Positive inotropic drugs and drugs used in dysrhythmias

J.K. Aronson

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Positive inotropic drugs and drugs used in dysrhythmias

CARDIAC GLYCOSIDES (SED-14, 523; SEDA-24, 197; SEDA-25, 205; SEDA-26, 198) There has been a multicenter, randomized, placebo-controlled, double-blind comparison of aprindine and digoxin in the prevention of atrial fibrillation and its recurrence in 141 patients with symptomatic paroxysmal or persistent atrial fibrillation who had converted to sinus rhythm (lC). They were randomized in equal numbers to aprindine 40 mg/day, digoxin 0.25 rag/day, or placebo, and were followed every 2 weeks for 6 months. After 6 months the Kaplan-Meier estimates of the numbers of patients who had no recurrences while taking aprindine, digoxin, and placebo were 33%, 29%, and 22% respectively. The rates of adverse events were similar in the three groups. This confirms that digoxin does not prevent relapse of symptomatic atrial fibrillation after conversion to sinus rhythm. Of 603 adults aged 79 (s.d. 7) years, of whom 59% were women and 18% AfricanAmerican, 376 patients (62%) were discharged taking digoxin, and 223 (37%) had no indication for its use, based on the absence of left ventricular systolic dysfunction or atrial fibrillation (2c). After adjustment for various factors, prior digoxin use (OR = 11; 95% CI = 5.7, 23) and pulse over 100/min (OR = 2.33; 95% CI = 1.1, 4.9) were associated with inappropriate digoxin use. Unfortunately, the authors did not report the frequency of adverse effects, and it is not therefore clear whether patients in whom digoxin is used inappropriately are more or less likely to suffer adverse reactions.

In a multicenter survey, conducted between 1988 and 1997, of 28411 patients aged 70 (s.d. 16) years admitted to 81 hospitals throughout Italy, 1704 had adverse drug reactions (3c). In 964 cases (3.4% of all admissions), adverse reactions were considered to be the cause of admission. Of these, 187 were regarded as severe. Gastrointestinal complaints (19%) were the most common, followed by metabolic and hemorrhagic complications (9%). The drugs most often responsible were diuretics, calcium channel blockers, non-steroidal anti-inflammatory drugs, and digoxin. Female sex (OR = 1.30: 95% CI = 1.10, 1.54), alcohol use (OR = 1.39: 95% CI = 1.20, 1.60), and number of drugs (OR = 1.24; 95% CI = 1.20, 1.27) were independent predictors of admission for adverse reactions. For severe adverse reactions, age (for age 65-79, OR = 1.50; 95% C I - 1.01, 2.23; for age 80 and over, OR = 1.53; 95% CI = 1.00, 2.33), co-morbidity (OR = 1.12; 95% CI = 1.05, 1.20 for each point on the Charlson Comorbidity Index), and number of drugs (OR = 1.18; 95% CI = 1.11, 1.25) were predisposing factors. Of the 28411 patients, about 6700 were taking digoxin, and they suffered 82 adverse effects, either gastrointestinal (n = 28) or unspecified dysrhythmias (n = 44), or presumably both (data not given); of those, 11 were graded as severe (two gastrointestinal and nine dysrhythmias). C a r d i o v a s c u l a r Digoxin has previously been reported to cause atrial tachycardia with Wenckebach atrioventricular block (SEDA-26, 198) and another case has been reported in a patient who in error took three times the recommended dose (4A). Special senses

9 2004 Published by Elsevier B.V.

Side Effects of Drugs, Annual 27 J.K. Aronson, ed.

Early studies suggested that

impairment of color vision, measured with sensitive tests, was related to serum digoxin concentrations and peripheral measures of Na/K 185

186 pump function (SEDA-5, 176; SEDA-10, 143). There have also been reports of patients with evidence of digoxin toxicity and serum concentrations in the usual target range who nevertheless had impaired color vision (SEDA23, 194). However, in a study of 30 patients (mean age 81 years) taking digoxin and an agematched control group there was no correlation between color vision impairment and serum digoxin concentration (5~). There was slight to moderate red-green impairment in 20-30% of those taking digoxin, depending on the test used; about 20% had a severe tritan defect. The authors suggested that color vision testing in elderly patients would have limited value in the detection of digitalis toxicity. However, this conclusion was based on using the digoxin concentration as a standard, while the point of pharmacodynamic tests, such as color vision measurement, is that they are supposed to reflect the effect of the drug better than the serum concentration.

Death

Sex-based differences in the effect of digoxin have been explored in a post-hoc analysis of the data from the Digitalis Investigation Group (DIG) study (SEDA-20, 173; 6c). There was an absolute difference of 5.8 percent (95 CI = 0.5, 11) between men and women in the effect of digoxin on the case fatality rate from any cause. Women who were randomly assigned to digoxin had a significantly higher fatality rate than women who were randomly assigned to placebo (33% vs. 29%), while the fatality rate was similar among men randomly assigned to digoxin or placebo (35% vs. 37%). However, serum digoxin concentrations were higher in the women at 1 month, and this may have contributed to the increased risk of death (7r). In another post-hoc analysis of the data from the DIG study the patients who had been randomized to digoxin were divided into three groups, according to serum digoxin concentration, 0.5-0.8 ng/ml, 0.9-1.1 ng/ml, and 1.2 ng/ml and over (8c). Higher concentrations were associated with higher all-cause fatality rates: 30%, 39%, and 48% respectively. Both of these studies suggest that lower serum concentrations of digoxin (0.5-1.0 ng/ml) may be beneficial for routine therapy of heart failure than have traditionally been recommended (0.8-2.0 ng/ml), and this has been discussed in a brief review (9r).

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Drug interactions Acarbose has previously been reported to reduce the absorption of digoxin after oral administration (SEDA-24, 202). There has been a further anecdotal report of this interaction (10 A) and a formal study of the pharmacokinetics of a single dose of digoxin 0.75 mg before and after the administration of acarbose 50 mg tds for 12 days in healthy volunteers (11~). Apart from a small increase in Cmax, the pharmacokinetics of digoxin were unaffected by acarbose. It is not uncommon for anecdotal reports of a possible interaction to be unconfirmed by formal kinetic studies, and it is possible in such cases that there is a subset of patients who are susceptible to the interaction who have not been included in the formal study. In this case, for example, it may be that the interaction occurs in people with diabetes and not in healthy subjects. There may also be a difference between the effect of acarbose on a single dose of digoxin, compared with steadystate therapy. Advice that acarbose and digoxin should be administered 6 hours apart is still reasonable. The thrombin inhibitor argatroban had no effect on the steady-state pharmacokinetics of oral digoxin 0.375 mg/day in 12 healthy volunteers; the argatroban was given as an intravenous infusion of 2 p.g/kg/min on days 11-15 (12c). Fondaparinux sodium, a selective inhibitor of factor Xa, is eliminated by the kidneys. In a randomized, crossover study in 24 healthy volunteers the pharmacokinetics and pharmacodynamics of digoxin 0.25 mg/day orally for 7 days were unaffected by fondaparinux sodium 10 mg/day subcutaneously for 7 days (13c). The macrolide antimicrobial drugs can reportedly interact with digoxin by at least two mechanisms: by reducing its metabolism in the gut before absorption (by inhibiting the growth of the bacterium Eubacterium glenum) and by inhibiting P glycoprotein (SEDA-26, 200). However, in a study of the latter mechanism in nine healthy Japanese men, clarithromycin 200 mg bd and erythromycin 200 mg qds did not alter the plasma concentration vs time curve of a single intravenous dose of digoxin 0.5 mg, but increased its renal clearance (14c). This contrasts with a previous observation of reduced renal clearance of digoxin in two patients taking clarithromycin (SEDA-23, 194). That inhibition of renal P glycoprotein may not reduce

Positive inotropic drugs and drugs used in dysrhythmias

the renal clearance of digoxin has also been suggested by studies with talinolol (SEDA-25, 172) and atorvastatin (15r Other transport mechanisms for digoxin, including the organic anion-transporting polypeptides, have not been well studied and may play a role in digoxin disposition and hence drug interactions. The quinolone antimicrobial drugs gemifloxacin and sparfloxacin have previously been shown not to interact with digoxin (SEDA-24, 203) and another study has shown the same with levofloxacin 500 mg bd for 6 days in 12 healthy volunteers ( 16r The effects of statins on the pharmacokinetics of digoxin have been variable. For example, cerivastatin had no effect on the steady-state pharmacokinetics of digoxin in 20 healthy men (SEDA-24, 202), and rosuvastatin 40 mg/day had no effect on the pharmacokinetics of a single oral dose of digoxin 0.5 mg in 18 healthy men (17c). In contrast, atorvastatin 80 mg/day increased the AUC and Cmax of digoxin 0.25 rag/day by 15% and 20% respectively during steady-state therapy, without affecting renal digoxin clearance (15c), and a single dose of fluvastatin increased the steadystate Cmaxof digoxin 0.125-0.5 mg/day by 11% and renal clearance by 15%, without changing AUC or tmax (18c). There is no simple explanation that reconciles these disparate findings. The alphal-adrenoceptor antagonist tamsulosin 0.4 and 0.8 mg/day had no effect on the pharmacokinetics of a single intravenous dose of digoxin 0.5 mg in 10 healthy men (19c). The effects of nitrates on the pharmacokinetics of digoxin are probably small. Nitroprusside has previously been shown to cause a small increase in the renal clearance of digoxin, perhaps by increasing renal blood flow (SEDA-7, 197). In eight patients with chronic heart failure taking digoxin 0.25 mg/day, isosorbide dinitrate 10 mg tds caused only a small increase in Cmax (15%) and had no effect on the mean steadystate serum concentration or AUC (20c). Studies of the effects of diltiazem on the pharmacokinetics of digoxin have yielded variable results. In one study, diltiazem reduced the steady-state total body clearance of betaacetyldigoxin in 12 healthy men, perhaps because of reduced renal and non-renal clearances (SEDA-10, 145). In some other studies diltiazem 120-240 mg/day increased steady-state plasma digoxin concentrations by about 2040% (SEDA-14, 146; 21c), although not in

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other studies (SEDA-14, 146), and reduced the total body clearance of digoxin, with changes in both renal and non-renal clearances (SEDA-11, 154), although others did not find this (22c). In at least one case digoxin toxicity was attributed to this interaction (SEDA-17, 216). In a recent study in eight patients with chronic heart failure taking digoxin 0.25 mg/day, diltiazem 180 mg/day increased the AUC and mean steadystate serum concentrations of digoxin by 50% and reduced its total clearance (20 c).

Interference with diagnostic tests

Crossreaction of spironolactone, canrenone, and their metabolites with antidigoxin antibodies used in radioimmunoassays is well known (SEDA24, 203; 23r). In most cases this results in falsely high digoxin concentrations, although interference, with apparently reduced digoxin concentrations, has also been reported. In nine assays (AxSYM, IMx, TDx, Emit, Dimension, aca, TinaQuant, Elecsys, and Vitros) interference by spironolactone, canrenone, and three metabolites was sought in vitro, and all routine digoxin measurements using the AxSYM system over 16.5 months (n = 3089) were reviewed (24cE). There was a reduction in the expected concentrations by canrenone (3125 p.g/1) in the following assays: AxSYM (42% of expected), IMx (51%), and Dimension (78%). There was positive bias in aca (0.7 gg/1), TDx (0.62 gg/1), and Elecsys (>0.58 p.g/1). Of 669 routinely monitored patients, 25 had falsely low results and 19 of them actually had potentially toxic digoxin concentrations; this was attributable to concurrent therapy with spironolactone, canrenone, hydrocortisone, or prednisolone. However, standard doses of spironolactone (up to 50 mg/day) in patients with heart failure produced less than 11% inhibition.

Diagnosis of adverse drug reactions

Plasma

In a retrospective analysis of 210 randomly selected digoxin plasma concentration determinations in in-patients, the indications were considered to have been inappropriate in 67, appropriate in 81, and unevaluable in four (25c). Timing of the blood sample was wrong in 17 cases. Of the measurements whose indications were considered to have been inappropriate, most (52) were performed as part of "routine" monitoring. or serum concentrations

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188 Management o f p o i s o n i n g Fab fragments of antidigoxin antibodies are considered to be the treatment of choice after self-poisoning with cardiac glycosides, although the evidence of their efficacy is anecdotal (SEDA-25, 173), and another anecdotal report has been published (26A). It is not known whether the antibody reduces mortality; one randomized controlled study (SEDA-23, 195) was too small to detect an effect on mortality after self-poisoning with seeds of the yellow oleander, which contains cardiac glycosides such as peruvoside. In 401 patients with acute self-poisoning with yellow oleander seeds, the fatality rate was reduced from 8.0% to 2.5% by the administration of repeated doses of activated charcoal, 50 g 6hourly for 3 days (27c). Activated charcoal, given in this way, should be standard treatment in glycoside self-poisoning in addition to Fab fragments of antibody or when antibody is not available. Because digoxin has a large volume of distribution, one would not expect exchange transfusion to be effective by itself in treating digoxin overdose. However, there have been two reports of the use of exchange transfusion to remove Fab antibody fragment~ligoxin complexes in patients with acute anuric renal insufficiency (28 A, 29A). 9 A 70-year-old man with alcoholic cirrhosis was given amiodarone and digoxin for atrial fibrillation after a hemicolectomy for adenocarcinoma (29A). He developed acute renal insufficiencyand digoxin toxicity, with a serum concentration of 4.4 ng/ml. A dose of Fab antidigoxin antibody fragments was followed 16 hours later by exchange transfusion and another dose was followed by two exchanges. He recovered slowly over the next few days. The total digoxin concentration (antibody bound and unbound) rose after the first dose of Fab fragments but did not fall until after the second plasma exchange (after the second dose of Fab fragments). Digoxin was recovered from the plasma collection bags, but the total amount recovered seems to have been less than 100 Izg, so the efficacy of plasma exchange in this case is not clear. The suggestion that intravenous calcium should be used to treat the hyperkalemia that can occur in digitalis intoxication (30 R) has been challenged, on the grounds that it may increase the risk of cardiac dysrhythmias in such cases (31 r).

J.K. Aronson

OTHER POSITIVE INOTROPIC DRUGS (SED-14, 532; SEDA-24, 204; SEDA-25, 208; SEDA-26, 201)

Enoximone Enoximone has been used to treat cardiogenic shock in a case of self-poisoning with verapamil 2.4 g in a 40-year-old woman; treatment with calcium and noradrenaline had been unsuccessful (32A).

Milrinone Intravenous milrinone has been used, with some success, to treat patients with severe cardiac failure (SEDA-22, 203). It can be particularly useful in tiding patients over while they are waiting for definitive treatment, as another anecdotal report has demonstrated (33A). 9 A 48-year-old man with an inflammatory aneurysm

of the ascending aorta and severe heart failure due to massive aortic regurgitation was given a continuous intravenous infusion of milrinone 0.5 I.tg/kg/minute. His pulmonary arterial pressure fell and his symptoms improved over 7 weeks while he was taking corticosteroids. The diseased tissue was successfully replaced at operation and the milrinone was tapered uneventfully. The authors suggested that continuous milrinone infusion may be suitable for patients with surgically correctable inflammatory cardiovascular diseases complicating severe heart failure in whom maintenance of optimal hemodynamics is necessary for several weeks before operation. However, milrinone did not prove valuable in a randomized, double-blind, placebocontrolled trial in 78 community and tertiary care hospitals in the USA, in which 951 patients admitted with an exacerbation of systolic heart failure (mean age 65 years; 92% with baseline NYHA class III or IV; mean left ventricular ejection fraction 23%) were randomly assigned to a 48-hour infusion of either milrinone (0.5 p.g/kg/minute initially for 24 hours) or saline (34c). The median number of days in hospital for cardiovascular causes within 60 days after randomization did not differ significantly between patients given milrinone

Positive inotropic drugs and drugs used in dysrhythmias (6 days) or placebo (7 days). Sustained hypotension requiring intervention (11% vs 3.2%) and new atrial dysrhythmias (4.6% vs 1.5%) were more common in the patients who received milrinone. There was no difference in hospital mortality (3.8% vs 2.3%), 60-day mortality (10% vs 8.9%), or the composite incidence of death or readmission (35% vs 35%). The authors concluded that these results do not support the routine use of intravenous milrinone as an adjunct to standard therapy in patients with an exacerbation of chronic heart failure. The disappointing results with positive inotropic drugs in treating acute and chronic heart failure may be due to the fact that they increase both systolic and diastolic calcium concentrations in the myocardium (35r).

Olprinone Olprinone, an inhibitor of phosphodiesterase type 1II, is given intravenously and is mostly eliminated by the kidneys. Its pharmacological effects have been reviewed (36R). Its major adverse effects are cardiac dysrhythmias and thrombocytopenia, the latter with a reported incidence of 0.43%.

DRUGS USED IN DYSRHYTHMIAS A d e n o s i n e (SED-14, 536; SEDA-24, 205; SEDA-25, 210; SEDA-26, 203) Cardiovascular Adenosine can occasionally cause serious cardiac dysrhythmias (SEDA-20, 175), and more cases of ventricular fibrillation have been reported in four patients with preexcited atrial fibrillation who had been given 12 mg of adenosine (37c). After resuscitation electrophysiological studies were carried out before catheter ablation of a single accessory pathway. In a control group of five patients with single accessory pathways, sustained atrial fibrillation was induced by rapid atrial pacing and adenosine 12 mg was given. The patients had shorter antegrade effective refractory periods in the accessory pathways than the controls:

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227 (s.d. 29) vs 289 (s.d. 37) ms respectively. The atrial effective refractory periods were 210 (s.d. 17) vs 219 (s.d. 2l) ins respectively. The shortest RR interval during atrial fibrillation was 246 (s.d. 51) ms in the patients and 301 (s.d. 60 ms) in the controls. After adenosine, none of the controls developed ventricular fibrillation. The authors concluded that adenosine can cause ventricular fibrillation when it is given during pre-excited atrial fibrillation, particularly in patients who have accessory pathways with short refractory periods. Nervous system Adenosine has been used intrathecally to treat pain, but can itself cause backache (SEDA-23, 197). In a placebo-controlled study in 40 healthy volunteers, who were given intrathecal adenosine 2 mg in 2 ml of saline, 13 had a mild headache, nine had mild to moderate backache, and one had mild aching in the thigh, compared with none of those who were given saline alone (38c). No headaches or leg aches occurred later than 6 hours after the injection, but the backaches occurred at 6-24 hours; there were no later symptoms. In a randomized, double-blind study of two doses of intrathecal adenosine in 35 volunteers with experimental hypersensitivity induced by capsaicin, intrathecal adenosine 0.5 or 2 mg in 2 ml of saline, but not saline alone, equally reduced areas of allodynia and hyperalgesia from capsaicin (39c). There were adverse effects in 1, 2, and 6 of the volunteers who received saline, 0.5 mg, and 2.0 mg of adenosine respectively. The adverse effects were headache, backache, and leg or groin ache. Intravenous aminophylline 5 mg/kg, given 2 hours after the adenosine, did not reverse the effects of adenosine. Backache was also observed in patients with chronic neuropathic pain after intrathecal adenosine (40c).

Amiodarone

(SED-14, 537; SEDA-24, 206; SEDA-25, 211; SEDA-26, 204) In a meta-analysis of five randomized, placebocontrolled trials of amiodarone 200-1200 mg/ day for 2-7 days in the treatment of postoperative atrial fibrillation and flutter in 764 patients, the incidence of adverse events with

190 amiodarone was no greater than with placebo (41M). In a meta-analysis of five randomized, placebo-controlled trials of intravenous amiodarone about 500-2200 mg over 24 hours in the treatment of recent-onset atrial fibrillation in 410 patients, the incidence of adverse events was 27% with amiodarone and 11% with placebo (42M). Intravenous amiodarone was significantly more effective than placebo in producing cardioversion. The most common adverse effects of intravenous amiodarone were phlebitis, bradycardia, and hypotension; most of these effects were not considered to be dose limiting. Of 85 patients with persistent atrial fibrillation after balloon mitral valvotomy given amiodarone (600 mg/day for 2 weeks and 200 mg/day thereafter), 33 converted to sinus rhythm (43c). Of the other 52 patients, who underwent DC cardioversion at 6 weeks, 41 converted to sinus rhythm. Six patients had adverse effects attributable to amiodarone. Five had mild gastrointestinal symptoms, such as abdominal discomfort and nausea. One developed hypothyroidism after 3 months, which resolved when the dosage of amiodarone was reduced to 100 mg/day. In 83 patients (27 women, 56 men; mean age 61 years) disopyramide, propafenone, or sotalol were used to prevent recurrence after elective electrical cardioversion for persistent atrial fibrillation (44c). If there was recurrence cardioversion was repeated and the patient was given one of the other antidysrhythmic drugs. If there was further recurrence, amiodarone was used, a third cardioversion was performed, and, if sinus rhythm was restored, amiodarone 100-200 mg/day was continued. Patients in whom the initial cardioversion was not successful were given amiodarone and underwent repeated cardioversion. The follow-up duration was 12 months. The first electrical cardioversion was effective in 44 (53%) patients, and after 1 year 23 (52%) of them were still in sinus rhythm. None of the patients who underwent a second cardioversion and received a second anfidysrhythmic drug stayed in sinus rhythm. Amiodarone as a third antidysrhythmic agent was effective in 10 (48%) patients. After 12 months of antidysrhythmic drug therapy sinus rhythm was maintained in 75% of patients in whom the first cardioversion had been effective, accounting for 40%

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of all the patients selected for cardioversion. In the 83 patients, sequential antidysrhythmJc treatment effectively maintained sinus rhythm in 54 (65%), of whom 31 (57%) took amiodarone. The authors concluded that repeated electrical cardioversion and antidysrhythmic drug therapy enabled maintenance of sinus rhythm in 68% of patients for 1 year, that there was limited efficacy of the first antidysrhythmic drug given after a first effective electrical cardioversion, regardless of the drug used, excluding amiodarone, and that when atrial fibrillation recurred, a second antidysrhythmic drug, other than amiodarone, was completely ineffective. There were very few adverse events in this study. One patient taking amiodarone developed hyperthyroidism and two had symptomatic bradycardia.

Cardiovascular Amiodarone can sometimes cause atrialflutter, even though it is also used to treat it (SEDA-25, 180). There has been a report of seven cases (six men and one woman, aged 34-75 years) of 1 : 1 atrial flutter with oral amiodarone (45 c). Four of them had underlying cardiac disease; none had hyperthyroidism. The initial dysrhythmia was 2 : 1 atrial flutter (n = 4), 1 : 1 atrial flutter (n ----2), or atrial fibrillation (n = 1). One patient was taking amiodarone 200 mg/day and one was taking 400 mg/day plus carvedilol. The other five all received loading doses of 9200 (s.d. 2400) mg over 10 (s.d. 4) days. There was an adrenergic trigger factor (exertion, fever, esophageal stimulation, or a beta-adrenoceptor agonist aerosol) in five patients. One required emergency cardioversion. T wave alternans has previously been attributed to amiodarone (SEDA- 18, 201; SEDA26, 204), and another case has been reported (46A). 9 A 65-year-old man with atrial fibrillation was given intravenous amiodarone 450 mg over 30 minutes followed by 900 mg over 24 hours. He reverted to sinus rhythm, but the electrocardiogram showed giant T wave alternans with a variable QT interval (0.52~).84 see). He had a short bout of torsade de pointes and was given magnesium. Two days later the electrocardiogram was normal.

Respiratory Two patients with dilated cardiomyopathy developed pneumonitis after 6 weeks and 8 months while taking amiodarone 400 and 200 mg/day respectively (47A). Cases

Positive inotropic drugs and drugs used in dysrhythmias that occurred as rapidly as the first of these have previously been reported (SEDA-26, 204). Several techniques have been used in the diagnosis of amiodarone-induced lung damage, including 67gallium scintigraphy (SEDA-15, 168). 9 A 75-year-old man, who had taken amiodarone 200 mg/day for 4 years, developed acute dyspnea, chest pain, fever, and sweats (48A). The chest X-ray showed diffuse alveolar and interstitial infiltrates, particularly at the lung bases. No pathogenic organisms were isolated and antibiotics had no effect. There was no evidence of sarcoidosis. Pulmonary 67gallium scintigraphy showed extensive uptake of tracer throughout both lungs, consistent with amiodarone pneumonitis on a background of asbestosis with interstitial fibrosis. Treatment with corticosteroids after withdrawal of amiodarone resulted in marked clinical improvement.

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correlate with clinical or electromyographic evidence of myopathy. In the peripheral nerves there was demyelination, some axon loss, and a variable number of characteristic lysosomal inclusions. Muscle specimens from two patients showed evidence of a vacuolar myopathy. After withdrawal of amiodarone, two patients improved and one died with a cardiac dysrhythmia. Benign orgasmic headache has been associated with amiodarone (51A). 9 A 52-year-old man, who had taken amiodarone 800 mg/day for 7 months, developed acute, severe, throbbing headaches precipitated by coitus and occasionally other forms of exertion. An MRI scan of the brain was normal. When the dose of anaiodarone was reduced to 200 mg/day the headaches diminished in frequency and severity. When the dose was increased again to 400 mg/day they increased in frequency and severity. The amiodarone was withdrawn and the headaches resolved.

The authors said that the extensive changes on gallium scanning, not present on the chest X-ray, had helped them to make the diagnosis, although a high-resolution CT scan had also shown widespread changes. Another scanning technique, 99mTc-diethylene triamine penta-acetic acid (DPTA) aerosol scintigraphy, has been compared with 67Ga scanning in 26 patients, seven with amiodaroneinduced lung damage, eight taking amiodarone without lung damage, and 11 healthy controls (49c). 67Ga scintigraphy was positive in four of the seven patients with lung damage but normal in the others. There was a positive correlation between 99mTc-DTPA clearance and the cumulative dose of amiodarone. The mean clearance values were 2 percent/min in those with amiodarone-induced lung damage, 1.3 percent/rain in those without lung damage, and 0.9 percent/rain in the controls. The authors concluded that 67Ga lung scinfigraphy is useful for detecting amiodarone-induced lung damage but that 99mTc-DTPA aerosol scintigraphy is better.

Special senses Of 22 patients taking longterm amiodarone, two who had otherwise healthy eyes had abnormal blue color vision (52':); color vision abnormalities have previously been described (SEDA-12, 153). Otherwise, color vision, contrast sensitivity, and visual fields were normal or could be explained by eye diseases such as cataract. There were corneal drug deposits in all of the eyes, slight anterior subcapsular lens opacities in 22%, and dry eyes in 9%, as previously reported (SEDA-23, 199).

Nervous system Amiodarone-induced neuromyopathy has been studied in three patients by a review of their records, electromyography, and histopathology of muscle and nerve (50At). Two patients had a slightly asymmetric, mixed, but primarily demyelinating sensorimotor polyneuropathy and the third had an acute neuropathy resembling Guillain-Barr6 syndrome. Creafine kinase activity did not

A 63-year-old man reduced his dietary sodium intake to combat fluid retention and was taking furosemide 40 mg/day, spironolactone 50 mg/day, and enalapril 2.5 mg/day (54A). He then took amiodarone 800 mg/day for 7 days and his serum sodium concentration fell to 119 mmol/1; his plasma vasopressin concentration was raised at 2.6 pmol/l. The dose of annodarone was reduced to 100 mg/day, with fluid restriction; his sodium rose to 130 mmol/1 and his vasopressin fell to 1.4 pmol/1.

Amiodarone was originally developed as a vasodilator, and that may have been the cause of headaches in this case.

Endocrine Amiodarone-induced hyponatremia, due to the syndrome of inappropriate secretion of antidiuretic hormone, is rare (SEDA21,199; 53A), but another three cases have been reported.

192 9 An 87-year-old man reduced his dietary sodium intake to combat fluid retention and was taking furosemide 40 mg/day and spironolactone 25 mg/day (54A). He then took amiodarone 200 mg/day for 7 days and 100 mg/day for 8 days and his serum sodium concentration fell to 121 mmol/1; his plasma vasopressin concentration was raised at 11 pmol/1. Amiodarone was continued, with fluid restriction; his sodium rose to 133 mmol/1 and his vasopressin fell to 2.4 pmol/l. 9 A 67-year-old man, who had taken amiodarone 200 mg/day for 3 months, developed hyponatremia (serum sodium concentration 117 retool/l) (55A). He was also taking furosemide 20 mg/day, spironolactone 25 mg/day, and lisinopril 40 mg/day. His urine osmolality was 740 mosmol/kg with a normal serum osmolality. Fluid restriction was ineffective, but when amiodarone was withdrawn the sodium rose to 136 mmol/l. In all three c a s e s other factors m a y have contributed to the h y p o n a t r e m i a that amiodarone seems to have caused. The m e c h a n i s m of this rare effect is unknown. Unlike other adverse effects of amiodarone, it seems to occur rapidly and to r e s o l v e rapidly after withdrawal.

Amiodarone and thyroid disease Many of the adverse effects o f amiodarone are a function o f both cumulative dose and time o f exposure and this may be true o f thyroid disease. In a nested case-control analysis of 5522 patients with a first prescription f o r an antidysrhythmic drug and no previous use of thyroid drugs, cases were defined as all patients who had started a thyroid-mimetic or antithyroid drug no sooner than 3 months after the start of an antidysrhythmic drug and controls were patients with a comparable follow-up period who had not taken any thyroid drugs during the observation period (56c). There were 123 patients who had started antithyroid drugs and 96 who had started a thyroid-mimetic drug. In users of amiodarone there were adjusted odds ratios o f 6.3 (95% CI = 3.9, lO) f o r hyperthyroidism and 6.6 (3.9, 1 1 ) f o r hypothyroidism compared with users of other antidysrhythmic drugs. Patients who were exposed to a cumulative dose o f amiodarone over 144 g had an adjusted odds ratio o f 13 (6, 27) f o r hyperthyroidism; the dose relation f o r hypothyroidism was less pronounced.

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l~pes of hyperthyroidism Amiodarone-induced hyperthyroidism is o f two types (SEDA-23, 199): type 1 occurs in those with latent disease and is due to the iodine that amiodarone contains; type 2 is due to a destructive thyroiditis in a previously normal gland. The distinction may be important, because type i typically responds to thionamides and perchlorate while type 2 responds to high-dose corticosteroids. Diagnosis is complicated by the effects that amiodarone has on thyroid hormone metabolism (SEDA-15, 170), and other diagnostic methods have been sought. Color-flow Doppler sonography o f the thyroid and measurement o f serum interleukin-6 (IL-6) have been studied as diagnostic tools in a retrospective case-note study of patients with amiodarone-associated hyperthyroidism (57c). There were 37 patients with amiodarone-associated hyperthyroidism (mean age 65, range 20-86 years), and 25 underwent color-flow Doppler sonography. Of those, 10 were classified as type 1 (based on increased vascularity) and 10 as type 2 (based on patchy or reduced vascularity); five were indeterminate. In those with type 1 hyperthyroidism, free serum thyroxine tended to be lower (52 vs 75 pmol/1), free serum triiodothyronine was lower (8.8 vs. 16 pmol/l), the cumulative amiodarone dose was lower (66 vs. 186 g), and less prednisolone was used (because the diagnosis of type 1 .disease encouraged steroid withdrawal); however, carbimazole doses were not different and the time to euthyroidism was the same in the two groups (81 vs. 88 days). IL-6 was raised in two patients with type 1 and in one patient with type 2 hyperthyroidism. The authors proposed that color-flow Doppler sonography could be used to distinguish the two subtypes, confirming an earlier report (58c), but that IL-6 measurement was unhelpful However, others have suggested that the differentiation o f amiodarone-induced hyperthyroidism into two types is not helpful in determining suitable therapy (59c). 0 f 2 8 consecutive patients there was spontaneous resolution of hyperthyroidism in five and 23 received carbimazole alone as first-line therapy. Long-term euthyroidism was achieved in 11, five became hypothyroid and required long-term thyroxine, and five relapsed after withdrawal of carbimazole and became euthyroid with either longterm carbimazole (n = 3) or radioiodine (n = 2). Four were intolerant o f carbimazole and

Positive inotropic drugs and drugs used in dysrhythmias received propylthiouracil, with good effect in three. One was resistant to thionamides and responded to corticosteroids. There was no difference in presentation or outcome between those in whom amiodarone was continued or stopped or between possible type 1 or type 2 disease (defined clinically and by serum IL-6 measurement). The authors concluded that continuing amiodarone has no adverse effect on the response to treatment of hyperthyroidism and that first-line therapy with a thionamide alone, whatever the type of disease, is appropriate in iodine-replete areas, thus avoiding potential complications of other drugs. However, it is not clear how good their differentiation of types 1 and 2 disease was. A previous prospective study in 24 patients showed that differentiation predicted response to treatment (60c). Susceptibility factors It has been suggested that men are more susceptible to hyperthyroidism due to amiodarone (6F). Of 122 600 patients in 12 practices in the West Midlands in the UK, 142 men and 74 women were taking amiodarone and 27 (12.5%) had thyroid disease. Of those, 11 men (7.7%) and four women (5.4%) had hypothyroidism, a nonsignificant difference; however, 12 men (8.5%) had hyperthyroidism compared with no women. This difference is particularly striking because hyperthyroidism is usually more common in women. Deaths Not only is amiodarone-induced hyperthyroidism difficult to treat, but it can also be fatal, as has been reported in two cases (62 A): 9 a 62-year-old man who tutd taken amiodarone for 2 years; carbimazole 40 mg/day, prednisolone, lithium, and colestyramine were ineffective and he died with hepatic encephalopathy and multiorgan failure; 9 a 55-year-old man who had taken amiodarone for 4 years," carbimazole 60 mg/day, prednisolone, and lithium were ineffective and he died with septicemia and multiorganfailure; In three other cases reported in the same papel, severe hyperthyroidism responded severally to treatment with carbimazole, carbimazole plus lithium, or propylthiouracil. In one case amiodarone therapy was restarted after prophylactic subtotal thyroidectomy.

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Treatment Agents used in oral cholecystography, such as ipodate and iopodate, which are rich in iodine and potent inhibitors of 51-deiodinase, have been used to treat amiodarone-induced hyperthyroidism (SEDA-26, 205). Three patients with type I diJease, two of whom had not responded to methimazole plus perchlorate, were successfully treated with a short course of iopanoic acid 1 g/day, resulting in a marked reduction in the peripheral conversion ofT4 to T3 (63A). Euthyroidism was restored in 7-12 days, allowing unevenO~ul thyroidectomy. The patients were then treated with levothyroxine for hypothyroidism and amiodarone was safely restarted. The authors suggested that iopanoic acid is the drug of choice for rapid restoration of normal thyroid function before thyroidectomy in patients with drug-resistant type 1 amiodarone-induced hyperthyroidism. The use of local anesthesia for total thyroidectomy in patients with amiodarone-induced hyperthyroidism and cardiac impairment has been reviewed in the context of six patients

( 64c ). H e m a t o l o g i c Bone-marrow granulomata have rarely been reported in patients taking amiodarone (SEDA-23, 199; SEDA-25, 182), but another case has been reported (65A). 9 A 76-year-old man, who had taken amiodarone

for an unspecified time, developed a monoclonal gammopathy with bone-marrow granulomata. After another 2 years he developed hepatic granulomata and the amiodarone was withdrawn. The bone-marrow granulomata resolved within a few months. Infections were excluded and there was no evidence of sarcoidosis. Skin The severe form of erythema multiforme known as toxic epidermal necrolysis has rarely been attributed to amiodarone (66A), but another case has been reported (67A). 9 A 7t-year-old woman, who had taken amiodarone 200 mg/day for 3 months and diltiazem for 8 months, developed extensive erythema, blistering, and erosions affecting 50% of the body surface area, with a maculopapular rash on the limbs. She developed bilateral pneumonia and septicemia and died after 7 days.

Lupus-like syndrome has rarely been attributed to amiodarone (SEDA-24, 208), but another case has been reported (68A). Immunologic

Chapter 17

194 9 A 59-year-old man, who had taken amiodarone 200 rag/day for 2 years, developed fever, pleuritic chest pain, dyspnea at rest, a non-productive cough, malaise, and joint pains. He had a verrucous endocarditis and a pleuropericardial effusion. He had raised titers of antinuclear antibodies (1 : 320) with anti-Ro specificity. Serum complement was normal and there were no circulating immune complexes, no cryoglobulins, and no anti-dsDNA, antiLa, anti-U1 ribonucleoprotein, anti-Sm, anti-Scl, 70, anti-Jo 1, antihistone, antiphospholipid, anticentromere, anticardiolipin, or anticytoplasmic antibodies. Within 7 days of withdrawal of amiodarone the signs and symptoms started to resolve, and he recovered fully with the addition of prednisolone. Drug formulations The steady-state plasma concentrations of amiodarone and desethylamiodarone in 77 patients taking two different formulations, a new generic formulation and Cordarone | were comparable (69c). Drug interactions The interaction of amiodarone with warfarin is well known (SEDA-24, 210). In a study of this interaction in 43 patients who took both amiodarone and warfarin for at least 1 year, the interaction peaked at 7 weeks and the mean dosage of warfarin fell by 44% from 5.2 to 2.9 mg/day (70c). The dosage of warfarin correlated inversely with the maintenance dose of amiodarone. There were minor bleeding episodes in five patients. The authors recommended reducing the daily warfarin dose by about 25%, 30%, 35%, and 40% in patients taking amiodarone 100, 200, 300, and 400 mg/day respectively. The interaction of amiodarone with Class I antidysrhythmic drugs is well known (SEDA18, 203), particularly because of the risk of QT interval prolongation (SEDA-19, 194). In 26 patients taking mexiletine plus amiodarone for 1 month and 155 taking rnexiletine alone, there was no significant difference in the apparent oral clearance of mexiletine (71c). However, the lack of a pharmacokinetic interaction does not reduce the risk that dangerous QT interval prolongation may occur with a combination such as this.

Aprindine

(SED-14, 541; SEDA-24, 210;

SEDA-26, 207) There has been a multicenter, randomized, placebo-controlled, double-blind comparison

J.K. Aronson

of aprindine and digoxin in the prevention of atrial fibrillation and its recurrence in 141 patients with symptomatic paroxysmal or persistent atrial fibrillation who had converted to sinus rhythm (lC). They were randomized in equal numbers to aprindine 40 mg/day, digoxin 0.25 mg/day, or placebo and followed every 2 weeks for 6 months. After 6 months the Kaplan-Meier estimates of the numbers of patients who had no recurrences with aprindine, digoxin, and placebo were 33%, 29%, and 22% respectively. The rates of adverse events were similar in the three groups. This shows that aprindine has a very small beneficial effect in preventing relapse of symptomatic atrial fibrillation after conversion to sinus rhythm. Furthermore, recurrence occurred later with aprindine than with placebo or digoxin (about 60% recurrence at 115 days compared with 30 days).

Bepridil

(SED-14, 541, 605)

Cardiovascular Bepridil is an antidysrhythmic drug with unusual pharmacological properties, in that it belongs to both Class I and Class IV. In other words, it blocks both the fast inward sodium current and the slow outward calcium current in excitable cardiac cells (SEDA-13, 141). Its main adverse effect is torsade de pointes due to QT interval prolongation. The effect of a beta-blocker (metoprolol 30-40 mg/day or bisoprolol 2.5-5.0 mg/day for 1 month) on the change in QT interval, QT dispersion, and transmural dispersion of repolarization caused by bepridil has been studied in 10 patients with paroxysmal atrial fibrillation resistant to various antidysrhythmic drugs (72c). Bepridil significantly prolonged the QTc interval from 0.42 to 0.50 sec, QT dispersion from 0.07 to 0.14 sec, and transmural dispersion of repolarization from 0.10 to 0.16 sec. The addition of a beta-blocker shortened the QTc interval from 0.50 to 0.47 sec, QTc dispersion from 0.14 to 0.06 sec, and transmural dispersion of repolarization from 0.16 to 0.11 sec. The authors therefore suggested that combined therapy with bepridil and a beta-blocker might be useful for intractable atrial fibrillation.

Positive inotropic drugs and drugs used in dysrhythmias

Cibenzoline

(SED-14, 541; SEDA-24, 210; SEDA-25, 217; SEDA-26, 207) Cardiovascular In three patients in whom cibenzoline had caused sinus node dysfunction, normal sinus node recovery time was restored by cilostazol (73c).

Susceptibility factors

Cibenzoline is 60% eliminated by the kidneys, and renal insufficiency may therefore reduce its elimination (SEDA-15, 174). The importance of this has been suggested by a report of three patients in whom severe renal insufficiency (creatinine clearance 10-16 ml/min) led to increased plasma cibenzoline concentrations during treatment with 300 mg/day (74A). They developed prolonged QTc intervals, widened QRS complexes, dysrhythmias, hypotension, and hypoglycemia. Their plasma cibenzoline concentrations were 1944-2580 p.g/l, 5-10 times higher than the usual target range. The half-lives of cibenzoline immediately after withdrawal were 69, 116, and 198 hours, 3-10 times longer than reported in patients with end-stage renal insufficiency (about 20 hours).

Disopyramide

(SED-14, 543; SEDA-24, 211; SEDA-25, 217; SEDA-26, 208)

Nervous system Neuropathy has rarely been attributed to disopyramide (75A), but another case has been reported (76A). 9 A 71-year-old woman, who had taken disopyramide 500 mg/day for 4 years, developed fatigue, paresthesia, pain, and cramps in her legs. She had proximal weakness in all four limbs and an unsteady gait. Electrophysiology showed a sensorimotor polyneuropathy, with reduced motor conduction velocity and muscle denervation. All antibodies were negative. The symptoms did not respond to prednisone but improved in the months after disopyramide withdrawal.

Dofetilide

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195

disease and sustained ventricular tachycardia (77c). There were significant reductions in heart rate, mean systemic pressure, and cardiac index ( - 1 3 % ) with sotalol, but cardiac index increased significantly with dofetilide (11%) with no effect on heart rate or systemic blood pressure. The authors suggested that oral dofetilide could be useful in patients with ventricular tachydysrhythmias associated with impaired left ventricular function. One patient taking dofetilide reported mild dizziness and there were no cardiac dysrhythmias.

Flecainide (SED-14, 545; SEDA-24, 211; SEDA-25, 217; SEDA-26, 212) A systematic review of 22 studies of the effects of flecainide used for at least 3 months in the treatment of supraventricular dysrhythmias suggested that flecainide is associated with a variety of adverse reactions, many of which are well tolerated, but carries a small risk of serious cardiac events (2%), which can lead to death (0.13%) (SEDA-21,200). In a meta-analysis of 122 prospective studies of the use of flecainide in 4811 patients with supraventricular dysrhythmias, 21 were placebo-controlled and 37 were comparative studies with other antidysrhythmic drugs (78M). The total exposure time was 2015 patient years, with a mean oral flecainide dose of 216 mg/day. There were eight deaths (total mortality 0.17%, fatality rate per 100 patient years 0.40; 95% CI = 0.17, 0.78), confirming the earlier finding. Three deaths were noncardiac (cancer, suicide, urinary sepsis). Of the cardiac deaths, all but two occurred in patients with coronary heart disease. In controls, there was one death. There were prodysrhythmic events in 120 patients taking flecainide (2.7%) and 88 controls (4.8%), 58 (7.4%) of which occurred in patients taking placebo. Non-cardiac adverse effects are listed in Table 1. Thus, fiecainide is safe in patients with supraventricular dysrhythmias with no cardiac damage, in contrast to patients with ventricular dysrhythmias after myocardial infarction.

(SEDA-26, 208)

The hemodynamic effects of dofetilide 500 p.g bd and sotalol 160 mg bd for 3-5 days have been studied in 12 patients with ischemic heart

Cardiovascular In 33 patients with symptomatic and inducible supraventricular tachycardias single doses of placebo, flecainide 3 mg/kg or diltiazem 120 mg plus propranolol

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Table 1. Numbers (%) of cardiac and non-cardiac adverse effects of flecainide in a meta-analysis of 4375 treatment courses compared with 1818 treatment courses in controls (78M) System

Adverse effect

Flecainide

Cardiovascular

Angina pectoris Palpitation Hypotension Syncope Heart failure/dyspnea Sinus node dysfunction Bundle branch block Atrioventricular block

Nervous system

Controls

43 (1.0) 17 (0.4) 33 (0.8) 5 (0.1) 40 (0.9) 52 (1.2) 29 (0.7) 24 (0.5)

25 (1.3) 6 (0.3) 24 (1.3)* 3 (0.2) 13 (0.7) 22 (1.2) 7 (0.4) 7 (0.4)

Total Headache Dizziness Vertigo

412 (9.4) 88 (2.0) 148 (3.4) 137 (3.1)

65 (3.4)* 53 (2.9)* 45 (2.5) 42 (2.3)

Sensory systems

Visual disturbances

175 (4.0)

16 (0.9)*

Gastrointestinal

Total Diarrhea Nausea

144 (3.3) 29 (0.7) 71 (1.6)

121 (6.7)* 50 (2.8)* 33 (1.8)

*Significantly different.

80 mg were used to terminate the dysrhythmia (79c). Conversion to sinus rhythm was achieved within 2 hours in 17 patients with placebo, in 20 with flecainide, and in 31 with diltiazem plus propranolol. Time to conversion was shorter with diltiazem plus propranolol (32 minutes) than with flecainide (74 minutes) or placebo (77 minutes). O f those who were given flecainide, two had hypotension and one had sinus bradycardia. Respiratory Interstitialpneumonitis has only rarely been attributed to flecainide (SEDA-16, 181; SEDA-25, 184), but another two cases have been reported (80A). 9 A 75-year-old man, who had taken flecainide

100 mg/day for 22 months, developed fever, headache, and a dry cough. A C T scan of the lungs was normal and he responded to prednisone. His symptoms disappeared, but when prednisone was withdrawn they returned, with breathlessness, a dry cough, and weight loss. A chest X-ray showed bilateral patchy opacities and a CT scan subpleural ground-glass opacities and septal thickening. He had impaired lung function, including a reduced diffusion capacity. Biopsy showed diffuse interstitial thickening with lymphocytic and eosinophilic infiltrates. Flecainide was withdrawn and prednisone given, and he made a full recovery within 1 month. 9 A 73-year-old man, who had taken flecainide 100 mg/day for 4 months, developed fever, weight

loss, breathlessness, and a dry cough. A chest X-ray showed patchy infiltrates and a CT scan ground-glass opacities and subpleural septal thickening. He had normal lung function, apart from a reduced diffusion capacity. Flecainide was withdrawn and prednisone given, and he made a full recovery within a few months. P r e g n a n c y Flecainide is occasionally used to treat fetal cardiac dysrhythmias by administration to the mother (81 c, 82c), although occasionally it can cause adverse effects in the child (SEDA-25, 184) and in the mother (83A). 9 At 30 weeks of gestation in a 41-year-old woman the fetus had hydrops, ascites, a pericardial effusion, and bilateral hydroceles. A supraventricular tachycardia with 1 : 1 conduction was treated by giving the mother oral flecainide 150 mg bd. However, during the next few weeks the mother developed evidence of hepatic cholestasis. The dosage of flecainide was reduced to 50 mg bd and the liver damage resolved. The child was born healthy but later required sotalol for a re-entry tachycardia.

Lidocaine (lignocaine) (SED-14, 546; SEDA 24, 212; SEDA-25, 218) S e n s o r y systems Pupillary mydriasis occurred in a neonate who was given intravenous lidocaine 3 mg/kg/hour as an anticonvulsant

(84A).

Positive inotropic drugs and drugs used in dysrhythmias D r u g a d m i n i s t r a t i o n r o u t e The pharmacokinetics of lidocaine in patches have been investigated in two studies. In 20 healthy volunteers 5% lidocaine patches were applied for 18 hours/day on 3 consecutive days (85c). The mean peak concentrations on days 1, 2, and 3 were 145, 153, and 154 ng/ml respectively; the median values of tmax were 18.0, 16.5, and 16.5 hours; and the mean trough concentrations were 83, 86, and 77 ng/ml. The patches were well tolerated; local skin reactions were generally minimal and self-limiting. In 20 healthy volunteers four lidocaine patches were applied every 12 or 24 hours on 3 consecutive days (86c). The mean maximum plasma lidocaine concentrations at steady state were 225 and 186 ng/ml respectively. There was no loss of sensation at the site of application. No patient had edema and most cases of erythema were very slight. No systemic adverse events were judged to be related to the patches. D r u g overdose Accidental overdose with viscous lidocaine has been reported in a child (87A). 9

An 18-month-old child took an unstated amount of 2% viscous lidocaine and developed malaise and had a cardiorespiratory arrest. He was resuscitated but developed seizures and died. Serum concentrations of lidocaine and monoethylglycinexylidide at 7 hours were 1.1 btg/ml and 0.94 gg/ml respectively.

D r u g interactions The thrombin inhibitor argatroban had no effect on the pharmacokinetics of intravenous lidocaine 1.5 mg/kg for 10 minutes followed by 2 mg/kg/hour for 16 hours in 12 healthy volunteers; the argatroban was given as an intravenous infusion of 2 p.g/kg/min for 16 hours (12c). An interaction of lidocaine with mexiletine, which resulted in toxic concentrations of lidocaine, has been reported (88A). 9

An 80-year-old man with a dilated cardiomyopathy was given a lidocaine infusion started at 90 mg/hour for a ventricular tachycardia. He was already taking mexiletine 400 mg/day, and the plasma concentration was within the usual target range; however, the dose was reduced to 200 mg/day to avoid possible adverse effects. Intermittent ventricular tachycardia persisted, and so the lidocaine infusion was increased to 120 mg/day, but adverse effects (involuntary movements, muscle rigidity) were observed. The lidocaine infusion

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was stopped and within 20 minutes the adverse effects abated; the lidocaine concentration was 6.84 btg/ml. The ventficular tachycardia persisted, lidocaine was restarted at a lower rate, and the oral dose of mexiletine was increased to 450 rag/day. This resulted in an unexpectedly high concentration of lidocaine and the lidocaine concentration was significantly higher while the mexiletine dose was high. Further studies suggested that mexiletine had displaced lidocaine from tissue binding sites. The authors suggested that this finding has implications for loading doses and acute effects of lidocaine in the concurrent therapy of lidocaine and mexiletine and highlighted the importance of close monitoring of lidocaine concentrations in this setting.

Mexiletine

(SED-14, 547; SEDA-24, 212; SEDA-25, 219; SEDA-26, 213) The analgesic efficacy of mexiletine 600 rag/ day and gabapentin 1200 rag/day has been investigated in 75 patients with acute and chronic pain associated with breast surgery in a doubleblind, randomized, placebo-controlled study for 10 days (89c). Pain at rest and after movement was reduced by both drugs on the third postoperative day and pain after movement was reduced by gabapentin at 2-5 days postoperatively. Two women given mexiletine withdrew from the study because of adverse events, one with an axillary vein thrombosis and one with

nausea and vomiting.

Procainamide

(SED-14, 548;

SEDA-24, 213; SEDA-26, 213) D r u g overdose Procainamide overdose has been reported (90A). 9 A 14-year-old boy took about 21 g ofprocainamide and developed abdominal pain, weakness, blurred vision, dry mouth, pain on swallowing, and headache. His pupils were dilated, his skin dry and pale, and his mucous membranes dry. His blood pressure was 106/49 mmHg, his heart rate 91/minute. Following a tonic-clonic seizure his blood pressure was 125/57 rnmHg and his heart rate 136/minute in sinus tachycardia. He became lethargic with slurred speech. He was given repeated doses

Chapter 17

198 of activated charcoal and made a full recovery. The serum procainamide and acecainide (Nacetylprocainamide) concentrations were 63 and 80 ~tg/mlrespectively. There have been two previous reports of overdose with procainamide in adults. 9 A 79-year-old man took about 19 g of procainamide and developed lethargy, vomiting, a wide-complex tachycardia, bypotension, and coma (91A). His serum procainamide concentration was 77 Izg/mlat 3 hours. He was treated with vasopressors and peritoneal dialysis. A 67-year-old woman took about 7 g of procainamide and developed nausea, vomiting, lethargy, a junctional tachycardia, hypotension, and oliguria (92A). She was treated with hemodialysis.

(SED-14, 551; SEDA-24, 214; SEDA-25, 220; SEDA-26, 214) Propafenone

Propafenone 450 mg/day and sotalol 240 mg/ day have been compared in a placebo-controlled study of 300 patients with atrial fibrillation (93c). The two drugs had similar efficacy. There were adverse events in 38 of the patients who took propafenone, compared with 12 of those who took placebo. These included gastroin-

testinal discomfort, neurological disturbances, asymptomatic bradycardia, a metallic taste, and general weakness. In nine patients the adverse effects were sufficient to cause withdrawal of propafenone. Cardiovascular In controlled trials in patients with recent-onset atrial fibrillation without heart failure oral propafenone (450--600 mg as a single dose) had a relatively quick effect (within 3-4 hours) and a high rate of efficacy (72-78% within 8 hours) (94R). A potentially

J.K. Aronson

harmful effect of propafenone in these cases is the risk of transforming atrial fibrillation into atrial flutter, which occurs in 3.5-5% of patients. However, atrial flutter with 1 : 1 atrioventricular conduction occurred in only two of 709 patients (0.3%) who received propafenone.

Quinidine

(SED-14, 552; SEDA-24, 214; SEDA-25, 221; SEDA-26, 214) Quinidine causes prolongation of the QT interval, and the relation be-

Cardiovascular

tween serum quinidine concentrations and QT interval dispersion has been studied in 11 patients with atrial dysrhythmias and subtherapeutic or therapeutic serum quinidine concentrations (1.48 and 3.78 ktg/ml respectively) (95c). The baseline QTc interval was 430 msec. At subtherapeutic and therapeutic serum quinidine concentrations, mean QTc intervals were 451 msec and 472 msec respectively. Mean QT dispersion was 47 msec at baseline, 98 msec at subtherapeutic concentrations, and 71 msec at therapeutic concentrations. Despite QT interval lengthening with increasing serum quinidine concentrations, QT dispersion was greatest at subtherapeutic concentrations. Drug interactions. In human liver microsomes diclofenac inhibited testosterone 6-betahydroxylation with characteristics that suggested that it inactivated CYP3A4 (96E). Quinidine, which stimulates CYP3A4-mediated diclofenac 5-hydroxylation, did not affect the inactivation of CYP3A4 assessed by testosterone 6-beta-hydroxylation activity but accelerated the inactivation assessed by diazepam 3-hydroxylation activity.

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patients. J Gerontol Ser A Biol Sci Med Sci 2002; 57: M138-43. 3. Onder G, Pedone C, Landi F, Cesari M, Della Vedova C, Bernabei R, Gambassi G. Adverse drug reactions as cause of hospital admissions: results from the Italian group of pharmacoepidemiology in the elderly (G1FA). J Am Geriatr Soc 2002; 50: 1962-8.

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Barold SS, Hayes DL. Images in cardiology: non-paroxysmal junctional tachycardia with type I exit block. Heart 2002; 88: 288. 5. Lawrenson JG, Kelly C, Lawrenson AL, Birch J. Acquired colour vision deficiency in patients receiving digoxin maintenance therapy. Br J Ophthalmol 2002; 86: 1259-61. 6. Rathore S-S, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. New Engl J Med 2002; 347: 140311. 7. Eichhorn EJ, Gheorghiade M. Digoxin--new perspective on an old drug. New Engl J Med 2002; 347: 1394-5. 8. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. J Am Med Assoc 2003; 289: 871-8. 9. Sameri RM, Soberman JE, Finch CK, Self TH. Lower serum digoxin concentrations in heart failure and reassessment of laboratory report forms. Am J Med Sci 2002; 324: 10-13. 10. Nagai Y, Hayakawa T, Abe T, Nomura G. Are there different effects of acarbose and voglibose on serum levels of digoxin in diabetic patients with congestive heart failure? Diabetes Care 2000; 23: 1703. 11. Cohen E, Almog S, Staruvin D, Garty M. Do therapeutic doses of acarbose alter the pharmacokinetics of digoxin? Isr Med Assoc J 2002; 4: 772-5. 12. Inglis AML, Sheth SB, Hursting MJ, Tenero DM, Graham AM, DiCicco RA. Investigation of the interaction between argatroban and acetaminophen, lidocaine, or digoxin. Am J Health-Syst Pharm 2002; 59: 1258-66. 13. Mant T, Fournie P, Ollier C, Donat F, Necciari J. Absence of interaction of fondaparinux sodium with digoxin in healthy volunteers. Clin Pharmacokinet 2002; 41 Suppl 2: 39-45. 14. Tsutsumi K, Kotegawa T, Kuranari M, Otani Y, Morimoto T, Matsuki S, Nakano S. The effect of erythromycin and clarithromycin on the pharmacokinetics of intravenous digoxin in healthy volunteers. J Clin Pharmacol 2002; 42:1159-64. 15. Boyd RA, Stern RH, Stewart BH, Wu X, Reyner EL, Zegarac EA, Randinitis EJ, Whitfield L. Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol 2000; 40: 91-8. 16. Chien S-C, Rogge MC, Williams RR, Natarajan J, Wong F, Chow AT. Absence of a pharmacokinetic interaction between digoxin and levofloxacin. J Clin Pharm Ther 2002; 27: 7-12. t7. Martin PD, Kemp J, Dane AL, Warwick M J, Schneck DW. No effect of rosuvastatin on the pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol 2002; 42: 1352-7. 18. Garnett WR, Venitz J, Wilkens RC, Dimenna G. Pharmacokinetic effect of fluvastatin in patients chronically receiving digoxin. Am J Med 1994; 96: 84S-86S. 19. Miyazawa Y, Paul Starkey L, Forrest A, Schentag JJ, Kamimura H, Swarz H, Ito Y. Effects of the

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