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Practical considerations in the treatment of ventricular arrhythmias with mexiletine
Practical considerations ventricular arrhythmias
in the treatment with mexiletine
of
Mexiletine can be administered by intravenous, intramuscular, or oral route. However, the intramuscular route is seldom used because it offers no advantage over the other routes. Loading doses of about 408 mg may result in unacceptable side effects and are unnecessary for management of chronic ventricular arrhythmias. Therapeutic efficacy as well as side effects increase in proportion to increasing blood levels. At plasma levels of 2.0 mg/L, side effects are encountered in a significant number of patients. Because of its lack of serious toxicity even in patients with various systemic illnesses and its long elimination half-life, mexiletine should be considered as a first-line drug for treatment of ventricular arrhythmias. (AM HEART J 107:1086, 1984.)
Masood Akhtar,
ROUTES
OF
M.D. Milwaukee,
ADMINISTRATION
AND
Wis.
DOSAGE
RANGE
Mexiletine is a versatile drug in terms of its administration; it can be given by intravenous, intramuscular, or oral route.‘-7 Rapid intravenous infusion of 200 to 250 mg of the agent in 5 minutes is possible.2 When this is followed by 1 to 1.5 mg/min as a constant infusion, a plasma concentration of 1 mg/L can be achieved in approximately ‘/z hour. However, this regimen may produce relatively high plasma leveis in 15 minutes and a consequently increased incidence of side effects. This rapid dosing by the intravenous route should be used only under urgent circumstances. When immediate establishment of a therapeutic level is not necessary, a more moderate dosing schedule is preferable. Mexiletine is much better tolerated when it is infused at a rate of 10 to 15 mg/min. In this way a total dose of 200 to 300 mg can be given over 30 minutes; then therapeutic levels can be maintained with an infusion of approximately 1 mg/min. The mean half-life of mexiletine is 13.2 hours after acute intravenous loading without a follow-up infusion.6 Although mexiletine can be given intramuscularly, this route provides no advantage over the intravenous route and is seldom utilized. The drug is absorbed almost completely after oral administration. With a single dose ranging from 100 to 400 mg, the peak concentrations are achieved From the Laboratory,
Natalie and Norman Soref University of Wisconsin-Mount
Reprint requests: Masood N. Twelfth St., P.O. Box
1086
Akhtar, M.D., 342, Milwaukee,
and
Family Electrophysiology Sinai Medical Center.
Mount Sinai WI 53201.
Medical
Center,
950
400 m g 195%) 300 m g 189%l 200 m g 162%1 I
L
1 0.0
I
1
I
I
I
I
I
1.0
2.0
3.0
4.0
5.0
6.0
7.0
I
8.0
HOUR AFTER blORNlNGOOSEOFMEXlLETlNE
Fig. 1. Relationship between dose and corresponding blood levels (in nanograms per milliliter) is depicted. The levels were determined after administration of the morning dose, after several days of oral therapy. The efficacy of mexiletine as measured by control of premature ventricular contractions also shows a linear relationship with dose and plasma concentrations.
within 1 to 3 hours. Therapeutic blood levels can be reached with doses of 10 to 15 mglkglday, and there is a linear relationship between the size of dose and plasma concentration of mexiletine (Fig. 1).3,7,* The elimination half-life of mexiletine during oral administration is 11.3 hours. Loading doses of mexiletine have been recommended to rapidly achieve therapeutic blood levels, but are unnecessary for the management of chronic ventricular arrhythmias. Loading doses in excess of 400 mg are associated with unacceptable side effects and should be avoided. With a fixed dose the mean steady-state plasma concentration is reached in
Volume Number
107
Treatment
5, Part 2
of
ventricular
2A I.
TOTALNO.OFPATlENTSWlTHSE:S0
d 70 g 60
1087
arrhythmias
Side Effects No. of Patients
21-30 PLASMA MEXILETINE
(pglml)
Fig. 2. Relationship between the efficacy of the plasma mexiletine concentration (milligrams per milliliter) and side effects in a series of patients. The results here are expressed as a percentage of total patients who experienced efficacy and/or side effects at various plasma mexiletine levels. The hatched bars represent patients in whom the plasma concentration was effective, open bars represent patients with side effects, and solid bars show patients with intolerable side effects. (Reproduced with permission from Bogaert.8)
31-40
41-50 51-60 AGE (Yrs)
61-70
71-80
Fig. 3. The overall numbers of side effects (SE) observed in various age groups are shown. The number at the top of each bar represents the actual number of cases in each age group. In our patient population most of the side effects were observed in patients 51 to 70 years of age.,However, this trend is primarily related to the fact that most of the patients who received mexiletine in our series were also in these age groups. (See also Fig. 4)
60
r 4
approximately 50 hours (i.e., 4.3 x plasma half-life) after the start of treatment.7 BLOOD
LEVELS
AND DOSAGE
TITRATION
Several reports suggest that therapeutic levels of mexiletine range between 0.5 and 2.0 mg/L,5-s The therapeutic,efficacy (Fig. 1) as well as the frequency of side effects (Fig. 2) proportionately increase as the blood level rises.8 At plasma levels of 2.0 mg/L side effects are encountered in a significant number of patients. A steady therapeutic level of 1.5 mg/L can be maintained with an intravenous infusion rate of 1 mg/min after an initial loading dose of 200 mg given over a lo- to 15-minute period. However, titration may be required in individual cases. During chronic oral therapy therapeutic blood levels can be attained and maintained with a total daily dose of 600 to 1200 mg on either a g-hour schedule or an 8-hour schedule. So-called therapeutic blood levels serve only as a rough guide in patients with ventricular arrhythmias. When managing malignant arrhythmias, the main goal is to prevent potentially lethal episodes; such situations warrant maximum therapy guided by patient tolerance and toxic reactions. Therefore, higher doses of mexiletine may be tried until the arrhythmia is controlled or intolerable side effects are encountered. The usual,maximum daily dose of mexiletine is 1200 mg, although higher doses may be tolerated in some cases.
SIDE EFFECTS 4. (as a percentage of total no. of 30 patients in that age wow)
20 10 I60
AGE (Yrs)
Fig. 4. When the data shown in Fig. 3 are presented as a percentage of total number of patients in a given age group, the relative incidence of side effects in different age groups is comparable.
DOSAGE ADJUSTMENTS WITH BODY WEIGHT, OR MULTIDRUG THERAPY
AGE
Since serum levels above 2 mg/L are associated with a high incidence of side effects, it seems prudent to utilize smaller total daily doses in patients with smaller body weights, and vice versa. The side effects and efficacy of mexiletine are quite comparable in patients within various age groups (Figs. 3 and 4), and no special considerations are necessary even in older patients. Because of mexiletine’s relatively long elimination half-life, doses can be spaced every 8 or even 12 hours. Unpublished and preliminary trials comparing the S-hour vs the 12-hour schedule have demonstrated comparable efficacy and tolerance. For bet-
1088
Akhtar
American
MEXILETINE
LIGNOCAINE
lOO[ % REDUCTION IN VEs
~ 01 5
PLASMA CONCENTRATION
:i;li-' c
A
Mexiletine therapy should be started with caution in patients receiving lidocaine to avoid serious central nervous system toxicity. The lidocaine dosage should be substantially reduced or the drug discontinued 1 to 2 hours after administration of oral mexiletine.
3
USE IN PATIENTS OTHER SYSTEMIC 800 Beats/5
min
Hay, 1984 Heart Journal
400 O[ -10
-10 MINUTES
Fig. 5. The effect of the intravenous infusion of mexile-
tine and lignocaine (lidocaine) at 0 to 2 mg/kg/min on ouabain-induced ventricular tachycardia in anesthetized dogs.The records, from top downward, showthe percentagereduction in ventricular ectopic beats (VEsJ expressed as a percentage of the number during the lo-minute period before the administration of the drug and for each &minute period during infusion of mexiletine and lignoCaine;plasmaconcentration (microgramsper milliliter) of the drug; and histograms representing the number of ventricular beats (top of the opencolumns) and number of sinus beats (solid columns) for 5-minute periods. The results are the mean and standard error of the mean derived from observations in three dogs for each drug. (Reproduced with permissionfrom Allen et al.‘)
ter patient compliance, the 12-hour schedule is valuable if it is effective in controlling arrhythmias. When mexiletine is used in combination with other class I agents such as quinidine, procainamide, or disopyramide, the dosage frequency of other antiarrhythmic agents should be considered and the schedule of mexiletine adjusted accordingly. For example, when patients are on a 6-hour schedule of the class I agent, a 6-hour or 12-hour regimen of mexiletine would be more appropriate, whereas when quinidine or disopyramide can be spaced every 8 hours, the &hour schedule of mexiletine will be more convenient. Owing to its lack of serious toxicity and long elimination half-life, mexiletine should be considered as a first-line drug. Mexiletine may even be a preferred initial choice in patients with a history of response to lidocaine, although clinical data supporting this preference are lacking. Comparable doses of mexiletine have been shown to be more potent than lidocaine in suppressing ventricular arrhythmias in animals (Figs. 5 and 6).s In clinical situations mexiletine may sometimes be effective in patients who have not responded to lidocaine.*O
WITH CARDIOVASCULAR DISEASES
AND
Significant systemic toxicity of various antiarrhythmic agents is frequently a limiting factor in their use. In this respect mexiletine has some advantages because the drug can be administered in clinical settings in which several conventional antiarrhythmics would be less desirable. Cardiovascular disease. The data available to date suggest no serious hemodynamic cardiovascular side effects that can be definitely attributed to mexiletine. The drug does not produce significant hypotension or aggravation of left ventricular function. In fact mexiletine is well tolerated by patients with left ventricular dysfunction, even those with a prior history of congestive heart failure. In patients with acute cardiovascular illness, however, the absorption or hepatic clearance of mexiletine may be reduced. The drug can be safely administered along with diuretics and its efficacy is not adversely altered by these agents. Absorption of mexiletine is significantly reduced in patients with acute myocardial infarction. However, in such patients it seems this effect on absorption is primarily a result of concomitant administration of narcotic analgesics, which are known to delay gastric emptying.” Mexiletine does not alter sinus node function or QR, QRS, and QT, intervals in patients without preexisting sinus node dysfunction, atrioventricular (AV) block, or bifascicular block.12* l3 The agent may, however, depress sinus node function and conduction in the His-Purkinje system, particularly in patients with preexisting abnormality of sinus node function and AV conduction.13s l4 The safety or efficacy of mexiletine in patients with ventricular arrhythmias associated with prolonged QT, syndrome is undetermined at this time. Renal disease. A study comparing the plasma kinetics of mexiletine in normal subjects and patients with renal insufficiency (creatinine clearance range of 2 to 40 ml/min) demonstrated a prolonged time for clearance of the drug in renal disease. After a single intravenous dose of 1.5 mg/kg, the half-life in patients with normal renal function was 7.5 hours, whereas in those with renal ins&iciency it was 12.5 hours.15 Another study that utilized an equivalent dose of intravenous mexiletine in
Volum* Number
107 5, Part 2
patients with a similar degree of renal dysfunction showed a plasma elimination half-time of 11.1 + 1.7 hours in patients with renal insufficiency.16 A relatively short half-life of 5.85 + 0.91 hours for mexiletine in the normal subjects in this study makes the data somewhat difficult to interpret. However, in both of these studies the elimination half-life was not excessively long in patients with significantly compromised renal function; in fact, as indicated above, it was comparable to the elimination half-life in subjects with normal renal function. Therefore it appears that in patients with renal insufficiency mexiletine may be used more safely than many other antiarrhythmic agents. Even in subjects without renal disease, a change in the urinary pH can significantly affect clearance of the nonmetabolized drug.17-1g There is an inverse relationship between the renal clearance and the urine pH. Despite this pH-dependent excretion of mexiletine, the physiologic variation in the urinary pH does not seem to have a significant impact on plasma half-life or steady state in most patients. Moreover, because only a small fraction of the drug is excreted in an unchanged form, the effect of pH is even less significant. Hepatic disease. Mexiletine is primarily eliminated by metabolism in the liver. It is therefore quite conceivable that reduced hepatic flow in patients with congestive heart failure or decreased activity of hepatic enzymes in the presence of hepatic disease may significantly affect the drug’s clearance. In such patients careful titration would be required to avoid toxicity.20 However, data on this point are lacking. Gastrointestinal problems. Although upper gastrointestinal side effects such as nausea, anorexia, and epigastric discomfort are common with oral mexiletine, they often can be relieved or minimized by taking the drug with food.4,6,21 There is no evidence that the agent might promote peptic ulcer, gastritis, or other gastrointestinal abnormalities, although no concrete data in this regard are available. Our own clinical experience involving more than 200 patients treated with mexiletine suggests that such an occurrence is exceedingly rare. However, it may be wise to exercise caution in the use of mexiletine in patients with a history of peptic ulcer disease or gastritis. On occasion antacids are utilized to reduce epigastric discomfort in patients who take mexiletine. Clinical experience indicates that concomitant use of nonabsorbable antacids does not significantly alter the efficacy of mexiletine, although there have been no controlled studies to evaluate this observation.
Treatment
of ventricular arrhythmias
1089
%REDUCTIDN INVENTRICULAR ECTOPIC BEATS
DOSE DFDRlJG(mg/kg)
Fig. 6. Effects of the intravenous administration of increasingdosesof mexiletine (five dogs), lignocaine (four dogs), or procainamide (three dogs) on the ventricular tachycardia 20 to 44 hours after ligation of a coronary artery. The reduction in the frequency of ventricular ectopic beats in the B-minute period after each doseof a drug is expressed as a percentage of the frequency of ventricular ectopic beatsin the B-minute period before the administration of any drug (mean & SE). (Reproduced with permissionfrom Allen et a1.g)
Central nervous system. Although mexiletine produced a number of side effects in the central nervous system, it is not clear if the agent will aggravate preexisting symptoms in patients with central nervous system disorders. These toxic reactions are related to the blood level and dose of the drug. Side effects are reversible when the dose is decreased or the drug discontinued. There is no evidence of any permanent effects. However, use of mexiletine should be avoided in patients with seizure disorders.4*6p21 CONCLUSIONS
Mexiletine can be administered through intravenous, intramuscular, and oral routes and has a convenient dosage schedule that helps in patient compliance. Because it lacks serious toxicity, particularly related to the cardiovascular system, and because it can be administered to patients with various systemic diseases, it is a desirable antiarrhythmic agent. REFERENCES
1. Clark RA, Talbot RG, Nimmo J, Prescott LF, Julian DG: Ko 1173-an effective anti-arrhythmic drug. Br Heart J 38558, 1973. 2. Roos JD, Paalman ACA, Dunning AJ: Electrophysiological effects of mexiletine in man. Br Heart J 38:1262, 1976. 3. Cereghino JJ, Wilder BJ, Kupferberg HJ, Yonekawa WD, Perchalski RJ, Ramsey RE, White BG, Penry JK, Smith LD: A single-dose study of mexiletine (Ko 1173). Epilepsia 16:665, 1975. 4. Campbell NPS, Chaturvedi NC, Shanks RG, Kelly JG,
1090
5.
6.
7. 8. 9.
10.
11.
12.
13.
May.1984
Al&tar
Strong JE, Adgey AAJ: The development of mexiletine in the management of ventricular dysrhythmias. Postgrad Med 53(suppl 1):114, 1977. Paalman ACA, Siebelink J, Roos JC, Dunning AJ: Development of a dosage scheme for simultaneous intravenous and oral administration of mexiletine. Postgrad Med 53(suppl 1):128, 1977. Campbell NPS, Kelly JG, Adgey AAJ, Shanks RG: The clinical pharmacology of mexiletine. Br J Clin Pharmacol 6:103, 1978. Pottage A: Oral dosage schedules of mexiletine. Postgrad Med 53(suppl 1):X5, 1977. Bogaert M: Adaptation of the dose of mexiletine according to pharmacokinetic data. Acta Cardiol [Suppl] 2567, 1980. Allen JD, Kelly JG, James RGG, Shanks RG, Saidi SA: Comparsion of the effects of lignocaine and mexiletine on experimental ventricular arrhythmias. Postgrad Med 53(suppl 1):35, 1977. Abinader EG, Cooper M: Mexiletine-Use in control of chronic drug-resistant ventricular arrhythmia. JAMA 242~337, 1979. Prescott LF, Clements JA, Pottage A: Absorption, distribution and elimination of mexiletine. Postgrad Med 53(suppl 1):50, 1977. Harper RW, Olsson SV, Varnauskas E: The effect of mexiletine on the electrophysiological properties of the intact human heart. Stand J Clin Lab Invest 37:503, 1977. Lang KF, dust H, Limbourg P: Investigations of the effect of mexiletine (Ko 1173) on the AV-conduction time and sinus
American
14.
15.
16.
17.
18.
19.
20.
21.
Heart Journal
impulse automatism in patients with and without diseases of the conduction system. Z Kardiol 64:389, 1975. Roos JC, Dunning AJ, Paalman ACA: Clinical electrophysiology and pharmacokinetics of mexiletine. Prog Pharmacol 2:47, 1979. Dresse A: Plasma kinetics of mexiletine in normal subjects and in patients with renal insufficiency: Single intravenous administration. Amsterdam, 1978, Excerpta Medica, pp 286287. Baudinet G, Henrard L, Quinaux N, Allaf D, Landsheere C, Carlier J, Dresse A: Pharmacokinetics of mexiletine in renal insufficiency. Acta Cardiol 25(suppl):55, 1980. Kiddie A, Kaye CM, Turner P, Shaw TRD: The influence of urinary pH on the elimination of mexiletine. Br J Clin Pharmacol 1:229, 1974. Johnston A, Burgess CD, Warrington Sd, Wadsworth J, Hamer NAJ: The effect of spontaneous changes in urinary pH on mexiletine plasma concentrations and excretion during chronic administration to healthy volunteers. Br J Clin Pharmacol 8:349, 1979. Beckett AH, Chidomere EC: The distribution, metabolism and excretion of mexiletine in man. Postgrad Med 53(suppl 1):60, 1977. Winter M, Brunner H, Horwatitsch H, Grabner G: Plasma levels of mexitil in patients with liver damage. In Hitzenberger G, Flener R, editors: Moderne Antiarrhythmika. Munich, 1978, Urban und Schwarzenberg, pp 29-32. Podrid Pd, Lown B: Mexiletine for refractory ventricular arrhythmia (abstr). Circulation 60~188, 1979.
in the treatment with mexiletine
of
Mexiletine can be administered by intravenous, intramuscular, or oral route. However, the intramuscular route is seldom used because it offers no advantage over the other routes. Loading doses of about 408 mg may result in unacceptable side effects and are unnecessary for management of chronic ventricular arrhythmias. Therapeutic efficacy as well as side effects increase in proportion to increasing blood levels. At plasma levels of 2.0 mg/L, side effects are encountered in a significant number of patients. Because of its lack of serious toxicity even in patients with various systemic illnesses and its long elimination half-life, mexiletine should be considered as a first-line drug for treatment of ventricular arrhythmias. (AM HEART J 107:1086, 1984.)
Masood Akhtar,
ROUTES
OF
M.D. Milwaukee,
ADMINISTRATION
AND
Wis.
DOSAGE
RANGE
Mexiletine is a versatile drug in terms of its administration; it can be given by intravenous, intramuscular, or oral route.‘-7 Rapid intravenous infusion of 200 to 250 mg of the agent in 5 minutes is possible.2 When this is followed by 1 to 1.5 mg/min as a constant infusion, a plasma concentration of 1 mg/L can be achieved in approximately ‘/z hour. However, this regimen may produce relatively high plasma leveis in 15 minutes and a consequently increased incidence of side effects. This rapid dosing by the intravenous route should be used only under urgent circumstances. When immediate establishment of a therapeutic level is not necessary, a more moderate dosing schedule is preferable. Mexiletine is much better tolerated when it is infused at a rate of 10 to 15 mg/min. In this way a total dose of 200 to 300 mg can be given over 30 minutes; then therapeutic levels can be maintained with an infusion of approximately 1 mg/min. The mean half-life of mexiletine is 13.2 hours after acute intravenous loading without a follow-up infusion.6 Although mexiletine can be given intramuscularly, this route provides no advantage over the intravenous route and is seldom utilized. The drug is absorbed almost completely after oral administration. With a single dose ranging from 100 to 400 mg, the peak concentrations are achieved From the Laboratory,
Natalie and Norman Soref University of Wisconsin-Mount
Reprint requests: Masood N. Twelfth St., P.O. Box
1086
Akhtar, M.D., 342, Milwaukee,
and
Family Electrophysiology Sinai Medical Center.
Mount Sinai WI 53201.
Medical
Center,
950
400 m g 195%) 300 m g 189%l 200 m g 162%1 I
L
1 0.0
I
1
I
I
I
I
I
1.0
2.0
3.0
4.0
5.0
6.0
7.0
I
8.0
HOUR AFTER blORNlNGOOSEOFMEXlLETlNE
Fig. 1. Relationship between dose and corresponding blood levels (in nanograms per milliliter) is depicted. The levels were determined after administration of the morning dose, after several days of oral therapy. The efficacy of mexiletine as measured by control of premature ventricular contractions also shows a linear relationship with dose and plasma concentrations.
within 1 to 3 hours. Therapeutic blood levels can be reached with doses of 10 to 15 mglkglday, and there is a linear relationship between the size of dose and plasma concentration of mexiletine (Fig. 1).3,7,* The elimination half-life of mexiletine during oral administration is 11.3 hours. Loading doses of mexiletine have been recommended to rapidly achieve therapeutic blood levels, but are unnecessary for the management of chronic ventricular arrhythmias. Loading doses in excess of 400 mg are associated with unacceptable side effects and should be avoided. With a fixed dose the mean steady-state plasma concentration is reached in
Volume Number
107
Treatment
5, Part 2
of
ventricular
2A I.
TOTALNO.OFPATlENTSWlTHSE:S0
d 70 g 60
1087
arrhythmias
Side Effects No. of Patients
21-30 PLASMA MEXILETINE
(pglml)
Fig. 2. Relationship between the efficacy of the plasma mexiletine concentration (milligrams per milliliter) and side effects in a series of patients. The results here are expressed as a percentage of total patients who experienced efficacy and/or side effects at various plasma mexiletine levels. The hatched bars represent patients in whom the plasma concentration was effective, open bars represent patients with side effects, and solid bars show patients with intolerable side effects. (Reproduced with permission from Bogaert.8)
31-40
41-50 51-60 AGE (Yrs)
61-70
71-80
Fig. 3. The overall numbers of side effects (SE) observed in various age groups are shown. The number at the top of each bar represents the actual number of cases in each age group. In our patient population most of the side effects were observed in patients 51 to 70 years of age.,However, this trend is primarily related to the fact that most of the patients who received mexiletine in our series were also in these age groups. (See also Fig. 4)
60
r 4
approximately 50 hours (i.e., 4.3 x plasma half-life) after the start of treatment.7 BLOOD
LEVELS
AND DOSAGE
TITRATION
Several reports suggest that therapeutic levels of mexiletine range between 0.5 and 2.0 mg/L,5-s The therapeutic,efficacy (Fig. 1) as well as the frequency of side effects (Fig. 2) proportionately increase as the blood level rises.8 At plasma levels of 2.0 mg/L side effects are encountered in a significant number of patients. A steady therapeutic level of 1.5 mg/L can be maintained with an intravenous infusion rate of 1 mg/min after an initial loading dose of 200 mg given over a lo- to 15-minute period. However, titration may be required in individual cases. During chronic oral therapy therapeutic blood levels can be attained and maintained with a total daily dose of 600 to 1200 mg on either a g-hour schedule or an 8-hour schedule. So-called therapeutic blood levels serve only as a rough guide in patients with ventricular arrhythmias. When managing malignant arrhythmias, the main goal is to prevent potentially lethal episodes; such situations warrant maximum therapy guided by patient tolerance and toxic reactions. Therefore, higher doses of mexiletine may be tried until the arrhythmia is controlled or intolerable side effects are encountered. The usual,maximum daily dose of mexiletine is 1200 mg, although higher doses may be tolerated in some cases.
SIDE EFFECTS 4. (as a percentage of total no. of 30 patients in that age wow)
20 10 I60
AGE (Yrs)
Fig. 4. When the data shown in Fig. 3 are presented as a percentage of total number of patients in a given age group, the relative incidence of side effects in different age groups is comparable.
DOSAGE ADJUSTMENTS WITH BODY WEIGHT, OR MULTIDRUG THERAPY
AGE
Since serum levels above 2 mg/L are associated with a high incidence of side effects, it seems prudent to utilize smaller total daily doses in patients with smaller body weights, and vice versa. The side effects and efficacy of mexiletine are quite comparable in patients within various age groups (Figs. 3 and 4), and no special considerations are necessary even in older patients. Because of mexiletine’s relatively long elimination half-life, doses can be spaced every 8 or even 12 hours. Unpublished and preliminary trials comparing the S-hour vs the 12-hour schedule have demonstrated comparable efficacy and tolerance. For bet-
1088
Akhtar
American
MEXILETINE
LIGNOCAINE
lOO[ % REDUCTION IN VEs
~ 01 5
PLASMA CONCENTRATION
:i;li-' c
A
Mexiletine therapy should be started with caution in patients receiving lidocaine to avoid serious central nervous system toxicity. The lidocaine dosage should be substantially reduced or the drug discontinued 1 to 2 hours after administration of oral mexiletine.
3
USE IN PATIENTS OTHER SYSTEMIC 800 Beats/5
min
Hay, 1984 Heart Journal
400 O[ -10
-10 MINUTES
Fig. 5. The effect of the intravenous infusion of mexile-
tine and lignocaine (lidocaine) at 0 to 2 mg/kg/min on ouabain-induced ventricular tachycardia in anesthetized dogs.The records, from top downward, showthe percentagereduction in ventricular ectopic beats (VEsJ expressed as a percentage of the number during the lo-minute period before the administration of the drug and for each &minute period during infusion of mexiletine and lignoCaine;plasmaconcentration (microgramsper milliliter) of the drug; and histograms representing the number of ventricular beats (top of the opencolumns) and number of sinus beats (solid columns) for 5-minute periods. The results are the mean and standard error of the mean derived from observations in three dogs for each drug. (Reproduced with permissionfrom Allen et al.‘)
ter patient compliance, the 12-hour schedule is valuable if it is effective in controlling arrhythmias. When mexiletine is used in combination with other class I agents such as quinidine, procainamide, or disopyramide, the dosage frequency of other antiarrhythmic agents should be considered and the schedule of mexiletine adjusted accordingly. For example, when patients are on a 6-hour schedule of the class I agent, a 6-hour or 12-hour regimen of mexiletine would be more appropriate, whereas when quinidine or disopyramide can be spaced every 8 hours, the &hour schedule of mexiletine will be more convenient. Owing to its lack of serious toxicity and long elimination half-life, mexiletine should be considered as a first-line drug. Mexiletine may even be a preferred initial choice in patients with a history of response to lidocaine, although clinical data supporting this preference are lacking. Comparable doses of mexiletine have been shown to be more potent than lidocaine in suppressing ventricular arrhythmias in animals (Figs. 5 and 6).s In clinical situations mexiletine may sometimes be effective in patients who have not responded to lidocaine.*O
WITH CARDIOVASCULAR DISEASES
AND
Significant systemic toxicity of various antiarrhythmic agents is frequently a limiting factor in their use. In this respect mexiletine has some advantages because the drug can be administered in clinical settings in which several conventional antiarrhythmics would be less desirable. Cardiovascular disease. The data available to date suggest no serious hemodynamic cardiovascular side effects that can be definitely attributed to mexiletine. The drug does not produce significant hypotension or aggravation of left ventricular function. In fact mexiletine is well tolerated by patients with left ventricular dysfunction, even those with a prior history of congestive heart failure. In patients with acute cardiovascular illness, however, the absorption or hepatic clearance of mexiletine may be reduced. The drug can be safely administered along with diuretics and its efficacy is not adversely altered by these agents. Absorption of mexiletine is significantly reduced in patients with acute myocardial infarction. However, in such patients it seems this effect on absorption is primarily a result of concomitant administration of narcotic analgesics, which are known to delay gastric emptying.” Mexiletine does not alter sinus node function or QR, QRS, and QT, intervals in patients without preexisting sinus node dysfunction, atrioventricular (AV) block, or bifascicular block.12* l3 The agent may, however, depress sinus node function and conduction in the His-Purkinje system, particularly in patients with preexisting abnormality of sinus node function and AV conduction.13s l4 The safety or efficacy of mexiletine in patients with ventricular arrhythmias associated with prolonged QT, syndrome is undetermined at this time. Renal disease. A study comparing the plasma kinetics of mexiletine in normal subjects and patients with renal insufficiency (creatinine clearance range of 2 to 40 ml/min) demonstrated a prolonged time for clearance of the drug in renal disease. After a single intravenous dose of 1.5 mg/kg, the half-life in patients with normal renal function was 7.5 hours, whereas in those with renal ins&iciency it was 12.5 hours.15 Another study that utilized an equivalent dose of intravenous mexiletine in
Volum* Number
107 5, Part 2
patients with a similar degree of renal dysfunction showed a plasma elimination half-time of 11.1 + 1.7 hours in patients with renal insufficiency.16 A relatively short half-life of 5.85 + 0.91 hours for mexiletine in the normal subjects in this study makes the data somewhat difficult to interpret. However, in both of these studies the elimination half-life was not excessively long in patients with significantly compromised renal function; in fact, as indicated above, it was comparable to the elimination half-life in subjects with normal renal function. Therefore it appears that in patients with renal insufficiency mexiletine may be used more safely than many other antiarrhythmic agents. Even in subjects without renal disease, a change in the urinary pH can significantly affect clearance of the nonmetabolized drug.17-1g There is an inverse relationship between the renal clearance and the urine pH. Despite this pH-dependent excretion of mexiletine, the physiologic variation in the urinary pH does not seem to have a significant impact on plasma half-life or steady state in most patients. Moreover, because only a small fraction of the drug is excreted in an unchanged form, the effect of pH is even less significant. Hepatic disease. Mexiletine is primarily eliminated by metabolism in the liver. It is therefore quite conceivable that reduced hepatic flow in patients with congestive heart failure or decreased activity of hepatic enzymes in the presence of hepatic disease may significantly affect the drug’s clearance. In such patients careful titration would be required to avoid toxicity.20 However, data on this point are lacking. Gastrointestinal problems. Although upper gastrointestinal side effects such as nausea, anorexia, and epigastric discomfort are common with oral mexiletine, they often can be relieved or minimized by taking the drug with food.4,6,21 There is no evidence that the agent might promote peptic ulcer, gastritis, or other gastrointestinal abnormalities, although no concrete data in this regard are available. Our own clinical experience involving more than 200 patients treated with mexiletine suggests that such an occurrence is exceedingly rare. However, it may be wise to exercise caution in the use of mexiletine in patients with a history of peptic ulcer disease or gastritis. On occasion antacids are utilized to reduce epigastric discomfort in patients who take mexiletine. Clinical experience indicates that concomitant use of nonabsorbable antacids does not significantly alter the efficacy of mexiletine, although there have been no controlled studies to evaluate this observation.
Treatment
of ventricular arrhythmias
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%REDUCTIDN INVENTRICULAR ECTOPIC BEATS
DOSE DFDRlJG(mg/kg)
Fig. 6. Effects of the intravenous administration of increasingdosesof mexiletine (five dogs), lignocaine (four dogs), or procainamide (three dogs) on the ventricular tachycardia 20 to 44 hours after ligation of a coronary artery. The reduction in the frequency of ventricular ectopic beats in the B-minute period after each doseof a drug is expressed as a percentage of the frequency of ventricular ectopic beatsin the B-minute period before the administration of any drug (mean & SE). (Reproduced with permissionfrom Allen et a1.g)
Central nervous system. Although mexiletine produced a number of side effects in the central nervous system, it is not clear if the agent will aggravate preexisting symptoms in patients with central nervous system disorders. These toxic reactions are related to the blood level and dose of the drug. Side effects are reversible when the dose is decreased or the drug discontinued. There is no evidence of any permanent effects. However, use of mexiletine should be avoided in patients with seizure disorders.4*6p21 CONCLUSIONS
Mexiletine can be administered through intravenous, intramuscular, and oral routes and has a convenient dosage schedule that helps in patient compliance. Because it lacks serious toxicity, particularly related to the cardiovascular system, and because it can be administered to patients with various systemic diseases, it is a desirable antiarrhythmic agent. REFERENCES
1. Clark RA, Talbot RG, Nimmo J, Prescott LF, Julian DG: Ko 1173-an effective anti-arrhythmic drug. Br Heart J 38558, 1973. 2. Roos JD, Paalman ACA, Dunning AJ: Electrophysiological effects of mexiletine in man. Br Heart J 38:1262, 1976. 3. Cereghino JJ, Wilder BJ, Kupferberg HJ, Yonekawa WD, Perchalski RJ, Ramsey RE, White BG, Penry JK, Smith LD: A single-dose study of mexiletine (Ko 1173). Epilepsia 16:665, 1975. 4. Campbell NPS, Chaturvedi NC, Shanks RG, Kelly JG,
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