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Side effects and possible contraindications of amiodarone use
Rakita et al.
American
I have been told of patients with pulmonary toxicity that responded to corticosteroids and discontinuing amiodarone. The chest x-ray findings cleared 3 to 4 months after amiodarone was stopped, but as steroids were tapered the infiltrates recurred. Again the infiltrates resolved as the dose of steroids was increased. If this was a cumulative phenomenon, was there any relationship to the serum concentration of amiodarone? Dr. Rakitu: I do not know. It would be interesting to see amiodarone blood levels in patients with different stages of pulmonary toxicity, from early to late and severe. Dr. Waxman: How often do you recommend performing x-ray studies? Dr. Rakita: Every 3 months. Dr. Singh: When blood levels have been measured, they are not very high, 1.2 to 1.5 lg/ml in several cases.
Side effects and possible amiodarone use
October, 1993 Heart Journal
The crucial issue, according to Holt’s data, may be the very high concentrations of both the drug and its metabolite in the lungs. Therefore, blood levels may not be particularly informative. Dr. Scheinman: We have seen pulmonary toxicity in eight of 270 patients. It is very important to obtain transbronchial biopsy specimens to confirm the diagnosis. One patient had all the “typical” clinical features of amiodarone pulmonary toxicity. On postmortem, however, we found that this patient had had pneumonia and congestive heart failure. Another patient given amiodarone and procainamide showed a resolution of infiltrates when procainamide alone was stopped. Dr. Zipes: Unfortunately, too much information is anecdotal. A central registry for patients who develop pulmonary complications should be established to gather and organize data.
contrtindications
of
With the increasing use of amiodarone, several unwanted effects have been recognized. We revtewed 140 patients treated with amiodarone over a !i-year period in an attempt to identify patients at risk, to assess the incidence of these effects and their possible relation to dose, and to determine their outcome. The most common effect was photosensitivity (57% of patients responding to a questionnaire), whereas asymptomatic cornea1 microdeposits were found in all patients undergoing ophthalmologic examination. In contrast, aymptomatfc eye changes (colored halos) and slate-gray skin pigmentation were rare. Of the metabolic alterations, the rise in hepatic enzymes correlated with dose and plasma drug and metabotfte concentrations (r = 0.59, p < 0.001; f= 0.62, p < 0.001, respectively) but was not associated with clinical disease. This relation to dose was not evident in patients developing clinical thyroid abnormalfties (two hypothyroidism, two hyperthyroidlam), all of whom had normal thyroid function prior to therapy. Four of the five hypothyroid patients were over 70 years of age. No patients developed peripheral neuropathy, but tremor and sleeplessness were common complaints (30% and 26% of patients, respectively) that responded to a decrease in dose. One patient with an abnormal chest x-ray film prior to therapy developed pulmonary fibrosis. We suggest the restricted use of high doses of amiodarone for protracted periods. Patients at particular risk are the older age group (hypothyroidism) and those with abnormal lung function prior to therapy who may be predisposed to pulmonary alveolitia. Most of the observed unwanted effects resolve when amiodarone is decreased in dose or discontinued. (AM HEART J 106~916, 1983.)
Louise Harris, M.B., William J. McKenna, M.D., Edward Rowland, and Dennis M. Krikler, M.D. London, England
From Royal
the Division Postgraduate
of Cardiovascular Medical School.
Based on data previously et al: Amiodarone: Side 1983. Reprint Hospital,
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Disease,
published in Harris effects of long-term
Department
of Medicine,
L, McKenna WJ, Roland E, therapy. Circulation 67:45,
requests: Dr. L. Harris, Division of Cardiology, Toronto 101 College St., Toronto, Ontario, Canada MSFG 1L7.
General
M.B.,
Amiodarone is a drug with unique pharmacodynamic and pharmacokinetic properties. Its increasing use as an antiarrhythmic agent attests to its potent efficacy but has also been accompanied by the increased recognition of unwanted effects. As with many other drugs, it is possible that these effects can
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be grouped into those which are dose or doseduration dependent and those which are idiosyncratic. For the drug’s benefit to be greatest, it is important that these reactions be differentiated so that patients at risk can be identified prior to therapy and dosage schedules can be optimized by balancing arrhythmia control against side effects. Recent reports evaluating neurologicl and pulmonary2 complications have assisted in this regard. We reviewed 140 patients treated with amiodarone over a 5-year period to identify patients at risk and to assess the incidence of side effects, their relation to dose, and their outcome. PATIENTS
AND DOSAGE
One hundred forty patients (95 men and 45 women with a mean age of 52 years) were treated with amiodarone (mean daily dose, 360 mg; range, 100 to 1200 mg) over a 5-year period (average duration of follow-up, 2 years). Patients with ventricular tachycardia (n = 46) and complex ventricular extrasystoles (n = 10) required larger doses (440 mg/day and 400 mg/day, respectively) than those with supraventricular arrhythmias. Thus the mean daily dose for patients with chronic atrial fibrillation and/or flutter (n = 15) was 310 mg, and for patients with paroxysmal atria1 arrhythmias (n = 38) it was 280 mg. Patients with supraventricular arrhythmias associated with Wolff-Parkinson-White syndrome received a mean dose of 350 mg/day. Following an initial loading period (600 to 1200 mg/day for 1 week and then 400 to 600 mg for 1 month), long-term dosages were adjusted according to individual patient requirements so that control of arrhythmia was balanced against side effects. Only 11 patients used doses of 600 mg/day or more over the long term. Half the patients were taking amiodarone for primary arrhythmias (n = 69), and the remaining patients were treated for arrhythmias associated with a variety of underlying cardiovascular conditions (Table I). METHODS
Before treatment began, a chest x-ray examination, ECG, and routine thyroid and hepatic function tests were performed. The thyroid function tests included the estimation of serum thyroxine, free thyroxine index, free binding capacity, and thyroid-stimulating hormone (TSH). Hepatic function tests measured aminotransferases,alkaline phosphatase,serum bilirubin, cholesterol, and total protein and albumin concentrations. At subsequentclinic visits these biochemical tests were repeated, and plasma concentrations of amiodarone and desethylamiodaronewere also determined by high-performance liquid chromatography.3A detailed history of side effects was taken, and patients were examined for drug-
Amiodarone
Table
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I. Details of cardiovascular conditions treated Condition
Primary arrhythmia Cardiomyopathy Hypertrophic Congestive Ischemic heart disease Valvular disease Hypertensive heart disease Atria1 septal defect
No.
of
patients 69 28 20 15 5 2 1
related stigmata. Asymptomatic patients were followed at 3- to B-month intervals but were advised to contact the unit directly in the event of any untoward symptoms, Similarly, any patient experiencing visual disturbancesor other ophthalmologic problems was referred to an ophthalmologist; in the first years of our experience with amiodarone,all patients had been followed up routinely in the ophthalmology clinic. A questionnaire designedto assessthe incidence and severity of known side effects and to identify any possible previously unrecognized effects was sent to patients who had been taking the drug for a minimum of 6 months. Plasmadrug concentrations taken at the time of reply to the questionnaire were assessedin relation to the total number of side effects reported by each patient, aswell as in relation to the severity of individual effects. RESULTS Dermatologic findings. Photosensitivity was the most common reaction (57% of patients responding to the questionnaire), varying from an increased propensity toward suntan during the summer months to intense burning, erythema, and swelling of the sun-exposed areas. Neither dosage nor plasma drug concentrations proved useful in distinguishing patients with and without photosensitivity. However, this reaction could be partially alleviated by a reduction in dosage in some patients. Others obtained relief by using sunscreen barrier creams, and no patient was required to discontinue the drug. The two patients who developed slate-gray pigmentation had been using 600 mg/day for 5 and 2 years, respectively. Both patients had high plasma concentrations of amiodarone (3.1 pg/ml in both) and desethylamiodarone (3.7 Fg/ml and 3.2 fig/ml, respectively). The slate-gray pigmentation occurred in the sun-exposed areas of the face and hands, and it was still evident 6 to 12 months after therapy was discontinued. An additional skin reaction was observed in six patients in the first weeks of therapy: an erythematous, pruritic rash with a predominantly truncal distribution. There was no relation to dose, and in
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Table
II. Patients with grossalterations in thyroid function tests on amiodarone*
American
October. 1903 Heart Journal
On amiodarone
Patients Decreased
JW FDI LH RM MD Increased MQ GE4 AF SB
Age (yr) fser function 70/M 77/F 76/M 77/M 59/M function 48/M 62/M 40/M 18/F
Dose (mglday)
Duration
AF SND
200 200
AF VT VT
200 200 600
39 10 29 36 32
8 33 44 24 25
VT &F
400 400 600 400
34 32 26 36
226 207 193 231
Arrhythmia
SVT/WPW
(ma)
Thyroxinet (nmol/L
Free T,f (pmol/L)
39.5 42.0 37.0 67.2
TSH
Amiodarone Wml)
Desethylamiodarone (hdml)
>25 >60 >20 19 >25
0.7 1.5 0.5 1.1
0.8 -
2.0 1.3 4.6 0.5
2.0 1.4 3.8 0.8
1.5 0.9 1.5
T, = thyroxine; AF = atria1 flutter; SND = sinus node disease; VT = ventricular tachycardia; CAF/F = chronic atria1 fibrillation/flutter; SVT = paroxysmal supraventricular tachycardia; WPW = Wolff-Parkinson-White syndrome. *From Harris L, McKenna WJ, Rowland E, Krikler DM: Side-effects of long-term amiodarone therapy. Circulation 67:45,1983. Used by permission of the American Heart Association, Inc. tNorma1 range-thyroxine, 45 to 160 nmolfi, free thyroxine, 0.8 to 24 pmol/L. tClinically myxedematous, §Clinically thyrotoxic.
all patients it resolved spontaneously despite continuation of therapy. Thyroid function. Biochemical aherations in thyroid function were common. The mean thyroxine level for the patients (124 nmol/L) was’elevated hy 20% above the mean for normal subjects (102 nmol/L) as measured by our laboratory. A similar increase was observed in the free thyroxine index, whereas free binding capacity fell. Four patients had thyroxine levels in excess of 25% above the upper limit of normal, whereas in five patients the thyroxine levels fell and TSH increased (Table II). Clinical evidence of thyroid disease, however, developed in only four patients, two becoming hypothyroid and two hyperthyroid (Table II). The myxedematous patients had the typical clinical features of weight gain, lethargy, and hoarseness, whereas the clinical picture in the thyrotoxic patients was more insidious. Both gave a history of recent weight loss, weakness, and increasing anxiety, and both had conspicuously elevated triiodothyronine levels (4.3 nmol/L and 5.3 nmol/L). Although the thyrotoxicosis resolved with diticontinuation of the amiodarone and no specific antithyroid treatment (1 to 2 months for complete biochemical and clinical resolution in both patients), the hypothyroid patients required thyroxine replacement therapy. The nine patients experiencing gross alterations in thyroid function tests while receiving amiodarone (Table II) were scrutinized for possible predisposing clinical factors. All but two were taking moderate doses, and the mean duration of treatment before
changes occurred was 30 months. Four of the five hypothyroid patients were over 70 years of age. All of the patients had normal thyroid function prior to treatment and negative antibody titers. In addition, there was no family history of thyroid disease. Gastrointestinal effects. Thirty-one percent of patients responding to the questionnaire reported gastrointestinal effects: nausea and loss of appetite were experienced only during the initial “loading phase” with high doses, whereas patienta using the drug over a long term complained of alterations in bowel habits with a tendency toward constipation. No patient developed clinicaily evident hepatic dysfunction, but biochemical alterations in hepatic function tests were common. A 1.5 to It-fold increase in serum aspartate aminotransferase levels was found in 15 of 100 patients. These changes were seen in patients receiving high doses and correlated with plasma concentrations of amiodarone (T = 0.59, p < 0.001; Fig. 1, A) and ita desethyl metabolite (r = 0.62, p < 0.001; Fig. 1, B). A similar increase occurred with alanine aminotransferase, but no changes were observed in serum bilirubm, alkaline phosphatase, cholesterol, total protein, or albumin levels. Liver biopsies from two patients with elevated enzyme levels revealed nonspecific changes only. Neurologic findings. None of our patients developed peripheral neuropathy. However, they reported a variety of other neurologic symptoms, the most
Volume
106
Number
4, Part 2
Amiodarone side effects
919
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Fig. 1. A, Log aspartate aminotransferase plotted against plasma amiodarone (mg/L) in 88 patients during treatment. B, Log aspartate aminotransferase plotted against plasma desethylamiodarone (mg/L) in 88 patients during treatment.. (From Harris L, McKenna WJ, Rowland E, Krikler DM: Side effects of long-term amiodarone therapy. Circulation 67:45, 1983. Used by permission of the American Heart Association, Inc.)
common being a fine tremor of hands (30% of patients responding to the questionnaire), sleep disturbance (‘28 % ), and headaches (14 % ) described as a “bandlike sensation.” All of these complaints responded to a reduction in dose, and discontinuation of therapy was not required. Another doserelated reaction was that of proximal muscle weakness (eight patients), seen only during the initial “loading phase” in patients using doses of 800 mg/day or more. changes. Pulmonary interstitial Pulmonary changes with an associated restrictive pattern on pulmonary function testing were observed in one patient after 30 months of treatment. However, this patient had had a positive Kveim test 4 years previously, and a review of his x-ray films suggested that such changes may have been present before treatment. There was no other evidence of sarcoidosis.
Ocular symptoms. Corneal deposits were found on slit-lamp examination as early as 10 days after starting amiodarone and were present in all patients examined after 1 month. The extent of these deposits is probably dose-duration dependent. Thus they were asymptomatic in all but two patients. These two patients had been using 600 mg/day for more than 1 year when they began to complain of bluegreen halos while looking at bright lights. Slitlamp examination revealed the deposits to have encroached on the cornea. Both became asymptomatic within 2 months after their dosage was reduced. We observed no other ophthalmologic complications.
DlSCUSSlON It must be conceded that patients experiencing problems with amiodarone may have had greater motivation to respond to the questionnaire than
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et al.
those who were asymptomatic, thereby giving the results a positive bias. Nevertheless, many of the unwanted effects observed appear to be dose related. Symptoms responding to a reduction in dosage include the gastrointestinal effects of nausea and anorexia and the neurologic effects of tremor, headaches, and sleep disturbance, whereas proximal muscle weakness was seen only in patients receiving the “loading dose.” Similar neurologic reactions have been reported by other investigators114 when doses in excess of 800 mg/day were used. The incidence of alterations in hepatic function was high (15 % ) among our patients but is consistent with that reported by others.4T5 Those investigators found the changes to be transient, of similar magnitude to those seen in our patients, and unassociated with clinical disease. However, two further patients6 developed clinical hepatitis while taking amiodarone. A liver biopsy from one patient showed nonspecific changes only. The authors do not discuss other possible contributory factors, such as concurrent illness or medication, and the association therefore remains speculative. The high incidence of biochemical hepatic alterations, together with the direct relation to dose, suggests a toxic effect rather than host idiosyncrasy as the causative mechanism of the hepatic injury. Since the changes are transient and can be corrected by decreasing the dose, we do not discontinue the drug in patients with raised enzyme levels but monitor hepatic function regularly. It is important to emphasize that serious hepatic toxicity was not encountered. Other unwanted effects that may be both dose and duration dependent are symptomatic ocular changes and the slate-gray skin pigmentation. Similar findings by other investigators are consistent with a dose-duration dependency for this latter reaction. Of 34 pigmented patients, 14 (40%)7-13 had been taking 600 mg daily or more for an average of 2 years before pigmentation developed. In addition, it is possible that photosensitivity may predispose these patients to this reaction, since both of our patients, as well as almost all of those reported, had experienced photosensitivity prior to the development of the unusual pigmentation. Photosensitivity, however, is not dose related, and at present there is no way of predicting which patients are at risk. Because it is a common complication, we therefore advise all patients to use prophylactic barrier creams during sun exposure. Previously, no clear relation to dose and/or duration of therapy was apparent in those patients developing peripheral neuropathy.6*‘4s’5 Although none of our patients experienced this complication,
American
October, 1983 Heart Journal
other investigators 14*15have reported a sensorimotor neuropathy, with segmental demyelination of nerve fibers shown by histologic examination. The neuropathy resolves with discontinuation of treatment, but this may be slow and is apparently incomplete. This is in contrast to the neurologic side effects described earlier (tremor and sleep disturbance), in which rapid resolution occurs when the dose is reduced. At present there does not appear to be a means of identifying patients at risk of neuropathy. Similarly, the mechanism of the pulmonary injury seen with amiodarone remains unclear. In our patient the pulmonary changes were difficult to interpret because they may have been present to a lesser extent before amiodarone use. However, there are a growing number of reports describing similar abnormalities,% 6216-18 with interstitial or alveolar fibrosis seen on histologic examination. It is possible that this reaction may be dose related, at least in part: 8 of the 14 patients reported were taking doses of 800 mg/day or more. A further possibility is drug-induced autoimmunity. Our patient had positive antinuclear antibody titers, but other investigators have not reported similar findings. Other factors, such as preexisting cardiac failure or genetic differences in metabolism of the drug, may also prove to be important in the pathogenesis of this reaction. More recently it has been suggested that pretreatment pulmonary function tests may be of predictive value in identifying patients at risk.2 Thus patients with an initial hemoglobin-corrected diffusion capacity of lungs for CO (DLCO) of 80% or less had a greater incidence of radiographic changes during treatment than those with a DLCO of more than 80% prior to therapy. However, no concurrent control series was studied, and the significance of these findings in the absence of unequivocal evidence of pulmonary fibrosis cannot be evaluated. Nevertheless, until we have a clearer understanding of the mechanism of this reaction, it would appear prudent to use the drug with caution for patients with preexisting lung abnormalities and to restrict the use of high doses of amiodarone for protracted periods. The development of clinical thyroid disease or gross alterations in thyroid biochemistry could not be predicted by dose or duration of therapy in our patients. This suggests a specific reaction in these individuals: thus four of the five patients who became hypothyroid (as determined by clinical and/ or biochemical evidence) were over 70 years of age. Since TSH does not rise in relation to age in an average community,1g it may be that older patients taking amiodarone are predisposed to the development of hypothyroidism. None of our patients expe-
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Amiodarone
riencing thyroid complications had a previous history or family history of thyroid disease, and none had evidence of autoimmune disturbance. The interaction between amiodarone and thyroid hormone metabolism has been dealt with elsewhere in this symposium.2o CONCLUSIONS
It appears that many of the side effects experienced with amiodarone can be corrected simply by a reduction in dose. Although the mechanisms of other unwanted effects remain to be clarified, the evidence suggests that amiodarone be used with caution in the older patient and in patients with a reduced diffusion capacity on pulmonary function testing. In the event of amiodarone-related complications, almost all (with the possible exception of hypothyroidism) will resolve once treatment is discontinued. At present it is not certain whether the routine monitoring of serum concentrations of amiodarone and its desethyl metabolite will be helpful in minimizing serious amiodarone toxicity, but our data indicate that careful attention to dose may be associated with a low overall incidence of side effects. REFERENCES
1. Charness M, Morady F, Shen EN, Shapiro WA, Scheinman MM, Hess DS: Frequent neurologic toxicity associated with amiodarone therapy. J Am Co11 Cardiol 1:630, 1983. Kudenchuk PJ, Pierson DJ, Greene HL, Gross BW, Graham EL, Sears GK: Pulmonary effects of amiodarone. J Am Co11 Cardiol 1:631, 1983. Holt DW, Tucker GT, Jackson PR, Storey GCA: Amiodarone nharmacokinetics. AM HEART J 106:840, 1983. Heger dd, Prystowsky EN, Jackman WM, Naccarelli GV, Warfel KA. Rinkenhereer RL. Zincs DP: Amiodarone clinical efficacy and electrophisiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 305:539, 1981. 5. Plomteaux G, Heusghem C, Ernould H, Vandeghen N: Long-term hepatic tolerance of amiodarone in the clinic. Eur J Pharmacol 8:369, 1969. 6. Waxman HL, Groh WC, Marchlinski FE, Buxton AE, Sadowski LM. Horowitz LN. Josenhson ME. Kastor JA: Amiodarone for control of sustained ventricular tachyarrhythmia: Clinical and electrophysiologic effects in 51 patients. Am J Cardiol 50:1066, 1982. 7. Labouche F, Balouet G, Daoulas R, Masse R, Le Moigne P, Coignard A, Baret MF: Les accidents cutanees de l’amiodarone. Arch Med Quest 5:37, 1973. 8. Texier L, Meunier J, Gauthier Y, Dubiau J-M, Gaillard G: Pigmentations cutanees accidentelles au tours de traitements par l’amiodarone. Contours Med 93:4859, 1971. 9. Morand PH, Benatre J. Viau G, Carli-Basser CL, Laine J-L, Neel J-L, Brochier M, Raynaud R: Etude clinique et histologique (ultrastructure) de la pigmentation par le chlorhydrate d’amiodarone. Sem Hop Paris 48:553, 1972. 10. Wanet J, Achten G, Barchewitz, Mestdagh G, Vastesaeger M: Amiodarone et depots cutanes: Etude clinique et histologique. Ann Dermatol Venereol 98:131, 1971. 11. Herne N, Marion J, Brisou B, Antiglio V, Rousselot M: Pigmentations cutanees induites par le chlorhydrate d’amiodarone. Lyon Med 226:205, 1971. I
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12. Vulliemin JF: Les effets secondaires cutanees de la Cordarone. Schweiz Rundschau Med (Praxis) 62:1426, 1973. 13. Lambert D, Noble J-P, Justrabo E, Hewitt J: Pigmentation cutanee secondaire a l’administration d’amiodarone: Problemes histogenetiques. Ann Dermatol Venereol 102:277, 1975. 14. Kaeser HE: Amiodarone-Neuropathie. Schweiz Med Wochenschr 104:606, 1974. 15. Meier C, Bauer B, Muller U, Ludin HP: Neuromyopathy during chronic amiodarone therapy. J Neurol 220:231, 1979. 16. Rotmensch HH, Liron M, Tupilski M, Laniado S: Possible association of pneumonitis with amiodarone therapy. AM HEART J 100:412, 1980. 17. Sobol SM, Rakita L: Pneumonitis and pulmonary fibrosis associated with amiodarone treatment: A possible complication of a new antiarrhythmic drug. Circulation 65:819, 1982. 18. Riley SA, Williams SE, Cooke NH: Alveolitis after treatment with amiodarone. Br Med J 184:161, 1982. 19. Tunbridge WMG, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Grimley Evans J, Young E, Bird T, Smith P: The prevalence of thyroid disorders in an English community. In Robbins J, Braverman LE, editors: Thyroid research. Amsterdam, 1976, Excerpta Medica, p 520. 20. Singh BN, Nademanee K: Amiodarone and thyroid function: Clinical implications during antiarrhythmic therapy. AM HEART J 106:857. 1983. DISCUSSION
Dr. Rosenbaum: I agree that it may be clinically convenient to separate the patients according to whether their complications are or are not dose or dose-time dependent. This requires some qualification. My clinical impression is that even in patients who develop some sort of “hypersensitivity” to amiodarone, the dose plays a role. If the patient is hypersensitive, he will be more likely to develop the complications when he is on high rather than low doses. Dr. Harris: Where we can identify a clear-cut relationship to dose, it is reversible. By reducing the dose we can correct these effects. However, there are likely to be reactions that are a mixture of the two, and they cannot be corrected by simply reducing the dose. Dr. Rosenbaum: Do you believe that the photosensitivity is related to the cumulative effect, or can it occur as an acute effect? If a young lady goes sunbathing often and takes 600 mg one day and goes into the sun, will she develop photosensitivity the same day or the next day? Dr. Harris: When we were trying to work out the pharmacokinetics of amiodarone with Dr. Holt, we were taking 600 mg a day and did not have any photosensitivity, but, then, there’s no sun in London anyway! Dr. Singh: I don’t believe that thyroid complications are dose dependent. The amount of iodine that is released by deiodination of amiodarone is considerable even at low doses; thus whether the patient is taking 200 mg or 600 mg per day, it makes no difference if he has a preexisting tendency for an abnormal reaction to iodine. If we believe that altered thyroid state is related to iodine rather than to the drug itself, then the question of dose does not arise. I believe that this is one side effect we can dissociate from dose.
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Dr. Marcus: You suggested that the photosensitivity and the skin discoloration were dose related. In Arizona, where we have sun 360 days a year, we have found four patients who have bluish discoloration out of 56 (about 7 % ); we also have over 10% of patients who have clear-cut sun sensitivity. The exposure to sun may enhance the susceptibility to the bluish discoloration. The dose that we use is under 400 mglday, and the average dose has been 335 mg in other patients. Thus I do not believe that the discoloration is related to dose. Dr. Harris: I wasn’t suggesting that sun sensitivity per se is dose related. With bluish discoloration, there appears to be more intense elastic degeneration in the skin biopsies of these patients. There is speculation that the areas that show intense degeneration are prone to developing these deposits. Dr. Marcus: In our area, where there is a lot of exposure to the sun, there may be some of this elastic degeneration occurring that predisposes to bluish discoloration. We have seen three patients who have had liver function abnormalities (but not clear-cut hepatitis) associated with anorexia. These patients have not been in severe congestive heart failure. They just had continued anorexia and weight loss until we stopped the amiodarone, at which point they recovered fully. There seems to be a subclinical hepatitis that occurs in some patients. Since many of the patients with congestive heart failure have anorexia, this must be looked for. Dr. Harris: We have had problems with nausea and anorexia only with the loading dose. Dr. Marcus: I again emphasize that we used low doses. Dr. Ruffy: I also agree with Dr. Marcus’ comment that anorexia is a very serious side effect in some of our patients. Dr. McGovern: Two of the six clear-cut cases of pneumonitis’we have had were with 400 mg or less as maintenance treatment. Although your hypothesis about heart failure is interesting and may be relevant, it’s not an exclusive explanation, as you would agree. Dr. Harris: Yes, I do. Dr. Ruffy: Dr. Zipes listed two possible causes of death from amiodarone. I would like to add a third one: peripheral neuropathy. Our only death attributable to amiodarone was in a patient with very severe peripheral neuropathy and dysphagia with fatal aspiration. Dr. Singh: That must be extremely rare. It must be the only death following peripheral neuropathy. We have seen peripheral neuropathy, but it was not fatal. One or two cases have been reported, but the disorder does not appear to be nearly as common as pulmonary fibrosis. Dr. Rotmensch: I would like to comment on the relationship between serum concentrations and side effects. In a group of 64 patients, we could clearly demonstrate that patients with serum concentrations of amiodarone above 2.5 pg/ml are clearly at an increased risk of developing side effects in general. Liver function abnormalities, CNS side effects, and peripheral neuropathy are usually, but not invariably, related to very high amiodarone concentrations. However, when you look at the
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October, 1083 Heart Journal
overall side effects profile, this significance disappears. With regard to the underlying mechanism of side effects, I do not believe that we have evidence today to assume that the hypersensitivity is an underlying mechanism in these cases. With regard to the low concentrations and development of pulmonary fibrosis (although in our experience, the majority of cases have been with high concentrations), in those two cases that have been seen with low concentrations, we believe that the patients had underlying pulmonary abnormalities and low diffusion capacities. These patients may more avidly take up the drug into their lungs and thus may be more predisposed to the development of pulmonary toxicity. Dr. Harris: We looked at drug levels in relation to individual side effects, and the only ones that showed a correlation with the plasma level were the liver enzyme changes. Dr. Holt: We have not found the measurement of either the parent drug or its metabolite in plasma to be very helpful overall in predicting or precluding the development of side effects. One must distinguish the trivial side effects common to all antiarrhythmic agents and even to placebo. I am not surprised that there is no correlation. The significant finding is that we have biochemical tests correlating with plasma concentration in terms of the enzyme liver function test. Here we have a tissue that is well perfused and that is probably likely to be at equilibrium with the central compartment. It should not be surprising that there is not a consistent relationship between pulmonary toxicity and drug levels. We cannot define the cause of the problem. Some of Dr. Rakita’s 40 patients may have had pulmonary amiodarone toxicity, the drug may have been a contributing factor, or it may have had no such effect at all. Pulmonary toxicity findings are reported at a wide range of times-some fairly early and some very late-relative to the dosing. A plasma concentration of, e.g., 2 pg/ml 2 weeks after the start of therapy differs in significance from the same concentration 6 months after the start of therapy, because the total body load would be entirely different early versus late. I think it is significant that in some of the cases that have been reported, the dose has been increased to 800 or 1000 mglday. That is the point at which the arrhythmia has reverted. When patients remain on that dose, 6 months later the total body load is vastly different because equilibration in the peripheral tissues will just begin at that time. Dr. Rakita: With regard to the turnover of the drug in the tissue involved, without knowing that parameter, it is not clear which of these two is the more important. How does the patient handle the drug? Those who use high doses are likely to see a correspondingly higher incidence and a greater diversity of side effects, especially over the long term. Dr. Ha#$jee: Our experience with photosensitivity is similar to that of Dr. Marcus in Arizona. There is a progressive increase in the severity of sunburn each year until it becomes intolerable. Why is there a progressive increase in severity? Dr. Harris: It may be related to increasing deposition
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of the drug in the skin. There seemsto be limited value for the usual ultraviolet barrier creams. It appears that the drug may be caught by the higher wavelengths. There is a new cream to be releasedshortly that covers the higher spectrum of wavelengths and appears to be more effective. Dr. Podrid: There seemsto be a relationship between the time on drug and the sunburn, but also lowering the dosein somepatients makesa difference in reversing some of the severesunburn. A biopsy specimenwas taken from our patient who had hepatitis. This patient had a typical drug-reaction hepatitis that was indistinguishable from any other type of drug reaction. One other complication we observed was Coumadin interaction. We had one patient who had an intracerebral hemorrhage with very erratic prothrombin times. Dr. Harris: We did observe interactions with anticoagulants. Lowering the dosage,although alleviating someof the photosensitivity, doesnot eliminate it. Dr. Mandel: We’ve had two additional skin problems that have not been mentioned. One is fairly common, a nonphotosensitive vermillion, bluish-reddish coloration of the hands and feet. The secondeffect, fairly uncommon but well documented, is ecchymotic lesions. They have been infrequent (5% of the patients) but tend to be distinctive in the upper extremity. Both these skin changes are seen early in the course of treatment and disappear despite continued drug therapy. Dr. Harris: We have not seen the first reaction you mention. We have had one or two patients who complained of purpuric reactions, and we were not sure whether they were related to the drug or not. Hematologic and autoimmune examinations were negative in both patients. Dr. Goldstein: We have recently seen a patient who appearsas though he might have developed thrombocytopenia. Has that been reported? Dr. Harris: I have not seenthat in any patients. Dr. B. Singh: I do not believe we have seenany reports about that, nor have we seensuch a caseourselves. Dr. Reiffel: We have had two deaths from the interaction between amiodarone and ventricular function in cardiovascular surgery. We have now had three patients with amiodarone ventricular function deterioration, and they were given amiodarone after cardiovascular surgery. Two died, one within 1% weeksand one within 2 months of receiving the drug. The third patient’s ventricular function dropped to 9%, but she has not died. Transvenousbiopsy showedfatty infiltration of the right ventricle. I do not know what the link between surgery and the drug is, but it occurred in three out of three in our seriesand in the only three patients we have had with ventricular function compromise. Dr. Harris: Our patients going to surgery were of a different type; they were generally patients with WolffParkinson-White syndrome. Dr. Akhtar: Have you seenexcessivehair loss?
Amiodarone
side effects
923
Dr. Harris: No, we have not, but Dr. Podrid mentioned one or two patients who had hair loss. Dr. Denes: How many patients had to discontinue medication becauseof side effects? Dr. Harris: Patients with skin pigmentation discontinued the drug. One patient who became hypothyroid while using the drug no longer required it. In another patient with hypothyroidism, we continued the drug with thyroid replacement becausethere was no other effective agent for that patient. Thus the numbers are very low. Dr. Denes: Your cases do not appear to be life threatening. You take off lessthan 1% for side effects. Dr. Rosen&urn: In a few patients we have observed symptomatic hypoglycemia. Amiodarone causes an increasein releaseof insulin. If you give a single doseof 600mg and draw samples,you will find the peak of insulin within the first hour. However, the few patients who developed hypoglycemia did so only after several months of treatment. It works like a mild antidiabetic agent. You must keep in mind the acute releaseof insulin that may occur following a large oral doseof amiodarone. Dr. Singh: The hypoglycemia, probably subclinical in most cases, might account for the weight gain and improved appetite we see in a few patients receiving amiodarone. Dr. Mandel: We have had one patient with iodide sensitivity who had an anaphylactic reaction to IVP dye. The patient had life-threatening ventricular arrhythmias. Has anybody had experience with that situation? A physician: We had a patient who developedan acute syndrome that appearedto be a pulmonary embolism.She developed “shock lung” asa result of pulmonary angiography and subsequently died. She had been on a regimen of amiodarone, but it is not certain whether the shock lung was due to an anaphylactic reaction to the iodine contained in amiodarone. Dr. Singh: Our extensive discussionabout the side effects of amiodarone clearly reflects the level of interest and concern about drug toxicity-the main limiting factor in the widespreaduse of amiodarone in cardiac arrhythmias. However, I think a reasonably clear perspective appears to be evolving, with the developing consensus that, if used judiciously and with careful attention to dosage,limiting side effects of amiodarone are few. The role of serum drug and metabolite concentrations in forestalling toxicity does not appear to be well defined. The varied experience suggeststhat we need to distinguish thoseside effects which are truly idiosyncratic in the pharmacologicsence(none appearsto be so), those which develop as a function of dose and/or duration of drug therapy (the vast majority), those which are unrelated to dose (e.g., altered thyroid state becauseof iodine in a predisposedpatient), and those which arise on the basisof drug interactions. A correct appreciation of these potential mechanismsis likely to minimize the adversereactions of amiodarone in the majority of patients exposed to the drug.
American
I have been told of patients with pulmonary toxicity that responded to corticosteroids and discontinuing amiodarone. The chest x-ray findings cleared 3 to 4 months after amiodarone was stopped, but as steroids were tapered the infiltrates recurred. Again the infiltrates resolved as the dose of steroids was increased. If this was a cumulative phenomenon, was there any relationship to the serum concentration of amiodarone? Dr. Rakitu: I do not know. It would be interesting to see amiodarone blood levels in patients with different stages of pulmonary toxicity, from early to late and severe. Dr. Waxman: How often do you recommend performing x-ray studies? Dr. Rakita: Every 3 months. Dr. Singh: When blood levels have been measured, they are not very high, 1.2 to 1.5 lg/ml in several cases.
Side effects and possible amiodarone use
October, 1993 Heart Journal
The crucial issue, according to Holt’s data, may be the very high concentrations of both the drug and its metabolite in the lungs. Therefore, blood levels may not be particularly informative. Dr. Scheinman: We have seen pulmonary toxicity in eight of 270 patients. It is very important to obtain transbronchial biopsy specimens to confirm the diagnosis. One patient had all the “typical” clinical features of amiodarone pulmonary toxicity. On postmortem, however, we found that this patient had had pneumonia and congestive heart failure. Another patient given amiodarone and procainamide showed a resolution of infiltrates when procainamide alone was stopped. Dr. Zipes: Unfortunately, too much information is anecdotal. A central registry for patients who develop pulmonary complications should be established to gather and organize data.
contrtindications
of
With the increasing use of amiodarone, several unwanted effects have been recognized. We revtewed 140 patients treated with amiodarone over a !i-year period in an attempt to identify patients at risk, to assess the incidence of these effects and their possible relation to dose, and to determine their outcome. The most common effect was photosensitivity (57% of patients responding to a questionnaire), whereas asymptomatic cornea1 microdeposits were found in all patients undergoing ophthalmologic examination. In contrast, aymptomatfc eye changes (colored halos) and slate-gray skin pigmentation were rare. Of the metabolic alterations, the rise in hepatic enzymes correlated with dose and plasma drug and metabotfte concentrations (r = 0.59, p < 0.001; f= 0.62, p < 0.001, respectively) but was not associated with clinical disease. This relation to dose was not evident in patients developing clinical thyroid abnormalfties (two hypothyroidism, two hyperthyroidlam), all of whom had normal thyroid function prior to therapy. Four of the five hypothyroid patients were over 70 years of age. No patients developed peripheral neuropathy, but tremor and sleeplessness were common complaints (30% and 26% of patients, respectively) that responded to a decrease in dose. One patient with an abnormal chest x-ray film prior to therapy developed pulmonary fibrosis. We suggest the restricted use of high doses of amiodarone for protracted periods. Patients at particular risk are the older age group (hypothyroidism) and those with abnormal lung function prior to therapy who may be predisposed to pulmonary alveolitia. Most of the observed unwanted effects resolve when amiodarone is decreased in dose or discontinued. (AM HEART J 106~916, 1983.)
Louise Harris, M.B., William J. McKenna, M.D., Edward Rowland, and Dennis M. Krikler, M.D. London, England
From Royal
the Division Postgraduate
of Cardiovascular Medical School.
Based on data previously et al: Amiodarone: Side 1983. Reprint Hospital,
916
Disease,
published in Harris effects of long-term
Department
of Medicine,
L, McKenna WJ, Roland E, therapy. Circulation 67:45,
requests: Dr. L. Harris, Division of Cardiology, Toronto 101 College St., Toronto, Ontario, Canada MSFG 1L7.
General
M.B.,
Amiodarone is a drug with unique pharmacodynamic and pharmacokinetic properties. Its increasing use as an antiarrhythmic agent attests to its potent efficacy but has also been accompanied by the increased recognition of unwanted effects. As with many other drugs, it is possible that these effects can
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be grouped into those which are dose or doseduration dependent and those which are idiosyncratic. For the drug’s benefit to be greatest, it is important that these reactions be differentiated so that patients at risk can be identified prior to therapy and dosage schedules can be optimized by balancing arrhythmia control against side effects. Recent reports evaluating neurologicl and pulmonary2 complications have assisted in this regard. We reviewed 140 patients treated with amiodarone over a 5-year period to identify patients at risk and to assess the incidence of side effects, their relation to dose, and their outcome. PATIENTS
AND DOSAGE
One hundred forty patients (95 men and 45 women with a mean age of 52 years) were treated with amiodarone (mean daily dose, 360 mg; range, 100 to 1200 mg) over a 5-year period (average duration of follow-up, 2 years). Patients with ventricular tachycardia (n = 46) and complex ventricular extrasystoles (n = 10) required larger doses (440 mg/day and 400 mg/day, respectively) than those with supraventricular arrhythmias. Thus the mean daily dose for patients with chronic atrial fibrillation and/or flutter (n = 15) was 310 mg, and for patients with paroxysmal atria1 arrhythmias (n = 38) it was 280 mg. Patients with supraventricular arrhythmias associated with Wolff-Parkinson-White syndrome received a mean dose of 350 mg/day. Following an initial loading period (600 to 1200 mg/day for 1 week and then 400 to 600 mg for 1 month), long-term dosages were adjusted according to individual patient requirements so that control of arrhythmia was balanced against side effects. Only 11 patients used doses of 600 mg/day or more over the long term. Half the patients were taking amiodarone for primary arrhythmias (n = 69), and the remaining patients were treated for arrhythmias associated with a variety of underlying cardiovascular conditions (Table I). METHODS
Before treatment began, a chest x-ray examination, ECG, and routine thyroid and hepatic function tests were performed. The thyroid function tests included the estimation of serum thyroxine, free thyroxine index, free binding capacity, and thyroid-stimulating hormone (TSH). Hepatic function tests measured aminotransferases,alkaline phosphatase,serum bilirubin, cholesterol, and total protein and albumin concentrations. At subsequentclinic visits these biochemical tests were repeated, and plasma concentrations of amiodarone and desethylamiodaronewere also determined by high-performance liquid chromatography.3A detailed history of side effects was taken, and patients were examined for drug-
Amiodarone
Table
side effects
917
I. Details of cardiovascular conditions treated Condition
Primary arrhythmia Cardiomyopathy Hypertrophic Congestive Ischemic heart disease Valvular disease Hypertensive heart disease Atria1 septal defect
No.
of
patients 69 28 20 15 5 2 1
related stigmata. Asymptomatic patients were followed at 3- to B-month intervals but were advised to contact the unit directly in the event of any untoward symptoms, Similarly, any patient experiencing visual disturbancesor other ophthalmologic problems was referred to an ophthalmologist; in the first years of our experience with amiodarone,all patients had been followed up routinely in the ophthalmology clinic. A questionnaire designedto assessthe incidence and severity of known side effects and to identify any possible previously unrecognized effects was sent to patients who had been taking the drug for a minimum of 6 months. Plasmadrug concentrations taken at the time of reply to the questionnaire were assessedin relation to the total number of side effects reported by each patient, aswell as in relation to the severity of individual effects. RESULTS Dermatologic findings. Photosensitivity was the most common reaction (57% of patients responding to the questionnaire), varying from an increased propensity toward suntan during the summer months to intense burning, erythema, and swelling of the sun-exposed areas. Neither dosage nor plasma drug concentrations proved useful in distinguishing patients with and without photosensitivity. However, this reaction could be partially alleviated by a reduction in dosage in some patients. Others obtained relief by using sunscreen barrier creams, and no patient was required to discontinue the drug. The two patients who developed slate-gray pigmentation had been using 600 mg/day for 5 and 2 years, respectively. Both patients had high plasma concentrations of amiodarone (3.1 pg/ml in both) and desethylamiodarone (3.7 Fg/ml and 3.2 fig/ml, respectively). The slate-gray pigmentation occurred in the sun-exposed areas of the face and hands, and it was still evident 6 to 12 months after therapy was discontinued. An additional skin reaction was observed in six patients in the first weeks of therapy: an erythematous, pruritic rash with a predominantly truncal distribution. There was no relation to dose, and in
918
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Table
II. Patients with grossalterations in thyroid function tests on amiodarone*
American
October. 1903 Heart Journal
On amiodarone
Patients Decreased
JW FDI LH RM MD Increased MQ GE4 AF SB
Age (yr) fser function 70/M 77/F 76/M 77/M 59/M function 48/M 62/M 40/M 18/F
Dose (mglday)
Duration
AF SND
200 200
AF VT VT
200 200 600
39 10 29 36 32
8 33 44 24 25
VT &F
400 400 600 400
34 32 26 36
226 207 193 231
Arrhythmia
SVT/WPW
(ma)
Thyroxinet (nmol/L
Free T,f (pmol/L)
39.5 42.0 37.0 67.2
TSH
Amiodarone Wml)
Desethylamiodarone (hdml)
>25 >60 >20 19 >25
0.7 1.5 0.5 1.1
0.8 -
2.0 1.3 4.6 0.5
2.0 1.4 3.8 0.8
1.5 0.9 1.5
T, = thyroxine; AF = atria1 flutter; SND = sinus node disease; VT = ventricular tachycardia; CAF/F = chronic atria1 fibrillation/flutter; SVT = paroxysmal supraventricular tachycardia; WPW = Wolff-Parkinson-White syndrome. *From Harris L, McKenna WJ, Rowland E, Krikler DM: Side-effects of long-term amiodarone therapy. Circulation 67:45,1983. Used by permission of the American Heart Association, Inc. tNorma1 range-thyroxine, 45 to 160 nmolfi, free thyroxine, 0.8 to 24 pmol/L. tClinically myxedematous, §Clinically thyrotoxic.
all patients it resolved spontaneously despite continuation of therapy. Thyroid function. Biochemical aherations in thyroid function were common. The mean thyroxine level for the patients (124 nmol/L) was’elevated hy 20% above the mean for normal subjects (102 nmol/L) as measured by our laboratory. A similar increase was observed in the free thyroxine index, whereas free binding capacity fell. Four patients had thyroxine levels in excess of 25% above the upper limit of normal, whereas in five patients the thyroxine levels fell and TSH increased (Table II). Clinical evidence of thyroid disease, however, developed in only four patients, two becoming hypothyroid and two hyperthyroid (Table II). The myxedematous patients had the typical clinical features of weight gain, lethargy, and hoarseness, whereas the clinical picture in the thyrotoxic patients was more insidious. Both gave a history of recent weight loss, weakness, and increasing anxiety, and both had conspicuously elevated triiodothyronine levels (4.3 nmol/L and 5.3 nmol/L). Although the thyrotoxicosis resolved with diticontinuation of the amiodarone and no specific antithyroid treatment (1 to 2 months for complete biochemical and clinical resolution in both patients), the hypothyroid patients required thyroxine replacement therapy. The nine patients experiencing gross alterations in thyroid function tests while receiving amiodarone (Table II) were scrutinized for possible predisposing clinical factors. All but two were taking moderate doses, and the mean duration of treatment before
changes occurred was 30 months. Four of the five hypothyroid patients were over 70 years of age. All of the patients had normal thyroid function prior to treatment and negative antibody titers. In addition, there was no family history of thyroid disease. Gastrointestinal effects. Thirty-one percent of patients responding to the questionnaire reported gastrointestinal effects: nausea and loss of appetite were experienced only during the initial “loading phase” with high doses, whereas patienta using the drug over a long term complained of alterations in bowel habits with a tendency toward constipation. No patient developed clinicaily evident hepatic dysfunction, but biochemical alterations in hepatic function tests were common. A 1.5 to It-fold increase in serum aspartate aminotransferase levels was found in 15 of 100 patients. These changes were seen in patients receiving high doses and correlated with plasma concentrations of amiodarone (T = 0.59, p < 0.001; Fig. 1, A) and ita desethyl metabolite (r = 0.62, p < 0.001; Fig. 1, B). A similar increase occurred with alanine aminotransferase, but no changes were observed in serum bilirubm, alkaline phosphatase, cholesterol, total protein, or albumin levels. Liver biopsies from two patients with elevated enzyme levels revealed nonspecific changes only. Neurologic findings. None of our patients developed peripheral neuropathy. However, they reported a variety of other neurologic symptoms, the most
Volume
106
Number
4, Part 2
Amiodarone side effects
919
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Fig. 1. A, Log aspartate aminotransferase plotted against plasma amiodarone (mg/L) in 88 patients during treatment. B, Log aspartate aminotransferase plotted against plasma desethylamiodarone (mg/L) in 88 patients during treatment.. (From Harris L, McKenna WJ, Rowland E, Krikler DM: Side effects of long-term amiodarone therapy. Circulation 67:45, 1983. Used by permission of the American Heart Association, Inc.)
common being a fine tremor of hands (30% of patients responding to the questionnaire), sleep disturbance (‘28 % ), and headaches (14 % ) described as a “bandlike sensation.” All of these complaints responded to a reduction in dose, and discontinuation of therapy was not required. Another doserelated reaction was that of proximal muscle weakness (eight patients), seen only during the initial “loading phase” in patients using doses of 800 mg/day or more. changes. Pulmonary interstitial Pulmonary changes with an associated restrictive pattern on pulmonary function testing were observed in one patient after 30 months of treatment. However, this patient had had a positive Kveim test 4 years previously, and a review of his x-ray films suggested that such changes may have been present before treatment. There was no other evidence of sarcoidosis.
Ocular symptoms. Corneal deposits were found on slit-lamp examination as early as 10 days after starting amiodarone and were present in all patients examined after 1 month. The extent of these deposits is probably dose-duration dependent. Thus they were asymptomatic in all but two patients. These two patients had been using 600 mg/day for more than 1 year when they began to complain of bluegreen halos while looking at bright lights. Slitlamp examination revealed the deposits to have encroached on the cornea. Both became asymptomatic within 2 months after their dosage was reduced. We observed no other ophthalmologic complications.
DlSCUSSlON It must be conceded that patients experiencing problems with amiodarone may have had greater motivation to respond to the questionnaire than
920
Harris
et al.
those who were asymptomatic, thereby giving the results a positive bias. Nevertheless, many of the unwanted effects observed appear to be dose related. Symptoms responding to a reduction in dosage include the gastrointestinal effects of nausea and anorexia and the neurologic effects of tremor, headaches, and sleep disturbance, whereas proximal muscle weakness was seen only in patients receiving the “loading dose.” Similar neurologic reactions have been reported by other investigators114 when doses in excess of 800 mg/day were used. The incidence of alterations in hepatic function was high (15 % ) among our patients but is consistent with that reported by others.4T5 Those investigators found the changes to be transient, of similar magnitude to those seen in our patients, and unassociated with clinical disease. However, two further patients6 developed clinical hepatitis while taking amiodarone. A liver biopsy from one patient showed nonspecific changes only. The authors do not discuss other possible contributory factors, such as concurrent illness or medication, and the association therefore remains speculative. The high incidence of biochemical hepatic alterations, together with the direct relation to dose, suggests a toxic effect rather than host idiosyncrasy as the causative mechanism of the hepatic injury. Since the changes are transient and can be corrected by decreasing the dose, we do not discontinue the drug in patients with raised enzyme levels but monitor hepatic function regularly. It is important to emphasize that serious hepatic toxicity was not encountered. Other unwanted effects that may be both dose and duration dependent are symptomatic ocular changes and the slate-gray skin pigmentation. Similar findings by other investigators are consistent with a dose-duration dependency for this latter reaction. Of 34 pigmented patients, 14 (40%)7-13 had been taking 600 mg daily or more for an average of 2 years before pigmentation developed. In addition, it is possible that photosensitivity may predispose these patients to this reaction, since both of our patients, as well as almost all of those reported, had experienced photosensitivity prior to the development of the unusual pigmentation. Photosensitivity, however, is not dose related, and at present there is no way of predicting which patients are at risk. Because it is a common complication, we therefore advise all patients to use prophylactic barrier creams during sun exposure. Previously, no clear relation to dose and/or duration of therapy was apparent in those patients developing peripheral neuropathy.6*‘4s’5 Although none of our patients experienced this complication,
American
October, 1983 Heart Journal
other investigators 14*15have reported a sensorimotor neuropathy, with segmental demyelination of nerve fibers shown by histologic examination. The neuropathy resolves with discontinuation of treatment, but this may be slow and is apparently incomplete. This is in contrast to the neurologic side effects described earlier (tremor and sleep disturbance), in which rapid resolution occurs when the dose is reduced. At present there does not appear to be a means of identifying patients at risk of neuropathy. Similarly, the mechanism of the pulmonary injury seen with amiodarone remains unclear. In our patient the pulmonary changes were difficult to interpret because they may have been present to a lesser extent before amiodarone use. However, there are a growing number of reports describing similar abnormalities,% 6216-18 with interstitial or alveolar fibrosis seen on histologic examination. It is possible that this reaction may be dose related, at least in part: 8 of the 14 patients reported were taking doses of 800 mg/day or more. A further possibility is drug-induced autoimmunity. Our patient had positive antinuclear antibody titers, but other investigators have not reported similar findings. Other factors, such as preexisting cardiac failure or genetic differences in metabolism of the drug, may also prove to be important in the pathogenesis of this reaction. More recently it has been suggested that pretreatment pulmonary function tests may be of predictive value in identifying patients at risk.2 Thus patients with an initial hemoglobin-corrected diffusion capacity of lungs for CO (DLCO) of 80% or less had a greater incidence of radiographic changes during treatment than those with a DLCO of more than 80% prior to therapy. However, no concurrent control series was studied, and the significance of these findings in the absence of unequivocal evidence of pulmonary fibrosis cannot be evaluated. Nevertheless, until we have a clearer understanding of the mechanism of this reaction, it would appear prudent to use the drug with caution for patients with preexisting lung abnormalities and to restrict the use of high doses of amiodarone for protracted periods. The development of clinical thyroid disease or gross alterations in thyroid biochemistry could not be predicted by dose or duration of therapy in our patients. This suggests a specific reaction in these individuals: thus four of the five patients who became hypothyroid (as determined by clinical and/ or biochemical evidence) were over 70 years of age. Since TSH does not rise in relation to age in an average community,1g it may be that older patients taking amiodarone are predisposed to the development of hypothyroidism. None of our patients expe-
Volume Number
106 4. Part 2
Amiodarone
riencing thyroid complications had a previous history or family history of thyroid disease, and none had evidence of autoimmune disturbance. The interaction between amiodarone and thyroid hormone metabolism has been dealt with elsewhere in this symposium.2o CONCLUSIONS
It appears that many of the side effects experienced with amiodarone can be corrected simply by a reduction in dose. Although the mechanisms of other unwanted effects remain to be clarified, the evidence suggests that amiodarone be used with caution in the older patient and in patients with a reduced diffusion capacity on pulmonary function testing. In the event of amiodarone-related complications, almost all (with the possible exception of hypothyroidism) will resolve once treatment is discontinued. At present it is not certain whether the routine monitoring of serum concentrations of amiodarone and its desethyl metabolite will be helpful in minimizing serious amiodarone toxicity, but our data indicate that careful attention to dose may be associated with a low overall incidence of side effects. REFERENCES
1. Charness M, Morady F, Shen EN, Shapiro WA, Scheinman MM, Hess DS: Frequent neurologic toxicity associated with amiodarone therapy. J Am Co11 Cardiol 1:630, 1983. Kudenchuk PJ, Pierson DJ, Greene HL, Gross BW, Graham EL, Sears GK: Pulmonary effects of amiodarone. J Am Co11 Cardiol 1:631, 1983. Holt DW, Tucker GT, Jackson PR, Storey GCA: Amiodarone nharmacokinetics. AM HEART J 106:840, 1983. Heger dd, Prystowsky EN, Jackman WM, Naccarelli GV, Warfel KA. Rinkenhereer RL. Zincs DP: Amiodarone clinical efficacy and electrophisiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 305:539, 1981. 5. Plomteaux G, Heusghem C, Ernould H, Vandeghen N: Long-term hepatic tolerance of amiodarone in the clinic. Eur J Pharmacol 8:369, 1969. 6. Waxman HL, Groh WC, Marchlinski FE, Buxton AE, Sadowski LM. Horowitz LN. Josenhson ME. Kastor JA: Amiodarone for control of sustained ventricular tachyarrhythmia: Clinical and electrophysiologic effects in 51 patients. Am J Cardiol 50:1066, 1982. 7. Labouche F, Balouet G, Daoulas R, Masse R, Le Moigne P, Coignard A, Baret MF: Les accidents cutanees de l’amiodarone. Arch Med Quest 5:37, 1973. 8. Texier L, Meunier J, Gauthier Y, Dubiau J-M, Gaillard G: Pigmentations cutanees accidentelles au tours de traitements par l’amiodarone. Contours Med 93:4859, 1971. 9. Morand PH, Benatre J. Viau G, Carli-Basser CL, Laine J-L, Neel J-L, Brochier M, Raynaud R: Etude clinique et histologique (ultrastructure) de la pigmentation par le chlorhydrate d’amiodarone. Sem Hop Paris 48:553, 1972. 10. Wanet J, Achten G, Barchewitz, Mestdagh G, Vastesaeger M: Amiodarone et depots cutanes: Etude clinique et histologique. Ann Dermatol Venereol 98:131, 1971. 11. Herne N, Marion J, Brisou B, Antiglio V, Rousselot M: Pigmentations cutanees induites par le chlorhydrate d’amiodarone. Lyon Med 226:205, 1971. I
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12. Vulliemin JF: Les effets secondaires cutanees de la Cordarone. Schweiz Rundschau Med (Praxis) 62:1426, 1973. 13. Lambert D, Noble J-P, Justrabo E, Hewitt J: Pigmentation cutanee secondaire a l’administration d’amiodarone: Problemes histogenetiques. Ann Dermatol Venereol 102:277, 1975. 14. Kaeser HE: Amiodarone-Neuropathie. Schweiz Med Wochenschr 104:606, 1974. 15. Meier C, Bauer B, Muller U, Ludin HP: Neuromyopathy during chronic amiodarone therapy. J Neurol 220:231, 1979. 16. Rotmensch HH, Liron M, Tupilski M, Laniado S: Possible association of pneumonitis with amiodarone therapy. AM HEART J 100:412, 1980. 17. Sobol SM, Rakita L: Pneumonitis and pulmonary fibrosis associated with amiodarone treatment: A possible complication of a new antiarrhythmic drug. Circulation 65:819, 1982. 18. Riley SA, Williams SE, Cooke NH: Alveolitis after treatment with amiodarone. Br Med J 184:161, 1982. 19. Tunbridge WMG, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Grimley Evans J, Young E, Bird T, Smith P: The prevalence of thyroid disorders in an English community. In Robbins J, Braverman LE, editors: Thyroid research. Amsterdam, 1976, Excerpta Medica, p 520. 20. Singh BN, Nademanee K: Amiodarone and thyroid function: Clinical implications during antiarrhythmic therapy. AM HEART J 106:857. 1983. DISCUSSION
Dr. Rosenbaum: I agree that it may be clinically convenient to separate the patients according to whether their complications are or are not dose or dose-time dependent. This requires some qualification. My clinical impression is that even in patients who develop some sort of “hypersensitivity” to amiodarone, the dose plays a role. If the patient is hypersensitive, he will be more likely to develop the complications when he is on high rather than low doses. Dr. Harris: Where we can identify a clear-cut relationship to dose, it is reversible. By reducing the dose we can correct these effects. However, there are likely to be reactions that are a mixture of the two, and they cannot be corrected by simply reducing the dose. Dr. Rosenbaum: Do you believe that the photosensitivity is related to the cumulative effect, or can it occur as an acute effect? If a young lady goes sunbathing often and takes 600 mg one day and goes into the sun, will she develop photosensitivity the same day or the next day? Dr. Harris: When we were trying to work out the pharmacokinetics of amiodarone with Dr. Holt, we were taking 600 mg a day and did not have any photosensitivity, but, then, there’s no sun in London anyway! Dr. Singh: I don’t believe that thyroid complications are dose dependent. The amount of iodine that is released by deiodination of amiodarone is considerable even at low doses; thus whether the patient is taking 200 mg or 600 mg per day, it makes no difference if he has a preexisting tendency for an abnormal reaction to iodine. If we believe that altered thyroid state is related to iodine rather than to the drug itself, then the question of dose does not arise. I believe that this is one side effect we can dissociate from dose.
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Harris
et al.
Dr. Marcus: You suggested that the photosensitivity and the skin discoloration were dose related. In Arizona, where we have sun 360 days a year, we have found four patients who have bluish discoloration out of 56 (about 7 % ); we also have over 10% of patients who have clear-cut sun sensitivity. The exposure to sun may enhance the susceptibility to the bluish discoloration. The dose that we use is under 400 mglday, and the average dose has been 335 mg in other patients. Thus I do not believe that the discoloration is related to dose. Dr. Harris: I wasn’t suggesting that sun sensitivity per se is dose related. With bluish discoloration, there appears to be more intense elastic degeneration in the skin biopsies of these patients. There is speculation that the areas that show intense degeneration are prone to developing these deposits. Dr. Marcus: In our area, where there is a lot of exposure to the sun, there may be some of this elastic degeneration occurring that predisposes to bluish discoloration. We have seen three patients who have had liver function abnormalities (but not clear-cut hepatitis) associated with anorexia. These patients have not been in severe congestive heart failure. They just had continued anorexia and weight loss until we stopped the amiodarone, at which point they recovered fully. There seems to be a subclinical hepatitis that occurs in some patients. Since many of the patients with congestive heart failure have anorexia, this must be looked for. Dr. Harris: We have had problems with nausea and anorexia only with the loading dose. Dr. Marcus: I again emphasize that we used low doses. Dr. Ruffy: I also agree with Dr. Marcus’ comment that anorexia is a very serious side effect in some of our patients. Dr. McGovern: Two of the six clear-cut cases of pneumonitis’we have had were with 400 mg or less as maintenance treatment. Although your hypothesis about heart failure is interesting and may be relevant, it’s not an exclusive explanation, as you would agree. Dr. Harris: Yes, I do. Dr. Ruffy: Dr. Zipes listed two possible causes of death from amiodarone. I would like to add a third one: peripheral neuropathy. Our only death attributable to amiodarone was in a patient with very severe peripheral neuropathy and dysphagia with fatal aspiration. Dr. Singh: That must be extremely rare. It must be the only death following peripheral neuropathy. We have seen peripheral neuropathy, but it was not fatal. One or two cases have been reported, but the disorder does not appear to be nearly as common as pulmonary fibrosis. Dr. Rotmensch: I would like to comment on the relationship between serum concentrations and side effects. In a group of 64 patients, we could clearly demonstrate that patients with serum concentrations of amiodarone above 2.5 pg/ml are clearly at an increased risk of developing side effects in general. Liver function abnormalities, CNS side effects, and peripheral neuropathy are usually, but not invariably, related to very high amiodarone concentrations. However, when you look at the
American
October, 1083 Heart Journal
overall side effects profile, this significance disappears. With regard to the underlying mechanism of side effects, I do not believe that we have evidence today to assume that the hypersensitivity is an underlying mechanism in these cases. With regard to the low concentrations and development of pulmonary fibrosis (although in our experience, the majority of cases have been with high concentrations), in those two cases that have been seen with low concentrations, we believe that the patients had underlying pulmonary abnormalities and low diffusion capacities. These patients may more avidly take up the drug into their lungs and thus may be more predisposed to the development of pulmonary toxicity. Dr. Harris: We looked at drug levels in relation to individual side effects, and the only ones that showed a correlation with the plasma level were the liver enzyme changes. Dr. Holt: We have not found the measurement of either the parent drug or its metabolite in plasma to be very helpful overall in predicting or precluding the development of side effects. One must distinguish the trivial side effects common to all antiarrhythmic agents and even to placebo. I am not surprised that there is no correlation. The significant finding is that we have biochemical tests correlating with plasma concentration in terms of the enzyme liver function test. Here we have a tissue that is well perfused and that is probably likely to be at equilibrium with the central compartment. It should not be surprising that there is not a consistent relationship between pulmonary toxicity and drug levels. We cannot define the cause of the problem. Some of Dr. Rakita’s 40 patients may have had pulmonary amiodarone toxicity, the drug may have been a contributing factor, or it may have had no such effect at all. Pulmonary toxicity findings are reported at a wide range of times-some fairly early and some very late-relative to the dosing. A plasma concentration of, e.g., 2 pg/ml 2 weeks after the start of therapy differs in significance from the same concentration 6 months after the start of therapy, because the total body load would be entirely different early versus late. I think it is significant that in some of the cases that have been reported, the dose has been increased to 800 or 1000 mglday. That is the point at which the arrhythmia has reverted. When patients remain on that dose, 6 months later the total body load is vastly different because equilibration in the peripheral tissues will just begin at that time. Dr. Rakita: With regard to the turnover of the drug in the tissue involved, without knowing that parameter, it is not clear which of these two is the more important. How does the patient handle the drug? Those who use high doses are likely to see a correspondingly higher incidence and a greater diversity of side effects, especially over the long term. Dr. Ha#$jee: Our experience with photosensitivity is similar to that of Dr. Marcus in Arizona. There is a progressive increase in the severity of sunburn each year until it becomes intolerable. Why is there a progressive increase in severity? Dr. Harris: It may be related to increasing deposition
Volume Number
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of the drug in the skin. There seemsto be limited value for the usual ultraviolet barrier creams. It appears that the drug may be caught by the higher wavelengths. There is a new cream to be releasedshortly that covers the higher spectrum of wavelengths and appears to be more effective. Dr. Podrid: There seemsto be a relationship between the time on drug and the sunburn, but also lowering the dosein somepatients makesa difference in reversing some of the severesunburn. A biopsy specimenwas taken from our patient who had hepatitis. This patient had a typical drug-reaction hepatitis that was indistinguishable from any other type of drug reaction. One other complication we observed was Coumadin interaction. We had one patient who had an intracerebral hemorrhage with very erratic prothrombin times. Dr. Harris: We did observe interactions with anticoagulants. Lowering the dosage,although alleviating someof the photosensitivity, doesnot eliminate it. Dr. Mandel: We’ve had two additional skin problems that have not been mentioned. One is fairly common, a nonphotosensitive vermillion, bluish-reddish coloration of the hands and feet. The secondeffect, fairly uncommon but well documented, is ecchymotic lesions. They have been infrequent (5% of the patients) but tend to be distinctive in the upper extremity. Both these skin changes are seen early in the course of treatment and disappear despite continued drug therapy. Dr. Harris: We have not seen the first reaction you mention. We have had one or two patients who complained of purpuric reactions, and we were not sure whether they were related to the drug or not. Hematologic and autoimmune examinations were negative in both patients. Dr. Goldstein: We have recently seen a patient who appearsas though he might have developed thrombocytopenia. Has that been reported? Dr. Harris: I have not seenthat in any patients. Dr. B. Singh: I do not believe we have seenany reports about that, nor have we seensuch a caseourselves. Dr. Reiffel: We have had two deaths from the interaction between amiodarone and ventricular function in cardiovascular surgery. We have now had three patients with amiodarone ventricular function deterioration, and they were given amiodarone after cardiovascular surgery. Two died, one within 1% weeksand one within 2 months of receiving the drug. The third patient’s ventricular function dropped to 9%, but she has not died. Transvenousbiopsy showedfatty infiltration of the right ventricle. I do not know what the link between surgery and the drug is, but it occurred in three out of three in our seriesand in the only three patients we have had with ventricular function compromise. Dr. Harris: Our patients going to surgery were of a different type; they were generally patients with WolffParkinson-White syndrome. Dr. Akhtar: Have you seenexcessivehair loss?
Amiodarone
side effects
923
Dr. Harris: No, we have not, but Dr. Podrid mentioned one or two patients who had hair loss. Dr. Denes: How many patients had to discontinue medication becauseof side effects? Dr. Harris: Patients with skin pigmentation discontinued the drug. One patient who became hypothyroid while using the drug no longer required it. In another patient with hypothyroidism, we continued the drug with thyroid replacement becausethere was no other effective agent for that patient. Thus the numbers are very low. Dr. Denes: Your cases do not appear to be life threatening. You take off lessthan 1% for side effects. Dr. Rosen&urn: In a few patients we have observed symptomatic hypoglycemia. Amiodarone causes an increasein releaseof insulin. If you give a single doseof 600mg and draw samples,you will find the peak of insulin within the first hour. However, the few patients who developed hypoglycemia did so only after several months of treatment. It works like a mild antidiabetic agent. You must keep in mind the acute releaseof insulin that may occur following a large oral doseof amiodarone. Dr. Singh: The hypoglycemia, probably subclinical in most cases, might account for the weight gain and improved appetite we see in a few patients receiving amiodarone. Dr. Mandel: We have had one patient with iodide sensitivity who had an anaphylactic reaction to IVP dye. The patient had life-threatening ventricular arrhythmias. Has anybody had experience with that situation? A physician: We had a patient who developedan acute syndrome that appearedto be a pulmonary embolism.She developed “shock lung” asa result of pulmonary angiography and subsequently died. She had been on a regimen of amiodarone, but it is not certain whether the shock lung was due to an anaphylactic reaction to the iodine contained in amiodarone. Dr. Singh: Our extensive discussionabout the side effects of amiodarone clearly reflects the level of interest and concern about drug toxicity-the main limiting factor in the widespreaduse of amiodarone in cardiac arrhythmias. However, I think a reasonably clear perspective appears to be evolving, with the developing consensus that, if used judiciously and with careful attention to dosage,limiting side effects of amiodarone are few. The role of serum drug and metabolite concentrations in forestalling toxicity does not appear to be well defined. The varied experience suggeststhat we need to distinguish thoseside effects which are truly idiosyncratic in the pharmacologicsence(none appearsto be so), those which develop as a function of dose and/or duration of drug therapy (the vast majority), those which are unrelated to dose (e.g., altered thyroid state becauseof iodine in a predisposedpatient), and those which arise on the basisof drug interactions. A correct appreciation of these potential mechanismsis likely to minimize the adversereactions of amiodarone in the majority of patients exposed to the drug.