Concentration Dependent Cardiotoxicity of Terodiline in Patients Treated for Urinary Incontinence
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Br HeartJ7 1995;74:53-56 53 Concentration dependent cardiotoxicity of terodiline in patients treated for urinary incontinence Simon H L Thomas, P Daniel Higham, Kenneth Hartigan-Go, Farhad Kamali, Peter Wood, Ronald W F Campbell, Gary A Ford Abstract Terodiline hydrochloride is an antimuscarinic Objective-Terodiline, an antimuscarinic drug with calcium antagonist properties' and calcium antagonist drug, was used to which was used for treating urinary inconti- treat detrusor instability but was with- nence caused by detrusor instability.2 The drawn in 1991 after provoking serious drug was withdrawn in 1991 after reports of ventricular arrhythmias associated with cardiac dysrhythmia including bradycardia, increases in the corrected QT interval heart block, ventricular fibrillation, and ven- (QTc). This research was performed to tricular tachycardia, usually of the torsade de relate drug induced electrocardiographic pointes-type34 and associated with QT pro- changes in asymptomatic recipients to longation. Plasma terodiline concentrations plasma concentrations of the R( +) and were very high in one affected patient. S(-) terodiline enantiomers. Predisposing factors for terodiline associated Setting-Urological and geriatric clinics torsade de pointes were old age, coexisting and wards. ischaemic heart disease, co-prescription of Subjects-Asymptomatic patients taking other cardioactive drugs, and hypokalaemia. terodiline in stable dose. Torsade de pointes is associated with Methods-Electrocardiograms (50 mm/s) abnormal prolongation of the ventricular were collected from patients while they refractory period which results in a long QT were taking terodiline and compared with interval on the electrocardiogram and is often ECGs obtained before or after terodiline. drug induced.5 Increased dispersion of ven- QT interval, heart rate corrected QT tricular recovery may be important in the interval (QTc), and QT dispersion (QTd) development of this arrhythmia and indirect were measured. Drug induced electro- evidence indicates that this is reflected by cardiographic changes were related to increased dispersion of QT interval durations plasma concentrations of R(+) and S(-) across the standard 12 lead electrocardio- terodiline. gram.67 The relation between torsade de Results-During terodiline treatment pointes and plasma drug concentrations is mean QTc and QTd were prolonged uncertain: while torsade may result from over- (491(43) and 84 (35) ms1l2) compared with dose of several drugs,5 many patients develop- measurements made offtherapy (443 (33) ing drug induced torsade do not have and 42 (17) ms'12, paired t tests, P < 0-002 excessive plasma drug concentrations and and P < 0 01 respectively) in the 12 some consider the arrhythmia to be an idio- patients in sinus rhythm. The mean (95% synchratic phenomenon.8 confidence interval) drug induced The effects of terodiline were therefore increases were 48 (23 to 74) Ms112 for QTc investigated by collecting electrocardiograms Wolfson Dept of Clinical and 42 (13 to 70) ms'12 for QTd. These from asymptomatic patients receiving the Pharmacology, increases correlated with total plasma drug for treatment of urinary incontinence, University of terodiline (QTc: r = 0-77, P < 0-006, comparing them with those taken before or Newcastle, Newcastle QTd: r = P < and with after and the terodi- upon Tyne 0*68, 0.025) drug treatment, relating S H L Thomas plasma concentrations of both terodiline line induced electrocardiographic changes K Hartigan-Go enantiomers. with plasma concentrations of each terodiline F Kamali Conclusions-Terodiline increases enantiomer. P Wood QTc G A Ford and QTd in a concentration dependent Academic manner. It is not clear whether this is a Department of stereoselective effect and, if so, which Patients and methods Cardiology, enantiomer is responsible. The results Electrocardiograms (50 mm/s) and plasma University of Newcastle, Newcastle suggest that drug induced torsade de samples were collected from patients who were upon Tyne pointes is a type A (concentration depen- taking terodiline in stable dose between 4 and P D Higham dent) adverse drug reaction. 24 h after the last dose. This process started R W F Campbell in June 1991, when reports of dysrhythmia Correspondence to: first appeared, and ended in September 1991 Dr S H L Thomas, Wolfson (Br HeartJ7 1995;74:53-56) Department of Clinical when the drug was withdrawn. Copies of elec- Pharmacology, Claremont Place, Newcastle NE1 7RU. trocardiograms predating terodiline treatment Accepted for publication Keywords: terodiline; cardiotoxicity; electrocardio- were also collected, when available, and, if 11 January 1995 graphy possible, electrocardiography was repeated at 54 Thomas, Higham, Hartigan-Go, Kamali, Wood, Campbell, Ford Table 1 Characteristics ofpatients in sinus rhythm FO ioo0 100- / taking terodiline 0 C 50 * . 50 * Mean (range) 0 Age (years) 73 (46-92) C'0 Height (cm) 161 (150-193) R= 0.78, P < 0.005 R 0.76, P<0.008 Weight (kg) 61 (44-90) u -50 - -50- Daily dose (mg)* 38 (12-5-50) 0 100 200 300 400 500 0 100 200 300 400 500 Duration of treatment (days) 231 (8-1050) 150 150 Sodium (mmol/l) 139 (136-142) 100 100- Potassium (mmol/l) 4-1 (3 4-4 8) .C Creatinine (umol/l) 110 (89-116) D 50 . *. 50 0 Ionised calcium (mmol/l) 1-30 (1-25-1-32) Magnesium (mmolIl) 0-8 (0 7-0 9) CO0 01 Albumin (g/l) 41 (37-46) -5 00. R 0-69, P < 002 R 0.67, P < 0.03 0 100 200 300 400 500 0 100 200 300 400 500 Values are mean (range). *Median daily dose was 25 mg. R(+)-terodiline (ng/ml) S(-)-terodiline (ng/ml) Figure 2 Relation between plasma concentrations of terodiline enantiomers and the extent ofdrug induced least 2 months after terodiline had been dis- prolongation in corrected QT intervals (QTc) and QT continued. Each patient's medical details dispersion (QTd). were recorded and the blood sample analysed for plasma drug concentrations, electrolytes, and creatinine. Electrocardiograms were analysed blind by patients with atrial fibrillation were not used an independent observer. RR, PR, and QT as this condition has major effects on QTd. intervals were measured using a digitiser For the 15 patients in sinus rhythm (table 1) (Calcomp 9000, Scottsdale, AZ, USA). The electrocardiograms were available before QT interval was measured from onset of the terodiline was started in two patients and after QRS complex to the end of the T wave, terodiline had been stopped in 11, although defined as a return to the TP baseline. In the one of these had developed atrial fibrillation. presence of U waves, the end of the T wave Electrocardiograms in sinus rhythm were was taken at the TU nadir. Three representa- therefore available during and before or after tive complexes were analysed for those leads treatment in 12 patients, of whom 11 agreed of the standard 12 lead electrocardiogram to give a blood sample. Of these, one had where the T wave could be clearly defined right bundle branch block and four were taking and a mean taken. When the end of the T other drugs which might affect QT interval wave could not be reliably identified the lead (dothiepin, imipramine, thioridazine, sotalol), was excluded from analysis. The largest QT the doses of which were not altered during the interval on the 12 lead electrocardiogram study, and five had cardiovascular disease (QTmax) was used to derive the corrected (cerebrovascular disease (three), coronary QT interval (QTc), which was calculated for artery disease (one), and hypertension (one)). each lead using Bazett's formula (QTc = QT/ Electrocardiograms of two patients receiving V (RR interval)). QT dispersion (QTd) was terodiline were collected after only 8 and 16 determined as the longest minus the shortest days of treatment, possibly before steady state QTc on the 12 lead electrocardiogram. concentrations and the maximal electrocar- Plasma concentrations of R( + )- and diographic effects of the drug would be S(-)- terodiline enantiomers were measured achieved. simultaneously by high performance liquid A total of 17 patients gave a blood sample. chromatography using a chiral column and an Plasma concentrations of the two terodiline ultraviolet detector. The limit of detection of enantiomers correlated closely (r = 0 99, the method is 25 ng/ml for each enantiomer P < 0 0001) with a mean (SD) R(+)-/S(-)- 600_ p < 0.002 and coefficients of variation are 5-5% for the ratio of 1 03 (0 14). No significant correla- ^550 S R(+)-enantiomer at 271 ng/ml and 7-6% for tions were observed between daily terodiline Ch dose and the plasma concentration of either 500 - the S(-)-enantiomer at 173 ng/ml. All { samples were analysed in duplicate and with- terodiline enantiomer. Apparent terodiline Q450 I 7 measured as dose divided C) 400 out knowledge of the electrocardiographic clearance, daily by - changes observed in each patient. plasma concentration, varied widely between 350 ' patients and did not correlate significantly P < 0.01 with age in this small group (data not shown). 150 Results Terodiline did not affect the PR interval or Nineteen patients taking terodiline took part heart rate but prolonged QTc and QTd 100 in this study. The electrocardiograms of four (fig 1, table 2) compared with measurements 50 0 On Off Table 2 Electrocardiographic effect of terodiline in 12 patients in sinus rhythmn Figure 1 Corrected QT Heart rate PR interval QTmax QTc QTd intervals (QTc) and QT (beatslmin) (ms) (ms) (msll2) (ms) dispersion (QTd) in 12 patients in sinus rhythm on Patients not receiving treatment 73 (16) 166 (22) 405 (49) 443 (33) 42 (17) Patients receiving treatment 72 (14) 178 (26) 456 (64) 491 (43) 84 (35) and offterodiline, together Mean difference -2 12 51 48 42 with means (SD). Four (95% CI) (-10 to 7) (-3 to 26) (17 to 85) (23 to 74) (13 to 70) patients taking other drugs Paired t test NS NS P < 0 01 P < 0-002 P < 0 01 that prolong QTc are shown as crosses.