Evaluat io ns on New Drugs Drugs 17: 161· 181 (1979) 00 12· 6667/79/0300-0161 /$05 .25/0 C ADIS Press Australasia Pty l td . All right s rese rved.
Mexiletine: A Review of its Pharmacological Properties and Therapeutic Efficacy in Arrhythmias' C. Y.C. Chew. J . Collett and B.N . Singh Section of Cardiology, Wadsworth VA Hospital , and the Depart ment of M edicine, UCLA School ot Medicin e, Los Angeles, Ca~fomia
Table oj Contents Summary I . PllarmacoJogical Studies ............... ..... ......... .••....
I I Effects on the Central and Peripheral Nervous System 1.2 Electro physiological Actions
,
,,,
',
,_
.
162 16. 16'
165
1.2. 1 EJ:.perimental Stud ies 165 1.2.2 Electroph.ysiological Studies in Man 165 1.3 Cardiovascular Hae modynamic Effects , . 168 1.4 Effect on Expenmemal Arrhyth mias .. 169 2. Therapeutic T rials . . 170 170 2. 1 Mexiletine and Arrhythmias in the Early Pha.~ of Acute Myocardial Infarctio n 2.2 Lolli Term Ora l An tiarrhythmic Therapy with Me~i1etine . 173 2.3 Oral MexiletiM in Prophyla~ is of Ve ntricular Arrhythmias after Acute Myocardial lnfarction 17' 3. Phar maookin etic Stud ies .. 175 175 3.1 Measurement of Plas ma Mel iletine Concentrations .. 3.2 Absorption . 175 3.3 Distribution . 17' 3.4 Elimination 177 • . Side Effects 178 5. Dosage and Administrat ion . 179
1 Supported in pan by grants from the Ame rican Hean Association-GrealU Los AlIlleles Affiliate, and by the National Institutes of Heahh (H L 239 70), Bethesda, Mary land, and the Medical Resear ch Service o r the Vete rans Ad ministratio n.
162
Mexiletine: A Review
Summa ry
Synopsis: Mexil elim? is a nell' local anaesthetic anti arrhyth m ic agent whose chemical structure and e1eclrophysiologicuf properties closely rl!S/'mble Ihose of lignocaine allhough us onttcanvtdsant and pharmacokinetic properties dtffer from that drug. Unlike lignocaine (lid,, · caine) ts is aClivefollowing oral admtnistrauon with a plasm a half-life varying between 8 and 10 hou rs so that tt can be administered twice or three limes daily to susta in therapeutic plasma levels . Tile drug is effective when given int ravenously or by me ural roule in controlling ventricular ar rhythmias esp,'Cially following acu te myocard ial inf arction bUI Ihe side effects are greater during parenteral adm inistrati on , Side effects durin g chronic oral therapy with mexilenn e have not posed a serious problem . Mexileline has the pharmaco dynamic and phormacokinetlc properties of an agent suitable for the chronic oral prophylaxis (if serious vent ricular arrhythm ias in pal ients wilh ischaemic heart disease. Anim al Pharmacology : In isolated cardiac tissues, therapeutically relevant concentrat ion s of mexilenne red uce the maximal rate of depolarisatio n of the action potential so that cc nd uctio n velocity is slowed, excita bility threshold is increased and effective refracto ry period lengthened without a significant change in the restin g membr ane potential o r the spo ntaneous frequency of the sinoatrial node . T he effective re fractory period is shortened but not to a grea ter extent than the actio n potential d urat ion so that the ratio of the effective period to the actio n poten tial duration is increased by mexuenne. Th ere are no data on the effects of the d rug in damaged o r ischaemic isolated myocard ial tissues, In intact animals. mexneune increases the fibr illation threshold of the ischaemi c myocardium and reverses ventricular tachyarr hythm ias resulting from ouabain intoxication or coronary ligat ion . Th e drug has in significa nt effects o n the aut onomi c nerv ous system. Hum an Pharma cology: Acute intraveno us administration of mexiletine in pat ients pro d uces little change in atri al refractoriness. sinus node automaticity or recovery time but in the sick sinus synd ro me severe brady card ia o r prolonged recovery tim e may become apparent . In patients with normal cond uct ion. sho nening of the A V and His-Purkinje refra ctonness may be seen; how ever . AV and His-P urkmje cond uctio n are both dela yed in patients with pre-existing disease, Th e effects of mexiletine on anomalous tracts in th e heart are not co nsistent bu t deserve fur ther study. Th e haemodynamic actions of intravenous mexiletine are comparable to those of lignocain e with min imal depressant effects in pat ients w ith normal or moderately impaired ventricular function, Pharma cnkm etics. The pharmacokineuc profile of mexiletine is chara cterised by high sys temic availab ility (88 % ) following o ra l ingestion . with peak levels being attained in 2 to 4 hour s; the plasma half-life in healthy voluntee rs is abou t 12 ho urs and app roximately 18 hours in patients with acute myocardial infarctio n in whom th e co ncomitant adm inist ratio n of narcot ic analg esics retard s gastric emptying, T he metaboli sm of mexiletine is not com pletely unde rstood but occurs lar gely in the liver, with only 10 % appearing unchanged in th e urine. Th e rena l clea rance of the dr ug is increased by urinary acidosis. About 70 % of seru m mexiletine is protein bo und. T herapeutic concentrations of mexilet ine (0 . 7S to 2.0 J,lgl m ll ar e us ually maintained by dail y oral doses of 600 to 1000 mg administered in divided dosa ge sched ules 8- to l Zvho urly. Therape utic Trials: Alth ough intravenousl y administered mexiterine is often effective in reverting ventr icular tach yarrhythrmas. the ma in therapeutic uti lity of th e dru g is in the chron ic oral proph ylaxis of ventricular arrh ythmias. especially in the survivors of acute
2
Meli til (Boehringer lngelheim).
Me~iletine:
A Review
163
myocardial infarction as indicated by a number of trials in which the efficacy of mexiletine proved comparable to that of procainamide. In one study the drug was found to be a more acceptable antiarrhythmic agent than procainarmde. producing somewhat better suppression of ventricular ectopic beats and complex ventricular arrhythmias. Trials designed to test the efficacy of mexiletine in reducing the incidence of sudden death in the survivors of acute infarction are awaited. Side Effects: In common with lignocaine. mexiletine has minimal negative inotropic propensity but following rapid intravenous injection. especially of large doses. bradycardia. hypotension and AV block may occur. Long term studies with mexneune have demonstrated excellent patient compliance. sustained efficacy and relative freedom from side effects. Only in a small number of patients had adverse effects been reponed: these are of central nervous system origin. including tremors. nystagmus. diplopia. dizziness. dysarthria, paraesthesia. ataxia and confusion. Gastrointestinal reactions have been uncommon and positive antinuclear factors and thrombocytopenia are rare. Do sage and AdminisrratiO/t : When therapeutic blood levels of mexiletine must be rapidly achieved and maintained. as in acute arrhythmias. a combination of a bolus intravenous injection of 150 to 250mg administered over 2 to 5 minutes. followed by a loading infusion of 250mg over 30 minutes. then 250mg over 2.5 hours and 500mg over 8 hours. has been used. A maintenance infusion of 500 to IOOOmg over 24 hours then follows. Such a regimen must be applied judiciously. especially in acutely ill and elderly patients. Alternatively. therapeutic plasma levels may be rapidly attained with an oral loading dose of 600mg. For prophylactic oral administration. 200 to 300mg 8-hourly produced a therapeutic plasma concentration (0.75 to 2"g/ mll in two-thirds of patients. Mexilitine may be used concomitantly with digoxin and g-acrencceotor blocking drugs. but not with other local anaesthetic type antiarrhythmic drugs Since the depressant erectrophysiological effects of the drug are more pronounced in patients with sick sinus syndrome. unstable AV block. and severe bradycardia. these conditions are contraindications to the use of the drug. The safety of the drug in advanced cardiac failure is not defined but merits study.
Until very recently there has been a st riking paucity in t he ava ilability of safe and potent antiarrhythmic compounds with the approp riate pharrnacokinetic characterist ics for the lo ng term oral prop hylaxis of life threatening vent ricular arrhythmias. Rapid advances in t he last 10 years in our knowledge of basic (Fozzard. 19 77 ; Arnsdorf, 1977 ; Ha uswirt h and Singh . 1979 ) and appl ied (Goldreyer. 197 3) cardiac electrophys iology and in the synthesis and characterisation of a plet hora of newer agents have con tributed greatly to the increasingly ratio nal basis for the control of card iac dysrhythmias in man (Singh. 19 78; Singh et af., 1979). Available antiarr hythmic drugs have been sho wn to produce thei r salutary effects essentially by altering the fast o r slow
depolarising membrane cur rents, by homogeneously reta rding repolarisation and by inhibiting ad rene rgic excitatio n in the heart. or by a combination of these processes (Singh and Vaughan Williams. 1971 , 1972 : Singh and Hauswi rth, 19 74; Hau swirt h and Singh , 197 9). Drugs which depress the fast response in the heart (class I agents) are also potent local anaesthet ics o n nerve. wh ile hav ing a wide spectrum of action on arrhythmias especially of ventricular o rigin. Mexiletine, toca inide . aprindine and disopyramide (fig. I) are am ong the newer class I agents wh ich have undergone experimental an d clinical eva luation (Ha rrison et al., 1977 ; Zipes and T roup , 19 78). From t he standpoint of long ter m pro phylaxis of vent ricu lar arrhythmias. mex iletin e and tocainide are of particular
164
Mexileline: A Rel/iew
interest because of their drug plasma half-lives following oral administration . In this review, the experimental and clinical data dealing with the action of mexiletine as an antiarrhythmic agent are discussed. It is of interest that mexiletine was initially developed as an anticonvulsant compound (Koppe, 1977) and its overall phar macological properties as an antiar rhythmic agent must, therefore, allow for simultaneous alterations in cardiac and neurological functions,
J. Pharm acological S tudies 1.1 Effectson the Central and Peripheral Nervous System Mexiletine has dose dependent anticonvulsant properties in both mice and rats, protecting the animals
from both electroshock and pentylenetrazole induced convulsions. The maximum protective effect of mexiletine under these experimental conditions was obtained within 15 minutes after oral and within I minute after intravenous administration . The effect disappeared 6 hours after oral, and was reduced to 20% 4 hours after intravenous, administration (unpublished data, Boehringer Ingelheim Ltd). In the cat model, the intraperitoneaJ application of mexiletine (!Omg /kg) prevented the episodic cramps induced by electrical stimulat ion of amygdaloid nucleus and the focal seizures induced by implanting aluminium hydroxide in the caudate nucleus. The accompanying EEG changes in these epileptic models were however unaffected by mexiletine (Danneberg and Shelley, 197 7). Mexiletine appears to exert a biphasic action on the central nervous system under these experimental con-
lidoc eine
Apli ndine
TOC8il'lide
Fig. I . Structu rel f ormulae of some recently introd UCed class t antie ntlythmic drugs.
M ll~illlt illll :
A Review
ditions. In th e lower dose range (I to 3mg / kg) intravenous mexiletine produced no EEG changes but prolonged the duration of after discharges following electric stimulation of both the hippocampus and amygdaloid regions. At higher doses (l Omg/kg IV ) there were signs of central nervous system depression with sho rtened duration of after discharges recorded at var ious cerebral sites. Althoug h th e exact mode of action of mexiletine's ant iconvul san t properties has yet to be defined, there is some recent evidence that it inh ibits the reuptake of the central nervous system inhibitory neurot ransm itter , gam ma am ino butyric acid (GA BA). Thus when rat cortex slices were incubated with tr itiated GA BA and th en perfused with Kreb's solution, electric stimulation of the brain slices pr oduced the release of tritiated GA BA. Wh en tr itiated GA BA slices were perfused with mexiletine (5 x 10- 4 M). GABA uptake was reduced by 16% compared to cont rols (Mitchell. 1969: quoted by Danneberg and Shel1ey, 1977). Mexiletine has no effect on the autonom ic nervous system and does not interfere with the function of biogenic arnines. It has neither antihistam inic activity nor alpha- or beta-adrenergic blocking propert ies.
1.2 Electrophysiological Actions The mode of antiarrhythmic action of mexiletine has been elucidated in a variety of in vitro and in vivo experimental models. as well as in man . The overall data, summarised below . are cons istent w ith the belief that the drug has cardiac effects very similar to those of lignocaine (Singh and Vau ghan Williams. 1972 ), depressing the fast response of the cardiac action potential in a manner characteristic of class I antiarrhythm ic agents (Singh and Vaughan Williams. 197 1). 1.2.1 Experimental St udies When tested in the frog sciatic nerve . mexiletme was found to be a stro ng local anaesthetic having a potency compar able to tha t of lignocaine (Singh and
165
Vaughan William s, 1972; Vaughan Williams, 1977). In isolated atrial or ventricular mu scle. as well as Purkinje fibres, the drug also exerts its majo r effects in a manner very sim ilar to that of lignocaine. For example. in concentrations between I and 5 ~g / m L mexiletine redu ces the maximal rate of depolansation of the action potential (fig. 2a, b), thus enhancing the thr eshold of excitabilit y. decreasing conduction velocity and prolon ging the effective refractory period while having little effect on the resting mem brane potential or on sinus node automaticity (Allen et al., 1972: Singh and Vaughan Williams, 1972; Vaughan Williams. 1977. Yamaguchi et al., 1979). Of parti cular interest has been the observation th at. as in the case of lignocaine. mexiletine produces a concentration dependent abbreviation of the action potential du ration (see fig. 2b) in Purk inje fibres, associated with modest shorte ning in the length of the effective refractory period (Yamaguchi et al., 1979). However , the abbreviation in the du ration of the action potent ial duration was always of a greater magnit ude than that in the effective refractory period . The precise significance of these somewhat disparate effects of mexiletine on repolari sation and effective refractory period rema ins unk nown; but in light of the reported finding of an exclusively depressant effect of lignocaine on all electroph ysiological parameters (El-Sherif et al., 1977: EI-Sherif and Lazzara, 1978), it will clear ly be of interest to exam ine the act ions of mexiletine on infarct lng myocardial fibres. Mexiletine has not been sho wn to have a significant effect on the calcium mediated slow respon se.
1.2.2 Electrophysiological Studies in Man The data from clinical observations with mexiletine are in general agreem ent with tho se from experim ental studies (Roe s et al., 1976 ; McComish et al ., 1977: Roos et al., 1977 ). However , marked differences in th e action of the dru g in patients with normal conduction compared 10 th ose with conduction distu rbances have emerged.
Me~iletine :
'"
A Review
---L-
1'\
1
Control
~ 2
Me~lIetlne
'"
lmg /l (4,62>< lO-IM)
3 3mg / l (1.39 >< 10- I M)
\j
f
~ (\/
V
A
r
--L
r ----L
r
» 5/minute. mu ltifoc:a.l or R on T type). ventricular tachycardia or recurrent ventricu lar fibrillation. 32 patients received the drug because of persistent ST elevation after myocardial infarct ion and the associated risk of ventricular fibrillation . A single 200 mg
injection given over 3 or 5 minutes was effective in only 8 of 18 patients (44 % ) in suppressing more than 50 % o f the ventricu lar ectopic counts compared to the control period. In 89 patients who received mexiletine by bolus injection (200mg) followed by infusion (J mg/mi nute for the first hour followed by 1.5mg/ min ute for J hours and finally Img / minute thereafter). the initial response was effective (i.e. > 50 % reduction in PVC counts) in 55 of 64 studies (86 % ) in which assessment was pos..s ible. Ventricular dysr hythmias wentricular fibrillation and ventricular tachycardia) recur red despite mexiletine in 26 (29 %) of the 89 patients treated in such a manner. Side effects att ributa ble to mexiletine were. however. common with this method of adm inistration . They were observed in 48 patients (5 4 %) and were severe in 39 (44 % ). These serious adverse effects (hypotension. bradycardia. widening of QRS comp lexes. toxic confusional states) were common when mextletme was given soon after the onset of myocardial infarct ion. occurring in 18 (64 % ) of 28 patients treated within 12 hours of the onset of infarct ion. and were often related to the initial 200mg bolus intravenous injection given over 5 minutes . However . severe side effects still occurred in nearly 2S % of patients even after steady-state concentra tion had been achieved. Mexiletine was particularly useful in lignocaine resistant dysrh yth mias. JS of the 191 patients had vent ricular dysrh ythm ias uncontr olled by lignocaine (i.e. either a plasma lignocaine concentration > 2 ~g/ m l or had doses in excess of a 100mg bolus and the sta ndard 2mg/ ml infusion). T hese dysr hythmi as responded well to mexiletine in 24 patients and 81 % of those with an assessable response benefited from the drug . Adverse haemodynam ic effects were observed in 3 patients who received both mexueune and lignocaine. Mexiletine was adm iniste red orally to 144 patients eithe r as a loading dose. transfer from intravenous therapy or as a maintenance dose without a loading dose. The usual loading dose was 300 or 400mg follo.....ed 2 hours later by 200 to 4oo mg. A further 200 to 400mg dose was given 6 hours later and
Mexiletine: A Review
172
thereafter mexiletine was admin istered at 6- or 8hour ly intervals. 137 patients were ultimately established on oral maintenance therapy Ii.e, treatment for longer than 24 hours). 57 patients received an oral loading dose and of the 20 patients whose response could be assessed, 18 (90 % ) had a satisfactory initial response Ii.e. 50 % or greater reduction in PVC counts). The incidence of severe side effects of patients maintained on oral therapy was related to the daily dosage. Thus , severe side effects were observed in 6
(35 % ) of the 17 patients receiving a daily dosage of 19 or more. As was noted in earlier reports, these authors found the margin between therapeutic and toxic plasma concentrations to be small. Thus, in their study the therapeutic plasma concentration of rnexiletine ranged between 0.75 and 2.001Jg/ ml. Above 2.001Jg /ml severe side effects occurred very frequently. There was a highly significant correlation between plasma concentration and the severity of side effects, particularly with oral therapy, indicating that
100 ECG AoP
\
(mm Hgl
I
,
,Nil
;
BO f-
..., "
a
,
.. I I ! ! ! i I i .
After mexiletine zOOmg N
ECG - - ' 100
,
't'11'I
II I I
, '
,
''
AoP I
Imm Hgl
BO
" .
4 seconds
I
I
a Fig . 3. Effec ts of intrave nously ad ministered mexiletine on ven mcu ter tachyca rdia in a patient with tscteemc heart disease.
The upper pane l shows phasic aonic press ure (AoPl and the ECG dem ons trating ventrkc jer tachycar dia (note atrioventricular dissociation and the consequent variation in the levels of a rte rial pres sure ). Mexiletine (zOOmg IV) restore s the rhythm to sinus lSlngh. unpublished observations).
173
M exileti ne: A Review
reduction in dosage might reduce the incidence of adverse effects. The overall data indicate that while intravenously administered mexiletine is often effective in reverting ventricular tachycardia to sinus rhythm (see fig. 3), this mode of therapy with the drug carries a greater incidence of side effects than comparable treatment with lignocaine. Thus, the drug is recommended largely for the oral therapy of ventricular arrhythmi as except for the occasional instances in which intravenous mexiletine may be used for recalcitrant dysrhythmias.
2.2 Long Term Oral Antiarrhythmic Therapy with Mexiletine Talbot et al. (J 976) studied the efficacy of long term oral mexileune in suppressing a variety of ventricular arrhythmias in a small uncontrolled series of 24 patients. The arrh ythmias consisted of ventricular tachycardia, ventricular fibrillation. R on T ventricular ectopic beats and multiform ventricular ectopic beats occurring in the setting of previous acute myocardial infarction, ischaemic heart disease with recurrent ventricular arrhythmias in the absence of recurrent infarction, or idiopathic arrhythmias in 6 patients. Mexiletine was administered at, a starting dose of 400 to 600mg followed 4 to 6 hours later by a maintenance dose of 150 to 350mg 8-hourly, administered for a total of 11.4 patient-years with individual periods of therapy ranging from I to 16 months. Outpatient assessment of the response consisted of a 12 lead electrocardiogram with a continuous 5 minute rhythm strip and, where arrhythmias were seen or suspected, a 24 hour ambulatory ECG was recorded. Table I presents the overall results. Mexiletine completely abolished arrhythmias in 19 of 24 patients (79 % ) and partially abolished arrhythmias (i.e. ventr icular ectopic beat rate reduced 75 96 with no ventricular tachycardia) in a further 4 patients. 8 patients experiencedtoxic symptoms but in only three were they severe enough to discontinue therapy.
Tab/e l . Result of Ofal mexiletine t herapy in 24 patients with ventric ular arrhythmias (aft er Talbot et et. 1916) Aetiology of arrhyth mias
No. of pat s,
Control of vent ricular arrhythm ias com plete ' disappearance
u
10
Ischaem ic heart disease
7
4
Idiopat hic
6
5
M yoc ardial inf arctio n
Tota l
24
19 (19%)
part ial f ai"re disappear _
.oc. 2
4 (11%)
1 (4 % )
Reduction of the dose was necessary in another 4 patients. No untoward haematological, biochemical or immunological effects were found. The range of plasma mexiletine associated with toxic symptoms ranged from 1.5 to 3.0.,.g/ ml (with a mean of 2~g /ml in each group) demonstrat ing the considerable overlap with therapeutic levels. 3 patients who either stopped or reduced their dose of mexiletine died suddenly 3 days to 3 weeks later. 6 other patients whose drug was stopped under electrocardiographic monitoring showed a reappearance of ventricular arrhythmias as their plasma mexiletine level fell. In a study by Jewitt et al . (J 976), mexiletine (200mg every 8 hours) was compared with sustained release procainamide (l.Sg every 8 hours), the ~ blocker tolamolol (I OOmg every 8 hours) and placebo in 20 patients with coronary artery disease who experienced more than 30 premature ventricular complexes per hour during a 24-hour period of ambulatory monitoring. Each medication was administered orally and in random order for successive z-week periods and each patient underwent two successive 24-hour ambulatory ECG recordings during the se-
Mexiletine : A Review
17'
cond week. Mexiletine reduced the frequency of pre- 0.37jJg/ml compared with 1.54 ± O. IBpg/ml matu re ventricular complexes by more than 75 % in which was associated with mild side effects. The difII of 20 patients, procainamide in 12 of 20 patients ference however was not statistically significant. and tolamo lol in 4 of 20 patients. 8 patients on procainamide had to reduce dosage because of side effects compared with only 2 patients receiving mexiletine 2.3 Oral Mexiletine in Prophylaxis of Ventricular Arrhythmias after Acute Myocardial In farction and 3 taking tolamolol. As an extension of the above study with 25 patients, the same authors Uewitt et al., In a prospective controlled randomised study from 1977) found essentially similar results with mexiletine as the most satisfactory agent for chronic use Edinbur gh (Campbell et al., 1975), oral mexiletine in patients with symptomatic ventricular ar- was compared to placebo and procainarnide in the rhyt hmias, being approximately as effective as pro- prevention of late ventr icular arrhythmias after acute cainamide in its antiarrhythmic actions but with myocardial infarction. The study population consisted of 60 male patients who had sustained a myocardial fewer side effects. Less satisfactory results were obtained by infarction within the preceding 48 hours and whose Campbell et al. ( 1978) with oral mexiletine therapy in arrhythmias (ventricular tachycard ia, ventricular ec48 patients with chronic ischaemic heart disease over topic beats tha t fell on the T wave or were multifocaf) a treatment period which varied from 2 days to more had all been controlled by standard doses of lignothan I year. 37 patients received mexiletine for ven- caine. 6 hours prior to the cessation of intravenous tricular ectopics, ventricular tachycardia or ventricu- lignocaine, the patients were randomised to each of 3 lar fibrillation, while II patients were treated because treatment groups and commenced on trial medicaof persistent ST segment elevation following myocar- tion . 20 patients were allocated at random to receive dial infarction on the grounds that there was an in- mexiletine given as a 400m g loading dose followed by creased risk of late ventricular dysrhythmias in this 250mg 8-hourly. 20 patients were allocated at ransubset of patients. 30 of the patients had received a dom to receive procainamide 500mg 4-hourly and the number of other antiarrhythmic agents which had final 20 patients were random ised to receive placebo. The 3 patient groups were comparable as regards age, proved ineffective or had produced side effects. A loading dose of mexiletine was admin istered peak C PK release and coronary risk factors. 24-hour either intravenousl y or orally to 29 patients who continuous electrocardiographic recordings were obreceived 800 to I IOOmg during the first 8 hours of tained on the fourth and tenth days. therapy. Thereafter , the most frequently used doses The results demonstrate that there was a high inciwere 200 , 250 and 300mg 8-hourly and therapy was dence of late complex arrhythmias on withdrawal of maintained for a median time of 3 months. While intravenou s therapy. Thus 13 of 17 patients (77 %) ventricular arrhythmias were not observed in more receiving placebo showed serious ventr icular dysthan 50% of the patients du ring therap y, severe side rhythmias as compared with 7 of 20 patients (35 %) effects (tremor, nystagmus , nausea, dyspepsia, brady- receiving procainamide and 6 of 19 0 2 % ) mexiletine cardia) occurred in 15 patients 0 I %). As in other treated patients (p < 0 .05 for the 2 drugs compared studies, there was considerable variation in the with placebo). The incidence of ventricular tachycarplasma levels which could be tolerated. Apart from dia and R on T ventricular ectopic beats was congastrointestinal irritat ion, adverse effects occurred in siderable [40 % or 7 of i7 patients in the placebo association with a mean trough concentration of group compared with 3 (15% ) of procainamide tre1.03 ± 0 .18 (SEM) pg/mt and a mean peak level ated patients and 2 ( 10 %) in the mexiletine treated of 1.77 ± O.17pg/ml; severe side effects occurred patients (p < 0.025)]. This study demonstrates that while both drugs were equally effective antia rat a higher mean peak concentration of 2.1 1 ±
Mexiletine: A Review
115
rhyt hmic agents, only a thi rd of the patients receiving this class of agents in curtailing the mortality from procainamide achieved acceptable therapeutic blood ischaemic heart disease (Wilhelmsson et al., 1974; level compared with 95 % of those receiving mex- Green 1975, 1977). iletine. While one patient receiving procainam ide developed a positive antin uclear factor, no toxicity to 3. Pharmacokinetic Studies oral mexiletine was noted. As an extension of the previous study, the prophylactic effect of oral mexiletine with in the first The development of a number of sensitive 48 hours of myocardial infarction was studied by methods to measure mexiletine in body fluids has perAchuff et al. (1977) in a double blind protocol with mitted various studies designed to elucidate its dis97 patients who had not received any prior treatment position in man. However, the data are still not comwith ant iarrhythmic therapy. Within 12 hours of the plete, especially in different disease states. onset of symptoms , patients were random ly assigned to treatment with mexiletine (600mg initially, 200mg at 2 and 4 hours then 250mg every 8 hours orally) or 3.1 Measurement of Plasma Mexiletine to treatment with placebo (53 patients). ElectrocarConcentrations diograms were recorded continuously for 48 hours and later analysed visually and by computer. VenConcentrat ions of mexiletine in biological material tricular fibrillation, ventricular tachycardia or R on T can be conveniently measured by gas liquid chromaevents occurred one or more times in the first 48 tograp hy (Kelly et al ., 1973; Kiddie et al., 1973). In hours in 42 patients out of 53 patients treated with the method of Kelly et al. ( 1973). mexiletine is explacebo and in 18 patients out of 44 patients (4 1%) tracted by organic solvents (diethyl ether) from samtreated with mexiletine. Multiple episodes of ar- ples made alkaline with 2N NaOH. To increase senrhythmias were observed in 34 placebo patients and sitivity and reproducibility, the extracted mexiletine is in 7 mexijenne patients. 2 patients in the placebo- converted to the acetyl derivative by acetic anhydride treated group had ventricular fibrillation. 3 patients which is then injected into a gas chromatograph using died while on mexiletine because of cardiac rupture or a nitrogen sensitive flame ionisation detector . A concardiogenic shock . venient internal standa rd is diphenhydramine . Using These overall data raise the hope that mexiletine this method , IOOng! ml mexiletine in plasma can be may well constitute a significant advance as an antiar - measured. Mexiletine in urine can be determined by a rhythmic agent for the chronic prophylaxis of ven- similar procedure except that ur ine samples are tricular arrhythmias. However, the available data do diluted to the concentration range 0 to 16).1g1ml. Using a linear electron capture detector. W illox not permit the conclusion that the drug will necessarily reduce the incidence of sudden death in patients and Singh ( 1976) were able to increase the sensitivity surv iving acute myocardial infarction , which is the of the gas liquid chrom atographic method to detect prime objective of antiarrhythmic therapy in this set- mexiletine in biological fluids. T he standard curve ting. Str ingently controlled clinical trials will be was linear to IO).lg/ ml and the limit of sensitivity of needed to resolve this possibility. Should the drug the method was for levels lower than l Ong! ml. prove efficacious in diminishing the incidence of sudden death in the survivors of acute myocardial infarc3.2 Absorption tion, its advantages and disadvantages as a therapeutic regimen in this regard will need to be compared to In a study of healthy male volunteers. Prescott et those of ~ -adrenoceptor blocking drugs since preliminary reports have indicated the effectiveness of al. ( 1977) found that mexiletine in solution or in cap-
Mexiletine: A Review
176
sules was virtually completely absorbed following oral admini st ration with peak plasma concent ration occurring within 2 to 4 hours. However. absorption was delayed and incomplete in patients with acute myocardial infarction. This was part icularly marked in patients who had received narcotic analgesics which are known to strongly inhibit gastric emptying in man (fig. 4). During long term oral therapy, therapeutic plasma concentrations (0.75 to 2 ~g / m l) can usually be maintained in adu lts with doses of 200 to 300mg every 6 to 8 hou rs (average daily doses 600 to IOOOmg). The mean steady-state plasma concentrations of mexiletine in 101 patients receiving the drug orall y for mor e than 48 hours were related directly to th e dose (Prescott et al., 1977). The level of, systemic availability of orally admin istered mexiletine is high, being 88 % compared with only about 30 % in the case of lignocaine (Prescott et al ., 1977).
3.3 Distribu tion After intravenous Injection, plasma mexiletine . concentrations fall rapidly as a result of extensive uptake and distribution in tissues (table ID; less than 1% of the total amount of the drug in the body is in the blood after distributi on . In the pharmacoklnetic study of plasma concentration data of health y volunteers and patients by Prescott et al. (J 977 ), the distr ibution kinetics of mexiletine were consistent with a 3-compart ment model: the first or rapid transit 'central' compart ment consists of blood volume and rap idly equilibrat ing highly perfused tissues such as myocardium, brain , liver , lung and kidney while the second and third compart ments represent tissue uptake by sk in, muscle and fat which take up the drug more slowly. The apparent volume of distribution is large, often exceeding 600L, reflecting extensive tissue uptake
400 mg
.. 0
He~lthy
subjects (5 )
0.'
06
e
400mg + 200rng at 2h Patients wit h MI + ne-cote (6)
0.4
~
1 .~
;
l
02 . 0
:.
Mexiletine: A Review of its Pharmacological Properties and Therapeutic Efficacy in Arrhythmias' C. Y.C. Chew. J . Collett and B.N . Singh Section of Cardiology, Wadsworth VA Hospital , and the Depart ment of M edicine, UCLA School ot Medicin e, Los Angeles, Ca~fomia
Table oj Contents Summary I . PllarmacoJogical Studies ............... ..... ......... .••....
I I Effects on the Central and Peripheral Nervous System 1.2 Electro physiological Actions
,
,,,
',
,_
.
162 16. 16'
165
1.2. 1 EJ:.perimental Stud ies 165 1.2.2 Electroph.ysiological Studies in Man 165 1.3 Cardiovascular Hae modynamic Effects , . 168 1.4 Effect on Expenmemal Arrhyth mias .. 169 2. Therapeutic T rials . . 170 170 2. 1 Mexiletine and Arrhythmias in the Early Pha.~ of Acute Myocardial Infarctio n 2.2 Lolli Term Ora l An tiarrhythmic Therapy with Me~i1etine . 173 2.3 Oral MexiletiM in Prophyla~ is of Ve ntricular Arrhythmias after Acute Myocardial lnfarction 17' 3. Phar maookin etic Stud ies .. 175 175 3.1 Measurement of Plas ma Mel iletine Concentrations .. 3.2 Absorption . 175 3.3 Distribution . 17' 3.4 Elimination 177 • . Side Effects 178 5. Dosage and Administrat ion . 179
1 Supported in pan by grants from the Ame rican Hean Association-GrealU Los AlIlleles Affiliate, and by the National Institutes of Heahh (H L 239 70), Bethesda, Mary land, and the Medical Resear ch Service o r the Vete rans Ad ministratio n.
162
Mexiletine: A Review
Summa ry
Synopsis: Mexil elim? is a nell' local anaesthetic anti arrhyth m ic agent whose chemical structure and e1eclrophysiologicuf properties closely rl!S/'mble Ihose of lignocaine allhough us onttcanvtdsant and pharmacokinetic properties dtffer from that drug. Unlike lignocaine (lid,, · caine) ts is aClivefollowing oral admtnistrauon with a plasm a half-life varying between 8 and 10 hou rs so that tt can be administered twice or three limes daily to susta in therapeutic plasma levels . Tile drug is effective when given int ravenously or by me ural roule in controlling ventricular ar rhythmias esp,'Cially following acu te myocard ial inf arction bUI Ihe side effects are greater during parenteral adm inistrati on , Side effects durin g chronic oral therapy with mexilenn e have not posed a serious problem . Mexileline has the pharmaco dynamic and phormacokinetlc properties of an agent suitable for the chronic oral prophylaxis (if serious vent ricular arrhythm ias in pal ients wilh ischaemic heart disease. Anim al Pharmacology : In isolated cardiac tissues, therapeutically relevant concentrat ion s of mexilenne red uce the maximal rate of depolarisatio n of the action potential so that cc nd uctio n velocity is slowed, excita bility threshold is increased and effective refracto ry period lengthened without a significant change in the restin g membr ane potential o r the spo ntaneous frequency of the sinoatrial node . T he effective re fractory period is shortened but not to a grea ter extent than the actio n potential d urat ion so that the ratio of the effective period to the actio n poten tial duration is increased by mexuenne. Th ere are no data on the effects of the d rug in damaged o r ischaemic isolated myocard ial tissues, In intact animals. mexneune increases the fibr illation threshold of the ischaemi c myocardium and reverses ventricular tachyarr hythm ias resulting from ouabain intoxication or coronary ligat ion . Th e drug has in significa nt effects o n the aut onomi c nerv ous system. Hum an Pharma cology: Acute intraveno us administration of mexiletine in pat ients pro d uces little change in atri al refractoriness. sinus node automaticity or recovery time but in the sick sinus synd ro me severe brady card ia o r prolonged recovery tim e may become apparent . In patients with normal cond uct ion. sho nening of the A V and His-Purkinje refra ctonness may be seen; how ever . AV and His-P urkmje cond uctio n are both dela yed in patients with pre-existing disease, Th e effects of mexiletine on anomalous tracts in th e heart are not co nsistent bu t deserve fur ther study. Th e haemodynamic actions of intravenous mexiletine are comparable to those of lignocain e with min imal depressant effects in pat ients w ith normal or moderately impaired ventricular function, Pharma cnkm etics. The pharmacokineuc profile of mexiletine is chara cterised by high sys temic availab ility (88 % ) following o ra l ingestion . with peak levels being attained in 2 to 4 hour s; the plasma half-life in healthy voluntee rs is abou t 12 ho urs and app roximately 18 hours in patients with acute myocardial infarctio n in whom th e co ncomitant adm inist ratio n of narcot ic analg esics retard s gastric emptying, T he metaboli sm of mexiletine is not com pletely unde rstood but occurs lar gely in the liver, with only 10 % appearing unchanged in th e urine. Th e rena l clea rance of the dr ug is increased by urinary acidosis. About 70 % of seru m mexiletine is protein bo und. T herapeutic concentrations of mexilet ine (0 . 7S to 2.0 J,lgl m ll ar e us ually maintained by dail y oral doses of 600 to 1000 mg administered in divided dosa ge sched ules 8- to l Zvho urly. Therape utic Trials: Alth ough intravenousl y administered mexiterine is often effective in reverting ventr icular tach yarrhythrmas. the ma in therapeutic uti lity of th e dru g is in the chron ic oral proph ylaxis of ventricular arrh ythmias. especially in the survivors of acute
2
Meli til (Boehringer lngelheim).
Me~iletine:
A Review
163
myocardial infarction as indicated by a number of trials in which the efficacy of mexiletine proved comparable to that of procainamide. In one study the drug was found to be a more acceptable antiarrhythmic agent than procainarmde. producing somewhat better suppression of ventricular ectopic beats and complex ventricular arrhythmias. Trials designed to test the efficacy of mexiletine in reducing the incidence of sudden death in the survivors of acute infarction are awaited. Side Effects: In common with lignocaine. mexiletine has minimal negative inotropic propensity but following rapid intravenous injection. especially of large doses. bradycardia. hypotension and AV block may occur. Long term studies with mexneune have demonstrated excellent patient compliance. sustained efficacy and relative freedom from side effects. Only in a small number of patients had adverse effects been reponed: these are of central nervous system origin. including tremors. nystagmus. diplopia. dizziness. dysarthria, paraesthesia. ataxia and confusion. Gastrointestinal reactions have been uncommon and positive antinuclear factors and thrombocytopenia are rare. Do sage and AdminisrratiO/t : When therapeutic blood levels of mexiletine must be rapidly achieved and maintained. as in acute arrhythmias. a combination of a bolus intravenous injection of 150 to 250mg administered over 2 to 5 minutes. followed by a loading infusion of 250mg over 30 minutes. then 250mg over 2.5 hours and 500mg over 8 hours. has been used. A maintenance infusion of 500 to IOOOmg over 24 hours then follows. Such a regimen must be applied judiciously. especially in acutely ill and elderly patients. Alternatively. therapeutic plasma levels may be rapidly attained with an oral loading dose of 600mg. For prophylactic oral administration. 200 to 300mg 8-hourly produced a therapeutic plasma concentration (0.75 to 2"g/ mll in two-thirds of patients. Mexilitine may be used concomitantly with digoxin and g-acrencceotor blocking drugs. but not with other local anaesthetic type antiarrhythmic drugs Since the depressant erectrophysiological effects of the drug are more pronounced in patients with sick sinus syndrome. unstable AV block. and severe bradycardia. these conditions are contraindications to the use of the drug. The safety of the drug in advanced cardiac failure is not defined but merits study.
Until very recently there has been a st riking paucity in t he ava ilability of safe and potent antiarrhythmic compounds with the approp riate pharrnacokinetic characterist ics for the lo ng term oral prop hylaxis of life threatening vent ricular arrhythmias. Rapid advances in t he last 10 years in our knowledge of basic (Fozzard. 19 77 ; Arnsdorf, 1977 ; Ha uswirt h and Singh . 1979 ) and appl ied (Goldreyer. 197 3) cardiac electrophys iology and in the synthesis and characterisation of a plet hora of newer agents have con tributed greatly to the increasingly ratio nal basis for the control of card iac dysrhythmias in man (Singh. 19 78; Singh et af., 1979). Available antiarr hythmic drugs have been sho wn to produce thei r salutary effects essentially by altering the fast o r slow
depolarising membrane cur rents, by homogeneously reta rding repolarisation and by inhibiting ad rene rgic excitatio n in the heart. or by a combination of these processes (Singh and Vaughan Williams. 1971 , 1972 : Singh and Hauswi rth, 19 74; Hau swirt h and Singh , 197 9). Drugs which depress the fast response in the heart (class I agents) are also potent local anaesthet ics o n nerve. wh ile hav ing a wide spectrum of action on arrhythmias especially of ventricular o rigin. Mexiletine, toca inide . aprindine and disopyramide (fig. I) are am ong the newer class I agents wh ich have undergone experimental an d clinical eva luation (Ha rrison et al., 1977 ; Zipes and T roup , 19 78). From t he standpoint of long ter m pro phylaxis of vent ricu lar arrhythmias. mex iletin e and tocainide are of particular
164
Mexileline: A Rel/iew
interest because of their drug plasma half-lives following oral administration . In this review, the experimental and clinical data dealing with the action of mexiletine as an antiarrhythmic agent are discussed. It is of interest that mexiletine was initially developed as an anticonvulsant compound (Koppe, 1977) and its overall phar macological properties as an antiar rhythmic agent must, therefore, allow for simultaneous alterations in cardiac and neurological functions,
J. Pharm acological S tudies 1.1 Effectson the Central and Peripheral Nervous System Mexiletine has dose dependent anticonvulsant properties in both mice and rats, protecting the animals
from both electroshock and pentylenetrazole induced convulsions. The maximum protective effect of mexiletine under these experimental conditions was obtained within 15 minutes after oral and within I minute after intravenous administration . The effect disappeared 6 hours after oral, and was reduced to 20% 4 hours after intravenous, administration (unpublished data, Boehringer Ingelheim Ltd). In the cat model, the intraperitoneaJ application of mexiletine (!Omg /kg) prevented the episodic cramps induced by electrical stimulat ion of amygdaloid nucleus and the focal seizures induced by implanting aluminium hydroxide in the caudate nucleus. The accompanying EEG changes in these epileptic models were however unaffected by mexiletine (Danneberg and Shelley, 197 7). Mexiletine appears to exert a biphasic action on the central nervous system under these experimental con-
lidoc eine
Apli ndine
TOC8il'lide
Fig. I . Structu rel f ormulae of some recently introd UCed class t antie ntlythmic drugs.
M ll~illlt illll :
A Review
ditions. In th e lower dose range (I to 3mg / kg) intravenous mexiletine produced no EEG changes but prolonged the duration of after discharges following electric stimulation of both the hippocampus and amygdaloid regions. At higher doses (l Omg/kg IV ) there were signs of central nervous system depression with sho rtened duration of after discharges recorded at var ious cerebral sites. Althoug h th e exact mode of action of mexiletine's ant iconvul san t properties has yet to be defined, there is some recent evidence that it inh ibits the reuptake of the central nervous system inhibitory neurot ransm itter , gam ma am ino butyric acid (GA BA). Thus when rat cortex slices were incubated with tr itiated GA BA and th en perfused with Kreb's solution, electric stimulation of the brain slices pr oduced the release of tritiated GA BA. Wh en tr itiated GA BA slices were perfused with mexiletine (5 x 10- 4 M). GABA uptake was reduced by 16% compared to cont rols (Mitchell. 1969: quoted by Danneberg and Shel1ey, 1977). Mexiletine has no effect on the autonom ic nervous system and does not interfere with the function of biogenic arnines. It has neither antihistam inic activity nor alpha- or beta-adrenergic blocking propert ies.
1.2 Electrophysiological Actions The mode of antiarrhythmic action of mexiletine has been elucidated in a variety of in vitro and in vivo experimental models. as well as in man . The overall data, summarised below . are cons istent w ith the belief that the drug has cardiac effects very similar to those of lignocaine (Singh and Vau ghan Williams. 1972 ), depressing the fast response of the cardiac action potential in a manner characteristic of class I antiarrhythm ic agents (Singh and Vaughan Williams. 197 1). 1.2.1 Experimental St udies When tested in the frog sciatic nerve . mexiletme was found to be a stro ng local anaesthetic having a potency compar able to tha t of lignocaine (Singh and
165
Vaughan William s, 1972; Vaughan Williams, 1977). In isolated atrial or ventricular mu scle. as well as Purkinje fibres, the drug also exerts its majo r effects in a manner very sim ilar to that of lignocaine. For example. in concentrations between I and 5 ~g / m L mexiletine redu ces the maximal rate of depolansation of the action potential (fig. 2a, b), thus enhancing the thr eshold of excitabilit y. decreasing conduction velocity and prolon ging the effective refractory period while having little effect on the resting mem brane potential or on sinus node automaticity (Allen et al., 1972: Singh and Vaughan Williams, 1972; Vaughan Williams. 1977. Yamaguchi et al., 1979). Of parti cular interest has been the observation th at. as in the case of lignocaine. mexiletine produces a concentration dependent abbreviation of the action potential du ration (see fig. 2b) in Purk inje fibres, associated with modest shorte ning in the length of the effective refractory period (Yamaguchi et al., 1979). However , the abbreviation in the du ration of the action potent ial duration was always of a greater magnit ude than that in the effective refractory period . The precise significance of these somewhat disparate effects of mexiletine on repolari sation and effective refractory period rema ins unk nown; but in light of the reported finding of an exclusively depressant effect of lignocaine on all electroph ysiological parameters (El-Sherif et al., 1977: EI-Sherif and Lazzara, 1978), it will clear ly be of interest to exam ine the act ions of mexiletine on infarct lng myocardial fibres. Mexiletine has not been sho wn to have a significant effect on the calcium mediated slow respon se.
1.2.2 Electrophysiological Studies in Man The data from clinical observations with mexiletine are in general agreem ent with tho se from experim ental studies (Roe s et al., 1976 ; McComish et al ., 1977: Roos et al., 1977 ). However , marked differences in th e action of the dru g in patients with normal conduction compared 10 th ose with conduction distu rbances have emerged.
Me~iletine :
'"
A Review
---L-
1'\
1
Control
~ 2
Me~lIetlne
'"
lmg /l (4,62>< lO-IM)
3 3mg / l (1.39 >< 10- I M)
\j
f
~ (\/
V
A
r
--L
r ----L
r
» 5/minute. mu ltifoc:a.l or R on T type). ventricular tachycardia or recurrent ventricu lar fibrillation. 32 patients received the drug because of persistent ST elevation after myocardial infarct ion and the associated risk of ventricular fibrillation . A single 200 mg
injection given over 3 or 5 minutes was effective in only 8 of 18 patients (44 % ) in suppressing more than 50 % o f the ventricu lar ectopic counts compared to the control period. In 89 patients who received mexiletine by bolus injection (200mg) followed by infusion (J mg/mi nute for the first hour followed by 1.5mg/ min ute for J hours and finally Img / minute thereafter). the initial response was effective (i.e. > 50 % reduction in PVC counts) in 55 of 64 studies (86 % ) in which assessment was pos..s ible. Ventricular dysr hythmias wentricular fibrillation and ventricular tachycardia) recur red despite mexiletine in 26 (29 %) of the 89 patients treated in such a manner. Side effects att ributa ble to mexiletine were. however. common with this method of adm inistration . They were observed in 48 patients (5 4 %) and were severe in 39 (44 % ). These serious adverse effects (hypotension. bradycardia. widening of QRS comp lexes. toxic confusional states) were common when mextletme was given soon after the onset of myocardial infarct ion. occurring in 18 (64 % ) of 28 patients treated within 12 hours of the onset of infarct ion. and were often related to the initial 200mg bolus intravenous injection given over 5 minutes . However . severe side effects still occurred in nearly 2S % of patients even after steady-state concentra tion had been achieved. Mexiletine was particularly useful in lignocaine resistant dysrh yth mias. JS of the 191 patients had vent ricular dysrh ythm ias uncontr olled by lignocaine (i.e. either a plasma lignocaine concentration > 2 ~g/ m l or had doses in excess of a 100mg bolus and the sta ndard 2mg/ ml infusion). T hese dysr hythmi as responded well to mexiletine in 24 patients and 81 % of those with an assessable response benefited from the drug . Adverse haemodynam ic effects were observed in 3 patients who received both mexueune and lignocaine. Mexiletine was adm iniste red orally to 144 patients eithe r as a loading dose. transfer from intravenous therapy or as a maintenance dose without a loading dose. The usual loading dose was 300 or 400mg follo.....ed 2 hours later by 200 to 4oo mg. A further 200 to 400mg dose was given 6 hours later and
Mexiletine: A Review
172
thereafter mexiletine was admin istered at 6- or 8hour ly intervals. 137 patients were ultimately established on oral maintenance therapy Ii.e, treatment for longer than 24 hours). 57 patients received an oral loading dose and of the 20 patients whose response could be assessed, 18 (90 % ) had a satisfactory initial response Ii.e. 50 % or greater reduction in PVC counts). The incidence of severe side effects of patients maintained on oral therapy was related to the daily dosage. Thus , severe side effects were observed in 6
(35 % ) of the 17 patients receiving a daily dosage of 19 or more. As was noted in earlier reports, these authors found the margin between therapeutic and toxic plasma concentrations to be small. Thus, in their study the therapeutic plasma concentration of rnexiletine ranged between 0.75 and 2.001Jg/ ml. Above 2.001Jg /ml severe side effects occurred very frequently. There was a highly significant correlation between plasma concentration and the severity of side effects, particularly with oral therapy, indicating that
100 ECG AoP
\
(mm Hgl
I
,
,Nil
;
BO f-
..., "
a
,
.. I I ! ! ! i I i .
After mexiletine zOOmg N
ECG - - ' 100
,
't'11'I
II I I
, '
,
''
AoP I
Imm Hgl
BO
" .
4 seconds
I
I
a Fig . 3. Effec ts of intrave nously ad ministered mexiletine on ven mcu ter tachyca rdia in a patient with tscteemc heart disease.
The upper pane l shows phasic aonic press ure (AoPl and the ECG dem ons trating ventrkc jer tachycar dia (note atrioventricular dissociation and the consequent variation in the levels of a rte rial pres sure ). Mexiletine (zOOmg IV) restore s the rhythm to sinus lSlngh. unpublished observations).
173
M exileti ne: A Review
reduction in dosage might reduce the incidence of adverse effects. The overall data indicate that while intravenously administered mexiletine is often effective in reverting ventricular tachycardia to sinus rhythm (see fig. 3), this mode of therapy with the drug carries a greater incidence of side effects than comparable treatment with lignocaine. Thus, the drug is recommended largely for the oral therapy of ventricular arrhythmi as except for the occasional instances in which intravenous mexiletine may be used for recalcitrant dysrhythmias.
2.2 Long Term Oral Antiarrhythmic Therapy with Mexiletine Talbot et al. (J 976) studied the efficacy of long term oral mexileune in suppressing a variety of ventricular arrhythmias in a small uncontrolled series of 24 patients. The arrh ythmias consisted of ventricular tachycardia, ventricular fibrillation. R on T ventricular ectopic beats and multiform ventricular ectopic beats occurring in the setting of previous acute myocardial infarction, ischaemic heart disease with recurrent ventricular arrhythmias in the absence of recurrent infarction, or idiopathic arrhythmias in 6 patients. Mexiletine was administered at, a starting dose of 400 to 600mg followed 4 to 6 hours later by a maintenance dose of 150 to 350mg 8-hourly, administered for a total of 11.4 patient-years with individual periods of therapy ranging from I to 16 months. Outpatient assessment of the response consisted of a 12 lead electrocardiogram with a continuous 5 minute rhythm strip and, where arrhythmias were seen or suspected, a 24 hour ambulatory ECG was recorded. Table I presents the overall results. Mexiletine completely abolished arrhythmias in 19 of 24 patients (79 % ) and partially abolished arrhythmias (i.e. ventr icular ectopic beat rate reduced 75 96 with no ventricular tachycardia) in a further 4 patients. 8 patients experiencedtoxic symptoms but in only three were they severe enough to discontinue therapy.
Tab/e l . Result of Ofal mexiletine t herapy in 24 patients with ventric ular arrhythmias (aft er Talbot et et. 1916) Aetiology of arrhyth mias
No. of pat s,
Control of vent ricular arrhythm ias com plete ' disappearance
u
10
Ischaem ic heart disease
7
4
Idiopat hic
6
5
M yoc ardial inf arctio n
Tota l
24
19 (19%)
part ial f ai"re disappear _
.oc. 2
4 (11%)
1 (4 % )
Reduction of the dose was necessary in another 4 patients. No untoward haematological, biochemical or immunological effects were found. The range of plasma mexiletine associated with toxic symptoms ranged from 1.5 to 3.0.,.g/ ml (with a mean of 2~g /ml in each group) demonstrat ing the considerable overlap with therapeutic levels. 3 patients who either stopped or reduced their dose of mexiletine died suddenly 3 days to 3 weeks later. 6 other patients whose drug was stopped under electrocardiographic monitoring showed a reappearance of ventricular arrhythmias as their plasma mexiletine level fell. In a study by Jewitt et al . (J 976), mexiletine (200mg every 8 hours) was compared with sustained release procainamide (l.Sg every 8 hours), the ~ blocker tolamolol (I OOmg every 8 hours) and placebo in 20 patients with coronary artery disease who experienced more than 30 premature ventricular complexes per hour during a 24-hour period of ambulatory monitoring. Each medication was administered orally and in random order for successive z-week periods and each patient underwent two successive 24-hour ambulatory ECG recordings during the se-
Mexiletine : A Review
17'
cond week. Mexiletine reduced the frequency of pre- 0.37jJg/ml compared with 1.54 ± O. IBpg/ml matu re ventricular complexes by more than 75 % in which was associated with mild side effects. The difII of 20 patients, procainamide in 12 of 20 patients ference however was not statistically significant. and tolamo lol in 4 of 20 patients. 8 patients on procainamide had to reduce dosage because of side effects compared with only 2 patients receiving mexiletine 2.3 Oral Mexiletine in Prophylaxis of Ventricular Arrhythmias after Acute Myocardial In farction and 3 taking tolamolol. As an extension of the above study with 25 patients, the same authors Uewitt et al., In a prospective controlled randomised study from 1977) found essentially similar results with mexiletine as the most satisfactory agent for chronic use Edinbur gh (Campbell et al., 1975), oral mexiletine in patients with symptomatic ventricular ar- was compared to placebo and procainarnide in the rhyt hmias, being approximately as effective as pro- prevention of late ventr icular arrhythmias after acute cainamide in its antiarrhythmic actions but with myocardial infarction. The study population consisted of 60 male patients who had sustained a myocardial fewer side effects. Less satisfactory results were obtained by infarction within the preceding 48 hours and whose Campbell et al. ( 1978) with oral mexiletine therapy in arrhythmias (ventricular tachycard ia, ventricular ec48 patients with chronic ischaemic heart disease over topic beats tha t fell on the T wave or were multifocaf) a treatment period which varied from 2 days to more had all been controlled by standard doses of lignothan I year. 37 patients received mexiletine for ven- caine. 6 hours prior to the cessation of intravenous tricular ectopics, ventricular tachycardia or ventricu- lignocaine, the patients were randomised to each of 3 lar fibrillation, while II patients were treated because treatment groups and commenced on trial medicaof persistent ST segment elevation following myocar- tion . 20 patients were allocated at random to receive dial infarction on the grounds that there was an in- mexiletine given as a 400m g loading dose followed by creased risk of late ventricular dysrhythmias in this 250mg 8-hourly. 20 patients were allocated at ransubset of patients. 30 of the patients had received a dom to receive procainamide 500mg 4-hourly and the number of other antiarrhythmic agents which had final 20 patients were random ised to receive placebo. The 3 patient groups were comparable as regards age, proved ineffective or had produced side effects. A loading dose of mexiletine was admin istered peak C PK release and coronary risk factors. 24-hour either intravenousl y or orally to 29 patients who continuous electrocardiographic recordings were obreceived 800 to I IOOmg during the first 8 hours of tained on the fourth and tenth days. therapy. Thereafter , the most frequently used doses The results demonstrate that there was a high inciwere 200 , 250 and 300mg 8-hourly and therapy was dence of late complex arrhythmias on withdrawal of maintained for a median time of 3 months. While intravenou s therapy. Thus 13 of 17 patients (77 %) ventricular arrhythmias were not observed in more receiving placebo showed serious ventr icular dysthan 50% of the patients du ring therap y, severe side rhythmias as compared with 7 of 20 patients (35 %) effects (tremor, nystagmus , nausea, dyspepsia, brady- receiving procainamide and 6 of 19 0 2 % ) mexiletine cardia) occurred in 15 patients 0 I %). As in other treated patients (p < 0 .05 for the 2 drugs compared studies, there was considerable variation in the with placebo). The incidence of ventricular tachycarplasma levels which could be tolerated. Apart from dia and R on T ventricular ectopic beats was congastrointestinal irritat ion, adverse effects occurred in siderable [40 % or 7 of i7 patients in the placebo association with a mean trough concentration of group compared with 3 (15% ) of procainamide tre1.03 ± 0 .18 (SEM) pg/mt and a mean peak level ated patients and 2 ( 10 %) in the mexiletine treated of 1.77 ± O.17pg/ml; severe side effects occurred patients (p < 0.025)]. This study demonstrates that while both drugs were equally effective antia rat a higher mean peak concentration of 2.1 1 ±
Mexiletine: A Review
115
rhyt hmic agents, only a thi rd of the patients receiving this class of agents in curtailing the mortality from procainamide achieved acceptable therapeutic blood ischaemic heart disease (Wilhelmsson et al., 1974; level compared with 95 % of those receiving mex- Green 1975, 1977). iletine. While one patient receiving procainam ide developed a positive antin uclear factor, no toxicity to 3. Pharmacokinetic Studies oral mexiletine was noted. As an extension of the previous study, the prophylactic effect of oral mexiletine with in the first The development of a number of sensitive 48 hours of myocardial infarction was studied by methods to measure mexiletine in body fluids has perAchuff et al. (1977) in a double blind protocol with mitted various studies designed to elucidate its dis97 patients who had not received any prior treatment position in man. However, the data are still not comwith ant iarrhythmic therapy. Within 12 hours of the plete, especially in different disease states. onset of symptoms , patients were random ly assigned to treatment with mexiletine (600mg initially, 200mg at 2 and 4 hours then 250mg every 8 hours orally) or 3.1 Measurement of Plasma Mexiletine to treatment with placebo (53 patients). ElectrocarConcentrations diograms were recorded continuously for 48 hours and later analysed visually and by computer. VenConcentrat ions of mexiletine in biological material tricular fibrillation, ventricular tachycardia or R on T can be conveniently measured by gas liquid chromaevents occurred one or more times in the first 48 tograp hy (Kelly et al ., 1973; Kiddie et al., 1973). In hours in 42 patients out of 53 patients treated with the method of Kelly et al. ( 1973). mexiletine is explacebo and in 18 patients out of 44 patients (4 1%) tracted by organic solvents (diethyl ether) from samtreated with mexiletine. Multiple episodes of ar- ples made alkaline with 2N NaOH. To increase senrhythmias were observed in 34 placebo patients and sitivity and reproducibility, the extracted mexiletine is in 7 mexijenne patients. 2 patients in the placebo- converted to the acetyl derivative by acetic anhydride treated group had ventricular fibrillation. 3 patients which is then injected into a gas chromatograph using died while on mexiletine because of cardiac rupture or a nitrogen sensitive flame ionisation detector . A concardiogenic shock . venient internal standa rd is diphenhydramine . Using These overall data raise the hope that mexiletine this method , IOOng! ml mexiletine in plasma can be may well constitute a significant advance as an antiar - measured. Mexiletine in urine can be determined by a rhythmic agent for the chronic prophylaxis of ven- similar procedure except that ur ine samples are tricular arrhythmias. However, the available data do diluted to the concentration range 0 to 16).1g1ml. Using a linear electron capture detector. W illox not permit the conclusion that the drug will necessarily reduce the incidence of sudden death in patients and Singh ( 1976) were able to increase the sensitivity surv iving acute myocardial infarction , which is the of the gas liquid chrom atographic method to detect prime objective of antiarrhythmic therapy in this set- mexiletine in biological fluids. T he standard curve ting. Str ingently controlled clinical trials will be was linear to IO).lg/ ml and the limit of sensitivity of needed to resolve this possibility. Should the drug the method was for levels lower than l Ong! ml. prove efficacious in diminishing the incidence of sudden death in the survivors of acute myocardial infarc3.2 Absorption tion, its advantages and disadvantages as a therapeutic regimen in this regard will need to be compared to In a study of healthy male volunteers. Prescott et those of ~ -adrenoceptor blocking drugs since preliminary reports have indicated the effectiveness of al. ( 1977) found that mexiletine in solution or in cap-
Mexiletine: A Review
176
sules was virtually completely absorbed following oral admini st ration with peak plasma concent ration occurring within 2 to 4 hours. However. absorption was delayed and incomplete in patients with acute myocardial infarction. This was part icularly marked in patients who had received narcotic analgesics which are known to strongly inhibit gastric emptying in man (fig. 4). During long term oral therapy, therapeutic plasma concentrations (0.75 to 2 ~g / m l) can usually be maintained in adu lts with doses of 200 to 300mg every 6 to 8 hou rs (average daily doses 600 to IOOOmg). The mean steady-state plasma concentrations of mexiletine in 101 patients receiving the drug orall y for mor e than 48 hours were related directly to th e dose (Prescott et al., 1977). The level of, systemic availability of orally admin istered mexiletine is high, being 88 % compared with only about 30 % in the case of lignocaine (Prescott et al ., 1977).
3.3 Distribu tion After intravenous Injection, plasma mexiletine . concentrations fall rapidly as a result of extensive uptake and distribution in tissues (table ID; less than 1% of the total amount of the drug in the body is in the blood after distributi on . In the pharmacoklnetic study of plasma concentration data of health y volunteers and patients by Prescott et al. (J 977 ), the distr ibution kinetics of mexiletine were consistent with a 3-compart ment model: the first or rapid transit 'central' compart ment consists of blood volume and rap idly equilibrat ing highly perfused tissues such as myocardium, brain , liver , lung and kidney while the second and third compart ments represent tissue uptake by sk in, muscle and fat which take up the drug more slowly. The apparent volume of distribution is large, often exceeding 600L, reflecting extensive tissue uptake
400 mg
.. 0
He~lthy
subjects (5 )
0.'
06
e
400mg + 200rng at 2h Patients wit h MI + ne-cote (6)
0.4
~
1 .~
;
l
02 . 0
:.
