intolerant of, therapy with quinidine, procainamide, propranolol, and disopyra- mide.18 Table I summarizes the comparison of com- bination therapy with single-agent therapy in 17 patients. Arrhythmia in three patients was con- trolled with mexiletine alone. Combination therapy in 17 patients (each drug given at well-tolerated doses) abolished ventricular tachycardia in all but one patient and suppressed 85.9% of ventricular extrasystoles. Side effects necessitated discontinua- tion of treatment in two patients on combination therapy. Thus the low-dose mexiletine-quinidine combination was more effective and better tolerated than the individual agents at higher dosages.

We investigated the electrophysiologic basis for

Page 4: Pharmacology, electrophysiology, and pharmacokinetics of mexiletine

Volume 107

Number 5, Part 2 Mexiletine pharmacology 1061

4.0 - 3.0 ’

2.0 .

Plasma Mexiletine @g/ml) 1.0 '

0.7

0.5

0.3 '

0.2 '

0.10

0.07 L 1111111111~

0 4 8 12 16 20 24

Time (hrs)

Fig. 3. Plasma concentrations of mexiletine (mean -+ SE) in 10 patients who received a 200 mg intravenous injection over 5 minutes. (Reproduced with permission from Campbell.lo)

this synergism in the Langendorff isolated heart preparation.lg As briefly summarized in Table II, at concentrations of mexiletine and quinidine that singly had no effect, the combination markedly increased the ventricular effective refractory period (VERP) and the VERP/APD ratio, without affect- ing other electrophysiologic parameters, including ventricular conduction time (CT) and excitability threshold. This is in contrast to the electropharma- cologic effects of the individual agents. At increasing concentrations, mexiletine alone slightly increased both ventricular refractoriness and CT without affecting APD. Quinidine, on the other hand, mark- edly increased VERP in the absence of changes in CT, but with a parallel prolongation of APD.

Since antiarrhythmic activity may be enhanced by a high ratio of VERP to APD, the mexiletine- quinidine low-dose combination clearly offers a more favorable electrophysiologic profile than does either agent alone. This synergism may be based on the differing effects of mexiletine and quinidine on sodium channel conductance. Although both agents block the fast channel, the duration of their effect during diastole, measured by recovery of Omax, differs. As mentioned, mexiletine, like lidocaine, allows rapid recovery of i7max while quinidine pro- longs it.“*21 Hondeghem and Katzung20 suggested that simultaneous blockade of the sodium channel by both types of agent would result in a synergistic depression of sodium conductance, particularly of early extrasystoles, a theory that our data also support.

SERUM MEXILETINE

(

ho/ml) 0.1 -

0.02 l-1 ’ ’ ’ ’ ’ ’ I I 012468 12 16

TIME (hrs)

I 24

Fig. 4. Serum concentrations (mean f SE) of mexiletine after an oral dose of mexiletine hydrochloride, 400 mg, in eight healthy volunteers before and after treatment with rifampicin, 300 mg twice a day for 10 days. (Reproduced with permission from Pentikainen et a1.31)

PLASMA MEXILETINE

@o/ml)

PATIENTS WITH MI

0 2 4 6 8 TIME (hrs)

Fig. 6. Plasma concentrations of mexiletine in healthy subjects (n = 5) and patients with myocardial infarction, with (n = 4) and without (n = 6) narcotic analgesics. (Re- produced with permission from Prescott et al.,,)

PHARMACOKINETICS

Mexiletine is effective after either oral or intrave- nous administration. Since it is a basic compound (ionization constant of 8.8), little absorption occurs in the stomach. Absorption starts in the upper part of the intestine, so drugs such as narcotic analge- sics,22 antacids,23 and atropine-like drugs,24 which slow gastric emptying, will delay absorption. Meto- clopramide, on the other hand, increases the absorp- tion rate.24 Bioavailability, however, is not altered by these agents.23*” After oral administration, uptake

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1062 Woosley et al. May, 1984

American Heart Journal

Table III. Clinical pharmacokinetic data of mexiletine

Healthy volunteers

IV Oral IV

Patients

Oral -

Plasma half-life (hr) Total body clearance (ml/min) Total volume of distribution (L) Volume of central compartment

CL) Loading dose (gm) for plasma

concentrations of 1.5 rg/ml Maintenance dose (gm/day) for

plasma concentration of 1.5

kdml

10.4 i 2.8 (4) 9.4 r 1.0 (6) 16.7 + 5.1 (12) 12.1 f 4.0 (6) 751 * 414 (4) 681* + 178 (6) 415 * 73 (3) 358* k 89 (101) 663 + 238 (4) 755 i: 517 (2) 185 f 97 (4) 193 k 6 (2) 241 k 41 (2)

1.00 1.13

1.62 1.63 0.90 0.86

values given are means f SD with number of patients in whom observations were made in parentheses. ., *Assuming 9O’r oral availability. Data reproduced with uermission from Prescott et al.“

and distribution of mexiletine are rapid; peak plas- ma levels are reached in 2 to 4 hours.16

Systemic bioavailability is about 90 % .25 The dis- position kinetics of mexiletine are consistent with a three-compartment model (Fig. 3), representing fast and slow distribution phases and a much slower elimination phase. The first compartment is repre- sentative of the blood volume and rapidly equilibra- ting, highly perfused tissues such as myocardium, brain, liver, kidney, and lung. Compartments 2 and 3 are “peripheral,” such as skin, muscle, and fat, and take up the drug more slowly.

Table III from Prescott et a1.25 displays the differ- ences in pharmacokinetics in normal volunteers and cardiac patients. The total volume of distribution is large and extremely variable (755 f 517 L, mean -t SD) ,= reflecting the extensive tissue uptake of the drug. Approximately 70% of mexiletine in serum is protein bound. l6 However, since only about 1% of the total body mexiletine is in the plasma compart- ment, displacement of mexiletine from protein bind- ing sites probably is not clinically important.

Mexiletine is primarily eliminated by metabolism in the liver; only 10 % to 15 % is excreted unchanged in the urine.“j Metabolism involves N-methylation and hydroxylation to parahydroxymexiletine, hydroxymethylmexiletine, and the corresponding a1cohols,26 which are devoid of antiarrhythmic activ- ity.27 The first-pass effect is less than 10% for mexiletinez8 but 70% for lidocaine, which partially explains why mexiletine is effective orally while lidocaine must be given parenterally. The mean plasma elimination half-life is 10 to 11 hours after intravenous administration and 9 to 10 hours after oral dosing.25,29 By use of kinetic constants derived

from intravenous dosing applied to data after oral administration, Haselbarth et a130 calculated a somewhat shorter elimination half-life of 6.34 +- 1.5 hours.

Agents that induce drug-metabolizing enzymes in the liver, such as rifampicin31 (Fig. 4) and pheny- toint2 decrease the elimination half-life of mexile- tine. Thus the mexiletine dosage should be increased when these agents are started during mexiletine therapy. Similarly, stopping therapy calls for a decrease in mexiletine dosage. Hepatic dysfunction might be expected to affect mexiletine pharmacoki- netics, and indeed, Nitsch et al.% found a decreased plasma clearance of mexiletine in patients with cirrhosis.

Other conditions that decrease hepatic blood flow, such as acute myocardial infarction, could be expected to decrease metabolic elimination of mexi- letine. However, in a single-dose study of the pharm- acokinetics of oral and intravenous mexiletine in the acute phase (first day) and recovery phase (1 to 2 weeks later) in patients with myocardial infarction, Pentikainen et al.% found an increased volume of distribution and an increase of approximately 50% in elimination half-life during the acute phase. Total body clearance, renal clearance, peak plasma levels, area under the plasma concentration-time curve, and plasma protein binding were similar during both phases. Time to reach peak plasma levels was longer during the acute infarction phase, suggesting delayed absorption of the drug. However, Prescott et a1.25 found that absorption was delayed and incomplete in patients with acute myocardial infarc- tion, particularly in patients who had received nar- cotic analgesics (Fig. 5).

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Number 5, Part 2 Mexiletine pharmacology 1063

Only 10% to 15% of mexiletine is eliminated in the urine; this percentage increases with decreasing urinary pH. The plasma half-life was 8.6 hours with alkaline urine and 2.8 hours with acidic urine25v35 (Fig. 6). Although Prescott et a1.25 suggested that this is unlikely to be clinically important within normal physiologic variation in urinary pH, John- ston et a1.36 found that spontaneous fluctuations in urinary pH in six healthy volunteers receiving mul- tiple subtherapeutic doses of mexiletine resulted in significant changes in urinary excretion and plasma concentration. They concluded that mexiletine in plasma could increase by more than 50% after spontaneous changes in urinary pH.

Since the kidneys are a minor route of elimina- tion, renal disease should have little effect on clear- ance of the drug. El Allaf et a1.37 showed that mexiletine clearance was essentially unaffected at creatinine clearance levels approximating 10 ml/ min, although a significant decrease in mexiletine clearance was evident at lower clearance levels. Our work has failed to show a linear relationship between impairment of renal function and mexile- tine clearance, although as a group patients with renal disease (creatinine clearance 10 to 69 ml/min) showed a significantly decreased mexiletine clear- ance.3s Hemodialysis, however, resulted in plasma clearance levels of mexiletine comparable to those of controls, suggesting that a supplemental dose may be required on days when patients are on hemodial- ysis.

Leahey et a1.3s investigated the kinetics of mexile- tine in patients with left ventricular failure (New York Heart Association functional class III or IV) who were free of hepatic or renal disease. Elimina- tion half-life in these patients ranged from 6.9 to 28.6 hours, with a mean of 15.4 + 5.8 hours, com- pared to 8.1 f 1.8 hours in normal volunteers. Thus patients with myocardial decompensation could possibly maintain adequate therapeutic plasma lev- els with a twice-daily dosing schedule.

In a study of 88 patients, many of them recovering from a myocardial infarction, oral or intravenous mexiletine showed a large interpatient variation in plasma concentrations (Fig. 7), although the thera- peutic range of plasma concentrations was quite narrow (0.75 to 2.0 mg/L).29 In general, a therapeutic concentration was obtained with oral mexiletine at 10 to 14 mglkglday, divided into three or four doses. Other studies have shown that a total daily dose of 600 to 1000 mg mexiletine is effective on an 8- or 12-hour basis.“j Because of mexiletine’s distribution kinetics, intravenous dosing is more complex if

PLASMA MEWLETINE cidw

URINE pHALKALlNE _ t l/28 8.6 hrs

t

I

0.2 (mean 2S.E.)

URINE pH ACIDIC 'II t l/20 2.8 hrs

-.

--. F

I~~.lI *Ial I I I I 1 012345678

TIME (hrs after dose)

Fig. 6. Mean plasma levels of mexiletine after intrave- nous injection of 200 mg of mexiletine to four healthy volunteers with acidic and alkaline urine. (Reproduced with permission from Kiddie et a1.35)

5

r 4

t

.

:

TROUGHPLASMA MEXILETINE @g/ml)

. 2. l- :

5 . oL

I I I 1 1 I <6 6-8 8-1010-12 12-14 X4

MEXILETINE DOSE (mg/kg'/daysl)

Fig. 7. Trough plasma concentrations of mexiletine in 88 patients after at least 5 days of therapy. Each dot represents the plasma concentration in one patient. The solid and interrupted horizontal bars show the mean and median concentrations for each dose range, respectively. Seventy-nine patients received a single-dosage regimen. Seven patients received two regimens and two received three. (Reproduced with permission from Campbell et a1.29)

adequate plasma concentrations are to be obtained without significant side effects. Prescott et al.% have suggested an initial bolus (150 to 200 mg over 2 to 5 minutes) followed by a steadily decreasing loading infusion over 11 hours (250 mg in 30 minutes, 250 mg in 2.5 hours, 500 mg in 8 hours), and a mainte- nance dose of 500 to 1000 mg over 24 hours.

Mexiletine appears in breast milk in a milk:plas-

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1064 Woosley et al. May, 1984

American HearI Journal

ma ratio of about 1 :&a However, the amount ingested by the nursing infant appears negligible.

Few data are available regarding potential drug interactions. Agents affecting absorption of mexile- tine and induction of mexiletine metabolism have been described above. Inhibition of drug metab- olism by agents such as cimetidine or amiodarone would be expected, but this has not yet been report- ed. A pharmacokinetic interaction such as that seen with digoxin and quinidine was not seen with digox- in and mexiletine in studies by Leahey et a141 A pharmacodynamic interaction between mexiletine and calcium antagonists or other local anesthetic agents is possible but has not yet been described.

CONCLUSIONS

Although mexiletine was not originally synthe- sized as an antiarrhythmic agent, its cardiac electro- physiologic properties, long half-life, and efficacy after oral administration make it a potential addi- tion to the limited number of therapeutic agents useful in the prophylaxis and treatment of ventricu- lar arrhythmias.

REFERENCES

1. Middleton D: Baseline pharmacology, electrophysiology and pharmacokinetics of mexiletine. Acta Cardiol (suppi) 25:45, 1980.

2. Allen JD, Kofi Ekue JM, Shanks RG, Zaidi SA: The effect of K6 1173, a new anticonvulsant agent, on experimental cardiac arrhythmias. Br J Pharmacol 45:561, 1972.

3. Allen JD, James RGG, Kelly JG, Shanks RG, Zaidi SA: Comparison of the effects of lignocaine and mexiletine on experimental ventricular arrhythmias. Postgrad Med J 53(suppl 1):35, 1977.

4. Marshall RJ. Muir AW. Winslow E: A comuarison of the 25. intensity and duration’of the antidysrhythmic effect of mexiletine and Org 6001 in anaesthetized rats. Br J Pharma- co1 74:381, 1981.

5. Singh BN, Vaughan-Williams EM: Investigations of the mode of action of a new antidysrhythmic drug Kii 1173. Br J Pharmacol44:1, 1972.

6. Gerin MG, Kulbertus HE: Effects of various antiarrhythmic agents on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in the dog. In Sandoe E, Julian DG, Bell JW, editors: Management of ventricular tachycardia-Role of mexiletine. Amsterdam, 1978, Excerpta Medica, p 229.

7. Vaughan-Williams EM Mexiletine in isolated tissue models. Postgrad Med J 53(suppl 1):30, 1977.

8: Yamaguchi I, Singh BN, Mandel WJ: Electrophysiological actions of mexiletine on isolated rabbit atria and canine ventricular muscle and Purkinje fibres. Cardiovasc Res 13:288, 1979.

9. Weld FM, Bigger JT Jr, Swistel D, Bordiuk J, Lau YH: Electrophysiological effects of mexiletine (Kij 1173) on ovine cardiac Purkinje fibres. J Pharmacol Exp Ther 210~222, 1979.

10. Campbell TJ: Resting and rate-dependent depression of maximum rate of depolarization (Vmax) in guinea pig ven- tricular action potentials by mexiletine, disopyramide and encainide. J Cardiovasc Pharmacol 5:291, 1983.

11. Burke GH, Berman ND: Differential electrophysiologic

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26.

27.

28.

effects of mexiletine on normal and hypoxic canine Purkinje fibres. Circulation 66:11-292, 1982. Frame L, Gintant G, Hoffman B: Mexiletine and tocainide differ from lidocaine in their use-dependent kinetics. Circula- tion 66:11-292, 1982. Singh B, Collett JT, Chew CYC: New perspectives in the pharmacologic therapy of cardiac arrhythmias. Prog Cardio- vast Dis 22:243, 1980. McComish M, Robinson C, Kitson D, Jewitt DE: Clinical electrophysiological effect of mexiletine. Postgrad Med J 53(suppl-1):85,-1977. Roos JC, Paalman ACA, Dunning AR: Electrophysiological effects of mexiletine in man. Br Heart J 36:1262, 1976. Singh BN, Cho YW, Kuemmerle HP: Clinical pharmacology of antiarrhythmic drugs: A review and overview. Part II. Int J Clin Pharmacol Ther Toxic01 19~185, 1981. Joseph SP, Holt DW: Electrophysiological properties of mexiletine assessed with respect to plasma concentrations. Eur J Cardiol 11:115, 1980. Duff HJ, Roden D, Primm RK, Oates JA, Woosley RL: Mexiletine in the treatment of resistant ventricular arrhyth- mias: Enhancement of efficacy and reduction of dose-related side effects by combination with quinidine. Circulation 67:1124, 1983. Duff HJ, Kolodgie FD, Roden DM, Woosley RL: Electro- pharmacologic synergism with mexiletine and quinidine. Clin Res 31:180A, 1983. Hondeghem L, Katzung B: Test of a model of antiarrhythmic drug action: Effects of quinidine and lidocaine on myocardial conduction. Circulation 61:1217, 1980. Sada H, Ban T, Oshita S: Effects of mexiletine on transmem- brane action potentials by external potassium concentration and by rate of stimulation in guinea-pig papillary muscle. Clin Exp Pharmacol Physiol 7:583, 1980. Prescott LF, Adjepon-Yamoah KK, Talbot RG: Impaired lignocaine metabolism in patients with myocardial infarction and cardiac failure. Br Med J 1:939, 1976. Herzog P, Holtermuller KH, Kasper W, Meinertz T, Trenk D, Jahnchen E: Absorption of mexiletine after treatment with gastric antacids. Br J Clin Pharmacol 14~746, 1982. Wing LMH, Meffin PJ, Grygiel JJ, Smith KJ, Birkett DJ: Effect of metoclopramide and atropine on the absorption of orally administered mexiletine. Br J Clin Pharmacol 9:505, 1980. Prescott LF, Clements JA, Pottage A: Absorption, distribu- tion and elimination of mexiletine. Postgrad Med J 53(suppl 1):50, 1977. Beckett AH, Chidomere EC: The distribution, metabolism and excretion of mexiletine in man. Postgrad Med J 53(suppl 1):60, 1977. Brown JE, Shand DG: Therapeutic monitoring of antiar- rhythmic agents. Clin Pharmacokinet 7:125, 1982. Baudinet G, Henrard L, Quinaux N, El Allaf D, Landsheere C, Carlier J, Dresse A: Pharmacokinetics of mexiletine in renal insufficiency. Acta Cardiol (suppl) 25:55, 1980.

29. Campbell NPS, Kelly IG, Adgey AAJ, Shanks RG: The clinical pharmacology of mexiletine. Br J Clin Pharmacol 6:103, 1978.

30. Haselbarth V, Doevendans JE, Wolf M: Kinetics and bio- availability of mexiletine in healthy subjects. Clin Pharmacol Ther 29:729, 1981.

31. Pentikainen PJ, Koivula IH, Hiltunen HA: Effect of rifampi- tin treatment on the kinetics of mexiletine. Eur J Clin Pharmacol 23:261, 1982.

32. Begg EJ, Chinwah PM, Webb C, Day RO, Wade DN: Enhanced metabolism of mexiletine after phenytoin adminis- tration. Br J Clin Pharmacol l&219, 1982.

33. Nitsch J. Doliwa R, Steinbeck G, Luderitz B: mexiletine- Spiegel bei Patienten mit ventrikularen Arrythmien und Nieren Leber oder Herzinsufhzienz. Verh Dtsch Ges Inn Med 87:429, 1981.

34. Pentikainen PJ, Halinen M, Helin M: Pharmacokinetics of

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intravenous mexiletine in patients with acute myocardial 38. Wang T, Stone W, Wuellner D, Woosley RL: Mexiletine phar- infarction. J Cardiovasc Pharmacol 6:1, 1964. macokinetics in renal failure. (Unpublished observations)

35. Kiddie MA, Kaye CM, Turner P, Shaw TRD: The influence 39. Leahey EB Jr, Giardina EGV, Bigger JT Jr: Effect of of urinary pH on the elimination of mexiletine. Br J Clin ventricular failure on steady state kinetics of mexiletine. Clin Pharmacol 1:229, 1974. Res 26:239A, 1980.

36. Johnston A, Burgess CD, Warrington SJ, Wadsworth J, Hamer NAJ: The effect of spontaneous changes in urinary pH on mexiletine plasma concentrations and excretion dur- ing chronic administration to healthy volunteers. Br J Clin Pharmacol 8:349, 1979.

40. Lewis AM, Pate1 L, Johnston A, Turner P: Mexiletine in human blood and breast milk. Postgrad Med J 57:546, 1981.

37. El Allaf D, Henrard L, Crochelet L, Delapierre D, Carlier J, Dresse A: Pharmacokinetics of mexiletine in renal insuffi- ciency. Br J Clin Pharmacol 14:431, 1982.

41. Leahey EB, Reiffel JA, Giardina EGV, Bigger JT: The effect of quinidine and other oral antiarrhythmic drugs on serum digoxin. A prospective study. Ann Intern Med 92:605, 1980.

Hemodynamic effects of mexiletine

A review of studies of mexiletine, a class I antiarrhythmic drug, supports its use in patients with ventricular arrhythmias or in sinus rhythm. Studies include patients likely to receive the drug in clinical use-patients with and without coronary disease and patients who have suffered acute myocardial infarction. Some studies are open and others are controlled to compare mexiletlne to placebo or to lidocaine. Mexiletine in therapeutic ranges was shown not to affect arterial pressure; to prolong aortic ball travel time, indicating depression of myocardial contractility; and not to adversely affect cardiac function. Adverse effects occurred as often in patients taking placebo as in mexiletine-treated patients, even in those with impaired cardiac function. Studies bear out early reports of mexiletine as an effective antiarrhythmic drug nearly devoid of adverse hemodynamic effects when administered intravenously or orally in a dosage to maintain a therapeutic plasma concentration. (AM HEART J 107:1065, 1984.)

R. G. Shanks Belfast, Northern Ireland

During the past 10 years several new effective drugs have been described for the treatment of ventricular arrhythmias. One of the most extensively studied is mexiletine, a class I antiarrhythmic drug based on the classification system of Vaughan-Williams.’ Mexiletine is a potent local anesthetic on the frog sciatic nerve preparation.2 In isolated atrial and ventricular muscle and Purkinje fibers, mexiletine reduces the maximal rate of depolarization of the action potential, increases the threshold of excitabil- ity, decreases conduction velocity, and prolongs the effective refractory period with little effect on rest- ing membrane potential or on sinus node automatic- ity.2-4

From the Department of Therapeutics and Pharmacology, The Queen’s University of Belfast, Northern Ireland.

Reprint requests: Professor R. G. Shanks, Department of Therapeutics and Pharmacology, Whitla Medical Building, 97 Lisburn Rd., Belfast, BT9 7BL, Northern Ireland.

These actions of mexiletine are similar to those of lidocaine; both drugs produce a concentration- dependent abbreviation of the action potential duration in Purkinje fibers.4 In contrast, quinidine, procainamide, and disopyramide are also class I drugs, but they prolong the action potential dura- tion.5 Mexiletine, more potent than lidocaine and procainamide? 7 abolished ventricular arrhythmias produced experimentally in animals. The drug is well absorbed on oral administration in man, and it is effective in preventing and treating ventricular arrhythmias when administered orally or intrave- nously.8

Since mexiletine will be used in the treatment of patients with cardiovascular disease who may have impaired cardiac function, it is important to docu- ment carefully the effects of the drug on cardiac hemodynamics. This article summarizes several studies of the effects of mexiletine on cardiac func- tion. It is particularly important that observations

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