Positive inotropic drugs and drugs used in dysrhythmias

John R. Charpie and Joshua M. Friedland-Little

17 Positive inotropic drugs and drugs used in dysrhythmias CARDIAC GLYCOSIDES [SED-15, 648; SEDA-32, 333; SEDA-33, 377; SEDA-34, 287] Observational studies In elderly Spanish patients (mean age 82 years, 84% women) studied during January to September 2008, digitalis intoxication was confirmed in 42 cases by plasma digoxin concentration measurement [1C]. The most prevalent comorbidities were cardiac valvulopathy (81%), hypertension (68%), and ischemic cardiomyopathy (46%); 95% had a background of cardiac insufficiency and 53% were in NYHA functional grade III. The mean serum digoxin concentration was 2.7 ng/ml, 23% of the patients had a creatinine clearance below 60 ml/minute/1.73m2, and 2.6% had a markedly reduced glomerular filtration rate (below 30 ml/minute/ 1.73m2). There was a weak negative correlation between digoxin concentration and clearance and between digoxin concentration and heart rate. In all, 48% had bradycardias and 88% dysrhythmias, most often atrial fibrillation. The most common symptoms were nausea (55%), fatigue (44%), vomiting (33%), and anorexia (29%). The authors concluded that digestive symptoms in elderly women who are taking digitalis, with bradycardia and impaired renal functioning, should raise the suspicion of digitalis intoxication. Side Effects of Drugs, Annual 35 J.K. Aronson (Editor) ISSN: 0378-6080 http://dx.doi.org/10.1016/B978-0-444-62635-6.00017-6 # 2014 Elsevier B.V. All rights reserved.

In a retrospective study of 40 patients with familial dilated cardiomyopathy and 80 patients with idiopathic cardiomyopathy in South Africa, of whom 20–25% had atrial fibrillation, the use of digoxin without serum concentration monitoring was a significant predictor of mortality in the latter (OR ¼ 1.62; 95% CI ¼ 1.04, 3.98) [2c]. However, the author of a subsequent editorial highlighted the fact that neither digoxin concentrations nor plasma potassium concentrations had been reported in the first article, and that the potassium concentration modifies the concentrations at which digoxin becomes toxic [3r]. He concluded that digoxin should be relegated to an optional extra in the management of heart failure, given in lower doses than previously described (0.125 mg/day), with the aim of achieving symptomatic rather than mortality benefit, and concluded that there is no clear place for digoxin in the therapy of heart failure and atrial fibrillation. Cardiovascular Ventricular dysrhythmias, including ventricular fibrillation, have again been attributed to digoxin toxicity [4A]. • A 79-year-old woman on hemodialysis developed a bidirectional ventricular tachycardia followed by ventricular fibrillation after taking digoxin for 4 weeks for atrial fibrillation. The serum digoxin concentration was 2.4 ng/ml, just above the usual target range. The serum potassium concentration was low at 2.7 mmol/l but the serum magnesium was in the reference range.

Tumorigenicity Digoxin resembles estrogen chemically and might have an estrogen-like effect and cause an increased incidence of breast cancer [5C]. Women using digoxin 327

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were identified in the nationwide Danish Prescription Database, between 1995 and 2008, and incident breast cancers were identified in the Danish Cancer Registry. Of 104 648 digoxin users, 2144 developed breast cancer. Current digoxin users were at increased risk of breast cancer (RR ¼ 1.39; 95% CI ¼ 1.32, 1.46), but the risk was not increased in former users. The higher risk of developing estrogen receptor-positive breast cancers supports an estrogen-mimicking mechanism. However, these results are at variance with previous findings. Digitalis increases serum concentrations of follicle-stimulating hormone (FSH) and estrogen and reduces concentrations of luteinizing hormone (LH) and testosterone [6–9C]. These effects are probably not related to any direct estrogenlike structure of digitalis (despite structural similarities), but rather to an effect involving the synthesis or release of sex hormones. There are three possible clinical outcomes of these effects: gynecomastia in men and breast enlargement in women [10C,11C]; stratification of the vaginal squamous epithelium in postmenopausal women [12C]; and a possible modifying effect on breast cancer. Digitalis can reportedly reduce the heterogeneity of breast cancer cell populations and reduce the rate of distant metastases, and when breast tumors occurred in women with congestive heart failure taking cardiac glycosides, tumor size was significantly smaller and the tumor cells more homogeneous [13C]. There is also evidence that the 5-year recurrence rate after mastectomy is lower in women who have been treated with digitalis [14c]. It was originally thought that this action was due to an estrogen-like effect of cardiac glycosides, but it may be because inhibition of the Na/K pump is involved in inhibiting proliferation and inducing apoptosis in various cell lines [15–18E]. Cardiac glycosides have different potencies in their effects on cell lines such as those of ovarian carcinoma and breast carcinoma (order of potency: proscillaridin A > digitoxin > digoxin > ouabain > lanatoside C) [19E]. Susceptibility factors Genetic Polymorphisms of the multidrug resistance gene

John R. Charpie and Joshua M. Friedland-Little

coding for P glycoprotein (ABCB1/MDR1) have been linked to changes in the processing of several commonly used medications. The effects of three ABCB1 single nucleotide polymorphisms on digoxin concentration have been examined in 112 dead Finnish subjects through RT-PCR genotyping of post-mortem blood samples (compared with a random sample of 143 Finns) [20c]. Mutant genotype frequencies showed a positive relation to post-mortem digoxin concentrations for all SNPs, particularly among female subjects. Age The narrow therapeutic index of digoxin and pharmacokinetic changes associated with aging increase the risk of toxicity [21R]. Potassium depletion In a case-control comparison of serum potassium concentrations between patients with chronic digoxin toxicity resulting in death over 7 years and survivors over 1 year; there were 13 fatalities and 13 survivors [22r,23c]. There were no statistically significant differences between cases and controls with respect to serum digoxin concentration, creatinine, age, or sex. Serum potassium was significantly associated with death both in mean difference and using a dichotomous cutoff of 5.0 mmol/l. In 86% of deaths, despite appropriate use of digoxin-specific antibody Fab fragments, the presentation included the combination of bradycardia and hyperkalemia. Calcium Hyperkalemia is common in patients with digoxin toxicity,. Although hyperkalemia is often treated with intravenous calcium, calcium is traditionally contraindicated in digoxin toxicity. In a retrospective review of the charts of all adults with digoxin toxicity over 17.5 years, the primary outcome measures were frequency of life-threatening dysrhythmias within 1 hour of calcium administration and mortality rate in patients who did or did not receive intravenous calcium. In 23 patients with digoxin toxicity who received calcium, no life-threatening dysrhythmias occurred within 1 hour of administration and mortality was similar among those who did not receive calcium (27/136, 20%) compared

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with those who did (5/23, 22%) [24C]. In a multivariate analysis, calcium was nonsignificantly associated with a reduced chance of death (OR ¼ 0.76; 95% CI ¼ 0.24, 2.5). Each 1 mmol/l rise in serum potassium concentration was associated with an increase mortality (OR ¼ 1.5; 95% CI ¼ 1.0, 2.3). Renal disease Renal function (for example, eGFR) needs to be assessed to prevent digoxin toxicity, and renal failure increases susceptibility to digoxin toxicity [25c,26A]. In a 5-year, retrospective analysis of 222 patients with serum digoxin concentrations over 3.0 nmol/l (2.3 ng/ml), statistically significant predictors of mortality included low creatinine clearance but not serum creatinine [27C]. The positive predictive value of lower creatinine clearance on mortality can be explained by digoxin pharmacokinetics— 70% of digoxin is eliminated unchanged by active kidney processes in those with normal renal function. No other patient characteristics or drug–drug interactions was significantly associated with mortality. The main limitations of this study were its retrospective character and the absence of a control group. Heart failure In a retrospective database review of patients with heart failure in whom digoxin therapy was associated with improved or worsened clinical outcomes, the Digitalis Investigation Group database was queried [28C]. The outcomes were allcause mortality and admissions for heart failure. An increase in mortality and admission for heart failure was associated with female sex, hypertension, a higher ejection fraction, and a higher systolic blood pressure. Thus, digoxin may need to be avoided in patients with this profile. Drug–drug interactions Macrolide antibiotics Another case of an interaction of digoxin with clarithromycin has been reported [29AR]. • An 83 year-old man with a history of hypertension, dyslipidemia, myocardial infarction, LV dysfunction, and COPD developed fatigue, dyspnea on exertion, cough, nausea, loss of appetite, and lightheadedness after taking oral clarithromycin 500 mg bd for 3 days for

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possible pneumonia. His cardiac medications included digoxin 0.125 mg/day. He had raised urea, creatinine, and digoxin concentrations.

This presentation was consistent with digoxin toxicity in the context of dehydration, recent renal dysfunction, and concomitant use of clarithromycin, which inhibits P glycoprotein-mediated efflux of digoxin. Sennoside In a population-based nested case-control study using the Taiwan National Health Insurance Research Database 524 subjects with digoxin toxicity were matched to 2502 randomly selected controls from a population of 222 527 patients with heart failure [30C]. Use of sennosides during the 14 days before hospitalization was associated with a 1.61 times increased risk of digoxin toxicity (95% CI ¼ 1.15, 2.25). Management of adverse drug reactions Standard treatment of digoxin toxicity involves the use of digoxin-specific Fab fragment antibodies. A recent report has emphasized the importance of managing symptoms, including electrolyte imbalances, dysrhythmias, and conduction abnormalities, if the antibodies are unavailable, despite severe toxicity [31A]. • A 45 year-old woman who took 100 tablets of digoxin 0.25 mg. In spite of rapid gastric lavage and activated charcoal, the digoxin concentration was 12 ng/ml. She had severe nausea and vomiting, serious dysrhythmias, and conduction disturbances, which required temporary endocardial pacing. Antidigitalis antibodies were not available, but symptomatic treatment (correction of electrolyte disturbances and heart rate control) were effective.

OTHER POSITIVE INOTROPIC DRUGS

[SED-15, 2822; SEDA-31, 323; SEDA-32, 336; SEDA-33, 378]

Milrinone

[SEDA-31, 323; SEDA-32, 336; SEDA-33, 378, SEDA-34, 290] Systematic reviews In a systematic review of four randomized controlled studies of

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milrinone in children with various forms of shock, the authors concluded that there is some evidence to support the use of milrinone in children after cardiac surgery and fluid resuscitated septic shock, but that the limited number of relevant studies in small numbers of patients make it difficult to appreciate the full reactions profile of milrinone in children [32R]. Cardiovascular In an observational study in 603 children undergoing 724 cardiac surgical procedures, the use of milrinone on admission to the cardiac intensive care unit was associated with an increase in the odds of postoperative tachydysrhythmias that resulted in an intervention (OR ¼ 2.9; 95% CI ¼ 1.3, 6.0) [33C]. On multivariate logistic regression, this association was independent of other factors, including age < 1 month, the use of cardiopulmonary bypass, the duration of cardiopulmonary bypass, a Risk Adjusted for Congenital Heart Surgery (RACHS) score > 3, and the use of adrenaline or dopamine. In an observational study of 14 patients with cerebral vasospasm after subarachnoid haemorrhage, there was significant angiographic improvement in the vasospasm and no adverse reactions during the intra-arterial administration of milrinone 2–15 mg [34c]. Three patients developed mild hypotension during maintenance intravenous milrinone infusion after intra-arterial administration, but none required intervention.

ANTIDYSRHYTHMIC DRUGS Adenosine and analogues [SED-15, 36; SEDA-32, 337; SEDA-33, 379; SEDA34, 291] Comparative studies In a meta-analysis of comparisons of adenosine and verapamil for stable paroxysmal supraventricular tachycardia in adults the two drugs were equally efficacious, but there was a higher

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incidence of pooled minor adverse events with adenosine and a higher incidence of hypotension with verapamil [35M]. Cardiovascular Coronary spasm has been reported as an adverse reaction to adenosine during stress myocardial perfusion imaging in a 42 year old woman with normal coronary arteries, who developed chest pain, ST changes, and then cardiac arrest several minutes after adenosine infusion [36A]. Two other patients also developed reversible ST changes and chest pain after adenosine infusion for stress testing. Intracoronary injection of adenosine has been used for acute management of in-stent stenosis and has been associated with dysrhythmias. In a 61-year-old man adenosine 100 micrograms resulted in complete heart block for 4 seconds, followed by torsade de pointes requiring defibrillation, and in a 60year-old man a dose of 40 micrograms resulted in complete heart block for 5 seconds followed by atrial fibrillation requiring cardioversion [37A]. The addition of lowlevel exercise to adenosine infusion reduced the incidence of adverse reactions (11% versus 20%) in 220 consecutive patients [38c]. In children undergoing cardiac surgery with cardiopulmonary bypass, patients who were pretreated with an infusion of adenosine (total dose 2.45 mg/kg at a rate of up to 350 micrograms/kg/minute) had lower postoperative serum troponin concentrations, required less postoperative inotropic support, and had shorter ICU stays. Adenosine caused relative hypotension in treated patients, but in no case was intervention required. One patient had a tachycardia after adenosine was withdrawn, and infusion was resumed until bypass was begun [39C]. In a retrospective review of adenosine infusion (140 micrograms/kg/minute) during cardiac MRI in 168 patients with suspected coronary artery disease there were mild or moderate adverse events in 28% [40c]. There was significant chest pain or dyspnea requiring withdrawal of adenosine in 8%. In a retrospective review of 27 patients who received adenosine to facilitate intracranial aneurysm ligation, the procedure was successful in all cases [41A]. Median

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doses of adenosine that resulted in bradycardia for over 30 seconds and hypotension for over 30 seconds were 15 mg and 30 mg respectively. One patient required brief chest compressions for prolonged hypotension before circulation was spontaneously restored. Drug administration route Accidental intraarterial administration of adenosine has been described [42A]. • A 12 year old girl with a supraventricular tachycardia was to be given adenosine, but the intravenous cannula was accidentally placed in the left brachial artery and the first dose (150 micrograms/kg) was given intraarterially. This resulted in transient pain and mottling of the skin of the forearm, blurred vision, dizziness, and nausea. Within 10 minutes the adverse reactions resolved and a new intravenous cannula was placed. Subsequent intravenous administration of adenosine resulted in conversion to sinus rhythm. There were no long-term sequelae in the arm.

ADENOSINE RECEPTOR AGONISTS [SEDA-32, 337; SEDA33, 379; SEDA-34, 292] The selective adenosine receptor agonists that have undergone trials in a broad range of indications have been reviewed, including capadenoson and tecadenoson (A1 receptor agonists) for atrial fibrillation and paroxysmal supraventricular tachycardia respectively, apadenoson and binodenoson (A2A receptor agonists) for myocardial perfusion imaging, and CF101 and CF102 (A3 receptor agonists) for inflammatory diseases and cancer respectively [43R].

Regadenoson Comparative studies In a retrospective study of regadenoson in 40 patients with orthotopic heart transplants who underwent regadenoson-SPECT before cardiac

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allograft vasculopathy and controls who had had prior adenosine-based SPECT, there was significant heart rate acceleration and asymptomatic hypotension [44c]. Cardiovascular Regadenoson has been reported to have precipitated myocardial ischemia [45Ar]. • A 90 year-old man with coronary artery disease, hyperlipidemia, peripheral vascular disease, and moderate aortic stenosis was referred for stress testing. His baseline electrocardiogram was normal. He was given intravenous regadenoson 400 mg over 10 seconds and immediately developed severe chest discomfort and became tachycardic and mildly hypotensive (systolic blood pressure 90–100 mmHg). Electrocardiography showed a sinus tachycardia with diffuse 4–5 mm ST segment depression in several leads. He was given a bolus of isotonic saline, which improved his blood pressure, intravenous metoprolol, and sublingual glyceryl trinitrate. His symptoms and electrocardiographic changes gradually resolved.

The authors reported that the incidence of ischemic electrocardiographic changes during coronary vasodilatation with regadenoson was 12% in one study. In the ADVANCE study, electrocardiographic changes consistent with ischemia were described in a comparable proportion of patients treated with regadenoson or adenosine (17% each). Aminophylline, a nonspecific adenosine receptor antagonist, may interfere with the vasodilatory activity of regadenoson and can be given intravenously to attenuate adverse reactions. Susceptibility factors Liver disease In 168 patients with end-stage liver disease, who had regadenoson stress-gated single photon emission CT before planned orthotopic liver transplantation and 168 controls, the heart rate increase in response to regadenoson was less in the patients, but the changes in systolic and diastolic blood pressures were similar; there were no deaths or medication-related adverse events that required hospitalization in either group within 30 days of the study [46C]. Lung disease In a retrospective study of 228 patients with COPD (n ¼ 126) or asthma

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(n ¼ 102) undergoing SPECT imaging with regadenoson, compared with 1142 patients without COPD or asthma, there were no cases of exacerbation of COPD or asthma after regadenoson [47C]. Patients with COPD had more non-significant dysrhythmias (58% versus 43%), and there were no cases of atrioventricular block and only two cases of brief SVT. Compared with a historical cohort with COPD who underwent intravenous dipyridamole–thallium imaging, the patients with COPD who were given regadenoson had more dyspnea and flushing, and compared with patients with COPD or asthma who underwent adenosine SPECT, the patients with COPD who were given regadenoson had more flushing and headache (25% versus 2.8%), but less bronchospasm and atrioventricular block. • A 58-year-old man in sinus rhythm with idiopathic pulmonary fibrosis was given Nacetylcysteine and developed progressive PR prolongation and eventual high grade atrioventricular block and asystole after intravenous administration of regadenoson 0.4 mg over 15–20 seconds [48A]. He was resuscitated and sinus rhythm was restored. Myocardial perfusion images showed a normal left ventricular cavity with normal perfusion and a left ventricular ejection fraction of 64%.

This case suggests that regadenoson may be contraindicated in patients with idiopathic pulmonary fibrosis, especially in those who are also receiving N-acetylcysteine, which inhibits adenosine deaminase.

Ajmaline

[SED-15, 45; SEDA-34, 292]

Susceptibility factors Age In a study of ajmaline challenge in 179 young individuals with suspected Brugada syndrome, ajmaline challenge provoked a higher degree of intraventricular conduction delay and a higher degree of prolongation of the ventricular repolarization phase in those aged under 18 years [49C]. The prodysrhythmic risk was comparable in those under and over 18, as was the inducibility of ventricular dysrhythmias in patients with a positive ajmaline test.

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Drug administration route Serious dysrhythmias occurred in a case of inadvertent intracoronary injection of ajmaline [50A]. • A 58 year-old man with a history of angina during exercise and cold underwent percutaneous coronary intervention of the left anterior descending coronary artery (70–90% stenosis). During the procedure, ajmaline was inadvertently injected into the coronary artery and caused ventricular fibrillation. After a series of DC shocks, he became asystolic but recovered after cardiopulmonary resuscitation.

Amiodarone [SED-15, 148; SEDA-32, 339; SEDA-33, 380; SEDA-34, 292] Comparative studies: The US MarketScan Claims database was used to compare adverse events associated with amiodarone and sotalol used for management of atrial fibrillation in 3459 adults (mean age 71 years) [51C]. There were increased numbers of adverse events in both groups compared with pre-treatment. Amiodarone produced a higher rate of cardiovascular adverse events (594 versus 339 per 1000 patient years) and pulmonary adverse events (128 versus 61 per 1000 patientyears) and a lower rate of treatment continuation at 12 months (31% versus 53%). Cardiovascular In a retrospective cohort study of 393 consecutive patients undergoing CABG, amiodarone was compared with ranolazine in prevention of postoperative atrial fibrillation [52C]. The patients who took amiodarone were more likely to develop atrial fibrillation than those who took ranolazine (OR ¼ 1.7; 95% CI ¼ 1.01, 2.91). There was no difference in adverse events between the groups. In a randomized active-controlled study of acute conversion of new-onset atrial fibrillation, 254 adults were randomized to either a 10 minute infusion of vernakalant 3 mg/kg followed by a 10 minute observation period and an additional 10 minute infusion of vernakalant 2 mg/kg if still in atrial fibrillation, or a 60 minute infusion of amiodarone 5 mg/kg followed by a maintenance infusion of 50 mg over another

Positive inotropic drugs and drugs used in dysrhythmias

60 minutes [53C]. Each patient also received a sham infusion of the nonrandomized medication. There was conversion to sinus rhythm within 90 minutes in 52% of those who received vernakalant compared with 5.2% of those who received amiodarone. There were two serious adverse events with amiodarone—asystolic cardiac arrest 37 minutes after amiodarone infusion, which resolved with atropine and CPR, and sinus bradycardia—and two with vernakalant. There were no cases of torsade de pointes, ventricular fibrillation, or polymorphous or sustained ventricular tachycardia in either group. Amiodarone can be prodysrhythmic, as another report demonstrates [54A]. • A 48 year old woman with idiopathic dilated cardiomyopathy suddenly developed palpitation and dyspnea. Electrocardiography showed sinus rhythm with occasional ventricular extra beats. Suddenly, she developed recurrent ventricular tachycardia at a rate of 170/minute. She was given intravenous amiodarone 125 mg over 10 minutes followed by 40 mg/hour and 1 hour later her heart rate had fallen to 150/min and the morphology of the initiating extra beats had changed to the same morphology as the ventricular tachycardia, which became more frequent and persistent than before amiodarone. Amiodarone was withdrawn and she was given 12 mg of nifekalant, a pure IKr blocker. About 7 minutes later the tachycardia disappeared completely.

Amiodarone-induced ventricular fibrillation has also been described in a patient with Wolff–Parkinson–White syndrome and atrial fibrillation [55A]. Respiratory In two systematic reviews of the epidemiology, pathophysiology, clinical presentation, treatment, and outcomes of adverse respiratory reactions to amiodarone, which occur in about 5% of patients, lung complications were associated with older age, duration of treatment, cumulative dosage, high concentrations of the desethyl metabolite, a history of cardiothoracic surgery and/or use of high oxygen mixtures, the use of iodinated contrast media, and probably pre-existing lung disease and co-existing respiratory infections [56M,57M]. Amiodarone-related adverse

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respiratory reactions can develop from as early as the first few days of treatment to several years later [58A]. The onset can be either insidious [59A] or rapidly progressive [60A,61A]. Pulmonary involvement falls into two categories, with different degrees of clinical significance: (a) “lipoid pneumonia”, which is usually asymptomatic and (b) several distinct clinical entities related to different patterns of lung inflammatory reactions, such as eosinophilic pneumonia, chronic organizing pneumonia, acute fibrinous organizing pneumonia, nodules or mass-like lesions, non-specific interstitial pneumonia-like and idiopathic pulmonary fibrosis-like interstitial pneumonia, desquamative interstitial pneumonia, acute lung injury/acute respiratory distress syndrome (ARDS), and diffuse alveolar hemorrhage. There can be pleural/pericardial involvement. Three different and inter-related mechanisms have been suggested: (a) a direct toxic effect; (b) an immune-mediated mechanism; and (c) renin–angiotensin system activation. Amiodarone-induced pulmonary toxicity is a diagnosis of exclusion. Cough, new chest infiltrates in imaging studies, and reduced lung diffusing capacity, after meticulous exclusion of infection, malignancy, and pulmonary edema, are the cardinal clinical and laboratory elements. Pulmonary evaluation with chest X-ray and pulmonary function testing, including carbon monoxide diffusing capacity, is recommended at the start of amiodarone treatment. A reduction in diffusing capacity of more than 20% suggests the need for closer monitoring or further diagnostic testing. Although the optimal frequency of follow-up has not been determined, most cases of amiodarone-induced lung injury develop during the first 2 years of treatment and the onset is usually slow. Treatment of amiodarone pulmonary toxicity consists primarily of withdrawing the drug. Glucocorticoid therapy can be lifesaving in severe cases and for patients with less severe disease in whom withdrawal of amiodarone is not desirable. Owing to accumulation in fatty tissues and the long half-life of amiodarone, pulmonary toxicity can progress initially, despite drug

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withdrawal, and may recur after glucocorticoid withdrawal. The prognosis is generally favorable, but mortality ranges from 9% in those who develop chronic pneumonia to 50% in those who develop ARDS. An uncommon pulmonary manifestation of amiodarone toxicity is a lung mass mimicking a lung carcinoma [62A]. Endocrine Amiodarone-induced thyroid disease has been extensively reported. Amiodarone can cause both hypothyroidism and two forms of hyperthyroidism. Type 1 amiodarone-induced hyperthyroidism is related to the iodine content of amiodarone and is treated best with thionamides; type 2 is related to direct toxicity against the thyroid gland and is treated primarily with glucocorticoids [63–65R]. In a retrospective cohort study in 248 consecutive Serbian patients who were taking amiodarone, there was clinical thyroid dysfunction in 16%, and an additional 21% had subclinical dysfunction [66c]. Hypothyroidism was more common among those with symptomatic disease—10% of the total cohort had clinical hypothyroidism and 6% became hyperthyroid. On multivariate analysis, the presence of a goiter predicted symptomatic disease, while female sex and the presence of a goiter predicted subclinical disease. The authors recommended avoidance of amiodarone and/or frequent checks of thyroid function in women with goiter. Several publications have addressed the role of amiodarone withdrawal in treating amiodarone-induced hyperthyroidism. In a matched retrospective cohort study, patients with previously untreated type 2 amiodarone-induced hyperthyroidism who were treated with prednisone and had amiodarone withdrawn were compared with patients who were treated with prednisone but kept taking amiodarone [67C]. There was found no difference in the time to first normal thyroid hormone concentrations between the groups, but more frequent recurrence of hyperthyroidism in those who kept on taking amiodarone, with a longer time to stable euthyroidism (median 140 days versus 47 days). In

John R. Charpie and Joshua M. Friedland-Little

another cohort study of 303 consecutive patients taking amiodarone for dysrhythmias, 8% developed amiodarone-induced hyperthyroidism and 6% developed amiodarone-induced hypothyroidism [68c]. Age under 62 years was a susceptibility factor for amiodarone-induced hyperthyroidism (HR ¼ 2.4; 95% CI ¼ 1.0, 5.7). There was spontaneous resolution in 42% of patients with amiodarone-induced hyperthyroidism without treatment. The rest were treated with varying regimens of prednisone, potassium perchlorate, and/or thiamazole. Thyroid function normalized in all cases. Withdrawal of amiodarone did not affect the time to normalization of thyroid function tests. This study was limited by small numbers and was probably underpowered to detect minor effects. Amiodarone-induced hypothyroidism is of particular concern in young patients, given the potentially dire consequences of hypothyroidism on neurodevelopmental outcomes. • A girl of Chinese origin born at full term had coarctation of the aorta, hypoplasia of the left ventricle, and an atrial septal defect diagnosed in utero [69A]. Neonatal screening for congenital hypothyroidism was normal. She underwent a primary repair of the coarctation at 5 days of age, and her overall condition deteriorated postoperatively. She developed necrotizing enterocolitis and acute renal insufficiency. Postoperatively, she developed a junctional ectopic tachycardia with hemodynamic compromise requiring pacing, cooling, and intravenous amiodarone. Over the next 3 weeks, she was given a cumulative amiodarone dose of 541 mg (155 mg/kg), most of it intravenously and 3 weeks later (age 7 weeks) her thyroid function tests showed severe hypothyroidism. Antithyroperoxidase antibody titers were negative and thyroid imaging was normal. She continued to take amiodarone and her TSH returned to normal after 17 days of thyroid hormone supplementation. Amiodarone was withdrawn at 6 months and thyroid hormone replacement at 12 months. At 2 years she was in sinus rhythm and euthyroid but had mild developmental delay.

Endocrine The syndrome of inappropriate antidiuretic hormone secretion (SIADH) and severe hyponatremia are rare but potentially dangerous adverse effects of amiodarone.

Positive inotropic drugs and drugs used in dysrhythmias • A 66-year-old man with a history of hypertension, hyperlipidemia, coronary artery disease, and class III New York Heart Association congestive heart failure developed a monomorphic non-sustained ventricular tachycardia [70A]. He was given a loading dose of amiodarone followed by a maintenance dose. The serum sodium concentration was 138 mmol/l on admission and it fell to 119 mmol/l by day 7. It rose to 133 mmol/l 16 days after withdrawal of amiodarone. • A 58-year-old man developed severe hyponatremia within 3 days of being loaded with amiodarone [71A].

Liver Hepatotoxicity related to oral amiodarone has been well reported, but acute liver damage after intravenous amiodarone is rarer [72A]. Acute hepatic damage after intravenous amiodarone has been reported after liver transplantation [73A]. • A 64-year-old man with non-alcoholic steatohepatitis and hepatocellular carcinoma and end-stage liver disease underwent orthotopic liver transplantation. Postoperative atrial fibrillation was treat with intravenous amiodarone and esmolol 50 micrograms/kg/min was added on postoperative day 5. On day 7, his liver enzyme activities started to rise. Alanine aminotransferase rose from 688 to 2028 U/l, aspartate aminotransferase from 375 to 932 U/l, and alkaline phosphatase from 66 to 104 U/l; bilirubin rose from 11 to 230 mmol/l. Ultrasonography showed normal flow in the hepatic blood vessels. Endoscopic retrograde cholangiography show no biliary obstruction. A liver biopsy showed canalicular cholestasis, increased mitotic activity, and numerous apoptotic hepatocytes, especially around the central veins; there was no acute cellular rejection. Amiodarone was withdrawn after 11 days and he was given metoprolol instead. His liver function tests gradually normalized over the next 2 weeks.

There were striking similarities between the clinical and laboratory characteristics of 22 patients with amiodarone related hepatotoxicity who were described in case reports and 25 age- and sex-matched patients with ischemic hepatitis from the authors’ own practice [74c]. The authors proposed that cases of apparent intravenous amiodaroneinduced liver damage may in fact represent cases of ischemic hepatitis. They stressed the importance of this distinction, because amiodarone may be life-saving and avoiding it because of concern about hepatotoxicity may have negative consequences.

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Skin Phototoxicity, with blue-gray skin pigmentation in sun-exposed areas, occurs in under 10% of patients taking amiodarone, predominantly men, as in the case of a 77-year-old man with blue-gray skin discoloration of the face that developed after several months of amiodarone 200 mg/day for atrial fibrillation [75A]. Long-pulse neodymium-doped yttrium aluminum garnet laser treatment may be effective [76A]. Musculoskeletal Acute severe muscle cramps have been described after intravenous amiodarone [77A]. • 32-year-old man, who was taking digoxin, sotalol, furosemide, lisinopril, and coumadin, and had normal serum electrolytes and hepatic and renal function, was given two 250 mg doses of intravenous amiodarone and then a continuous infusion of 900 mg over the next 24 hours. After about 12 hours he started to have episodic, severe muscle cramps in the neck, back, thighs, and calves. He described these episodes as involuntary, sustained, painful contractions of the muscles, about 6–8 per hour, each lasting up to 2 minutes, and not associated with tremors or paresthesia. Serum chemistry, including creatine kinase activity, was normal. He was given low-dose cyclobenzaprine and had partial improvement. Oral amiodarone 400 mg tds was continued. The muscle cramps persisted until the dose of amiodarone was reduced to 200 mg/day, and over the next 12 hours his cramps resolved completely.

The rapid resolution after dosage reduction in this case is inconsistent with a cause-andeffect relation, since the half-life of amiodarone is several weeks. Immunologic Anaphylactic shock occurred in a 24 year old man with atrial fibrillation during intravenous loading with amiodarone; the infusion was stopped, but amiodarone was later resumed and tolerated after a dose of methylprednisolone [78A]. Death In a propensity-matched prospective cohort study in 3734 patients with newly diagnosed heart failure over 7 years, amiodarone was associated with increased allcause mortality (HR ¼ 1.70; 95% CI ¼ 1.50, 1.91), particularly among women (HR ¼ 1.77; CI ¼ 1.55, 2.00) and patients with non-systolic heart failure (HR ¼ 1.87;

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CI ¼ 1.66, 2.09), even after adjustment for the propensity to take amiodarone or other medications and other potential confounders [79C]. Susceptibility factors Lung disease In a retrospective cohort study of 137 patients with lung or heart–lung transplants, there was a high incidence of atrial dysrhythmias (45% within 26 days) [80C]. Patients taking amiodarone had a higher risk of mortality (63% versus 12%) and a higher incidence of chest x-ray findings consistent with amiodarone related damage (61% versus 39%). The authors speculated that lung transplant patients and other patients with severe lung disease may be at increased risk of lung damage, possibly related to increased amiodarone exposure in lung segments with normal perfusion. In a retrospective cohort study of susceptibility factors for amiodarone-related lung toxicity using linked administrative databases in Quebec, Canada, even low-dose amiodarone (up to 200 mg/day) was associated with an increased risk of pulmonary disease (HR ¼ 1.62; 95% CI ¼ 1.35, 1.96) and the risk did not appear to increase with increasing amiodarone dose [81C]. This suggests that lung damage due to amiodarone is a hypersusceptibility reaction, with its dose-response curve to the left of the beneficial dose-response curve. Other susceptibility factors for pulmonary disease among amiodarone users were increasing age (HR ¼ 1.01/year; 95% CI ¼ 1.00, 1.02), male sex (HR ¼ 1.37; CI 1.19, 1.57), and chronic obstructive pulmonary disease (HR ¼ 1.26; CI ¼ 1.06, 1.50). This study was limited by the lack of granular data in the administrative databases used. Idiopathic pulmonary hypertension puts patients at increased risk of amiodarone induced thyroid dysfunction [82c]. In a retrospective study, 21 patients with idiopathic pulmonary hypertension (IPAH) who took amiodarone for at least 3 months were compared with 72 patients with idiopathic pulmonary hypertension who did not take amiodarone and 23 with chronic thromboembolic pulmonary hypertension (CTEPH) who took amiodarone for at least

John R. Charpie and Joshua M. Friedland-Little

3 months. The patients with idiopathic pulmonary hypertension who took amiodarone were more likely to develop thyroid dysfunction than those who did not take it (57% versus 17%) and also more likely to develop thyroid disease than the patients with chronic thromboembolic pulmonary hypertension who took amiodarone (57% versus 17%). The authors recommended close monitoring of thyroid function in patients with idiopathic pulmonary hypertension taking amiodarone, and aggressive treatment if thyroid dysfunction is identified. Drug formulations In a cohort study of patients aged 66 years and older with atrial fibrillation, using linked administrative databases in Canada, 2804 patients who used branded amiodarone were compared with 6278 patients who used a generic formulation [83C]. Baseline characteristics and median dosages of amiodarone were comparable. The incidence of thyroid dysfunction was 14 per 100 person years with each formulation. Factors associated with thyroid dysfunction were female sex, increasing age, and chronic obstructive pulmonary disease. Intravenous amiodarone infusion can cause thrombophlebitis concentrationdependently. In a single institution retrospective study, the rate of amiodaronerelated thrombophlebitis peaked at 27% when the hospital pharmacy used a concentration of 900 mg/500 ml [84c]. The rate of thrombophlebitis fell when the concentration was reduced to 600 mg/500 ml and rose again when the pharmacy reverted to a concentration of 900 mg/500 ml. Drug overdose Inadvertent amiodarone overdose has been reported [85A]. • A 64-year-old woman continued to take the loading dose of amiodarone (400 mg bd) for 7 months and developed progressive shortness of breath, followed by nausea, vomiting, and diarrhea. She then developed a sinus bradycardia with extra beats and a QTc interval greater than 690 msec followed by torsade de pointes and cardiac arrest. Abnormalities in her laboratory tests included raised aminotransferases, a low thyroid-stimulating

Positive inotropic drugs and drugs used in dysrhythmias hormone concentration, and a raised free thyroxine. Chest radiography showed prominent interstitial markings with a nodular opacity in the right upper lobe. Amiodarone was withdrawn and an isoprenaline (isoproterenol) infusion started. A CT scan showed emphysema and dense consolidations in the right and left upper lobes, dense atelectasis in the lower lobes, and dense attenuation of the liver, suggestive of amiodarone exposure. Her thyroid studies and radioactive iodine uptake scan were consistent with amiodarone-induced hyperthyroidism, and she was given methimazole. Her liver enzymes returned to normal several weeks later.

Drug–drug interactions Citalopram Torsade de pointes has been reported in an 83 year old woman with atrial fibrillation, hypertension, and depression who was taking amiodarone 200 mg/day and took citalopram 20 mg for 3 weeks [86A]. She developed palpitation and runs of selflimiting torsade de pointes. Her QTc interval was 526 milliseconds. HMG co-enzyme A inhibitors (statins) Several reports have described rhabdomyolysis in patients taking amiodarone and a statin, and another case has been reported [87A]. • An 80-year-old Turkish man, who had taken simvastatin 40 mg/day for 36 months without adverse reactions, developed proximal pain and weakness of the lower limbs when he was given amiodarone 200 mg/day, lowmolecular-weight heparin, and bumetanide 1 mg/day for atrial fibrillation. He was also taking insulin, ranitidine, spironolactone, valsartan, aspirin, and bisoprolol. There was impaired renal function, hyperkalemia, and myoglobinuria. Simvastatin was withdrawn because of suspected drug-induced rhabdomyolysis; other medications, including amiodarone, were not. Serum creatine kinase activity peaked at 34 520 IU/l on day 5 and then fell. Proximal pain and weakness of the lower limbs resolved progressively.

The authors recommended reducing the dose of simvastatin to 20 mg/day if a CYP3A4 inhibitor such as amiodarone is given or switching to a statin that is not metabolized by CYP3A4, such as pravastatin or fluvastatin. • A 67 year old man developed severe rhabdomyolysis after being given amiodarone, atorvastatin,

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and fluconazole; the medications were withdrawn and he gradually recovered [88A].

Itraconazole Cardiac arrest occurred repeatedly in a man who was given itraconazole while taking amiodarone [89A]. • A 65-year-old man was given intravenous amiodarone for atrial fibrillation associated with an extensive ischemic stroke and a few days later itraconazole for presumed candidemia. After the first dose of itraconazole he became profoundly hypotensive but responded rapidly to fluids and adrenaline. Itraconazole was again prescribed for confirmed fungemia 2 months later and after the first dose he became hypotensive and had a cardiac arrest. He was resuscitated successfully, and his antifungal treatment was changed to caspofungin. The electrocardiogram immediately after the arrest showed QTc prolongation. Itraconazole was given again and he immediately had another cardiac arrest and was once again resuscitated. Itraconazole was withdrawn and he remained stable.

The authors concluded that the arrests had been due to an interaction of itraconazole with amiodarone, although they could have been due solely to the itraconazole.

Bepridil [SED-15, 445; SEDA-33, 384; SEDA-34, 295] Cardiovascular Long-term bepridil, mean dose 127 mg/day, has been studied retrospectively in 62 patients with multidrugresistant paroxysmal atrial fibrillation and in a 5 year follow-up study of 28 of the patients, mean dose 100 mg/day [90c]. In the retrospective study, reversible torsade de pointes occurred in two elderly women and bradycardia and hepatic dysfunction in one patient each. There were no adverse reactions during the follow-up study. In a retrospective study of 284 patients who took bepridil for atrial fibrillation with a median follow-up of 17 (4–157) months, the cumulative rates of cardiovascular events were 2.4%, 8.1%, and 10% at 1, 3, and 5 years respectively, and the probability of progression to permanent atrial fibrillation was 24% at 5 years [91c]. Sudden

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death occurred in a patient with a prior myocardial infarction who was taking 200 mg/day, and torsade de pointes occurred in two patients without structural heart disease taking 200 mg/day. There was QTc interval prolongation to over 500 msec when plasma concentrations were over 800 ng/ml.

Disopyramide

[SED-15, 1145; SEDA32, 347; SEDA-33, 385; SEDA-34, 296] Metabolism Hypoglycemia has again been attributed to disopyramide [92Ar].

• A non-diabetic 72-year-old woman on hemodialysis for end-stage kidney disease who took disopyramide 150 mg/day for paroxysmal atrial fibrillation for 3 days developed severe hypoglycemia (plasma glucose 1.8 mmol/l, 32 mg/dl). Concentrations of counterregulatory hormones, serum insulin, and Cpeptide were increased.

John R. Charpie and Joshua M. Friedland-Little

recurrent attacks of syncope. Her medications included disopyramide 300 mg/day and methimazole and she had taken lansoprazole 15 mg/ day for 1 month. Electrocardiography showed sinus bradycardia with marked QT interval prolongation (QTc 69o msec, increased from 570 msec 3 months before) and episodic torsade de pointes. There were no electrolyte abnormalities or thyroid abnormalities. Disopyramide was withdrawn and 3 days later the QT interval was only mildly prolonged (QTc 520 msec).

The authors pointed out that disopyramide increases the QT interval slightly and reduces left ventricular ejection fraction by 5–10% in patients with hypertrophic cardiomyopathy, in whom the QT interval is prolonged. The addition of lansoprazole, which is mainly metabolized by the same CYP isoenzyme as disopyramide, produced marked QT prolongation and torsade de pointes, suggesting that it might alter the pharmacokinetics of disopyramide.

Dofetilide

[SED-15, 1173; SEDA-29,

The plasma concentration of disopyramide was below the usual target range, suggesting that the sustained insulin secretion was due to a metabolite of disopyramide, not disopyramide itself. Disopyramide blocks ATP-sensitive channels in the pancreas and may alter insulin secretion. Factors that increase the blood concentration of disopyramide increase the risk of hypoglycemia, although there is evidence that disopyramide-induced hypoglycemia results from endogenous insulin secretion and can occur in patients with therapeutic blood concentrations of the drug; other factors can also increase the risk even when disopyramide concentrations are in the target range. Patients at risk include those with renal impairment, advanced age, and malnutrition, in whom blood glucose concentrations should be monitored carefully.

Observational studies In a retrospective cohort study of dofetilide, mean dose 778 micrograms/day, in 18 adults with implantable cardioverter–defibrillators and persistent frequent ventricular tachycardia/ventricular fibrillation who had failed or did not tolerate conventional antidysrhythmic drug therapy, rhythm control was achieved in nine [94c]. The mean QTc interval increased significantly compared with baseline (494 versus 461 msec), but no patient required a reduction in the dose of dofetilide because of adverse reactions or excessive QT interval prolongation and none developed torsade de pointes.

Drug–drug interactions Lansoprazole An interaction of disopyramide with lansoprazole has been described [93A].

34, 296]

• A73 year-old woman with a history of hyperthyroidism, hypertrophic cardiomyopathy, and paroxysmal atrial fibrillation developed

187]

Dronedarone

[SEDA-33, 386, SEDA-

Dronedarone was approved in the USA in 2009 as an alternative to amiodarone for non-permanent atrial fibrillation. Its efficacy and adverse reactions to it have been

Positive inotropic drugs and drugs used in dysrhythmias

widely reviewed [95–97r,98–102R,103M]. Dronedarone reduces hospitalization and death in patients with paroxysmal atrial fibrillation, though it is not as effective as amiodarone at maintaining sinus rhythm. It probably causes fewer serious adverse reactions than amiodarone and may be less prodysrhythmic. However, it may increase mortality in patients with decompensated heart failure, in whom it is contraindicated. Dronedarone also has dysrhythmogenic effects, including bradycardia and QT interval prolongation. Other adverse reactions include diarrhea, nausea and vomiting, and skin disorders. Transient rises in creatinine concentrations are also common and renal insufficiency has been reported. Little is known about potential long-term adverse reactions, especially pulmonary fibrosis. Cardiovascular The hypothesis that dronedarone would reduce major vascular events in patients with high-risk permanent atrial fibrillation has been tested in a large-scale randomized placebo-controlled study (the PALLAS trial) [104C]. However, the study was stopped early, because of increases in the rates of heart failure, stroke, and death from cardiovascular causes. Dronedarone should not be used in patients with permanent atrial fibrillation. A post-hoc analysis of the large, randomized placebo-controlled ATHENA trial showed that dronedarone was effective in controlling both rate and rhythm in moderate- to high-risk patients with atrial fibrillation [105C]. Compared with those taking placebo, patients taking dronedarone were less likely to develop recurrent atrial fibrillation or to require electrical cardioversion. They also had a significantly lower mean heart rate. Nervous system In a meta-analysis of four randomized, placebo-controlled studies in patients with paroxysmal or persistent atrial fibrillation, dronedarone significantly reduced the incidence of stroke and transient ischemic attacks (3.3% versus 2.1%), according to a fixed-effects model [106M]. However, using a random-effects model in which the large ATHENA trial received

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less statistical weight, the difference did not reach statistical significance. Liver The risk of severe liver damage due to dronedarone prompted the FDA to issue a warning because of two cases of acute hepatic failure requiring liver transplantation in women aged about 70 years after they had taken dronedarone for 4–6 months [107S]. The FDA gave the following advice: • advise patients to contact a health-care professional immediately if they have signs and symptoms of hepatic damage or toxicity (anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching) while taking dronedarone; • consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment, although it is not known whether monitoring will prevent the development of severe liver damage; • if hepatic damage is suspected, dronedarone should be promptly withdrawn and serum liver enzymes and bilirubin should be measured; if hepatic damage is found, appropriate treatment should be initiated; • in patients who experience hepatic damage without another explanation, dronedarone should not be restarted.

Liver damage and hepatic encephalopathy requiring liver transplantation has also been reported in a 70-year-old woman with coronary artery disease and COPD who had taken dronedarone for atrial fibrillation for 6 months [108A]. Histology showed widespread necrosis of liver acini, massive canalicular and ductular cholestasis, a mixed cellular inflammatory infiltrate, and bile duct proliferation.

Flecainide [SED-15, 1370; SEDA-32, 348; SEDA-33, 387; SEDA-34, 297] The pharmacological characteristics and efficacy of flecainide in the management of atrial fibrillation and adverse effects and reactions have been comprehensively reviewed, as have the 2006 ACC/AHA/ ESC evidence-based treatment guidelines for atrial fibrillation that list flecainide as a first-line therapy in the absence of

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structural heart disease [109R]. The authors concluded that when used in appropriately selected patients, flecainide has a good safety profile, with a low incidence of prodysrhythmic and other cardiac and noncardiac adverse events. Systematic reviews In a systematic review of the main antidysrhythmic drugs used to treat atrial fibrillation, including flecainide, only randomized controlled studies were included [110M]. Outcomes included mortality, stroke, recurrence of atrial fibrillation, the incidence of serious adverse events, treatment withdrawals, and prodysrhythmic events (sudden death, new symptomatic dysrhythmias, bradycardia, and drug withdrawal because of new QRS or QT interval prolongation). Flecainide increased the risk of serious adverse events and was associated with an increased risk of dysrhythmias compared with placebo. A mixed treatment comparison analysis suggested that there was no effect of flecainide on all-cause mortality; however, no studies involved more than 100 patients in the treatment and placebo arms. In a multi-institutional retrospective cohort study of flecainide in addition to conventional therapy for patients with catecholaminergic polymorphous ventricular tachycardia in 33 patients (median age 28 years, range 7–68), there was complete or partial suppression of ventricular dysrhythmias in 76% [111c]. The median dose of flecainide in responders was 150 (range 100–300) mg/day. There were no prodysrhythmic effects of flecainide. Cardiovascular Flecainide has been reported to induce Brugada-like electrocardiographic effects, particularly when excessive doses are used [112A]. Advice about Brugada-like changes in patients taking flecainide has been provided in the light of a case report [113A]. • A 58 year-old man with paroxysmal atrial fibrillation was given flecainide 50 mg bd with initial success for 6 months. However, his episodes of atrial fibrillation recurred, with a progressive increase in frequency, despite an increase in the dosage of flecainide to 100 mg

John R. Charpie and Joshua M. Friedland-Little

bd and then 150 mg bd. During a protracted episode he took extra flecainide, a total of 600 mg over a few hours. Sinus rhythm returned, and electrocardiography showed a new pattern suggestive of Brugada type 1. Subsequent electrocardiography during therapy with 150 mg bd suggested a Brugada type 3 pattern. Flecainide was withdrawn and he underwent catheter ablations, with no clinical or electrocardiographic evidence of syncope, ventricular dysrhythmias, or Brugada pattern.

The authors suggests that a Brugada pattern, when precipitated during therapy, should preclude the use of a class IC antidysrhythmic drug for the treatment of atrial fibrillation, even in the absence of any other overt structural heart disease. In a retrospective study of 112 patients, mean age 60 years, with paroxysmal or persistent atrial fibrillation, who took oral flecainide, mean dosage 203 mg/day, the primary outcome measure was death and secondary outcomes included cardiac syncope or life-threatening dysrhythmias [114c]. There were eight deaths during a mean follow-up of 3.4 years; three were classified as sudden cardiac deaths. Compared with the general population, the standardized mortality ratios were 1.57 (95% CI ¼ 0.68, 3.09) for all-cause mortality and 4.16 (95% CI ¼ 1.53, 9.06) for death from cardiovascular disease. There were prodysrhythmic events in six patients. In a retrospective review of 12 patients, median age 68 (60–79) years, 10 of whom were women, takotsubo cardiomyopathy was diagnosed based on chest symptoms, a raised troponin, transient apical dysfunction, and absence of significant coronary artery stenosis on angiography that could explain the apical dysfunction [115c]. Four patients had taken long-term flecainide (compared with 23 of 3323 patients, 0.7%, who underwent coronary angiography during the same period). During follow-up, two patients had a recurrence of takotsubo cardiomyopathy, and both had taken flecainide before their first episodes. The authors speculated that left ventricular dysfunction in takotsubo cardiomyopathy may have been triggered or facilitated or exaggerated by the use of flecainide. They concluded that, as a precaution, flecainide should be

Positive inotropic drugs and drugs used in dysrhythmias

avoided in patients with a history of takotsubo cardiomyopathy. Flecainide is not generally thought to prolong the QT interval significantly, but extreme QTc interval prolongation with ventricular tachycardia has been reported [116A]. • A 54-year-old man was given flecainide 200 mg/ day and atenolol for newly diagnosed atrial fibrillation with a rapid ventricular response and after 5 days experienced repeated attacks of loss of consciousness. Electrocardiography showed a uniform, sine wave-like tachydysrhythmia. After electrical cardioversion, a slow escape rhythm with ventricular extra beats appeared. During bradycardia, there were negative T waves and the QTc interval was 680 msec Multiple episodes of sustained or non-sustained tachydysrhythmias with the same pattern occurred in succession. Cardiac enzymes and serum electrolytes were normal. After a continuous infusion of isoprenaline, the bradycardia improved and the tachydysrhythmia was suppressed. Follow-up electrocardiography showed a prolonged QTc interval (556 msec) and T wave inversion during sinus rhythm. Flecainide was withdrawn and 1 week later the atrial fibrillation persisted but the QT interval was normal.

The authors hypothesized that properties of flecainide, such as slowing conduction, had partly contributed, in a use-dependent manner, to the development of a uniform tachycardia, as opposed to the typical torsade de pointes associated with QT interval prolongation. They pointed out that prolongation of the QT interval by flecainide is exceedingly rare; however, it may be one of the mechanisms of flecainide-induced dysrhythmias. Drug overdose Accidental overdose in an child has been reported [117A]. • An 18 month old boy with orthodromic reentrant tachycardia who was being given flecainide 5 mg/kg/day had a tonic–clonic seizure after accidentally taking 10 tablets (1000 mg) of flecainide. Electrocardiography showed atrioventricular dissociation with QRS widening (200 msec) and QTc prolongation (512 msec). He was initially treated with gastric lavage, activated charcoal, mannitol, colloid fluids, and high-dose sodium bicarbonate (2 mg/kg/dose) but developed a ventricular tachycardia without hemodynamic compromise and was given amiodarone. The QRS complex gradually narrowed, atrioventricular conduction improved, and 12 hours later he

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was in sinus rhythm with a QRS duration of 100 msec, a PR interval of 160 msec, and a persistently prolonged QTc interval of 485 msec.

The authors discussed the literature on alkalinization with sodium bicarbonate as a treatment for flecainide overdose and provided insights into the mechanism by which alkalinization may reduce the effect of flecainide on cellular sodium channels.

Mexiletine [SED-15, 1370; SEDA-31, 330; SEDA-33, 389, SEDA-34, 298] Placebo controlled studies In a doubleblind, crossover, randomized, placebo controlled study in 59 patients with nondystrophic myotonias mexiletine reduced the signs and symptoms and there were no serious study-related adverse events [118C]. The most common adverse reactions were gastrointestinal discomfort (nine with mexiletine and one with placebo). There was one minor cardiovascular event in each group. None of the adverse events required withdrawal. The authors concluded that mexiletine is effective in the treatment of non-dystrophic myotonia, but that the study lacked sufficient power to assess adverse events adequately. Cardiovascular In a review of data on the use of mexiletine in patients with myotonic dystrophy type 1 (DM1), the author discussed the risk of life-threatening dysrhythmias in this population, argued that the available evidence on the safety of mexiletine in this population is inadequate, particularly given the progressive nature of conduction abnormalities in patients with DM1, and suggested that mexiletine should be avoided in these patients [119r]. Drug overdose The use of hemodialysis to treat mexiletine overdose has been described [120A]. • A 23-year-old man took and of mexiletine 4 g and 1 hour later he was alert, oriented, and

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cooperative, with stable vital signs. Electrocardiography showed sinus rhythm at a rate of 72/minute. Complete blood count, venous blood gases, and other biochemistry were normal. After gastric lavage and administration of activated charcoal 1 g/kg he developed hypotension and bradycardia. He was given atropine, transcutaneous pacing, aggressive fluid resuscitation, and an infusion of dopamine. He became stuporose and developed a dysarthria. After hemodialysis his vital signs improved rapidly.

The authors suggested that hemodialysis should be considered in severe mexiletine poisoning.

John R. Charpie and Joshua M. Friedland-Little

The authors cautioned that care should be taken when giving propafenone to patients with a history of bronchospasm and that the first dose may need to be administered in hospital. Metabolism An attack of variegate porphyria was precipitated in a 40-year-old man 1 week after he started to take propafenone for paroxysmal atrial fibrillation [122A]. He had abdominal pain and bloody urine and there was an increase in urinary porphobilinogen. Drug overdose Inadvertent overdose of propafenone has been described [123A].

Propafenone

[SED-15, 2939; SEDA-32, 351; SEDA-33, 389, SEDA-34, 298] Respiratory Propafenone is a betaadrenoceptor antagonist and even a relatively small dose can exacerbate obstructive airways disease in a susceptible subject [121A].

• A 78-year-old woman with asthma was given propafenone 150 mg tds for recurrent supraventricular tachycardia. After the second dose she developed progressively severe dyspnea at rest, with widespread wheezes and coarse crackles. She was hypoxemic with a respiratory acidosis. She was given oxygen, methylprednisolone, furosemide, and salbutamol and recovered after 3 days.

• A 17-year-old boy had a seizure lasting 2 minutes after taking six tablets that he had purchased from a classmate. He felt weak and dizzy after about 3 hours, just before the seizure. His QRS complex was prolonged at 168 ms. A bolus dose of sodium bicarbonate bolus and infusion shortened the QRS length to 90 ms.

The tablets were identified as propafenone hydrochloride 225 mg. The classmate had misleadingly sold the pills as Percocet® (paracetamol + oxycodone) because of their similar “512” imprint. Intravenous fat emulsion therapy has been used to treat two cases of propafenone intoxication in which standard sodium bicarbonate therapy was inadequate [124A,125A].

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