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Drug interactions with amiodarone
Drug interactions
with amiodarone
There are a number of important drug interactions with amiodarone. This agent appears to have a marked effect on the kinetics of some commonly used cardiovascular drugs, such as warfarin, digoxin, quinidine, and procainamide, and has dynamic interactions with others, such as the beta blockers and some calcium antagonists. Bleeding has been reported, apparently caused by a potentiation of the anticoagulant effect of warfarin by amiodarone. Tofsades de pointes has been observed when quinidine, propafenone, or mexiletine is given together with amiodarone. Furthermore, amiodarone may interact with beta-blocking agents and some of the calcium antagonists to produce symptomatic sinus bradycardia and sinus arrest, especially in a latent or overt sick sinus syndrome. During surgery, amiodarone may induce hypotension and an atropine-resistant bradycardia, possibly by interacting with anesthetic agents. A knowledge of the time of onset, extent, duration, and possible mechanisms of the interactions of amiodarone with other cardioactive drugs is still incomplete, but further studies are of great therapeutic importance. (AM HEART J 106:924, 1983.)
Frank I. Marcus, M.D. Tucson,
Ark
Amiodarone, like propranolol, has an extremely wide therapeutic/toxic ratio during short-term administration. Drug interactions with amiodarone are of consequence, however, because this agent appears to have a marked effect on the kinetics of several important cardiovascular drugs, such as warfarin, digoxin, quinidine, and procainamide, and has hemodynamic and electrophysiologic interactions with others, such as the beta-blocking drugs and calcium antagonists (Table I). This paper will focus on the onset, extent, duration, and mechanism of the known interactions. AMIODARONE
AND WARFARIN
INTERACTIONS
That amiodarone potentiates the anticoagulant effect of warfarin was first reported in 1979 by Simpson,’ who surveyed the British experience with 275 patients treated with amiodarone and found an enhanced anticoagulant effect in three patients. Subsequently other investigators reported seven patients with bleeding caused by amiodarone potentiation of the anticoagulant effect of warfarin.2-4 Prothrombin time may double after amiodarone therapy in patients taking warfarin (Fig. 1). This effect has been observed as early as 3 or 4 days after
From Arizona
the Department Health Sciences
Reprint Arizona 85724.
requests: Frank Health Sciences
924
of Medicine, Center. I. Marcus, Center,
Cardiology
Section,
University
M.D., Cardiology Section, University 1501 North Campbell Ave., Tucson,
of of AZ
Table I. Clinical consequencesof drug interactions with amiodarone Concomitant
Toxic
drug
interaction
Warfarin Digoxin
Bleeding Sinoatrial and AV node depression; gastrointestinal and central nervous system toxicity
Quinidine Propafenone Disopyramide Mexiletine Aprindine Procainamide Beta blockers
Torsades
Calcium antagonists Verapamil Diltiazem Anesthetic drugs
de pointes
Increased side effects; possibly cardiovascular effects Symptomatic bradycardia; sinus arrest Sinus arrest; AV blockade Hypotension; bradycardia
starting amiodarone5 but may be delayed for as long as 3 weeks.3 After discontinuation of amiodarone, the potentiating effect on the activity of warfarin persists for weeks3v4 or months.6 The mechanism of the potentiation of anticoagulant effects of warfarin has not been established. Some data suggest that the mechanism of interaction may be interference of warfarin metabolism by amiodarone. In one patient evaluated 4 days after amiodarone was started, plasma concentration of warfarin increased by 100% .5 Plasma protein
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Drug interactions
with amiodorone
925
; : 4-
l
p
during
tnetmnt Fig. 1. Prothrombin time in nine patients treated with amiodarone. (From Martinowitz U, Robinovici J, Goldfarb D, Many A, Banks H: Interaction between warfarin sodium and amiodarone. N Engl J Med 304:671, 1981.) aflliderala
binding of warfarin, measured by equilibrium analysis, was not altered, however, and peripheral antifactor activity was not found.3 The effect of amiodarone on prothrombin activity appears to be dose independent. Although increases in prothrombin time vary, it is recommended that the maintenance dose of warfarin be reduced by one third to one half when amiodarone is begun (Fig. 2; Table 11)3,6 and that careful surveillance be maintained. Amiodarone may also influence heparin activity.7 AMIODARONE-DIGOXIN
p
INTERACTION
In 1981 Moysey et al.* observed that when amiodarone was added to maintenance digoxin therapy in seven patients, all showed progressive increases in serum digoxin concentration; the average increase was 69% (Fig. 3). These observations were subsequently confirmed by mostg-12 but not aIlL investigators. Plasma digoxin increases were evident within 24 hours after amiodarone, 200 mg three times a day,
anioda~a\e treatment Fig. 2. Weekly dose of warfarin sodium (Coumadin) in nine patients treated with amiodarone. Dose of warfarin sodium was reduced by 16 % to 45% after amiodarone treatment to maintain prothrombin time within therapeutic range. (From Martinowitz U, Robinovici J, Goldfarb D, Many A, Bank H: Interaction between warfarin sodium and amiodarone. N Engl J Med 304:671, 1981.)
and rose linearly for 6 or 7 days; then the digoxin level appeared to reach a plateau.s Of these seven patients, four developed symptoms compatible with digoxin toxicity. The toxic effects of digitalis include sinus arrest, gastrointestinal symptoms, and “neurologic toxicity.““, l2 The fact that none of these patients developed atrial or ventricular ectopy may be attributed to the antiarrhythmic effects of amiodarone. The magnitude of this interaction appears to be dose related8 and is correlated with the plasma concentration of amiodaroneg (Fig. 4). When amiodarone is withdrawn, plasma digoxin concentration decreases progressively over 2 weeks. The mechanism of this interaction has not been described. The time course, with interaction beginning within 24 hours and attainment of steady-state digoxin level by 7 days (or five half-lives of digoxin), resembles the digoxin-quinidine interaction. This suggests that one mechanism of this interaction may
926
Marcus
American
October, 1983 Heart Journal
+75 digcain digain + amiodarone
.I..-----
o/--o ,,* -0t
1
+%I-
Digoxin concentration tv. char1gc)
2
+ 25 -
I 0.5
1 AMlODAROtVE
- 25
J 1 Days
2
3
f.
5
6
7
Mean percentage change in daily plasma digoxin concentrations in seven patients treated with digoxin. Amiodarone, 600 mg daily, was added from day 3 (o ). Six controls were treated with digoxin alone (x). (From Moysey JO, Jaggarao NSV, Grundy EN, Chamberlain DA: Amiodarone increases plasma digoxin concentrations. Br Med J 282:272, 1981.)
Fig.
3.
be a decrease in elimination. Digoxin is excreted primarily by the kidneys, by both glomerular filtration and tubular secretion. Since the glomerular filtration rate is not decreased by amiodarone, it may be that amiodarone reduces the elimination of digoxin by renal tubular secretion. Other mechanisms that may contribute to the increase in serum digoxin levels include a decrease in extrarenal excretion and tissue displacement of digoxin by amiodarone. These hypotheses await experimental proof. Our experience with 40 patients treated with amiodarone and digoxin is consistent with that previously reported. Serum digoxin levels usually doubled when amiodarone was given. Two patients developed symptoms of digitalis toxicity associated with serum digoxin levels greater than 2 rig/ml; one had nausea, the other visual disturbances. Digitalis toxic arrhythmias were not observed. Based on our experience and that of others, we recommend that the dose of digoxin be decreased by half when the two drugs are given together (Table II). AYIODARONE
INTERACTION
WITH
ANTIDYSRHYTHMIC
DRUGS
Some of the most hazardous drug interactions with amiodarone are those which occur with other
Fig.
4.
1.5
2 t?ICg/t?I
Plot of plasma amiodarone and plasma digoxin
concentrations in 33 patients treated for an average of 52
months. There was a correlation between these two parameters (r = 0.66). Dose of digoxin was 0.25 mg 0); that of P-methyl digoxin was 0.2 mg (0). Mean daily dose of amiodaronewas 154 t- 24 mg in 23 patients treated for paraxysmal supraventricular tachycardia, and it was 238 + 73 mg in 10 patients treated for ventricular arrhythmias. (From Furlanello F, Inama G, Ferrari M, Padrini R, Piovan D, Guarnerio M, Vergara G, Del Fauvero A, Dal Farno P, Disertori M: Amiodarone and amiodarone plus digitalis in the treatment of paroxysmal supraventricular reciprocating tachyarrhythmias. Pharmacol Res Commun l&731,1982.)
antidysrhythmic drugs, such as quinidine, disopyramide, mexiletine, propafenone, aprindine, and procainamide. Drug-induced torsades de pointes has been reported for combinations of amiodarone and quinidine, disopyramide, propafenone, or mexiletine.l* In each case the QT interval was markedly prolonged prior to the onset of the torsades de pointes (Fig. 5). When amiodarone, 200 mg three times a day, was given to a normal volunteer taking maintenance doses of quinidine, there was an increase in the plasma quinidine level, as well as an additive effect on prolongation of the QT intervalI (Fig. 6). This enhanced effect was observed after 2 days of combination therapy. Other investigators have also documented increased serum concentrations of quinidine and reduced dosage requirements with this combination of drugs’” (Table III). Thus it appears that the marked QT prolongation associated with quinidine and amiodarone therapy is due in part to a pharmacokinetic interaction and that some patients given these drugs can be expected to develop torsades de pointes. Therefore, in
Volume Number
la6 4, Part 2
Table
Drug interactions
with amiodarone
927
II. Pharmacokinetic drug interactions with amiodarone Interaction
Concomitant
drug
Onset
Warfarin
3 to 4
Digoxin
1
Quinidine
2
Procainamide
NAPA
(days)
<7
Magnitude
Recommended dose correction
Duration
Increases prothrombin time by 100% Increases serum concentration by 70% Increases serum concentration by 33% Increases plasma concentration by 55 % ; NAPA concentration by 33%
2wkto4mo 2 wk
1 l/3 1 112
?
1 l/3 (or avoid)
?
1 l/3 (or avoid)
= N-acetylprocainamide.
Table III. Serum concentrations and daily requirements of quinidine and procainamide before and during amiodarone, 800 to 1200 mg/day, for less than a weekI Mean +_ SD Antiarrhythmic
agent
Serum concentration (pg/ml) Quinidinet Procainamidel N-acetyl procainamide Procainamide plus N-acetyl procainamide Daily dose (mg/day) Quinidine Procainamide
Before
A
During
A
4.4 +- 1.1 6.8 i 1.8 6.9 + 4.8 13.7 + 6.2
5.8 r 0.9 9.1 + 4.7 19.7 * 8.7
2960 zt 1115 3708 r 1391
1875 ? 794 2958 f 1501
10.6
+ 4.8
% Change
p Value*
t 33 t 55 t 33 T 44
133
<0.005 0.01
120
<0.05
A = amiodarone. *Paired t test. tll patients. t12 patients.
general, class I drugs should either be avoided with amiodarone or used with caution. It is not known whether serum concentrations of propafenone or mexiletine are increased when amiodarone is given concomitantly, but increases in aprindine17 and procainamide 1evehP (Table III) have been found when these drugs were given in conjunction with amiodarone. It would seem reasonable to decrease by half the dose of any class I drug given with amiodarone (Table II). At any rate the value of combining class I agents with amiodarone for the control of serious arrhythmias has not been critically evaluated. AMIODARONE INTERACTIONS BETA-ADRENERGIC-BLOCKING ANTAGONISTS
WITH DRUGS AND CALCIUM
Another type of drug interaction is that between two classes of drugs that have similar effects. Amiodarone has sympathetic blocking activity but is not a competitive antagonist of the beta-adrenergic
receptors.18 Amiodarone decreases sinus node automaticity and prolongs the refractory period of the atrioventricular (AV) node. In patients with sinus bradycardia, sick sinus syndrome, or partial AV block, either amiodarone, a beta-blocking drug, or certain calcium antagonists (e.g., verapamil and diltiazem) can further slow the sinus rate or worsen AV block. The combination can have additive effects? occasionally with adverse consequences. For example, Derrida et al.lg described a patient who had a rapid ventricular response to atrial flutter even with amiodarone and digitalis therapy. After one dose of propranolol given by mouth, the patient had cardiac arrest. The ECG showed complete absence of ventricular activity. Fortunately the patient responded to isoproterenol infusion. Another patient with an acute myocardial infarction was given amiodarone intravenously because of continued pain. When the pain persisted for 24 hours, amiodarone was discontinued, and he received two doses of oral propranolol. One and one-half hours
92%
Marcus
American
October. 1983 Heart Journal
QT msuc 200 I
700 u,
00
1W
00
hr
.
Fig. 5. QT interval in six patients who developed torsades
de pointes before (0) and after (0) a class1 antiarrhythmic drug wasgiven in addition to amiodarone.QT interval wasgreater than 0.50 secondin all six patients who developed torsades de pointes. (From Tartini R, Kappenberger L, Steinbrunn W: Gefahrliche interaktionen Zurischen amiodaron und antiarrhythmika der klasse 1. Schweig Med Wochenschr 1129585, 1982.)
later he developed marked bradycardia that was soon followed by ventricular fibrillation, successfully treated with electrical defibrillation. Amiodarone should be used with caution with beta-blocking drugs or calcium antagonists, particularly if there is suspicion of underlying dysfunction of the sinus node, such as bradycardia or sick sinus syndrome, or if there is partial AV block. It would be prudent to exercise the same caution with verapamil and diltiaxem. One area that should be fruitful for further study of drug interactions with amiodarone is that with anesthetic agents, because of the observation that hypotension and atropine-resistant bradycardia may occur during surgery.20 CONCLUSIONS
The large number of serious drug interactions with amiodarone make this a potentially hazardous drug because so many patients with cardiovascular disease receive multiple drugs. Undoubtedly, interactions of amiodarone with drugs other than those already observed will be uncovered. Amiodarone and its major metabolite, desethylamiodarone, concentrate in the liver21 and have the potential of interfering with the hepatic metabolism of drugs. In addition, the kinetics of the interaction with digoxin
suggest that amiodarone may interfere with renal clearance of some drugs. Therefore we must be alert to these many interactions in order to prevent toxic effects of concomitantly administered cardiovascular drugs. I thank Ms. Catherine Abe& for her expert secretarial assistance and Dr. Paul Fenster for his review of the manuscript. REFERENCES
1. Simpson WT: Amiodarone in cardiac arrhythmias. International Congress Series No. 16, Royal Society of Medicine. New York, 1979, Grune & Stratton, Inc, p 50. 2. Rees A, Palal JJ, Reid PG, Henderson AH: Dangers of amiodarone and anticoagulant treatment. Br Med d 282:1757, 1981. 3. Hamer A, Peter T, Mandel WJ, Scheinman MM, Weiss D: The potentiation of warfarin anticoagulation by amiodarone and anticoagulant treatment. Circulation 65:1025, 1982. 4. Broekmans AW, Meyboom RHB: Potentiering van het cumarine-effect door amiodaron (Cordarone). Ned Tijdschr Geneeskd 1263415, 1982. 5. Serlin MJ, Sibeon RG, Green GJ: Dangers of amiodarone and anticoagulant treatment. Br Med J 283:57, 1981. 6. Martinowitz U. Rabinovici J. Goldfarb D. Manv A. Bank H: Interaction between warfarin sodium and amiodarone. N Engl J Med 304:671, 1981. 7. Tolstopyatov BI: Study of interrelations of etmozin, Cordarone, and phenycaberan with heparin. Farmakol Toksikol 44:586, 1981. 8. Moysey JO, Jaggarao NSV, Grundy EN, Chamberlain DA:
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13. Achilli A, Giacci M, Capezzuto A, DeLuca F, Guerra R, Serra N: Quinidine, digoxin and amiodarone-digoxin interactions: Effects on serum and digoxin levels. G Ital Cardiol 11:918, 1981. 14. Tartini R, Kappenberger L, Steinbrunn W: Gefahrliche interaktionen zwischen amiodaron und antiarrhythmika der klasse 1. Schweiz Med Wochenschr 112:1585, 1982. 15. Tartini R, Kappenberger L, Steinbrunn W, Meyer UA: Dangerous interactions between amiodarone and quinidine. Lancet 1:1327, 1982. 16. Saal AK, Werner JA, Gross BW, Gorham JR, Graham EI, Sears GK, Green HL: Interaction of amiodarone with quinidine and nrocainamide (abstr). Circulation 66(suppl 11):224, 1982. _ 17. Southworth W, Friday KJ, Ruffy R: Possible amiodaroneaprindine interaction (Letter to the Editor). AM HEART J 104~323, 1982. 18. Charlier R: Cardiac actions in the dog of a new antagonist of adrenergic excitation which does not produce competitive blockade of adrenoceptors. Br J Pharmacol 39:674, 1970. 19. Derrida JP, Ollagner J, Benami R, Haiat R, Chiche P: Amiodarone and propranolol, a dangerous association. Nouv Presse Med 8:1429, 1979. 20. Gallagher JD, Lieberman RW, Meranze J, Spielman SR, Ellison N: Amiodarone-induced complications during coronary artery surgery. Anesthesiology 55:186, 1981. 21. Adams PC, Nicholson MR, Storey GCA, Holt DW, Campbell RWF: Amiodarone tissue distribution: Relation to adverse effects (abstr). Br Heart J 49:297, 1983. DISCUSSION
Dr. Akhtar:
When did the casesof torsades de pointes
occur? 6. Changesin plasmaquinidine levels, QT interval, and heart rate after administration of amiodarone, 600 mglday, to healthy subject receiving quinidine sulfate, 1.2 gm daily for 6 days. Plasma quinidine levels increased from baseline of 4.4 and 6.6 pmol/L to 9.5 pmol/L after combination therapy. Quinidine alone caused a 20% increase in QT interval, whereas combination therapy resulted in a 40% increase(From Tartini R, Kappenberger L, Steinbrunn W, Meyer UA: Dangerousinteractions between amiodarone and quinidine. Lancet 1:1327, 1982.) Fig.
9.
10.
11.
12.
Amiodarone increases plasma digoxin concentrations. Br Med J 282:272, 1981. Furlanello F, Inama G, Ferrari M, Padrini R, Piovan D, Guarnerio M, Vergara G, Del Fauvero A, Dal Forno P, Disertori M: Amiodarone and amiodarone plus digitalis in the treatment of paroxysmal supraventricular reciprocating tachyarrhythmias. Pharmacol Res Commun 14:731, 1982. Furlanello F, Inama G, Ferrari M, Padrini R, Guarnerio M, Vergara G, Dal Forno P: Digoxin-amiodarone: A further example of digoxin-antiarrhythmic agents interaction on long-term treatment. G Ital Cardiol 11:1725, 1981. Oetgen WJ, Sohel SM, Tri TB, Heydron WH, Davia JE, Rakita L: Amiodarone-digoxin interaction: Clinical and experimental observations (abstr). Circulation 66(suppl 11):382, 1982. Nademanee K, Kannan R, Hendrickson JA, Burnam M, Kary I, Singh B: Amiodarone-digoxin interaction during treatment of resistant cardiac arrhythmias (abstr). Am J Cardiol 49:1026, 1982.
Dr. Singh: The one reported recently in Lancet occurred early. Dr. Zipes: You stressthat amiodaronehas more interactions than other drugs, making its potentially dangerous. I wonder if that stressis needed. Other drugs show interactions and affect the metabolism, excretion, pharmacokinetics,or pharmacodynamicsof other drugs. Amiodarone is no different. We must be careful when adding or subtracting any drug in patients. Dr. Marcus: Your point is well taken. On the other hand, I know of no drug with so many reported interactions, and I don’t believe that we’ve even scratched the surface. Dr. Zipes: Maybe we have to scratch the surface of someof the others. We combined digoxin and quinidine for a long time before we appreciated their interaction. Dr. Scheinman: Is the effect of amiodaronecausedby protein binding? Dr. Marcus: I don’t know whether there is a common mechanism.My hypothesis is that amiodaronemay affect both hepatic metabolism and renal excretion of drugs. Therefore it produces an unusually large number of interactions. Dr. Sobol: We presented data at the American Heart Association meeting in November; although our data were similar in terms of the mean increment in serum digoxin level, we found increases in all patients receiving the combination. There was at least one patient who had a quadrupling of his serum digoxin level, and others who
October, 1983 930
Marcus
had threefold increases.Therefore more marked elevations of serum digoxin concentrations can occur. Dr. Singh: I think that’s worth emphasizing. Responsesvary greatly. I don’t think the problem is as great during maintenance therapy as it is during the loading phases,when digoxin concentrations go up very steeply. Our unpublished data indicate that the increases are much smaller during maintenance at 200 and 400 mglday than when we use 1500to 1600 mg daily loading doses. Dr. Prystowsky: Does a state of relative hypothyroidism affect renal clearanceof digoxin? Dr. Marcus: Yes, Dr. Doherty’s work seemsto indicate that hypothyroidism changesthe renal excretion of digoxin. Dr. Prystowsky: Do you think that some of the effects you sawcould be related to a relative hypothyroid state that might be induced in somepatients with amiodarone? Dr. Marcus: No. The effects we saware reproducible, occur very early, and are not related to hypothyroidism. Dr. McGovern: A number of the so-calledinteractions between type 1 drugs and amiodarone have been due to prolonged QT interals and the development of torsadesde pointes, or polymorphic ventricular tachycardia, for days to weeks after starting the combination. Similar QT prolongation has been causedby amiodarone alone at the samedose. You emphasize that a beta blocker combined with amiodarone may cause bradycardia and sinus arrest. I know of 11 published casesof sinus arrest. Only one of
American
Heart
Journal
thesepatients wasreported to be receiving a beta blocker, but someof the others may have been. Most patients were receiving digoxin and amiodarone.Digoxin levels were not known in most cases. I agreethat we must observepatients carefully when we combinebeta blockersand amiodarone,but what do we do for our many patients with angina? Do we stop beta blockers?Amiodarone alone can causeboth exacerbation of arrhythmias or sinus arrest and worsening of heart block. Dr. Marcus: Certainly, amiodarone may cause torsadesde pointes. Determining whether theseother drugs can be implicated is still in a preliminary stage; there is just one report. Prolongation of the QT interval may be the mechanismof the interaction. With regard to the use of beta blockers, we need more information as to which patients would be likely to develop problems. There have beenseveral reports in the French literature of high-grade sinusarrest or even, in one patient, complete absenceof any rhythm. The interactions of amiodarone, beta blockers, someof the calcium blockers, and digoxin together would tend to facilitate depression of the sinus node, as well as the AV node. Dr. Singht It is evident that the complex pharmacologic properties of amiodaroneprovide a significant potential for not only pharmacodynamic but also pharmacokinetic interactions with numerouscardioactive compounds.The severity of such interactions may be determined by the underlying clinical features, but a great deal of work remains to be done in this area, especially regarding the basic mechanismsthat might be involved.
with amiodarone
There are a number of important drug interactions with amiodarone. This agent appears to have a marked effect on the kinetics of some commonly used cardiovascular drugs, such as warfarin, digoxin, quinidine, and procainamide, and has dynamic interactions with others, such as the beta blockers and some calcium antagonists. Bleeding has been reported, apparently caused by a potentiation of the anticoagulant effect of warfarin by amiodarone. Tofsades de pointes has been observed when quinidine, propafenone, or mexiletine is given together with amiodarone. Furthermore, amiodarone may interact with beta-blocking agents and some of the calcium antagonists to produce symptomatic sinus bradycardia and sinus arrest, especially in a latent or overt sick sinus syndrome. During surgery, amiodarone may induce hypotension and an atropine-resistant bradycardia, possibly by interacting with anesthetic agents. A knowledge of the time of onset, extent, duration, and possible mechanisms of the interactions of amiodarone with other cardioactive drugs is still incomplete, but further studies are of great therapeutic importance. (AM HEART J 106:924, 1983.)
Frank I. Marcus, M.D. Tucson,
Ark
Amiodarone, like propranolol, has an extremely wide therapeutic/toxic ratio during short-term administration. Drug interactions with amiodarone are of consequence, however, because this agent appears to have a marked effect on the kinetics of several important cardiovascular drugs, such as warfarin, digoxin, quinidine, and procainamide, and has hemodynamic and electrophysiologic interactions with others, such as the beta-blocking drugs and calcium antagonists (Table I). This paper will focus on the onset, extent, duration, and mechanism of the known interactions. AMIODARONE
AND WARFARIN
INTERACTIONS
That amiodarone potentiates the anticoagulant effect of warfarin was first reported in 1979 by Simpson,’ who surveyed the British experience with 275 patients treated with amiodarone and found an enhanced anticoagulant effect in three patients. Subsequently other investigators reported seven patients with bleeding caused by amiodarone potentiation of the anticoagulant effect of warfarin.2-4 Prothrombin time may double after amiodarone therapy in patients taking warfarin (Fig. 1). This effect has been observed as early as 3 or 4 days after
From Arizona
the Department Health Sciences
Reprint Arizona 85724.
requests: Frank Health Sciences
924
of Medicine, Center. I. Marcus, Center,
Cardiology
Section,
University
M.D., Cardiology Section, University 1501 North Campbell Ave., Tucson,
of of AZ
Table I. Clinical consequencesof drug interactions with amiodarone Concomitant
Toxic
drug
interaction
Warfarin Digoxin
Bleeding Sinoatrial and AV node depression; gastrointestinal and central nervous system toxicity
Quinidine Propafenone Disopyramide Mexiletine Aprindine Procainamide Beta blockers
Torsades
Calcium antagonists Verapamil Diltiazem Anesthetic drugs
de pointes
Increased side effects; possibly cardiovascular effects Symptomatic bradycardia; sinus arrest Sinus arrest; AV blockade Hypotension; bradycardia
starting amiodarone5 but may be delayed for as long as 3 weeks.3 After discontinuation of amiodarone, the potentiating effect on the activity of warfarin persists for weeks3v4 or months.6 The mechanism of the potentiation of anticoagulant effects of warfarin has not been established. Some data suggest that the mechanism of interaction may be interference of warfarin metabolism by amiodarone. In one patient evaluated 4 days after amiodarone was started, plasma concentration of warfarin increased by 100% .5 Plasma protein
Volume Number
106 4, Part 2
Drug interactions
with amiodorone
925
; : 4-
l
p
during
tnetmnt Fig. 1. Prothrombin time in nine patients treated with amiodarone. (From Martinowitz U, Robinovici J, Goldfarb D, Many A, Banks H: Interaction between warfarin sodium and amiodarone. N Engl J Med 304:671, 1981.) aflliderala
binding of warfarin, measured by equilibrium analysis, was not altered, however, and peripheral antifactor activity was not found.3 The effect of amiodarone on prothrombin activity appears to be dose independent. Although increases in prothrombin time vary, it is recommended that the maintenance dose of warfarin be reduced by one third to one half when amiodarone is begun (Fig. 2; Table 11)3,6 and that careful surveillance be maintained. Amiodarone may also influence heparin activity.7 AMIODARONE-DIGOXIN
p
INTERACTION
In 1981 Moysey et al.* observed that when amiodarone was added to maintenance digoxin therapy in seven patients, all showed progressive increases in serum digoxin concentration; the average increase was 69% (Fig. 3). These observations were subsequently confirmed by mostg-12 but not aIlL investigators. Plasma digoxin increases were evident within 24 hours after amiodarone, 200 mg three times a day,
anioda~a\e treatment Fig. 2. Weekly dose of warfarin sodium (Coumadin) in nine patients treated with amiodarone. Dose of warfarin sodium was reduced by 16 % to 45% after amiodarone treatment to maintain prothrombin time within therapeutic range. (From Martinowitz U, Robinovici J, Goldfarb D, Many A, Bank H: Interaction between warfarin sodium and amiodarone. N Engl J Med 304:671, 1981.)
and rose linearly for 6 or 7 days; then the digoxin level appeared to reach a plateau.s Of these seven patients, four developed symptoms compatible with digoxin toxicity. The toxic effects of digitalis include sinus arrest, gastrointestinal symptoms, and “neurologic toxicity.““, l2 The fact that none of these patients developed atrial or ventricular ectopy may be attributed to the antiarrhythmic effects of amiodarone. The magnitude of this interaction appears to be dose related8 and is correlated with the plasma concentration of amiodaroneg (Fig. 4). When amiodarone is withdrawn, plasma digoxin concentration decreases progressively over 2 weeks. The mechanism of this interaction has not been described. The time course, with interaction beginning within 24 hours and attainment of steady-state digoxin level by 7 days (or five half-lives of digoxin), resembles the digoxin-quinidine interaction. This suggests that one mechanism of this interaction may
926
Marcus
American
October, 1983 Heart Journal
+75 digcain digain + amiodarone
.I..-----
o/--o ,,* -0t
1
+%I-
Digoxin concentration tv. char1gc)
2
+ 25 -
I 0.5
1 AMlODAROtVE
- 25
J 1 Days
2
3
f.
5
6
7
Mean percentage change in daily plasma digoxin concentrations in seven patients treated with digoxin. Amiodarone, 600 mg daily, was added from day 3 (o ). Six controls were treated with digoxin alone (x). (From Moysey JO, Jaggarao NSV, Grundy EN, Chamberlain DA: Amiodarone increases plasma digoxin concentrations. Br Med J 282:272, 1981.)
Fig.
3.
be a decrease in elimination. Digoxin is excreted primarily by the kidneys, by both glomerular filtration and tubular secretion. Since the glomerular filtration rate is not decreased by amiodarone, it may be that amiodarone reduces the elimination of digoxin by renal tubular secretion. Other mechanisms that may contribute to the increase in serum digoxin levels include a decrease in extrarenal excretion and tissue displacement of digoxin by amiodarone. These hypotheses await experimental proof. Our experience with 40 patients treated with amiodarone and digoxin is consistent with that previously reported. Serum digoxin levels usually doubled when amiodarone was given. Two patients developed symptoms of digitalis toxicity associated with serum digoxin levels greater than 2 rig/ml; one had nausea, the other visual disturbances. Digitalis toxic arrhythmias were not observed. Based on our experience and that of others, we recommend that the dose of digoxin be decreased by half when the two drugs are given together (Table II). AYIODARONE
INTERACTION
WITH
ANTIDYSRHYTHMIC
DRUGS
Some of the most hazardous drug interactions with amiodarone are those which occur with other
Fig.
4.
1.5
2 t?ICg/t?I
Plot of plasma amiodarone and plasma digoxin
concentrations in 33 patients treated for an average of 52
months. There was a correlation between these two parameters (r = 0.66). Dose of digoxin was 0.25 mg 0); that of P-methyl digoxin was 0.2 mg (0). Mean daily dose of amiodaronewas 154 t- 24 mg in 23 patients treated for paraxysmal supraventricular tachycardia, and it was 238 + 73 mg in 10 patients treated for ventricular arrhythmias. (From Furlanello F, Inama G, Ferrari M, Padrini R, Piovan D, Guarnerio M, Vergara G, Del Fauvero A, Dal Farno P, Disertori M: Amiodarone and amiodarone plus digitalis in the treatment of paroxysmal supraventricular reciprocating tachyarrhythmias. Pharmacol Res Commun l&731,1982.)
antidysrhythmic drugs, such as quinidine, disopyramide, mexiletine, propafenone, aprindine, and procainamide. Drug-induced torsades de pointes has been reported for combinations of amiodarone and quinidine, disopyramide, propafenone, or mexiletine.l* In each case the QT interval was markedly prolonged prior to the onset of the torsades de pointes (Fig. 5). When amiodarone, 200 mg three times a day, was given to a normal volunteer taking maintenance doses of quinidine, there was an increase in the plasma quinidine level, as well as an additive effect on prolongation of the QT intervalI (Fig. 6). This enhanced effect was observed after 2 days of combination therapy. Other investigators have also documented increased serum concentrations of quinidine and reduced dosage requirements with this combination of drugs’” (Table III). Thus it appears that the marked QT prolongation associated with quinidine and amiodarone therapy is due in part to a pharmacokinetic interaction and that some patients given these drugs can be expected to develop torsades de pointes. Therefore, in
Volume Number
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Table
Drug interactions
with amiodarone
927
II. Pharmacokinetic drug interactions with amiodarone Interaction
Concomitant
drug
Onset
Warfarin
3 to 4
Digoxin
1
Quinidine
2
Procainamide
NAPA
(days)
<7
Magnitude
Recommended dose correction
Duration
Increases prothrombin time by 100% Increases serum concentration by 70% Increases serum concentration by 33% Increases plasma concentration by 55 % ; NAPA concentration by 33%
2wkto4mo 2 wk
1 l/3 1 112
?
1 l/3 (or avoid)
?
1 l/3 (or avoid)
= N-acetylprocainamide.
Table III. Serum concentrations and daily requirements of quinidine and procainamide before and during amiodarone, 800 to 1200 mg/day, for less than a weekI Mean +_ SD Antiarrhythmic
agent
Serum concentration (pg/ml) Quinidinet Procainamidel N-acetyl procainamide Procainamide plus N-acetyl procainamide Daily dose (mg/day) Quinidine Procainamide
Before
A
During
A
4.4 +- 1.1 6.8 i 1.8 6.9 + 4.8 13.7 + 6.2
5.8 r 0.9 9.1 + 4.7 19.7 * 8.7
2960 zt 1115 3708 r 1391
1875 ? 794 2958 f 1501
10.6
+ 4.8
% Change
p Value*
t 33 t 55 t 33 T 44
133
<0.005 0.01
120
<0.05
A = amiodarone. *Paired t test. tll patients. t12 patients.
general, class I drugs should either be avoided with amiodarone or used with caution. It is not known whether serum concentrations of propafenone or mexiletine are increased when amiodarone is given concomitantly, but increases in aprindine17 and procainamide 1evehP (Table III) have been found when these drugs were given in conjunction with amiodarone. It would seem reasonable to decrease by half the dose of any class I drug given with amiodarone (Table II). At any rate the value of combining class I agents with amiodarone for the control of serious arrhythmias has not been critically evaluated. AMIODARONE INTERACTIONS BETA-ADRENERGIC-BLOCKING ANTAGONISTS
WITH DRUGS AND CALCIUM
Another type of drug interaction is that between two classes of drugs that have similar effects. Amiodarone has sympathetic blocking activity but is not a competitive antagonist of the beta-adrenergic
receptors.18 Amiodarone decreases sinus node automaticity and prolongs the refractory period of the atrioventricular (AV) node. In patients with sinus bradycardia, sick sinus syndrome, or partial AV block, either amiodarone, a beta-blocking drug, or certain calcium antagonists (e.g., verapamil and diltiazem) can further slow the sinus rate or worsen AV block. The combination can have additive effects? occasionally with adverse consequences. For example, Derrida et al.lg described a patient who had a rapid ventricular response to atrial flutter even with amiodarone and digitalis therapy. After one dose of propranolol given by mouth, the patient had cardiac arrest. The ECG showed complete absence of ventricular activity. Fortunately the patient responded to isoproterenol infusion. Another patient with an acute myocardial infarction was given amiodarone intravenously because of continued pain. When the pain persisted for 24 hours, amiodarone was discontinued, and he received two doses of oral propranolol. One and one-half hours
92%
Marcus
American
October. 1983 Heart Journal
QT msuc 200 I
700 u,
00
1W
00
hr
.
Fig. 5. QT interval in six patients who developed torsades
de pointes before (0) and after (0) a class1 antiarrhythmic drug wasgiven in addition to amiodarone.QT interval wasgreater than 0.50 secondin all six patients who developed torsades de pointes. (From Tartini R, Kappenberger L, Steinbrunn W: Gefahrliche interaktionen Zurischen amiodaron und antiarrhythmika der klasse 1. Schweig Med Wochenschr 1129585, 1982.)
later he developed marked bradycardia that was soon followed by ventricular fibrillation, successfully treated with electrical defibrillation. Amiodarone should be used with caution with beta-blocking drugs or calcium antagonists, particularly if there is suspicion of underlying dysfunction of the sinus node, such as bradycardia or sick sinus syndrome, or if there is partial AV block. It would be prudent to exercise the same caution with verapamil and diltiaxem. One area that should be fruitful for further study of drug interactions with amiodarone is that with anesthetic agents, because of the observation that hypotension and atropine-resistant bradycardia may occur during surgery.20 CONCLUSIONS
The large number of serious drug interactions with amiodarone make this a potentially hazardous drug because so many patients with cardiovascular disease receive multiple drugs. Undoubtedly, interactions of amiodarone with drugs other than those already observed will be uncovered. Amiodarone and its major metabolite, desethylamiodarone, concentrate in the liver21 and have the potential of interfering with the hepatic metabolism of drugs. In addition, the kinetics of the interaction with digoxin
suggest that amiodarone may interfere with renal clearance of some drugs. Therefore we must be alert to these many interactions in order to prevent toxic effects of concomitantly administered cardiovascular drugs. I thank Ms. Catherine Abe& for her expert secretarial assistance and Dr. Paul Fenster for his review of the manuscript. REFERENCES
1. Simpson WT: Amiodarone in cardiac arrhythmias. International Congress Series No. 16, Royal Society of Medicine. New York, 1979, Grune & Stratton, Inc, p 50. 2. Rees A, Palal JJ, Reid PG, Henderson AH: Dangers of amiodarone and anticoagulant treatment. Br Med d 282:1757, 1981. 3. Hamer A, Peter T, Mandel WJ, Scheinman MM, Weiss D: The potentiation of warfarin anticoagulation by amiodarone and anticoagulant treatment. Circulation 65:1025, 1982. 4. Broekmans AW, Meyboom RHB: Potentiering van het cumarine-effect door amiodaron (Cordarone). Ned Tijdschr Geneeskd 1263415, 1982. 5. Serlin MJ, Sibeon RG, Green GJ: Dangers of amiodarone and anticoagulant treatment. Br Med J 283:57, 1981. 6. Martinowitz U. Rabinovici J. Goldfarb D. Manv A. Bank H: Interaction between warfarin sodium and amiodarone. N Engl J Med 304:671, 1981. 7. Tolstopyatov BI: Study of interrelations of etmozin, Cordarone, and phenycaberan with heparin. Farmakol Toksikol 44:586, 1981. 8. Moysey JO, Jaggarao NSV, Grundy EN, Chamberlain DA:
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Drug
interactions
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929
13. Achilli A, Giacci M, Capezzuto A, DeLuca F, Guerra R, Serra N: Quinidine, digoxin and amiodarone-digoxin interactions: Effects on serum and digoxin levels. G Ital Cardiol 11:918, 1981. 14. Tartini R, Kappenberger L, Steinbrunn W: Gefahrliche interaktionen zwischen amiodaron und antiarrhythmika der klasse 1. Schweiz Med Wochenschr 112:1585, 1982. 15. Tartini R, Kappenberger L, Steinbrunn W, Meyer UA: Dangerous interactions between amiodarone and quinidine. Lancet 1:1327, 1982. 16. Saal AK, Werner JA, Gross BW, Gorham JR, Graham EI, Sears GK, Green HL: Interaction of amiodarone with quinidine and nrocainamide (abstr). Circulation 66(suppl 11):224, 1982. _ 17. Southworth W, Friday KJ, Ruffy R: Possible amiodaroneaprindine interaction (Letter to the Editor). AM HEART J 104~323, 1982. 18. Charlier R: Cardiac actions in the dog of a new antagonist of adrenergic excitation which does not produce competitive blockade of adrenoceptors. Br J Pharmacol 39:674, 1970. 19. Derrida JP, Ollagner J, Benami R, Haiat R, Chiche P: Amiodarone and propranolol, a dangerous association. Nouv Presse Med 8:1429, 1979. 20. Gallagher JD, Lieberman RW, Meranze J, Spielman SR, Ellison N: Amiodarone-induced complications during coronary artery surgery. Anesthesiology 55:186, 1981. 21. Adams PC, Nicholson MR, Storey GCA, Holt DW, Campbell RWF: Amiodarone tissue distribution: Relation to adverse effects (abstr). Br Heart J 49:297, 1983. DISCUSSION
Dr. Akhtar:
When did the casesof torsades de pointes
occur? 6. Changesin plasmaquinidine levels, QT interval, and heart rate after administration of amiodarone, 600 mglday, to healthy subject receiving quinidine sulfate, 1.2 gm daily for 6 days. Plasma quinidine levels increased from baseline of 4.4 and 6.6 pmol/L to 9.5 pmol/L after combination therapy. Quinidine alone caused a 20% increase in QT interval, whereas combination therapy resulted in a 40% increase(From Tartini R, Kappenberger L, Steinbrunn W, Meyer UA: Dangerousinteractions between amiodarone and quinidine. Lancet 1:1327, 1982.) Fig.
9.
10.
11.
12.
Amiodarone increases plasma digoxin concentrations. Br Med J 282:272, 1981. Furlanello F, Inama G, Ferrari M, Padrini R, Piovan D, Guarnerio M, Vergara G, Del Fauvero A, Dal Forno P, Disertori M: Amiodarone and amiodarone plus digitalis in the treatment of paroxysmal supraventricular reciprocating tachyarrhythmias. Pharmacol Res Commun 14:731, 1982. Furlanello F, Inama G, Ferrari M, Padrini R, Guarnerio M, Vergara G, Dal Forno P: Digoxin-amiodarone: A further example of digoxin-antiarrhythmic agents interaction on long-term treatment. G Ital Cardiol 11:1725, 1981. Oetgen WJ, Sohel SM, Tri TB, Heydron WH, Davia JE, Rakita L: Amiodarone-digoxin interaction: Clinical and experimental observations (abstr). Circulation 66(suppl 11):382, 1982. Nademanee K, Kannan R, Hendrickson JA, Burnam M, Kary I, Singh B: Amiodarone-digoxin interaction during treatment of resistant cardiac arrhythmias (abstr). Am J Cardiol 49:1026, 1982.
Dr. Singh: The one reported recently in Lancet occurred early. Dr. Zipes: You stressthat amiodaronehas more interactions than other drugs, making its potentially dangerous. I wonder if that stressis needed. Other drugs show interactions and affect the metabolism, excretion, pharmacokinetics,or pharmacodynamicsof other drugs. Amiodarone is no different. We must be careful when adding or subtracting any drug in patients. Dr. Marcus: Your point is well taken. On the other hand, I know of no drug with so many reported interactions, and I don’t believe that we’ve even scratched the surface. Dr. Zipes: Maybe we have to scratch the surface of someof the others. We combined digoxin and quinidine for a long time before we appreciated their interaction. Dr. Scheinman: Is the effect of amiodaronecausedby protein binding? Dr. Marcus: I don’t know whether there is a common mechanism.My hypothesis is that amiodaronemay affect both hepatic metabolism and renal excretion of drugs. Therefore it produces an unusually large number of interactions. Dr. Sobol: We presented data at the American Heart Association meeting in November; although our data were similar in terms of the mean increment in serum digoxin level, we found increases in all patients receiving the combination. There was at least one patient who had a quadrupling of his serum digoxin level, and others who
October, 1983 930
Marcus
had threefold increases.Therefore more marked elevations of serum digoxin concentrations can occur. Dr. Singh: I think that’s worth emphasizing. Responsesvary greatly. I don’t think the problem is as great during maintenance therapy as it is during the loading phases,when digoxin concentrations go up very steeply. Our unpublished data indicate that the increases are much smaller during maintenance at 200 and 400 mglday than when we use 1500to 1600 mg daily loading doses. Dr. Prystowsky: Does a state of relative hypothyroidism affect renal clearanceof digoxin? Dr. Marcus: Yes, Dr. Doherty’s work seemsto indicate that hypothyroidism changesthe renal excretion of digoxin. Dr. Prystowsky: Do you think that some of the effects you sawcould be related to a relative hypothyroid state that might be induced in somepatients with amiodarone? Dr. Marcus: No. The effects we saware reproducible, occur very early, and are not related to hypothyroidism. Dr. McGovern: A number of the so-calledinteractions between type 1 drugs and amiodarone have been due to prolonged QT interals and the development of torsadesde pointes, or polymorphic ventricular tachycardia, for days to weeks after starting the combination. Similar QT prolongation has been causedby amiodarone alone at the samedose. You emphasize that a beta blocker combined with amiodarone may cause bradycardia and sinus arrest. I know of 11 published casesof sinus arrest. Only one of
American
Heart
Journal
thesepatients wasreported to be receiving a beta blocker, but someof the others may have been. Most patients were receiving digoxin and amiodarone.Digoxin levels were not known in most cases. I agreethat we must observepatients carefully when we combinebeta blockersand amiodarone,but what do we do for our many patients with angina? Do we stop beta blockers?Amiodarone alone can causeboth exacerbation of arrhythmias or sinus arrest and worsening of heart block. Dr. Marcus: Certainly, amiodarone may cause torsadesde pointes. Determining whether theseother drugs can be implicated is still in a preliminary stage; there is just one report. Prolongation of the QT interval may be the mechanismof the interaction. With regard to the use of beta blockers, we need more information as to which patients would be likely to develop problems. There have beenseveral reports in the French literature of high-grade sinusarrest or even, in one patient, complete absenceof any rhythm. The interactions of amiodarone, beta blockers, someof the calcium blockers, and digoxin together would tend to facilitate depression of the sinus node, as well as the AV node. Dr. Singht It is evident that the complex pharmacologic properties of amiodaroneprovide a significant potential for not only pharmacodynamic but also pharmacokinetic interactions with numerouscardioactive compounds.The severity of such interactions may be determined by the underlying clinical features, but a great deal of work remains to be done in this area, especially regarding the basic mechanismsthat might be involved.