Br J Clin Pharmaco/1996; 41: 73-75

Effect of oxybutynin on the QTc interval in elderly patients with urinary incontinence

R. M. HUSSAIW, K. HARTIGAN-G02, S. H. L. THOMAS2 & G. A. FORDL2 Departments of 1 Medicine (Geriatrics) and 2Pharmacological Sciences, University of Newcastle upon Tyne, UK.

I Terodiline, an anticholinergic drug with calcium antagonist properties, is associated with QT prolongation and ventricular arrhythmias. It is not known if oxybutynin, a drug with a similar pharmacological profile, causes QT prolongation. ECGs were obtained before and at least 4 weeks after commencement of oxybutynin (mean daily dose 7.6, range 2.5-10 mg), in 21 elderly (mean age 75, range 58-88 years) patients treated for urinary incontinence. Heart rate, (mean±s.d.) 74± 11 vs 69± 11 beats min- 1, -6 (-13,2), before vs during oxybutynin therapy, mean difference (95% confidence intervals); PR interval, 168±27 vs 156±27 ms, -11 (-26,3); QTc 454±27 vs 447±31 ms 112, -9 (-23,5), and QTc dispersion, QTc max-QTc min, 68±24 vs 63±26 ms 112, -1 (-15,14) were all unaltered by oxybutynin therapy. The lack of an effect on resting heart rate suggests that oxybutynin has little anticholinergic action at cardiac M2 receptors at usually administered doses. Oxybutynin therapy is not associated with QTc interval prolongation and is unlikely to produce ventricular arrhythmias.

Keywords QT interval oxybutynin agemg

Introduction prevalence of cardiovascular disease and are therefore at particular risk of cardiovascular adverse drug reac­ Urinary incontinence is a common disability in the tions. Cholinergic receptors in bladder smooth muscle elderly. Anticholinergic drug therapy to treat detrusor are predominantly M3 subtype, whereas the M2 subtype instability is often prescribed, although efficacy is modest predominates in the heart [8,9]. Drugs with significant [I]. Terodiline, a racemic drug with anticholinergic and anticholinergic effects on bladder smooth muscle M3 calcium channel blocker effects. apparently properties receptors might have little effect at cardiac M2 receptors. of the R + and S- enantiomers respectively, is associ­ Oxybutynin demonstrates some selectivity for the M1 ated with QT interval prolongation and ventricular and M3 receptors compared with M2 and also has weak arrhythmias. including torsade de pointes [ 1,2]. In affinity to (3H)-nitrendipine binding calcium channel asymptomatic patients terodiline therapy produces some sites [ 10,11]. We were unable to find any published degree of dose-related QTc prolongation [3,4]. data on the effects of oxybutynin on QT interval or Prolongation of the QT interval by disease or drugs is electrocardiogram. One case report of poisoning with associated with an increased risk of ventricular arrhyth­ 100 mg oxybutynin describes the occurrence of a sinus mias, syncope and sudden death [5,6]. In view of these tachycardia, ventricular ectopics and bigeminy in a findings increasing attention is being paid to the effects healthy 34-year-old woman [ 12]. The QT interval is of both cardiac and non-cardiac drugs on QT interval. not recorded in this case, but this report suggests that It is unclear which enantiomer is responsible for the QT oxybutynin may have adverse cardiac effects in addition prolongating effects of terodiline and whether this action to anticholinergic effects, at high dosage. In the present is due to effects at M2, H1• H2 receptors or potassium study we sought to determine whether oxybutynin has or calcium channels. significant effects on the electrocardiogram. and Oxybutynin. an anticholinergic drug. with a similar additionally to provide insight into whether the QT Pharmacological profile to terodiline is increasingly prolonging effects of terodiline might be related to its being used to treat detrusor instability [7]. Many anticholinergic effects. Heterogeneity or dispersion of Patients receiving oxybutynin arc elderly, with a high the duration of ventricular rcpolarization has also been

Correspondence: Dr Ci. A. Ford. Wolfson Unit of Clinical Pharmawlogy, The University. Claremont Place. Newcastle upon­ Tyne. NE:! 4HH. UK.

~ 1996 Blackwell Science Ltd 73 74 Short report suggested to be a factor that may be important in the standard deviation of repeated measurements to be 10 genesis of arrhythmias separate from the effects of QTc ms 112 (unpublished observations). Using these data a interval prolongation [13,14] so QT dispersion across power calculation indicated that studying 20 subjects, the standard 12 lead ECG was also determined. would enable a change in QTc of 9 ms 1' 2 to be detected from a baseline QTc of 400 ms 1' 2 (tx=0.05, ~=0.8). 95% confidence intervals were calculated for the differences before and during oxybutynin therapy. Methods

Subjects Results Twenty-one patients (nine female; median age 77, range 58-88 years) with urinary incontinence clinically con­ The patients had a high prevalence of cardiovascular sidered caused to be due to detrusor instability who and cerebrovascular disease including ischaemic heart were receiving or about to receive oxybutynin, were disease ( 4 ), heart failure ( 3 ), hypertension ( 3) and studied from Urology out-patient clinics, care of the cerebrovascular disease (7). Concurrent drug treatment elderly wards and day hospital. Data from patients with was as follows: loop diuretics (5), ~-adrenoceptor­ atrial fibrillation, recent myocardial infarction or bundle blockers (2), amiodarone, thioridazine, dothiepin and branch block were excluded because of the effects of quinine ( 1 each). None of these drugs or their doses was these on QT interval and dispersion. Data from patients altered between acquisition of the two ECGs. The taking other drugs known to prolong QT interval were median daily dose of oxybutynin prescribed was 7.5 included, provided that the dose of any such drug was (range 2.5-10) mg. Median duration of therapy was 38 not changed between acquisition of the two ECGs. A (25-400) days. Plasma electrolytes, calcium and albumin medical, drug history and the results of haematology measured during oxybutynin therapy were within the and electrolytes were obtained. normal range in all patients. No adverse cardiac events were observed in any subject during the period of oxybutynin treatment. There were no changes in heart Electrocardiogram analysis rate, PR interval, QTc interval (Figure 1a) or QT dispersion (Figure 1b) following oxybutynin therapy. Twelve lead electrocardiographs at 25 or 50 mm s -t Mean values off and on oxybutynin therapy, the mean were obtained at least 4 weeks after the start of differences and their 95% confidence intervals were: oxybutynin therapy and either before commencement heart rate 74±11 vs 69±11 beats min-I, -6 (-13,2); or at least 7 days following discontinuation of drug, the PR interval 168 ± 27 vs 156 ± 27 ms, -11 (- 26,3 ); QT latter usually occurring because of failure to respond to interval408± 25 vs 417 ±25 ms, 9 ( -4,22); QTc 454± 27 oxybutynin treatment. ECGs performed on oxybutynin vs 445 ± 29 ms, -9 (-23,5 ); QTc dispersion 63 ± 24 vs were obtained 2 h after drug dosing; the half-life of 63 ± 26 ms112, -1 (-15,14 ). oxybutynin being 7 h. ECGs were analysed blind by an independent observer (KHG) with measurement of RR interval, PR interval and QT interval. The end of the T wave was defined as the point where the T wave Discussion returned to the TP baseline. Where the T wave was interrupted by a U wave before a return to the baseline, QT prolongation has been noted with several drugs the QT interval was measured to the nadir between the which have anticholinergic effects, including terodiline, T and the U waves. Whenever possible, three representa­ quinidine, disopyramide and tricyclic antidepressants tive complexes were analysed for each lead of the [ 16]. This raises the possibility that delayed ventricular standard 12 lead ECG. Leads where the end of the T repolarization might be related to cholinergic antagon­ wave could not be discerned, were excluded from the ism, although this seems unlikely. Atropine shortens analysis. Corrected QT interval (QTc) was calculated measured QT interval but because of its effect on heart for each lead using Bazett's formula; QTc = QTI J( RR rate, QTc is increased when calculated using Bazett's interval) [15]. The mean of QTc in all leads was taken formula [ 17]. However, if heart rate is held constant to be the QTc interval. QT dispersion (QTd) was by atrial pacing, atropine shortens the QT and QTc determined as the longest minus the shortest QTc on interval, suggesting that cholinergic rather than antichol· the 12 lead ECG. inergic influences might delay ventricular repolarization and QT interval. Ancillary properties of anticholinergic drugs are probably more important in producing the Analysis QTc prolongation associated with some of these drugs. Most drug-induced QTc prolongation appears to be Results are given as mean± s.d. A previous study by associated with antagonism of potassium dependent this group of terodiline effects on QTc interval had ventricular repolarization [ 16]. Nevertheless, as a large demonstrated in 13 patients an increase of 48 ( 23 to 74) number of anticholinergic drugs produce QTc pro· ms 112; mean and 95% confidence intervals. We have longation it seems prudent to examine the effects of previously determined between day reproducability of other anticholinergic drugs on the QT interval, especiallY QTc interval in 18 healthy volunteers and observed the those which are used in high risk populations.

:0 1996 Blackwell Science Ltd British Journal of Clinical Pharmacology 41, 13-15 Short report 75

a that serious ventricular arrhythmias, such as those 550 associated with terodiline, will be provoked by oxybutynin therapy. s; E References co c: 450 Connolly MJ, Astrige PS, White EG, Morley CA, Cowan ....Q) c: JC. Torsade de pointes ventricular tachycardia and terodi­ line. Lancet 1991; 338: 344-345. ~ 0 1 2 McCloud AA, Thorogood S, Barnett S. Torsade de pointes complicating treatment with terodiline. Br Med J 1991; 302:1469. 3 Stewart DA, Taylor J, Gosh S, McPhee GJS, Abdullah JM. McLenachan JM. Stott OJ. Terodiline causes poly­ morphic ventricular tachycardia due to reduced heart rate and prolongation of QT interval. Eur J Clin Pharmacal b 1992; 42: 577-580. 4 Thomas SHL, Higham PD. Hartigan-Go K, Kamali F, Wood P, Campbell RWF, Ford GA. Concentration­ dependent cardiotoxicity of terodiline in patients treated ,..... for urinary incontinence. Br Heart J 1995; 74: 53-56. ·cn 5 Schwartz PJ, WolfS. QT interval prolongation as predictor E of sudden death in patients with myocardial infarction. c: 0 Circulation 1987; 57: 1074-1077. ·;n... 6 Laasko M, Aberg ASA, Savoia J, Pentikalinen PJ, Pyorala Q) 0. K. Diseases and drugs causing prolongation of the QT -~ "0 50 interval. Am J Cardia/ 1987; 59: 862-865. 1- 0 7 Hussain RM, Campbell M, Ford GA. Prescribing for urinary incontinence in the Northern Region and effect of f terodiline withdrawal. Age Ageing 1995; 24: P25. 8 Hoover DB, Baisden RH, Xi-Moy SX. Localization of 0 muscariniic receptor mRNAs in rat heart and intrinsic Off On cardiac ganglia by in situ hybridization. Circ Res 1994: Figure I Effects of oxybutynin therapy on a) QTc interval 75; 813-820. 9 Kondo S, Morita T. A study of muscarinic cholinergic (ms 112 ) and b) QT dispersion (ms 112 ) in 21 elderly patients receiving therapy. Data are after at least 4 weeks after receptor subtypes in human detrusor muscle using radioli­ commencement of therapy and either berfore or following gand binding techniques. Jap J Ural 1993: 84: 1255-1261. discontinuation of oxybutynin therapy. No significant 10 Noronha-Blob L, Kachur JF. Enantioners of oxybutynin: changes in QTc or QTd were observed. In vitro pharmacological characterization at M I> M2 and M3 muscarinic receptors and in vivo effects on urinary bladder contraction, mydriasis and salivary secretion in This study demonstrates that oxybutynin therapy guinea pigs. J Pharmacal Exp Ther 1991; 256: 562-567. does not produce prolongation of QTc or increased QT 11 Abbiati GA, Ceserani R, Nardi D, Pietra C, Testa R. dispersion in usual doses prescribed for urinary inconti­ Receptor binding studies of the flavone, REC 15/2053, and nence even in patients with a high prevalence of other bladder spasmolytics. Pharm Res 1988; 5: 430-433. 12 Bannerjee S, Routledge PA, Pugh S, Smith PM. Poisoning cardiovascular disease. The confidence intervals for the with oxybutynin. Hum Exp Toxical 1991; 10: 225-226. change in QTc interval on oxybutynin therapy indicate 13 Day CP, McComb JM, Campbell RWF. QT dispersion: 112 that an increase in QTc of greater than 5 ms has been an indication of arrhythmia risk in patients with long QT excluded. The dose of oxybutynin being taken by the intervals. Br Heart J 1990; 63: 342-344. elderly patients in this study was at the lower range of 14 Barr CS, Nass A. Freeman N. Lang CC, Struthers AD. the dose for adults, although probably typical of the QT dispersion and sudden unexplained death in chronic usual doses received by the elderly. It is possible that heart failure. Lancet 1994; 343: 237-239. an increase in QTc interval would be seen with higher 15 Bazett HC. An analysis of the time relations of electrocar­ doses of oxybutynin. No change in heart rate was seen diograms. Heart 1920; 7: 353-370. With oxybutynin suggesting that significant cardiac 16 Thomas SHL. Drugs. QT interval abnormalities and anticholinergic effects do not occur with doses of ventricular arrhythmias. Adtwse Drug React Toxicol Rer oxybutynin used to treat detrusor instability in elderly 1994; 13: 77- I02. 17 Browne K F. Zipes DP. Heger JJ. Prystowsky EN. Influence Patients. This could reflect a relative selectivity of of the autonomic nervous system on the Q-T interval in oxybutynin for bladder smooth muscle M3 receptors. Man. Am J Cardiol 1982; 50: 1099-1103. Alternatively resting heart rate may not have been a Very accurate indicator of vagal tone in this series of (Recl'irecl 30 March 1995. Patients. These findings arc reassuring as the drug is acceptec/4 Septemha 1995) being used increasingly to treat urinary incontinence since the withdrawal of terodiline. It is therefore unlikely