Positive inotropic drugs and drugs used in dysrhythmias

J.K. Aronson

18

Positive inotropic drugs and drugs used in dysrhythmias

C A R D I A C GLYCOSIDES (SED-12, 385; SEDA-12, 148; SEDA-13, 138; SEDA-14, 141; SEDA-15, 165) Cardiovascular I have previously discussed in these volumes the question of whether longterm digitalis therapy increases mortality among patients with ischemic heart disease (SEDA-10, 142; SEDA-11, 153; SEDA-15, 165). In previous retrospective studies of the effects of digoxin in patients who had had a myocardial infarction there was an increased mortality rate among patients who took digoxin compared with those who did not. However, in most of the studies there were many significant differences between the groups in regard to several variables, and when statistical adjustment was made for those variables the difference between the groups disappeared. None the less, meta-analysis o f some of the studies did suggest that there was an increased risk of mortality from digoxin, and the question has not been settled. A recent study of digitoxin-associated mortality in similar circumstances has added to the doubt (lC). Of 620 patients with acute myocardial infarction, 159 were taking digitoxin. Over a follow-up period of 1 - 3 years the patients taking digitoxin had a significantly higher mortality rate, with a relative risk ratio of 2.3. However, as in the previous studies of digoxin, there were differences between the groups in relation to many other variables, including age, previous myocardial infarction, diabetes meUitus, atrial fibrillation, renal function, and the use of diuretics. However, even when these were taken into account, there was still a residual risk attributable to the use of digitoxin,

@ 1993 ElsevierSciencePublishers. All rights reserved Side Effects of DrugsAnnum 16 M.N.G. Dukes and J.K. Aronson, eds.

the relative risk ratio being 1.41 (95~ confidence interval 1 . 0 7 - 1.86). Although clearly it is possible that the reason for the increased rate of mortality in patients taking cardiac glycosides may be that they were more ill than those who were not treated with digitalis, there must remain some doubt about the safety of digitalis during long-term treatment after acute myocardial infarction. The value of digitalis in the treatment of paroxysmal atrial fibrillation is unclear, but it is generally regarded as being ineffective in preventing attacks or reducing their frequency. This has been confirmed in a recent retrospective study of the frequency of attacks of atrial fibrillation during Holter monitoring in 72 patients (2c). There were 60 episodes in 31 patients taking digoxin compared with 79 episodes in 41 patients not taking it. However, although there was no difference between the groups in relation to the number of attacks, the patients taking digoxin had significantly more episodes lasting for 30 minutes or more, and the relative risk of prolonged attacks in those taking digoxin was 4.3 (95~ confidence interval 1.6 - 11.9). This action of digoxin may be due to increased vagal tone, increasing the refractory period of the AV node. Gastrointestinal Digitalis not uncommonly causes diarrhea, particularly in old people, and this has been stressed in the light of a recent case-report of profuse watery diarrhea in a 72year-old woman with a serum digoxin concentration of 3.7 nmol/l (3c). Dysphagia is a rare adverse effect of digoxin (SEDA-3, 152). Recently a case of dysphagia in a 93-year-old woman has been reported in association with dysphonia, nausea, anorexia, and weight loss. Her serum digoxin concentration was 6.1 nmol/1, and the dysphagia and dyspnea improved over the few days after withdrawal of digoxin (4c).

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Risk situations Magnesium deficiency It is generally thought that hypomagnesemia increases the risk of digitalis toxicity (SEDA-13, 138). However, the data are few and difficult to interpret, and digitalis toxicity with hypomagnesemia may simply reflect coexisting hypokalemia. In a recent study of 14 digitalized patients with chronic atrial fibrillation, magnesium deficiency was measured by the amount of magnesium retained after an intravenous infusion (5c). There was a relation between the degree of magnesium deficiency measured in this way and the numbers of ventricular extra beats. These results suggest that ventricular extra beats in digitalized patients with chronic atrial fibrillation may be increased in number if there is also magnesium deficiency. Only one of the patients in this study had a serum potassium concentration below the reference range, although total body potassium was not measured. Age The risk factors and effects of digoxin toxicity in the elderly have recently been reviewed (6R, 7R). Interactions Indomethacin has been reported to increase plasma digoxin concentrations in neonates, perhaps because of impairment of renal function (SEDA-6, 178). This has been confirmed in 10 adult patients in whom indomethacin (50 mg t.d.s.) increased digoxin concentrations from 0.7 to 1.0 nmol/l (8c). In the same study, ibuprofen given to 8 of the patients did not affect the digoxin concentration. The serum creatinine concentration did not change when indomethacin was given, suggesting that the effect was not due to a general inhibitory effect on renal function. It is not clear what the basis of this interaction might be, or what its clinical significance is. Verapamil has previously been reported to inhibit both the tubular secretion and the nonrenal clearance of digoxin, consequently increasing steady-state plasma digoxin concentrations by about 60070 (SEDA-7, 196). The size of the non-renal effect may be quite large, as has been shown in a study of 8 patients who were on chronic hemodialysis with virtually no renal function and in whom serum digoxin concentrations increased from 1.1 to 1.7 nmol/1 during the co-administration of verapamil 120 mg/pd (9c). However, the change in digoxin concentration was highly variable, between

Chapter 18 J.K. Aronson 0 and 200~ of baseline values. The effect of verapamil was not greater at a higher dose of 240 mg/d. The interaction of digoxin with antibiotics such as erythromycin or tetracycline was discussed in SEDA-7 (p. 197). There has since been a report that this interaction may be of clinical importance (10c).

Treatment of digitalis toxicity The use of Fab fragments of digoxin antibodies in the treatment of digitalis intoxication has again been reviewed (11R). In a recent study of 717 adults who were given the antibody fragments, 50070 had a complete response to treatment, 24070had a partial response, and 12070 had no response (12c). The responses of the other 14070of the patients were not reported or were reported as being uncertain. Allergic reactions to the antibody occurred in 6 of the patients, 3 of whom had a history of allergy to antibiotics (12c). In 4 cases there was a rash, and in the other 2 cases shaking and thrombocytopenia respectively. In 2 other cases fever, wheezing, and dyspnea were reported, but the association with the antibody was not clear; neither of those patients had a history of allergic reactions. In 4 of the 6 patients in whom allergy was thought to be likely the reactions occurred on the day of treatment and in the other 2 cases they occurred 11 and 16 days after. In 20 cases digitalis toxicity recurred after withdrawal of the antibody; in 16 cases toxicity recurred within 3 days of treatment, including 5 within 12 hours; in the other 4 cases toxicity recurred between 4 and 11 days. In 10 of these cases initial treatment had produced a complete response, and the same was true of 5 of the 6 patients who were given extra antibody after recurrence of toxicity. The risk of recurrence was related to the initial dose of antibody. In 26 patients there was an adverse effect of the antibody other than an allergic response. In 14 cases there were cardiovascular disorders (1 heart block, 4 ventricular dysrhythmias, 5 cases of asystole, and 4 cases of heart failure). In 4 cases this was attributed to inadequate treatment with antibody and in some of the other cases it was presumably due to a recurrence of the cardiac condition which had originally required treatment with digitalis. Three patients had neurological disorders, 3 gastrointestinal disorders, and 6 metabolic disorders (3

Positive inotropic drugs and drugs used in dysrhythrnias Chapter 18 hyperkalemia, 2 hypokalemia, and 1 hypoglycemia). It was not clear to what extent these apparent adverse effects were related to the antibody.

OTHER INOTROPIC DRUGS Amrinone (SED-12, 393; SEDA-13, 139; SEDA-14, 146) The most common adverse effect of amrinone is thrombocytopenia. There has now been a report of pancytopenia in a 64-year-old man with severe heart failure who was given intravenous infusions of dopamine 7/tg/kg per minute and amrinone 5/zg/kg per minute after an initial bolus infusion of 0.75 mg/kg over 5 minutes (13c). Ten hours later the blood count was normal and the amrinone infusion was increased to a rate of 15 ~g/kg per minute. Over the next 2 days the blood count fell. The lowest values recorded were: red cell count 2.4 x 1012/1, white cell count 2.8 • 109/1, and platelet count 67• 109/1. The diagnosis of amrinone-induced pancytopenia was made on the basis of the temporal relation of events and not on rechallenge. Enoximone (SED-12, 393; SEDA-12, 150;

SEDA-13, 139; SEDA-15, 166) The adverse effects of enoximone have recently been reviewed (14R, 15R). Cardiovascular effects occur in about 10%, ventricular and supraventricular dysrhythmias being the most common. Hypotension occurs in 2 - 3% of patients and may occur when enoximone is used in combination with diuretics or ACE inhibitors. Common effects on the central nervous system include headache, insomnia, and anxiety, and 3% of patients have nausea, vomiting, abdominal pain, and diarrhea. Occasionally enoximone can cause an increase in liver enzyme activity and blood glucose concentration, usually in patients with pre-existing liver disease or diabetes respectively. As with other inhibitors of phosphodiesterase type III, enoximone may cause thrombocytopenia. In a study of 35 patients who were given enoximone in end-stage cardiac failure the risk of adverse effects was high: 46% of patients had adverse effects, 40% requiring withdrawal (16c). In

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this series gastrointestinal effects were the most common and consisted of nausea and vomiting or diarrhea; in 3 cases there was severe dehydration as a result. The dosages at which these adverse effects occurred (50 or 75 mg t.d.s.) were lower than have been used in previous studies. Some reports have suggested that enoximone may be prodysrhythmic in some patients, and may particularly cause ventricular extra beats (SEDA-15, 166), although in general enoximone seems to be relatively safe in this respect (17c). In a recent study (18C) of 12 patients with advanced cardiac failure, enoximone did not cause ventricular tachycardia in patients in whom tachycardia could not be stimulated beforehand; however, it did aggravate ventricular tachycardia in 4 of the 5 patients who had spontaneous sustained tacbycardia. Milrinone (SED-12, 394; SEDA-12, 151) The clinical pharmacology, clinical effects and adverse effects of milrinone have been reviewed (19R). The most common adverse effect is an increased risk of ventricular dysrhythmias, which occur in about 12~ of cases after intravenous administration and in 5% during oral administration. In most cases there are asymptomatic increases in ventricular extra beats or increases in the frequency of ventricular tachycardia. Supraventricular tachycardias have also been reported. Gastrointestinal disturbances are also frequent (about 11% of patients on oral therapy). Other common adverse effects include headache (7%), light headedness and dizziness (6%), and palpitation (6%). Fatigue and muscle weakness have been reported in about 3 %, increased hepatic enzymes in 2%, and hypotension in 3%. Thrombocytopenia has been reported in up to 1% of cases. The prodysrhythmic effects of milrinone have been studied in 29 patients, all of whom had pre-existing ventricular dysrhythmias (20c). Milrinone did not alter the numbers of individuals with particular kinds of ventricular dysrhythmias, but it did increase the frequency of ventricular coupled beats and of ventricular tachycardia. In all, 8 patients satisfied specific prodysrhythmic criteria, and those 8 had a slightly lower mean left ventricular ejection fraction than the other patients.

176 DRUGS USED IN DYSRHYTHMIAS (SED-

12, 384; SEDA-12, 151; SEDA-13, 140; SEDA-14, 146; SEDA-15, 166) The prodysrhythmic effects of antidysrhythmic drugs continue to be reviewed in numerous articles (e.g. 21 R - 24R).

Adverse hemodynamic effects of antidysrhythmic drugs Although the adverse hemodynamic effects of antidysrhythmic drugs are well known (SEDA- 15, 167), their propensity to cause or worsen heart failure has not been as thoroughly covered as their prodysrhythmic effects. In one study of 407 patients who were treated with encainide, lorcainide, mexiletine, moricizine, propafenone, or tocainide, heart failure was made worse in 1 . 6 - 9 . 3 % of patients with a previous history of heart failure, the highest incidence being with propafenone and the lowest incidence with lorcainide (25c). Heart failure also occurred in patients who did not have a history o f heart failure, and the risk was about half of that in those who did.

Hematological

Several antidysrhythmic drugs, notably aprindine, procainamide, and tocainide, have been reported to cause neutropenia. This has been the subject of a recent review (26R). Three basic mechanisms have been identified: immune, toxic, and autoimmune. Immune-mediated neutropenia occurs when the drug binds to the leukocyte cell membrane, stimulating the production of an antibody which then combines with the drug; the complex of drug with antibody reacts with the cells, causing the production of a cellular antibody. Toxic neutropenia is due to direct effects of drugs on cellular production in the bone-marrow. Autoimmune neutropenia is associated with a lupus-like syndrome. Immune neutropenia has been associated with aprindine, quinidine, and flecainide. Toxic neutropenia has been associated with quinidine, procainamide, and tocainide. Autoimmune neutropenia has been associated with procainamide, aprindine, and tocainide.

Adenosine In recent years adenosine and its phosphorylated derivative A T P have been in-

Chapter 18 J.K. Aronson troduced for the treatment of acute paroxysmal supraventricular tachycardias, and have been shown in a variety of clinical trials to be as effective as verapamil (27 c - 29c). Adenosine has also been used in the diagnosis of narrow- and broad-complex tachycardias (30c). After intravenous administration adenosine enters ceils, disappearing from the blood with a half-life of less than 10 seconds; intracellularly it is phosphorylated to cyclic A M P . Its mechanism of action as an antidysrhythmic drug is not known, but it may act by an effect at adenosine receptors on the cell membrane (31R). Its electrophysiological effects are to prolong AV nodal conduction time by prolonging the A H interval, without an effect on the HV interval (32 c - 34c). It also prolongs sinus cycle length (32c). Its phosphorylated derivative ATP has similar effects (35c). In all studies adverse effects have been frequently reported, but they have generally been mild and, because o f the rapid elimination o f adenosine from the blood, transient. Adverse effects have been reported in 81% of patients given adenosine and 94% of patients given A T P (28c). The most common adverse effects are chestpain, which occurs in 3 0 - 50% of patients (28 c - 30c), dyspnea and chest discomfort in 35 - 55o70 (28 C - 30c), flushing in 2 0 - 30o/0 (27 c - 30c), and headache in about 10070 (27 r 28 c, 30c). Light-headedness has also been reported (28r The most common cardiac effects are A V block (27c), sinus bradycardia (27 c, 30c), and ventricular extra beats (27 c, 28c, 30c). A T P has been reported to cause transient atrial fibrillation (28 C, 36c). Antagonists at adenosine receptors should inhibit the action of adenosine, and theophylline has been shown to increase the doses of adenosine needed for conversion of supraventricular tachycardia (33c). Dipyridamole inhibits the uptake of adenosine by ceils and thus increases its effects. In one study this reduced the effective dose of adenosine from 8.8 to 1 mg (37c). Interactions have not been noted with digoxin, disopyramide, flecainide, and quinidine. Several reviews of the clinical pharmacology, actions, therapeutic uses, and adverse drug reactions and interactions of adenosine and A T P have appeared (38 R - 43R).

Positive inotrop& drugs and drugs used in dysrhythmias Chapter 18 Amiodarone (SED-12, 397; SEDA-12, 151; SEDA-13, 141; SEDA-14, 147; SEDA-15, 167) Cardiovascular The hemodynamic effects of amiodarone after intravenous injection have recently been reviewed (44R). They depend on both the rate of infusion and the time at which measurements are made after administration. Soon after administration the vasodilatory effects predominate, but later on there is also a negative inotropic effect, which counteracts any beneficial effects which may arise from systemic vasodilatation. The early effects occur within the first 2 - 3 minutes and the later effects at about 5 - 10 minutes. Patients with preexisting impairment of ventricular function are at greater risk of hemodynamic deterioration. In contrast, amiodarone causes little or no change in cardiac function during long-term oral therapy. The prodysrhythmic effects of amiodarone are less frequent than with most other antidysrhythmic drugs (SEDA- 15, 168). In a recent study (45 c) 4.1% of 194 patients taking amiodarone for ventricular dysrhythmias had worsening of their dysrhythmias attributable to amiodarone. Seven o f the patients had ischemic heart disease and 6 had congestive heart failure. In all cases the antecedent dysrhythmia had been monomorphous, and in only 2 cases did it become polymorphous. There was no relation between the dose or duration of administration and the worsening of the dysrhythmias. In another prospective study of 50 patients with symptomatic hypertrophic cardiomyopathy, 7 patients died suddenly, 6 of them within 5 months of the start of treatment. The risk of sudden death was significantly worse among patients who had ventricular tachycardias (46c). In another study of 33 patients there was no difference in the risk of sudden death in those who had ventricular tachycardia and those who had ventricular fibrillation (47c). However, there was a greater risk of sudden death in those who had a ventricular dysrhythmia inducible during an electrophysiological study before discharge from hospital after a period of loading with amiodarone. The results of this study are somewhat at variance with previous reports that electrophysiological studies do not provide a good prediction of the risk of

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dysrhythmias in patients taking amiodarone, and the authors suggested that this may have been because of the selection of patients in different studies. Similar results were found in a group of 35 patients with hypertrophic cardiomyopathy, 4 of whom either died suddenly (2 cases) or required cardioversion from an implanted defibrillator (48c). All 4 had been patients in whom amiodarone had increased the ease with which ventricular tachycardia could be induced, and there were no deaths or serious dysrhythmias in patients in whom induction of ventricular tachycardia had been difficult or impossible. In 2 patients with idiopathic dilated cardiomyopathy being treated with amiodarone, lipid deposits were found in cardiac biopsies, similar to those which have been reported in many other tissues (49c). However, the authors reported that of over 300 patients with idiopathic dilated cardiomyopathy, of whom more than 40~ had been taking amiodarone, no other cases of similar pathology had been found, and it is likely therefore that the ultrastructural changes described were coincidental rather than etiological. Respiratory Attempts continue to find tests which might help to substantiate a diagnosis of amiodarone-induced lung damage. The clinical symptoms and signs, the changes on chest radiography, and abnormalities of lung function tests are all non-specific. Although measurement of the diffusing capacity of carbon monoxide has been suggested to be helpful, such changes can occur in patients who do not have lung damage (SEDA-15, 168). The presence of lymphocytes and foamy macrophages in bronchial lavage fluids has been suggested to be helpful, but can also occur in those who do not have lung damage (50 c - 52c). A study of the value of measuring the serum concentration of angiotensin converting enzyme as a possible marker for lung damage has not shown it to be of any value (53c). However, in another study of patients who had subclinical pulmonary toxicity related to amiodarone therapy there was a good relation between the lowering of carbon monoxide diffusing capacity and the concomitant fall in the activity of superoxide dismutase in their erythrocytes (54c). The authors suggested that the latter might be a marker of a role of free radicals in the

Chapter 18 J.K. Aronson

178 pathogenesis of pulmonary toxicity due to amiodarone. The abnormalities which are seen in computed tomograms of patients with amiodaroneinduced lung damage have previously been described (SEDA-15,168). In some cases there may be a pattern of basal peripheral highdensity pleuroparenchymal linear opacities, although in other cases CT scanning is normal. Similar changes have now been reported in 8 out of 11 patients with amiodarone-associated lung damage (55c) and have been shown to correlate with the gross and histological changes found in the lungs (56c). The mechanism whereby amiodarone causes lung damage is not known, but may be via 2 factors: deposition of phospholipid and an immunologically mediated effect. The evidence for both of these has previously been reported (SEDA-15, 168) and there is now further evidence of the latter mechanism from a report of lung damage and a peripheral eosinophilia in a 53-year-old man taking amiodarone (57c). The treatment of amiodarone-induced lung toxicity is usually with corticosteroids after discontinuation of amiodarone. However, occasionally withdrawal alone is sufficient to cause regression of the damage, as has been demonstrated in 2 cases (58c). Nervous system The usual adverse effects of amiodarone on the nervous system include tremor, a peripheral neuropathy, and ataxia. These effects have been confirmed in a recent survey of neurological problems with amiodarone in New Zealand (59c), in which 192 events were assessed as being due to adverse reactions in 112 patients with neurological events. Paraesthesiae, ataxia, vertigo, and tremor were the most common (about 8~ and the overall rate of neurological reactions was 28070. Other effects included muscle weakness, diplopia, and speech disorders. There has also been a report of an optic neuropathy attributed to amiodarone (60c). Amiodarone may occasionally cause aproximal myopathy (SEDA-15, 171) and there has been a recent report of coexisting myopathy and neuropathy in a 62-year-old man (61c). Endocrine

The effects of amiodarone on

thyroid function and thyroid function tests have again been reviewed (62 C, 63R).

The mechanisms whereby amiodarone causes thyroid disease may be either via a direct effect of the iodine that amiodarone contains or because of some autoimmune action. However, direct follicular damage may also be a mechanism, as has been suggested in a report of 3 cases, although in no case was there direct evidence that that was so (64c). In one case the presentation was similar to that of a painful thyroiditis; this has been described before (SEDA-13, 140; SEDA-15, i70) and has been confirmed in another 3 patients (65c, 66c), in two of whom hyperthyroidism was followed, after the withdrawal of amiodarone, by hypothyroidism. Amiodarone-induced hyperthyroidism is often resistant to treatment with traditional antithyroid drugs, such as carbimazole or propylthiouracil, and often needs treatment with corticosteroids or potassium perchlorate (SEDA-15, 170). Recently plasmapheresis has been reported to be beneficial in a 68-year-old man with hyperthyroidism attributed to amiodarone (67c). The effect was attributed to the extensive removal of thyroxine from the blood. Amiodarone increases serum cholesterol concentrations (SEDA-14, 149) and Metabolic

it is not clear whether alterations in thyroid function have anything to do with this. However, the results of 3 recent studies have suggested that the changes in serum cholesterol are independent of changes in thyroid function (68 c - 70c). Liver

Five further cases of acute severe

hepatitis after intravenous amiodarone have been reported (71c-73c). However, liver damage is more common during long-term treatment with amiodarone, and a recent study of 30 patients has shown that those who have higher baseline activities of alanine transaminase have an increased risk of developing liver damage (54c). The pathological features of the skin which can result from amiodarone therapy have been reviewed in the context of a case-report of grey-blue facial pigmentation in a 55-year-old man and a 65year-old woman (74cr). Six morphological types are described: those with electron-lucent Skin

pigmentation

Positive inotropic drugs and drugs used in dysrhythmias Chapter 18 membrane-bound granules, those with granules with electron-dense nuclei, those with lamellar myelin-like granules, those with granules with combined electron-dense and electron-lucent areas, those with granules which are electron-dense and membranebound, and those whose granules are electrondense but not bound to the membrane. However, it is not clear how these different patterns relate to the pathogenesis of skin damage due to amiodarone. Henoch-Sch6nleinpurpura has been described in a 55-year-old patient taking amiodarone (75c). It has been suggested that mucosal and cutaneous toxicity due to radiotherapy may be enhanced in patients taking amiodarone (76c). Special senses In addition to corneal opacities, amiodarone may cause opacities in the lens of the eye (77c). However, an 8-year follow-up study of the first reported cases has shown that they are of no clinical significance (78c). Interactions The possibility of torsades de pointes with the combination of amiodarone and Class I antidysrhythmics has been reinforced by a report of this dysrhythmia in a 73-yearold woman (79c). Aprindine (SED-12, 401) The risk of neutropenia with aprindine is well known (SEDA-3,157). This has been reinforced in a report of a study of 181 patients with neutropenia, attributable in 8 cases to antidysrhythmic drugs, in each case related to aprindine. The risk of aprindine-associated neutropenia was about 2 per 1000 patient-years (89c), which is less than has been previously reported. In the same series there were no cases of neutropenia in patients taking amiodarone, propafenone, or quinidine. Aprindine has also been reported to have causedpneumonitis in a 73-year-old man, an effect of the drug which does not seem to have been reported previously (81c). Disopyramide (SED-12, 402; SEDA-12, 151;

SEDA-13, 143; SEDA-15, 174) Nervous system The anticholinergic effects of

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disopyramide are well described and common. They usually consist of dry mouth, constipation, and/or urinary retention, and in a recent study these adverse effects were reported in 6% of 217 patients given disopyramide for a variety of ventricular and supraventricular dysrhythmias (82c). Although disopyramide generally has little effect on pupil size, it has been reported to cause glaucoma (83c). The anticholinergic effects of disopyramide are not reduced by using a slow-release formulation (84c). Liver Another case of cholestatic liver damage associated with disopyramide has been reported (85c), and the authors suggested that the mechanism was an allergic one, because of the clinical presentation, including eosinophilia. Gastrointestinal There has been a report of 2 cases of paralytic ileus in patients taking disopyramide, an effect which has not previously been reported (86c). This seems most likely to have been due to the anticholinergic effects of disopyramide, although the authors suggested that the drug might also have an effect on a variety of gastrointestinal hormones. Interactions It is well known that disopyramide can cause hypoglycemia (SEDA-15, 174) and it has recently been suggested that this effect may be potentiated by beta-blockers (87c). The effects of disopyramide have been reported to be reduced by the enzyme inducer, rifampicin (88c). After discontinuation of rifampicin it took about 5 days before the effect of enzyme induction disappeared. Eneainide (SED-12, 403; SEDA-13, 150;

SEDA-14, 150; SEDA-15, 175) The complete results of the Cardiac Arrhythmia Suppression Trial (CAST) have now been published (89c). They have confirmed the original finding (SEDA-15, 175) that both encainide and flecainide increased the risk of death from dysrhythmias or shock after acute recurrent myocardial infarction in patients who had had ventricular dysrhythmias after a myocardial infarction and in whom the

180 dysrhythmias could be suppressed with the drugs used. The relative risk of death or cardiac arrest due to dysrhythmia was 2.64 and due to all causes 2.38. The risks of non-fatal cardiac adverse effects were no different in those treated from those in the placebo group. There was no difference in the use of other drugs across the groups. However, amongst those who died with dysrhythmias fewer were taking aspirin and more were taking digitalis, diuretics, or nitrates. Although this may have suggested that those who died in the treatment groups were more seriously ill, there was no other evidence from the study that that was so, and in particular the incidence of poor left ventricular function was the same in the 3 groups. The high risk of sudden death in patients taking encainide for ventricular dysrhythmias after myocardial infarction has been confirmed in a retrospective analysis of the manufacturers' database (90c). The incidence of sudden cardiac death in those who did not have a history of myocardial infarction was very low, but these patients had ventricular dysrhythmias which were not considered to be immediately life-threatening, and it is debatable whether these people need to be treated at all. CAST was designed to see whether suppressing asymptomatic or mildly symptomatic ventricular dysrhythmias in patients who have poor left ventricular function after a myocardial infarction would reduce the rate of death due to dysrhythmias. Other studies have addressed the question of whether encainide is effective in treating more serious ventricular dysrhythmias. In one study of 16 patients with spontaneous or inducible sustained ventricular tachycardia the dysrhythmias became worse in 5 patients, and this was particularly likely in those with poor left ventricular function. Furthermore, encainide was not very effective in suppressing inducible ventricular tachycardia (91c). In contrast to these data, the use of encainide in supraventricular dysrhythmias has been found in several studies to be effective and relatively safe, although it must be pointed out that these studies have all been rather small, and it took a study the size of CAST, in which 1498 patients were randomized, to show the increased risk of sudden death with treatment. In a study of 14 patients with AV node re-entrant tachycardia encainide was effective in suppressing the dysrhythmia and only I patient dropped

Chapter 18 J.K. Aronson out of the study because of neurological adverse effects (blurred vision and vertigo) (92c). It is of interest that that patient was thought to be a poor metabolizer of encainide, although 2 other patients in the series were also poor metabolizers, and no firm conclusions can be drawn from this observation. In another study of 10 patients with chronic resistant paroxysmal atrial tachydysrhythmias encainaide was effective in 5 patients, partly effective in 2, and ineffective in 3. The only adverse effect reported was vertigo in 2 cases (93c). Finally, a retrospective analysis of the manufacturers' data on 301 patients treated with oral encainide for supraventricular dysrhythmias showed a very low rate of mortality (90c). There has been a report that hypertonic saline may be effective in the treatment of encainideinduced ventricular tachycardia (93c). However, the risks of this treatment were serious, and included hypernatremia, hyperosmolarity, hypocalcemia, and hypophosphatemia.

Nervous system The most common adverse effects of encainide, apart from the risk of dysrhythmias, are on the central nervous system (SEDA-14, 150), but they are usually mild. However, recently there has been a report of encephalopathy in a 72-year-old woman who was taking encainide for ventricular dysrhythmias (95c). She also had severe renal failure, and it may be that this effect of encainide was an interaction with some effect of renal impairment. Alternatively, it is possible that she was a poor metabolizer of encainide who failed to excrete the parent compound or that she failed to excrete the active metabolites of encainide, desmethylencainide and methoxydesmethylencainide. Metabolism Encainide is reported to have caused hypoproteinemia in a 53-year-old man who was taking it for ventricular dysrhythmias (96c). The diagnosis in this case was based on exclusion of other causes, and the possible mechanism is obscure. Flecainide (SED-12, 404; SEDA-12, 153;

SEDA-13, 143; SEDA-14, 150; SEDA-15, 175) The use of flecainide in children has recently been the subject of review (97R).

Positive inotropic drugs and drugs used in dysrhythmias Chapter 18 The increased risk of sudden death in patients taking flecainide for asymptomatic or mild symptomatic ventricular dysrhythmias in CAST has been mentioned above under encainide. As with encainide, flecainide has been less thoroughly studied in patients with more severe ventricular dysrhythmias. In one study of 20 patients with refractory ventricular tachycardia flecainide w as completely or partially effective in 8 (98c). However, adverse effects were not uncommon: there was weakness in 2 patients and light-headedness, nausea, and worsening heart failure in 1 patient each; 1 patient had worsened dysrhythmia. In another study o f 50 patients given flecainide for sustained ventricular tachycardia or fibrillation, flecainide was effective in 84070 of the patients being treated in hospital, but had to be withdrawn in 6 patients because of dysrhythmias (99c). Thirty-eight patients continued treatment for 1 year after leaving hospital; in them the success rate was 54%, but in 5 cases congestive heart failure became worse, requiring withdrawal in 2, and other adverse effects were not uncommon, including dizziness, nausea, visual disturbances, headache, and fever. In a study of 33 patients with spontaneous or inducible ventricular dysrhythmias flecainide was poorly effective and there was a high incidence of worsening of dysrhythmia (91c). As with encainide, flecainide may be safer in patients with supraventricular dysrhythmias, although there have only been small studies and the real risks may not have been detected. In 10 patients given flecainide for resistant paroxysmal atrial tachydysrhythmias 5 had a good response and 5 a fair response (93c); 3 patients had mild adverse effects and 3 had more severe effects, including fatigue, vertigo, hypertension, and erectile impotence. In 77 patients with symptomatic atrial fibrillation flecainide completely suppressed the dysrhythmia in 52% and in a further 14% when it was combined with amiodarone (100c). Four patients had heart failure and in 2 cases treatment had to be withdrawn; 2 patients had sinoatrial block requiring a pacemaker; other adverse effects were mild and transient and included tremor, nausea, dizziness, and hypertension. In 43 patients with paroxysmal atrial fibrillation and flutter flecainide completely suppressed the dysrhythmia in 50% (101c). However, adverse effects occurred in 74% o f the patients and

181

there was 1 sudden death. The most common adverse effects were dizziness and gastrointestinal adverse effects (constipation and nausea being the most common). Other disturbances, particularly blurred vision, were also common. There were 3 cases ofprodysrhythmia, one of dyspnea on exercise, and one of sinus bradycardia. In 28 patients with paroxysmal supraventricular tachycardia and 45 with paroxysmal atrial fibrillation or flutter flecainide was effective in 86~ of the former and 61%o of the latter (102r Non-cardiac adverse effects were common, and usually consisted of dizziness,

headache, nausea, disturbance of vision, dyspnea, and fatigue. However, these adverse effects were only more frequent than in the placebo group in those who were taking the highest dose used (150 mg twice daily). Two patients had worsen-

ed dysrhythmias. A specific study of the dysrhythmogenic effects of flecainide in 100 patients with atrial fibrillation and flutter showed that 9070 had severe dysrhythmias (103c). One patient died suddenly and 5 were successfully resuscitated after cardiac arrest. Two patients had severe bradycardia and 1 had sinus arrest.

Cardiovascular Acute hypotension has been reported in 22~ of 51 patients given intravenous flecainide for atrial fibrillation (I04C). In a parallel group given placebo, only 6~ developed hypotension. Torsades de pointes occurred in 1 patient without prolongation of the QT interval.

Respiratory Interstitial pneumonitis, which seems not to have been reported before, has recently been reported in 2 patients taking flecainide (105 c, 106c).

Overdosage Another case of overdose of flecainide has been reported (SEDA-15, 177). A 72-year-old woman inadvertently took 1.8 grams of flecainide orally and developed

blurred vision, dry mouth, dizziness, nausea, and fatigue (107c). An ECG showed sinus arrest, A V junctional escape with Wenckebach phenomenon, and right bundle-branch block. She recovered completely after continuous infusion of isoprenaline over 5 hours.

Interactions

Flecainide

is

normally

182 metabolized by O-dealkylation followed by oxidation and dehydrogenation. It is also actively secreted by the renal tubules. In a study of 10 healthy volunteers quinine reduced the total clearance of flecainide without altering its renal clearance (108c). This was attributed to inhibition of both steps in the sequential metabolism of flecainide. It is not clear what the clinical relevance of this interaction might be, if any.

Lidocaine (lignocaine) (SED-12, 405;

SEDA-14, 151; SEDA-15, 177) A meta-analysis of 14 randomized controlled trials of the use of lidocaine to prevent dysrhythmias in patients who have had an uncomplicated acute myocardial infarct has shown that it confers no benefit at any time and may in fact increase mortality in patients in whom myocardial infarction has been proven (109R). In a subsequent review of the use of lidocaine in the early phase of acute myocardial infarction the authors concluded that it should be used only in patients who present with frequent complex ventricular dysrhythmias (110R).

Cardiovascular In a study of 199 patients with ventricular fibrillation who did not respond to a single DC shock, lidocaine was reported to have caused an increased risk of asystole after subsequent attempts at defibrillation ( l l l C ) . The authors recommended that at least 5 shocks should be tried in patients with ventricular fibrillation before drug therapy is given. Mexiletine (SED-12, 406; SEDA-12, 153;

SEDA-14, 151; SEDA-15, 178) The pharmacology, clinical pharmacology, hemodynamic effects, clinical use, and adverse reactions and interactions of mexiletine have been reviewed (112R). Adverse effects of mexiletine are frequent, and in some series have occurred in as many as 63% of patients. Neurological effects (dizziness, light-headedness, tremor, nervousness, and ataxia) are common, as are gastrointestinal effects (nausea, anorexia, and gastric irritation). Prodysrhythmias have also been reported in up to 29~ of cases, although in the review it was suggested that the average incidence was lower than has been reported with other antidysrhythmic drugs.

Chapter 18 J.K. Aronson This pattern of adverse effects has been confirmed in 2 more recent small trials of the use of mexiletine in 99 patients with suspected acute myocardial infarction (113 c) and in 29 patients with chronic ventricular extra beats (114c). However, in the first of these 2 studies, 20% o f the patients being treated wiht mexiletine died suddenly compared with 12% in the placebo group; although this difference was not statistically significant, it is large enough to raise the concern that mexiletine may cause an increase in mortality in patients who have had an acute myocardial infarction. This concern is compounded with the fact that mexiletine more frequently caused left ventricular failure, hypotension, A V block, or asystole than placebo. In contrast, mexiletine did not alter left ventricular ejection fraction in the second study and only 1 patient had a prodysrhythmic effect; however, the study was too small for definitive conclusions to be reached about the long-term safety of mexiletine in these patients.

Hematological A bayesian analysis of 9 cases of neutropenia in patients taking mexiletine has suggested that this is not a true association (115c). Gastrointestinal There has been a further report of mexiletine-induced esophagitis (116c). Interactions It has previously been reported (SEDA-10, 314) that the adverse effects of mexiletine may be reduced when it is combined with 13-adrenoceptor antagonists, quinidine, or amiodarone. This suggestion has been confirmed in a study in which mexiletine was combined with amiodarone (ll7C); only 3 out of 46 patients had adverse effects attributable to mexiletine, and these seem to have been mild; however, there was no control group for comparison. In contrast, in a study of the combination of mexiletine and propranolol the risk of adverse effects was approximately the same in patients taking mexiletine alone and in those taking the combination. Moracizine (moricizine) (SED-12, 407) Moracizine is a phenothiazine derivative with mixed Class I antidysrhythmic actions. Its pharmacology, clinical pharmacology, clinical uses, and adverse effects and interactions have

Positive inotropic drugs and drugs used in dysrhythmias Chapter 18 recently been the subject of several reviews (l19R--122R). Its most common adverse effects are dizziness, nausea, headache, fatigue, palpitation, and dyspnea. It also commonly causes intraventricular conduction delay and prodysrhythmias. Other less common effects include paraesthesiae, muscle pain, sleep disorders, weakness, dry mouth, mild gastrointestinal disturbances, and blurred vision. Moracizine is cleared by the liver, and dosages should be reduced in liver disease (123c). Its metabolism is inhibited by cimetidine and it in turn inhibits the metabolism of theophylline.

Procainamide (SED-12, 407; SEDA-12, 153;

SEDA-13, 143; SEDA-14, 152; SEDA-15, 178) Nervous system There have been further reports of muscle weakness attributed to procainamide. In 2 cases this was associated with respiratory insufficiency (124 c, 125c) and in a third with weakness of the arms and muscles of the face (126c). In I case (124c) the plasma procainamide concentration was 7.2 #g/ml and acecainide was not detectable; for this reason the myopathy was attributed to the parent compound rather than to its metabolite. Hematological There has been another report of a case of severe neutropenia attributed to procainamide given in a slow-release formulation, Procan-SR (127c). Liver A case of intrahepatic cholestasis has been reported in a 71-year-old man who was taking procainamide for ventricular extra beats (128c). The illness was accompanied by fever, and in the absence of evidence of infection a hypersensitivity reaction was suspected. Although granulomatous hepatitis has previously been reported, there appear to have been no previous reports of intrahepatic cholestasis.

183

reported as part of a drug-induced lupus-like syndrome in a 66-year-old woman taking procainamide in a sustained-release formulation (Procan SR) (130c). Lupus-like syndrome Anti-phospholipid antibodies may act as anticoagulants in patients with a lupus-like syndrome due to procainamide (SEDA-14, 152). This has been emphasized in the context of the case of a 70-yearold man in whom anti-phospholipid antibodies were associated with a marked shortening of the bleeding time and a greatly prolonged activated partial thromboplastin time but a normal prothrombin time. This case was complicated by the presence of an inhibitor with specific activity against factor XII and a congenital defect of factor XI (131c). The mechanisms whereby procainamide causes the production of autoantibodies are not known, but 2 major mechanisms have been suggested: first, procainamide may act as a hapten, binding to DNA, nuclear protein, or some membrane constituent, the h a p t e n - p r o t e i n complex stimulating the production of antibodies; second, it may alter suppressor cell function. A recent report has provided evidence of the latter mechanism (132c). In 18 patients who were given a 2-hour infusion of procainamide there was a marked reduction in suppressor cell activity in 17. The effect was dosedependent.

Interaction Reports that cimetidine can inhibit the renal clearance of both procainamide and its major metabolite acecainide (SEDA-14, 147, 152) have been confirmed in 10 patients taking procainamide and cimetidine (133c). Steady-state procainamide and acecainide concentrations increased by 55% and 36% respectively when cimetidine was introduced. Twelve of 36 patients given this combination experienced symptoms suggestive of procainamide toxicity. Propafenone (SED-12, 409; SEDA-12, 154;

There has been a report of 2 cases of urticarial vasculitis attributed to procainamide in 2 men in their seventies (129c). It is not clear whether or not the vasculitis was part of a lupuslike syndrome in these cases.

Skin

Special senses A case of scleritis has been

SEDA-13, 143; SEDA-14, 152; SEDA-15, 179) Further reviews of the pharmacology, clinical pharmacology, uses, and adverse effects and interactions of propafenone have appeared (134R - 136R).

Chapter 18 J.K. Aronson

184 The efficacy and adverse effects of propafenone in 27 studies of its use in 684 patients with ventricular dysrhythmias have been reviewed (137R). During long-term treatment suppression of dysrhythmias was achieved in about 7007o of cases, and this did not correlate with the efficacy of propafenone during electrophysiological studies. Propafenone had to be discontinued in 17070of cases, 6070 of which were due to non-cardiac effects. The cardiac effects which forced discontinuation were prodysrhythmias in 4.5 070, congestive heart failure in 2.6070, and conduction abnormalities in I. 5 070.There were 18 sudden deaths (2.6 070),and in 4 of these the left ventricular ejection fraction was very low.

Cardiovascular There has been a report of acceleration o f conduction through an accessory pathway attributed to propafenone in a 40year-old woman (138c). The authors suggested 2 possible mechanisms: first, reduced cardiac function causing a reflex increase in sympathetic drive; second, coarsening of flutterfibrillation which was present in this patient, with an increase in cycle length just beyond the effective refractory period of the accessory pathway. The latter suggestion has received some support from a report of atrial flutter in 14 patients taking propafenone, in 8 of whom the dysrhythmia was completely new (139c).

Respiratory Propafenone is a beta-blocker as well as a Class I antidysrhythmic drug. It is not surprising, therefore, that the U.K. Committee on Safety of Medicines had received 5 reports on shortness of breath or worsening of asthma by March 1990 from a total of 42 reports of adverse reactions. The case of a 50-year-old woman who developed coughing and wheezing 1 week after starting propafenone has also been described (140c). However, she had previously taken metoprolol and atenolol without any adverse respiratory effect and the mechanism of her asthma was therefore unclear. None the less, its association with propafenone was confirmed by rechallenge.

Nervous system Propafenone has been reported to cause muscle weakness (141c), perhaps because it blocks fast sodium channels or perhaps because of its anticholinergicaction.

Quinidine (SED-12, 410; SEDA-12, 155; SEDA-13, 144; SEDA-14, 153; SEDA-15, 178) The adverse effects of quinidine have been reported in a study of 397 patients treated for asymptomatic ventricular dysrhythmias (142c). Adverse effects occurred in 46070 of the patients during the first 2 weeks of therapy. In the remainder adverse effects occurred in only 207o. There were no differences in the rates of sudden death between those taking quinidine and those taking no antidysrhythmic drugs. The most common adverse effects were anorexia, nausea, vomiting, abdominal pain, and diarrhea. Other effects included rash, headache,

fever, vertigo, confusion, tinnitus, disturbed vision, and thrombocytopenia. Cardiovascular The hemodynamic effects of quinidine have been studied in 19 patients with severe chronic heart failure (143c). The major effect of quinidine was vasodilatory, and since this was greater than its negative inotropic effect, no adverse effect on left ventricular function was detected. Of course, hypotension occurs not uncommonly after the intravenous administration of quinidine, and this can largely be attributed to its vasodilatory action, which is mainly on the arterial side. Cases of torsades de pointes attributed to quinidine continue to be reported. In one case the tachycardia occurred in a patient with a pacemaker only when it was in a hysteresis mode (144c). The authors suggested that quinidine should not be used in patients whose pacemaker is programmed for hysteresis. In another case verapamil was reported to have been used with success to treat quinidineinduced torsades de pointes (145c). In other cases overdrive pacing has been used successfully (SEDA-13, 144). A case of primary coronary artery dissection has been reported in a 56-year-old man taking quinidine (146c). The clinical presentation was associated with a severe skin rash, and at autopsy there was infiltration of macrophages, eosinophils, and mast cells in the left ventricle. A hypersensitivity reaction was therefore suspected. Nervous

system

Another

case

of

acute

Positive inotropic drugs and drugs used in dysrhythmias Chapter 18 psychosis in a 62-year-old man who was taking quinidine for a recurrent supraventricular tachycardia has been reported (147c). Since he suffered a similar attack some months later when quinidine had been withdrawn, the authors suggested that the quinidine had increased his natural propensity to psychosis. H o w e v e r , it was also possible that quinidine therapy was just coincidental.

Hematological

Quinidine-induced thrombocytopenia is not generally fatal, but there has been a recent report that it may result in death f r o m intracerebral hemorrhage (148c). In both cases transfusions of fresh platelets were given and in 1 case prednisone, 40 nag daily, was tried. In another case o f thrombocytopenia high-dose intravenous gammaglobulin rapidly reversed thrombocytopenia (149c). A l t h o u g h quinidine has been reported to cause agranulocytosis, it is not c o m m o n . H o w e v e r , there has been a report in a 60-yearold man who was taking quinidine for atrial fibrillation (150c). The fall in neutrophil count occurred within 3 days of starting quinidine, and this is quicker than in the handful o f previously reported cases. A case o f lymphadenopathy attributed to

185

quinidine has been reported (151c). There was no evidence of a lupus-like syndrome, in contrast to the one previously reported case (SEDA-13, 145). Skin Quinidine may occasionally cause skin pigmentation (SEDA-12, 155). There has now been a report of pigmentation of the oral mucosa in a 58-year-old w o m a n who had been taking quinidine for 10 years for dysrhythmias (152c). Biopsy showed accumulations of melanin-like granules in the papillary layer of the lamina propria. The authors described another similar case in a 75-year-old man who had been taking quinidine for 5 years, but did not report biopsy changes. Tocainide (SED-12, 412; SEDA-12, 155; SEDA-13, 145; SEDA-14, 153; SEDA-15, 180) There has been another report of a case of interstitialpneumonitis in a 76-year-old man who had been taking tocainide for 3 months (153c). He responded to corticosteroid therapy after withdrawal of the tocainide. The concurrence of an eosinophilia suggested that this may have been a hypersensitivity reaction.

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186 Manny RP (1990) Pancytopenia secondary to shortterm, high-dose intravenous infusion of amrinone. Drug Intell. Clin. Pharm. Ann. Pharmacother., 24, 1172- 1174. 14. Gilfrich HJ, Dieterich H A (1991) Vertr~iglichkeit von Enoximon bei Patienten mit Herzinsuffizienz. Z. Kardiol., 80, 9 3 - 97. 15. Vernon MW, Heel RC, Brogden RN (1991) Enoximone. A review of its pharmacological properties and therapeutic potential. Drugs, 42, 997 - 1017. 16. Coghlan JG, Norell M, Ilsley CD, Mitchell AG (1991) Oral treatment with enoximone in patients referred for cardiac transplantation. Int. J. Cardiol., 32, 5 7 - 64. 17. Atallah G, George M, Lehot J J, Bastien O, Bejuit R, Durand PG, Estanove S (1990)Arhythmies chez les patients en bas d6bit cardiaque apr~s chirurgie valvulaire, l~tude randomis6e aveugle et comparative dobutamine versus enoximone. Arch. Mal. Coeur, 83, 6 3 - 68. 18. Beurrier D, Brembilla-Perrot B, Bock F, Danglas P (1990) Effet de l'enoximone sur les troubles du rythme cardiaque, l~tude pr61iminaire. Ann. M~d. Nancy Eat, 29, 289-293. 19. Hilleman DE, Forbes WP (1989) Role of milrinone in the management of congestive heart failure. Drug Intell. Clin. Pharm. Ann. Pharmacother., 23, 357-362. 20. Ferrick KJ, Fein SA, Ferrick AM, Doyle ]T (1990) Effect of milrinone on ventricular arrhythmias in congestive heart failure. Am. J. Cardiol., 66, 431-434. 21. Campbell TJ (1990) Proarrhythmic actions of antiarrhythmic drugs: a review. Aust. NZ J. Med., 20, 275 - 282. 22. Feld GK, Chen P-S, Nicod P, Fleck P, Meyer D (1990) Possible atrial proarrhythmic effects of Class IC antiarrhythmic drugs. Am. J. Cardiol., 66, 378-383. 23. Campbell RWF 0990) Arrhythmogenesis and antiarrhythmic drugs. Adverse Drug React. Bull., 144, 5 4 0 - 543. 24. Kennedy HL (1990) Late proarrhythmia and understanding the time of occurrence of proarrhythmia. Am. J. Cardiol., 66, 1139- 1143. 25. Ravid S (1990) Congestive heart failure as a complication of antiarrhythmic drug therapy. Cardiol. Board Rev., 7, 5 3 - 6 2 . 26. Brna TG (1991) Agranulocytosis from antiarrhythmic agents. Postgrad. Med., 89, 181 - 188. 27. Till J, Shinebourne EA, Rigby ML, Clarke B, Ward DE, Rowland E (1989) Efficacy and safety of adenosine in the treatment of supraventricular tachycardia in infants and children. Br. Heart J., 62, 204-211. 28. Rankin AC, Oldroyd KG, Chong E, Dow JW, Rae AP, Cobbe SM (1990) Adenosine or adenosine triphosphate for supraventricular tachycardias?

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Positive inotropie drugs and drugs used in dysrhythmias 43. O'Rangers EA (1990) Adenosine. Conn. IVied., 54, 635 - 636. 44. Remme WJ, van Hoogenhuyze DCA (1990) Hemodynamic profile of amiodarone during acute and long-term administration in patients with ventricular dysfunction. Cardioscience, 1, 169- 176. 45. Gallastegui JL, Bauman JL, Anderson JL, Winkle RA, Ezri MD, Westveer DC, Swiryn S (1988) Worsening of ventricular tachycardia by amiodarone. J. Clin. Pharmacol., 28, 406 - 41 I. 46. Fananapazir L, Leon MB, Bonow RO, Tracy CM, Cannon RO, Epstein SE (1991) Sudden death during empiric amiodarone therapy in symptomatic hypertrophic cardiomyopathy. Am. jr. CardioL, 67, 1 6 9 - 174. 47. Strasberg B, Kusniec J, Zlotikamien B, Mager A, Sclarovsky S (1990) Long-term follow-up of postmyocardial infarction patients with ventricular tachycardia or ventdcular fibrillation treated with amiodarone. Am. J. Cardiol., 66, 6 7 3 - 678. 48. Fananapazir L, Epstein SE (1991) Value of electrophysiologic studies in hypertrophic cardiomyopathy treated with amiodarone. Am. J. Cardiol., 67, 175 - 182. 49. ArbustiniE, Orasso M, Salerno JA, Gavazzi A, Pucci A, Bramerio M, Calligaro A, Ferrans VJ (1991) Endomyocardial biopsy finding in two patients with idiopathic dilated cardiomyopathy receiving long-term treatment with amiodarone. Am. J. Cardiol., 67, 661-662. 50. Jolly E, Belloti MS, Lowenstein J, Luna C, Avagnina A, Eisner B, Mazzei JA (1991) Alteraclones citologicas en el lavado broncoalveolar de los pacientes en tratamiento con amiodarona. Medieina, 51, 1 9 - 25. 51. Nicolet-Ch~ttelain G, Pr6vost M-C, Escamilla R, Migu~res J (1991) Amiodarone-induced pulmonary toxicity. Immunoallergologic tests and bronchoalveolar lavage phospholipid content. Chest, 99, 3 6 3 - 369. 52. Akoun GM, Cadranel JL, Blanchette G, Milleron BJ, Mayaud CM (1991) Bronchoalveolar lavage cell data in amiodarone-associated pneumonitis. Evaluation in 22 patients. Chest, 99, 1177 -

1182.

53. Foresti V, Pepe R, Parisio E, De Filippi G, Scolari N, Frigerio C (1989) Angiotensin-converfing enzyme as a possible marker for lung toxicity in amiodarone-treated patients. Int. J. Clin. Pharm. Res., 10, 261-267. 54. Pollak PT, Sharma AD, Carruthers SG (1990) Relation of amiodarone hepatic and pulmonary toxicity to serum drug concentrations and superoxide dismutase activity. Am. J. Cardiol., 65, 1185- 1191. 55. Kuhlman JE, Teigen C, Ren H, Hurban RH, Hutchins GM, Fishman EK (1990) Amiodarone pulmonary toxicity: CI" findings in symptomatic patients. Radiology, 177, 121 - 125.

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