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Pharmacokinetics: the secret to understanding amiodarone
As predicted by pharmacology, the hepatic effects of amiodarone have been demonstrated to be proportional
to serum drug concentration
[22,32]. Although drug concentration is proportional to dose administered
(
Fig. 4.1A), the concentration produced by a given dose varies widely between patients according to their geneti-
cally determined pharmacokinetics (
Fig. 4.1B), as illustrated by the scatter in plateau concentrations plotted as
gray lines for a population of 77 patients, all receiving the same dose of amiodarone 200 mg/d. Although no indi-
viduals receiving 200 mg/d would be expected to exceed the “Red Line” threshold for toxicity, 11 (14.5%) would
exceed the optimal zone, of which 6 would exceed the concentrations developed by the typical patient receiving
400 mg/d. Given that another 11 patients would fall below the threshold of efficacy, a total of 29% of the patient
population would be better served by personally adjusted maintenance doses. Waiting for steady state to make
dose adjustments is impractical, making it useful for the prescriber to be both knowledgeable of the drug’s phar-
macology and aware of the range in interpatient pharmacokinetics. For most drugs in daily use, dose titration is
almost a matter of subconscious routine, based on previous experience. However, the pharmacokinetic profile of
amiodarone differs so completely from routinely used drugs, that safe administration and monitoring depends
on conscious application of pharmacokinetic knowledge to account for the long delay in effect.
Pharmacokinetics: the determinant of drug exposure
Both amiodarone and its active metabolite, DEA, segregate preferentially into fatty tissues, including the liver
and lung, and distribute into an apparent volume of well above 10,000 L
[2]. Although hepatic tissue concentrations
of amiodarone nominally appear to be 500-fold higher than serum
[33], direct comparison of drug per unit of mass
in tissue with drug per unit of volume of serum is somewhat abstract. However, it is the immense size of the
apparent volume of distribution that underlies amiodarone’s unusual pharmacology.
The interchange of drug between the small central and vast peripheral compartments, acts as a concentration
buffer, dampening the effects of any changes in dosing regimen, absorption, or elimination. The distribution half-
life between central and peripheral compartments is 80 times more rapid than its elimination half-life, making
serum concentration remarkably stable and frustrating attempts to modify it quickly. When dosing rate is
increased, intercompartmental equilibrium is tipped in favor of drug moving toward peripheral tissues, resulting
in the rise in serum concentrations being slowed, similar to how a leaky buc ket slows attempts to fill it (
Fig. 4.2).
In acute intravenous therapy, the serum concentrations produced by a bolus instantly reach an effective threshold
but collapse within hours because of peripheral redistribution. Thus continuous intravenous infusion is required
to maintain efficacy early in therapy. In chronic oral therapy, high loading doses are slowly absorbed to achieve
and sustain effective serum concentrations while pharmacokinetic compartments are coming into equilibrium.
When dosing is discontinued or the rate is titrated downward, drug eliminated from the circulation is partially
replaced by distribution back from the periphery until equilibrium is rebalanced. Thus variations in amiodarone
concentrations are highly constrained by intercompartmental drug buffering and it takes at least 6 months after a
dose change for its effect on serum concentration/efficacy to be complete. This explains why effects persist well
after discontinuation of amiodarone dosing.
Drug absorption varies widely between patients
[35], such that the serum concentrations observed in a popula-
tion of patients after being administered the same dose of amiodarone can vary by more than fourfold (
Fig. 4.1B).
Renal excretion accounts for ,1% of elimination, eliminating any requirement for dose adjustment in renal dis-
ease
[36]. Almost all drug is eliminated through hepatic metabolism and biliary excretion with some drug subject
to enterohepatic recirculation. Age, sex, renal and hepatic disease were not found to markedly affect the disposi-
tion of amiodarone or DEA and although the half-life of amiodarone has been reported to range from 16 to 180
days, the typical value in the population is 55 days
[2]. Slower accumulation and elimination of DEA provide a
dampened record of amiodarone intake and elimination. Being lipophilic, amiodarone crosses the placenta and is
secreted into breast milk, exposing the fetus and infant to enough iodine to alter thyroid function
[37].
Although the proportionality between serum and tissue concentrations is in flux prior to steady state, the
observed hepatic effects are better correlated to serum drug concentration than daily dosing rate
[38] and the
relationship to concentration gets better after steady state. No hepatic effects were observed in patients with
serum amiodarone concentrations , 1.5 mg/L, while in those with concen trations . 2.5 mg/L, 7% developed ala-
nine transaminase (ALT) .3x upper limit of normal (ULN), and changes in ALT correlated with serum amiodar-
one concentrations
[22,32]. The active metabolite, DEA, shares many of the properties of amiodarone, and likely
has equal adverse hepatic effects
[32].
34 4. Drugs at the crossroads of heart and liver
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Pharmacokinetics predicts that during initiation of any drug serum concentrations will continue to rise until
steady state. What sets amiodarone apart is that achieving complete steady-state equilibrium can take as long as
18 months. The higher the daily dose, the sooner the threshold for efficacy will be reached (
Fig. 4.1A). However,
since efficacy is reached before steady state, continuing a daily dose that is too high means that further increases
in concentration could potentially surpass thresholds of toxicity before they level off (
Fig. 4.1A). Thus early
attainment of efficacy should not be taken as confirmation that the correct daily dose is being administered, but
rather an indication that a lower daily dose is likely required to reduce the risk of toxicity as steady state is
reached.
Despite being administered a “standard” 200 mg/d dose, a patient who has twice the fractional absorption of
the population-typical patient will effectively be receiving 400 mg/d. TDM can identify patients with higher
accumulation, guide dose titration, and prospectively lower the risk of toxicity. With no dose adjustment,
Fogoros et al. reported that 73% of patients had adverse effects with long-term therapy and 15% were withdrawn
from treatment as a consequence
[39].
Pharmacokinetics: the untenable concept of total cumulative dose of amiodarone
While actual mechanisms for amiodarone toxicity remain largely unproven, total cumulative dose (TCD), is
frequently cited as a gauge of risk in studies
[40] and reviews [41]. However, TCD, calculated from the sum of
(dosing rates) 3 (durations the drug administration) is incompatible with basic pharmacological principles for
drugs used in human therapeutics, those that have concentration thresholds for efficacy that are lower than that
for toxicity. Consider acetaminophen exposure as an example. Ingesting a TCD of 20 g of acetaminophen at a
rate of 20 g/d (acute overdose) is fatal if not treated. This is because the concentration achieved at this input rate
is sufficient to shunt drug down the toxic N-acetyl-p-benzoquinone imine (NAPQI) pathway. However, the same
FIGURE 4.2 Pharmacokinetics of amiodarone loading dosing and elimination. The pharmacokinetic behavior of amiodarone demon-
strates a pattern of slow accumulation in a large volume of distribution comprising two compartments. Drug in the central compartment
exchanges back and forth with the much larger deep compartment with a half-life of only 17 h. (A) Curves for population average serum
amiodarone concentration over 1 year in patients receiving loading doses used to achieve effective concentrations more rapidly. Without load-
ing doses, the typical patient receiving 200 mg/d will attain efficacy (Yellow Band) within a week. Elevations of ALT are seldom observed
below the upper limit of the yellow zone. Upper Blue Line shows transient elevations of serum amiodarone concentration in response to mod-
erately aggressive loading with oral amiodarone providing a total dose of 19.6 g in 28 days. Lower blue line shows accumulation of amiodar-
one in the larger deep compartment. Prior to steady state, the ability of serum concentrations to reach efficacy is dampened by buffering
between the central and deep compartments. Highly perfused heart tissues rapidly equilibrate with central compartment drug concentrations
achieving efficacy relatively quickly, while larger volume organs lag behind, showing delayed toxicity more proportional to concentrations in
the deep compartment. Upper Orange Line shows response to a less aggressive loading protocol of oral amiodarone 22.2 g provided over
42 days, as used in the Vanish Trail
[34]. Serum concentrations become a more reliable predictor of effect as the deep compartment approaches
the target range at 38 days (lower Orange Line). Note that with loading (blue line) or without loading (black line), a 200 mg/d maintenance
dose always converges on the same serum concentration after 180 days. Dashed Purple Line shows the more damped accumulation curve of
desethylamiodarone metabolite in serum, more closely reflecting systemic exposure to drug than does amiodarone prior to steady state.
Dashed Blue Line depicts concentration decrement after discontinuation of dosing. (B) First 200 days of therapy depicted in panel A with con-
centration and time axes magnified.
35Part 1: amiodarone
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TCD administered over 20 days is far from hepatotoxic, as it does not achieve concentrations above the toxic
threshold. Similarly, amiodarone at dosing rates that keep concentrations below a toxic threshold has no lifetime
TCD limit. Pharmacology shows that TCD becomes meaningless in a system in which steady state concentration
can be maintained below a threshold for toxicity since concentrations cease to increase beyond steady state, the
point at which drug input is matched by drug elimination.
In the case of amiodarone, it may take 18 months for some patients to reach steady state. When a relationship
to TCD is reported, it suggests that the study is of insufficient duration to detect the leveling-off of toxicity risk
with time. A closer examination of “long-term” amiodarone studies in which toxicity correlated to TCD will usu-
ally find that median follow-up is ,12 months. This means that in many of the patients, concentration exposure
had continued to increase until the end of follow-up and TCD was merely an indirect measurement of the time
that accumulating concentrations were inadvertently allowed to exceed the toxicity threshold. Studies of less
than 24 months duration hugely bias data analysis to pre-steady-state conditions during which accumulation is
proportional to TCD. More logically, pharmacology predicts that concentration, i.e., the amount of drug to which
tissue is exposed, is the parameter driving the risk of toxicity. If a patient who has received a stable dose of amio-
darone for 510 half-lives has not yet exhibited any physical or biochemical signs of toxicity, further cumulative
dosing does not increase risk of being exposed to concentrations above the threshold of toxicity. Any anxiety con-
cerning “inevitable toxicity” in such patients is not grounded in the science of ph armacology. The danger of
accepting an illogical TCD link is the unnecessary withdrawal of essential therapy based on an arbi trary total
dose.
In a fashion analogous to acetaminophen, when amiodarone concentration goes above a toxic threshold, there
is probably increased metabolic free radical formation. Although concentration is proportional to dose, an expec-
tation that a given dose will produce a specific concentration in all patients is foiled by interpatient variation in
pharmacokinetics. However, most patients receiving 200 mg/d will not develop concentrations above their toxic
threshold and could continue this dosing rate for the rest of their life, despite an ever-increasing TCD. Yet, a cou-
ple of measurements of amiodarone concentration in the first two years can provide reassurance that a given
patient is at low risk, because it confirms they do not have pharmacokinetic irregularities that would expose
them to abnormally high concentrations. When assessing the potential that amiodarone is the cause of hepatic
abnormalities, data regarding exposure to high serum amiodarone concentrations is much more relevant than
calculating TCD.
The concept of a toxic concentration threshold is borne out in animal and hepatocyte models. Both demonstrate
that hepatic adverse effects occur only at concentrations higher than patients are normally exposed to when dosing
is properly adjusted
[42]. Attempts made to correlate dose with the degree of amiodarone hepatic effects are com-
plicated by the interpatient variability in the concentrations developed with any given dose (
Fig. 4.1B). Thus while
a prospective study of 104 patients, observed that higher mean daily dose was associated an upward trend in trans-
aminases, dose did not prove to be a statistically significant factor
[43]. On the other hand, a statistically significant
relationship between drug exposure (concentration) and hepatic effects can be demonstrated
[44], because directly
measuring amiodarone concentrations eliminates the confounding effect of variability in drug absorption.
Mathematical modeling further improves the understanding of the protracted concentration-effect relationships
seen with long half-life drugs, allowing demonstration of inter-individual variation in sensitivity of ALT to serum
amiodarone concentration
[22]. Such a relationship of ALT to amiodarone exposure was clearly apparent in a
patient who had insisted on adjusting their own dosing. This created wide swings in serum concentrations over
time during which each undulation in amiodarone was accompanied by a concordant swing in ALT concentration
(
Fig. 4.3). After 15 years of therapy, no hepatic damage was detectable, and ALT continued to normalize every time
amiodarone dosing was returned to prescrribed doses and serum concentration fell to expected levels.
Amiodarone: separating direct and indirect toxicity
At higher concentrations, amiodarone causes direct toxicity to tissues [42], a problem that can be largely
avoided by adjusted dosing. However, even at low serum concentrations, the excess of iodine provided by amio-
darone can indirectly disturb thyroid homeostasis. Each 200-mg amiodarone tablet contains B75 mg of iodine.
With an average 50% drug absorption and 10% deiodination, each tablet can supply another 3.7 mg of iodine, or
about 25 times the recommended daily iodine intake of 150 μg. In the 8% of the population who cannot escape
from the WolffChaikoff effect associated with iodine loads, hypothyroidism may develop. This has been well
36 4. Drugs at the crossroads of heart and liver
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documented in populations exposed to excess environmental iodine (high-level salt iodination or seaweed), while
3% are susceptible to developing a hyperthyroid state
[4547].
Clearly, amiodarone dosing cannot be adjusted to the ,8 mg/d that would be required to avoid iodine-
related effects. Nonetheless, when screened for and detected early, these effects are easily treated. Thyroxine
replacement is extremely common in the general population and such patients are not affected by coadministra-
tion of amiodarone. A hyperthyroid state in a patient taking amiodarone is most often related to a transient
underlying thyroiditis that usually responds to antithyroid medications, such as methimazole. Stopping amiodar-
one dosing has no effect, as iodine takes about a year to eliminate. However, even when amiodarone dosing con-
tinues, the thyroiditis usually settles and within a few months the antithyroid therapy can be stopped. In many
asymptomatic patients receiving amiodarone, elevations in thyroid stimulating hormone (TSH) cause
physician concern. Yet, further testing usually finds free thyroxine concentration to be high-normal, not low, and
thyroid replacement is not required.
A high frequency of iodine-related thyroid issues inflates the perception that amiodarone is innately toxic. For
example, the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) reported about 12% of
patients discontinued amiodarone for organ-specific adverse effects, typical of amiodarone-placebo-controlled
trials
[48]. However, 4%, or a third of these discontinuations were for iodine-related thyroid abnormalities. As a
practical point, the presence of thyroid abnormalities does not increase the likelihood that hepatic changes are
related to overexposure to amiodarone.
Amiodarone: lessons from pulmonary toxicity when considering hepatotoxicity
Any inquiries about amiodarone on the Internet quickly highlight amiodarone-induced pulmonary toxicity,
creating a high index of suspicion for pulmonary effects, both by patients and physicians. Both pulmonary and
hepatic toxicity are associated with amiodarone-induced alterations in lipid homeostasis
[42] and can therefore
be largely prevented by concentration-guided dose adjustment (
Fig. 4.2). There are also many parallels to be
found in assessing hepatic and pulmonary toxicity. A patient being assessed for hepatic effects should also be
screened for pulmonary toxicity, as its presence would increase the probability that amiodarone is causally
associated.
FIGURE 4.3 Relationship of serum ALT to amiodarone and desethylamiodarone (DEA) concentrations in one patient. Plot of 15 years (96
half-lives) of concentrations in a patient who self-adjusted amiodarone dosing. Serum ALT was consistently elevated following each elevation in mea-
sured amiodarone concentration to .1.5 μmol/L (0.97 μg/L), suggesting the patient was more sensitive to amiodarone than the typical patient as mod-
eled by Pollak & Shafer
[22]. Each time the dose was reduced to allow amiodarone concentration to fall, serum ALT normalized. Amiodarone
concentration in mg/L 5 0.645 • μmol/L and DEA in mg/L 5 0.617 • μmol/L.
37Part 1: amiodarone
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Further perspective can be gained by critically weighing the evidence in the literature regarding amiodarone-
associated pulmonary and hepatic toxicity. Without a gold-standard diagnostic tool, assessment of the probability
that a medication has caused an adverse effect depends on eva luation of six criteria:
1. The adverse event is a previously known response to the suspected agent.
2. Other causes can be ruled out and the adverse event is not linked to the disease state.
3. Timing of the adverse event is concordant with onset and offset of drug exposure, not merely dosing.
4. There is resolution with dechallenge (discontinuing the suspected agent).
5. There is recurrence with rechallenge (resuming the suspected agent).
6. Serum drug concentration was higher than that normally associated with therapeutic respons e.
The fact that most amiodarone case reports do not address more than three of the above criteria brings into
question the reliability of attribution of cause. Seldom is the concentration of amio darone measured in estim ating
the degree of drug exposure. Signs of normal exposure to amiodarone, such as increased liver radiodensity or
lamellar inclusion bodies (
Fig. 4.4), are often incorrectly assumed to indicate causality. However, these signs are
present in all specimens from patients exposed to amiodarone, not just those with pathology
[49]. The protracted
time frames for onset and offset of drug effects present practical deterrents to dechallenge/rechallenge and are
seldom properly documented. When an event occurs quickly following initiation of amiodarone, long before
even a single half-life-period of dosing has been absorbed, or wh en a symptom vanishes quickly, soon after dos-
ing is stopped, the observed time frame would not fit with a pharmacological explanation for amiodarone toxic-
ity. In the absence of reported serum drug concentrations, evidence of exposure to sufficient drug to cause toxic
symptoms is difficult to evaluate. Of course, the most challenging barrier to certainty in attribution of cause is
the lack of a pathog nomonic sign to confirm amiodarone toxicity.
When case reports are used to estimate incidence of toxicity, values are often quoted in the double digits as
exemplified by a 2003 review citing the rate of pulmonary toxicity at 2%17%
[50]. Such estimates have little con-
cordance with the incidence reported in prospective placebo-controlled trials, such as STAT-CHF. In this trial,
pulmonary fibrosis occurred in 4 of the 336 patients receiving amiodarone compared to 3 of the 338 patients
receiving placebo
[51]. This might suggest that in the sick population most likely to receive amiodarone, pulmo-
nary abnormalities are found with equal frequency in patients whether receiving active drug or not. Similarly, in
another prospective study evaluating regular pulmonary function testing in 193 patients receiving amiodarone,
not a single case of pulmonary fibrosis was observed, nor was any reduction in lung function
[52]. Perhaps the
most reliable estimate of the incidence, a metaanalysis of 11,395 patients in placebo-controlled trials was recently
published, in which pulmonary toxicity occurred in 0.74% of patients per year of exposure to placebo, while in
patients receiving amiodarone, the rate was 1.29% per patient-year
[53].
Although it is clear is that amiodarone can produce pulmonary and hepatic adverse effects, there is no evi-
dence that clinically effective concentrations of amiodarone are innately more toxic than other medications that
we use regularly. However, there is enough interpatient variability in amiodarone pharmacokinetics that without
individual dose adjustment, some patients prescribed “standard” doses will develop concentrations that are
FIGURE 4.4 Sketch of typical electron micrography appearance of lysosomes containing multilamellar bodies (MLB) inclusions. Many
tissues exposed to amiodarone are found to have foamy macrophages with MLB thought to be formed from impaired lysosomal degradation
of glycoproteins and glycolipids in phagocytized membranes. Source: Image courtesy Teodora Pollak.
38 4. Drugs at the crossroads of heart and liver
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higher than desirable and associated adverse effects. What makes amiodarone more difficult to use safely is the
frustrating delay between a change in dosing and subsequent effects. Lack of familiarity and its exaggerated rep-
utation for toxicity often leads to unwarranted cessation of amiodarone therapy without confirmation of cause.
This is compounded by the unusual pharmacokinetics of amiodarone increasing the chances of drug overexpo-
sure. The only defense against over attribution of amiodarone toxicity is a thorough and systemic ruling out of
other causes and evaluation of the degree of exposure through concentration measurement.
Timelines for amiodarone hepatotoxicity
While the average reported latency between drug initiation and liver injury is approximately 10 months (the
typical time at which serum amiodarone concentrations reach steady state), hepatic injury has been reported as
early as a few days after starting oral amiodarone
[17] and as late as several months after withdrawal of dosing
[54]. Such isolated reports of toxicity outside the expecte d time frame are difficult to assess without knowing
serum drug concentrations and further emphasize the need to carefully rule out other causes of hepatic disease
in any patient who develops abnormal hepatic enzymes. Definitive interpretation is elusive without a pathogno-
monic indicator of causality, especial ly with the burden of disease associated with cardiac patients who require
amiodarone. In particular, physicians should keep in mind that cardiac dysfunction can alter liver chemistry and
cause “cardiac hepatopathy,” that is, hepatic congestion/ischemia occurring even in the absence of clinically evi-
dent heart failure
[3].
Reports of intravenous amiodarone causing acute hepatotoxicity after minimal exposure are also difficult to
reconcile with pharmacology. A patient receiving standard doses of amiodarone might typically have a steady
state serum concentration up to 1.5 mg/L. Given a typical volume of distribution of 10,000 L, this would mean a
total body burden in the range of 15 g of amiodarone. Although acute administration of a 300-mg bolus of intra-
venous amiodarone briefly produces a clinically effective concentration prior to distribution occurring, it would
take 50 such 300-mg doses plus replacement of any eliminated drug to expose the patient to the above typical
steady state body burden. Thus causality remains unclear when a severely ill patient is reported to develop
hepatic abnormalities following exposure to only 1/50th of the steady-state burden of drug
[55,56]. One reason-
able hypothesi s is that the polysorbate-80 and benzyl alcohol required to formulate intra venous amiodarone are
both capable of inducing hepatotoxicity
[57] and fulminant hepatitis [5860]. Another possibility is that the very
ill patient population treated with intravenous amiodarone often suffers from hepatic ischemia
[61]. In the end,
many patients suspected of acute intravenous amiodarone hepatotoxicity do not suffer recurrent toxicity when
rechallenged with oral amiodarone, that is, drug in absence of vehicle
[55]. Thus hepatic disturbances encoun-
tered with short-term intravenous therapy in a drug-naı
¨
ve patient with complex medical diseases are difficult to
attribute to the effects of amiodarone with any degree of scientific certainty
[62].
Amiodarone: a drug outside the comfort zone of mainstream therapeutics
The best-in-class efficacy of amiodarone appears to be inextricably linked to its uniquely long half-life.
However, it is this same pharmacokinetic rarity that requires the practitioner to adjust the usual time frame of
their therapeutic expectations in order to avoid toxicity. Amiodarone’s reputation for being difficult or
dangerous is acquired through user frustration with its failure to adhere to a therapeutic time frame normally
experienced by the prescriber. By moving through the body at a rate 100-fold slower than other cardiac drugs,
amiodarone generates prescriber impatience. Although amiodarone acts within the rules of pharmacokinetics,
pharmacodynamics, and toxicology, it does not conform to expectations developed from prescribing drugs that
have half-lives of ,24 hours, leaving the impression of inexplicable toxicity over an unanticipated time period.
The 55-day half-life of amiodarone ranks it among the longest found in the pharmacopeia, longer than seen for
mefloquine at 21 days, or hydroxychloroquine at 22 days, yet not equaling bedaquiline at 5.5 months
[63].
Not being dosed at each half-life, because of the impracticality of taking 55 tablets at once, it is easy to forget
that unlike familiar daily-dosed agents, half of the prev ious dose of amiodarone is not eliminated before the next
dose. With daily dosing, trough amiodarone concentrations only vary by , 2% even following a missed dose, yet
this “high frequency” dosing does not shorten the extended time required to attain steady state. Loading doses
can be somewhat compensated for the diluting effect of the large apparent volume of distribution of amiodarone.
However, despite speeding the onset of efficacy by attaining pseudo-steady-state concentrations earlier, concen-
trations still fall when loading is stopped until the peripheral compartment is sufficiently saturated to slow the
39Part 1: amiodarone
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net movement from of drug from blood to periphery. Unfortunately, loading doses can also confuse decisions
needed for long-term dosing to achieve desirable steady-state drug exposure. Failure to down titrate from load-
ing doses will eventually cause overexposure and toxicity (
Fig. 4.1B).
Because of its unusual time relationships, choosing an optimal maintenance dose of amiodarone prior to reach-
ing steady state is key to avoiding toxicity. Early decisions are best guided through clinical observations and use
of available lab tools. Final long-term dosing decisions are best verified using further observations post-steady
state and backed up with measurement of serum concentration. Simply being aware of the long period of obser-
vation needed before systemic stability is assured can improve patient safety. Patience is required to observe the
onset of drug effects and in continuing to reassess dosing well into the second year of therapy.
Amiodarone hepatotoxicity: plausible pathogenesis
Although hepatotoxicity is easily demonstrated with exposure to abnormally high amiodarone concentrations
[42], the drug is far from universally toxic in clinical use. Many drugs alter the production of the reactive oxygen
species. Although toxic, free radicals are naturally present as part of immune defenses, cell signaling, thyroxine
production, and nitric oxide vasodilation. However, metabolism of drugs can upset the natural balance between
production and inactivation that takes place inside many organelles such as the mitochondria and lysosomes.
Toxicity occurs when capacity to neutralize these free radicals is exceeded
[64,65]. Tissues that interact with ultra-
violet light (skin, cornea), oxygen (lungs), and metabolism of exogenous compounds (liver, gut) are at highest
risk.
Excess exposure to amiodarone may tip free radical homeostasis in favor of toxicity, much as seen with excess
exposure to acetaminophen
[66]. As acetaminophen concentrations exceed a safe threshold, production of its
unstable metabolite, N-acetyl-p-benzoquinone imine (NAPQI), outpaces the liver’s ability to detoxify it
[67].
Similarly, the metabolic effects of amiodarone are tolerated at low concentrations, but at high concentrations,
amiodarone increases expression of many proteins associated with oxidative stress
[68]. The amphiphilic nature
of amiodarone allows it to penetrate mitochondrial and lysosomal membranes where it associates with protons
left behind by the respiratory chain, causing it to be retained in the acidic intramembrane environment.
Interpatient variation in hepatic response to amiodarone exposure
[22] seems to reflect genetic variations in P450
CYP1A1 and 3A4 isoforms
[69], drug transporters [70], mitochondrial production of reactive oxygen species [71],
and Tumor Necrosis Factor expression
[69].
Animal models provide evidence that supratherapeutic concentrations of amiodarone: interfere with mito-
chondrial energy production and lipid homeostasis
[72,73]; disrupt the electron transport chain enzyme com-
plexes; and uncouple oxidative phosphorylation
[74]. High intramitochondrial amiodarone concentrations
inhibit beta-oxidation of free fatty acids and intracellular respiration, downregulating ATP production.
Triglyceride accumulation resulting from impairment of beta-oxidation
[75] can produce steatosis [76].Much
as seen in alcoholic liver disease, ATP depletion induces lipid peroxidation and t he generation of toxic 4-
hydroxynonenal and malondialdehyde. However, exposing rat liver cells to an analog of amiodarone devoid
of the benzofuran ring does not result in liver damage
[77], suggesting this structure participates in mito-
chondrial t oxicity
[78].
Mice receiving amiodarone 150 mg/kg (50 times the daily human dose of ,3 mg/kg) developed hepatic
microvesicular lipid accumulation and reduced plasma triglycerides, while lower magnitudes of exposure of 10,
40, and 80 mg/kg did not exhi bit these effects
[42]. Doseresponse studies examining 24-h exposure to
supratherapeutic concentrations of amiodarone and DEA from 0.1 to 100 μmol/L, demonstrated direct toxicity of
both molecules, albeit at a very high apparent LD
50
. In HepG2 cells, LD
50
for amiodarone and DEA were 43 and
9 μmol/L, and in rat hepatocytes 28 and 10 μmol/L
[42]. These results imply that DEA metabolite is more harm-
ful than the parent drug. Fortunately, both amiodarone and DEA produce successful clinical therapy at much
lower concentrations, usually in the range of 13 μmol/L, at least 10-fold below LD
50
thresholds observed in
these models (amiodarone mg/L 5 μmol/L • 0.645; DEA mg/L 5 μmol/L • 0.617).
What remains unknown is what determines the balance between hepatic injury and repair, or why so few
patients manifesting minor histological changes of “amiodarone exposure” progress to developing pathologi-
cal lesions. Most patients who develop mild toxicity (transaminitis) never progress to clinically significant
liver disease, despite continued drug exposure (
Fig. 4.3). Much of the interpatient variation in toxicity may
reflect differences in drug burden produced by varying pharmacokinetic handling of amiodarone between
patients.
40 4. Drugs at the crossroads of heart and liver
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Amiodarone hepatotoxicity: clinical picture and histological findings
Like alcohol, some patients receiving amiodarone will develop liver injury. As the dose/exposure is escalated,
the quantity of drug processed by the hepatocytes increases, and steatosis occurs
[22,79]. Given that the histology
of amiodarone-liver injury is strikingly similar to both alcoholic hepatitis
[80,81] and nonalcoholic steatohepatitis
[82], it is not surprising that pseudo-alcoholic hepatitis is reported in 1%3% of amiodarone recipients and trans-
aminase elevations are reported in up to 25% of amiodarone recipients
[43]. Almost any hepatic disorder that
might occur in a patient not receiving amiodarone has been reported to have a causal association with amiodar-
one in patients receiving the drug. Without a gold-standard diagnostic test to prove causality, there is no sure
way to know if amiodarone is the culprit, a problem compounded by the inability to estimate the frequency of
drug hepatotoxicity from collating case reports.
A comprehensive review of drug-induced liver injury (DILI) points out that any pattern of primary liver dis-
ease can be mimicked by drug injury
[83]. Although steatohepatitis, which includes steatosis, lobular inflamma-
tion, hepatocellular ballooning or pericellular fibrosis, and often Mallory hyaline, is an uncommon picture in
DILI, it is well described with alcohol, tamoxifen, and estrogens in the presence of obesity or diabetes. The other
exception is amiodarone. A microvesicular steatosis pattern is often associated with mitochondrial injury, while
alcoholic liver disease is usually associated with macrovesicular steatosis (
Fig. 4.5). Although not pathognomonic,
both alcohol and amiodarone steatohepatitis can be associated with microvesicular fat globules, Mallory hyaline
and neutrophils (
Fig. 4.6). The histological similarity to alcoholic hepatitis, including the pre sence of inflamma-
tory polymorphonuclear leukocytes, steatosis, hepatocyte balloo ning, abundant Mallory bodies, and fibrosis was
already noted in early reports of amiodarone-liver injury
[80].
Amiodarone complexed with phospholipids inhibits phospholipase-A
1
and leads to the accumulation of phos-
pholipids seen as myeloid bodies in lysosomes
[84]. Phospholipid-drug complexes form concentric whorls seen
as inclusions commonly referred to as multilamellar bodies (MLB) on electron microscopy (
Fig. 4.4) [83]. These
cause the foamy appearance often seen in macrophages collected from patients receiving amiodarone
[79,8588].
In hepatocyte cultures exposed to amiodarone, the proportion of cells that exhibit MLB rises from 2% to 100%
between the 4th and 14th day of supratherapeutic drug exposure
[89]. In whole animal experiments, cells exhibit-
ing abnormal lysosomes progressively increase over 5 weeks with exposure to amiodarone
[90]. Somani et al.
found lamellar inclusions in 100% of patients receiving amiodarone, despite normal liver chemistry and no indi-
cation of toxicity
[91]. Therefore, while it is tempting to equate the presence of lysosomal MLB to evidence of
amiodarone toxicity
[43,79,92], inclusion bodies correlate more with the degree of amiodarone exposur e than
with the presence or absence of toxicity
[93].
FIGURE 4.5 Microvesicular steatosis. Histopathology of microvesicular steatosis, with foamy hepatocytes (arrows), contrasted with
macrovesicular steatosis (upper right inset). Purple 5 hepatocyte nuclei. White areas surrounding nuclei 5 lipid droplets of steatosis. Source:
Obtained from https://commons.wikimedia.org/wiki/File:Histopathology_of_microvesicular_steatosis.jpg; Wikipedia File: Histopathology of microvesicular
steatosis.jpg; Created: 22 May 2021; Original Source: Ronen J, Shaheen S, Steinberg D, Justus KR. Acute Fatty Liver of pregnancy: a thorough examina-
tion of a harmful obstetrical syndrome and its counterparts. Cureus. 2018 Feb 6;10(2):e2164. doi: 10.7759/cureus.2164. PMID: 29644153; PMCID:
PMC5889153. Source reproduced from (Figure 2) AFLP Histology Liver disease in pregnancy The Lancet. (2017). Accessed: March 12, 2017:
http://
www.thelancet.com/cms/attachment/2019854554/2039785456/f04-05-9780128173947_lrg.jpg
. This image was used by Cureus from The Lancet (online)
with consent. “This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 3.0” You are free to: Share
copy and redistribute the material in any medium or format; Adapt remix, transform, and build upon the material or any purpose, even commercially.
41Part 1: amiodarone
I. Liver and heart
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Unfortunately, the growing prevalence of nonalcoholic fatty liver disease (NAFLD) further obscures the diag-
nosis of DILI . In Western countries, NAFLD is already the most frequent cause of abnormal liver biochemistry
and even transplantation. Progression to nonalcoholic steatohepatitis (NASH) is commonly observed in patients
with insulin resistance, hyperlipidemia, obesity, and other features of “metabolic syndrome”
[94,95]. This is the
very population of patients with frequent cardiac disease and arrhythmias
[96,97]. Because both ischemic heart
disease and NAFLD share underlying risk factors, many patients with one condition also have the other
[98].
One-third of the patients in the Dallas Heart Study had coexisting NAFLD
[94] and the antihypertensive, antihy-
perglycemic and hypolipidemic agents used to treat their underlying metabolic syndrome all potentially interact
with amiodarone
[97,99]. Because patients with undiagnosed NAFLD/NASH will increasingly be started on
amiodarone therapy for intercurrent cardiac disease
[94,95], the diagnosis of DILI will be commens urately more
challenging. Fortunately, no apparent signal has been observed to suggest that preexisting liver conditions, such
as NASH, increase the risk of idiosyncratic amiodarone hepatotoxicity.
Although anecdotal reports of cirrhosis have been published, histologic changes of cirrhosis are rarely found
in patients taking amiodarone or identified in the literature
[79]. No cases of cirrhosis were observed in two stud-
ies designed to detect amiodarone hepatic effects
[22,43].
In the end, the histology of nonalcoholic steatohepatitis, alcoholic steatohepatitis, and amio darone-liver
injury is remarkably similar. The epidemiologic features reported for metabolic, alcohol, and amiodarone-
induced hepatotoxicity are similarly broad and unhelpful at differentiating the three conditions. Only the
absence of alcohol consumption a nd exposure to amiodarone can be used to confirm the di agnosis of nonalco-
holic steatohepatitis. Of course, a patient with underlying nonalcoholic or alcoholic steatohepatitis is not pro-
tected from having cardiac disease that might lead them to be treated with amiodarone. T he picture may be
further complicated in patients with undiagnosed NAFLD/ASH who start receiving amiodarone, as the
inevitable inclusion bodies associated with amiodarone exposure may be incorrectly assumed to denote causal-
ity. Thus differentiation whether hepatic injury is related to NAFLD, ASH or amiodarone pseudo-alcoho lic
hepatitis remains a diagnostic challenge for Hepatologists, often based on the veracity of the patient’s history
of alcohol consumption.
Amiodarone hepatotoxicity: diagnosis
Patients who develop hepatic effects related to receiving amiodarone quite likely have been unknowingly
exposed to higher-than-expected concentrations of the drug. As noted earlier, TCD is meaningless if dosing has
remained below a rate that produces toxic concentrations. Given the wide variability of amiodarone absorption
in the population, the magnitude and duration of drug exposure can be most reliably assessed by measurement
of serum amiodarone concentrations. For a patient dependent upon amiodarone for successful treatment of
severe arrhythmia, a consultant needs a dependable estimate of drug exposure to render a clinically helpful opin-
ion regarding the likelihood of drug toxicity. However, access to concentration testing is required for this to be a
useful diagnostic factor. Just as with case repor ts of pulmonary toxicity, interpretation of causality in case reports
of hepatotoxicity can be unreliable when the only evidence is an association in time between a symptom and a
drug exposure of unspecified magnitude.
FIGURE 4.6 Amiodarone steatohepatitis. Hepatocyte ballooning (lower right corner), numerous Mallory-Denk hyaline bodies (lower
right), neutrophils, and minimal steatosis. Source: Liver histopathology photomicrograph and interpretation kindly provided by Dr. Stefan Urbanski,
Department of Histopathology, Alberta Precision Labs, Calgary, Alberta.
42 4. Drugs at the crossroads of heart and liver
I. Liver and heart
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While case reports might suggest that amiodarone can induce almost any hepatic pathology, ranging from
asymptomatic tran saminase elevations, to parenchymal and canalicular disease, to fulminant hepatic failure and
death
[54,56,86,100,101], case reports lack both a numerator and a reliable estimate of the denominator as the
population size from which cases are derived is not specified. In the end, a key clinical practice point is that
despite hepatic injury being widely cited as being relatively frequent, well-monitored patients treated with amio-
darone, seldom develop hepatotoxicity
[102,103].
Historically, when used as low-dose antiantianginal therapy, no signal of adverse hepatic effects was detected.
Only after routine exposure to high-dose amiodarone was introduced in the management of ventricular arrhythmias,
did reports of toxicity occur in any numbers
[39,43,86,87,104]. Even then, estimates ranging from 14% to 82% seemed
unreliable, suggesting inconsistent definitions for reporting
[23,32,105110]. In 1989 Lewis et al. [43] found asymp-
tomatic elevation of serum transaminases in 23% of 1036 patients pooled from 11 case series [23,32,105110].Other
studies found varying rates of toxicity depending on its definition. A threshold set as transaminases rising .2x base-
line found a 24% rate of hepatotoxicity
[43], while using transaminases .2 3 ULN identified a 17% rate [111],and
using the Food and Drug Administration threshold of transaminases .3 3 ULN, the rate fell to 7% [22].
Furthermore, measurement of transaminitis can be confounded by obesity, alcohol intake, and multiple medications
for cardiac disease, all common in this population. More recently, reporting isolated transaminase elevation as drug
toxicity has been called into question, as values often exceed ULN in healthy patients not receiving any medications
[112]. Therefore most elevations of transaminases to # 3 times ULN, which are asymptomatic, usually normalize
when amiodarone administration rate is reduced
[44]. As predicted by pharmacology, even adverse biochemical
effects associated with symptoms will reverse within weeks of lowering or withdrawing dosing to reduce drug expo-
sure (
Fig. 4.3).
Nonetheless, questions regarding the advisability of prescribing amiodarone to patients with transaminases
above ULN at baseline frequently arise in clinical medicine. Increased baseline ALT was not found to correlate
with risk of amiodarone damage in a population studied for risk of cirrhosis
[113,114]. Although there are no
guidelines for initiating amiodarone in the presence of preexisting liver disease, the risk appears no greater than
with normal liver function
[36,113,114]. Thus where the potential benefit of amiodarone is deemed to be large,
this medication can be successfully initiated without promoting progression in existing hepatic disease.
Unfortunately, patients found to have had abnormalities in hepatic chemistry before or after initiation of amio-
darone commonly have therapy discontinued
[115].
In a patient developing hepatic abnormalities with limited exposure to amiodarone, prompt resolution within
23 days of dose discontinuation would argue against attribution of causality to amiodarone as the temporal
association is not consistent with the pharmacokinetics of the drug
[43]. Cholestasis related to amiodarone would
also be very unusual. In fact, the parameter most closely associated with cholestasis in patients receiving amio-
darone is age .62 y, suggesting this is a manifestation of the overlap between the age of the popu lation at risk
for atrial fibrillation and those with higher risk of cholestasis
[54].
Like pulmonary toxicity, much of amiodarone’s reputation for drug-induced hepatotoxicity appears to have
originated from case reports. Given that pharmacologic principles would suggest that for any drug, higher rates
of toxicity are associated with exposure to unusually high concentrations
[22], it is regrettable that most accounts
do not report a serum amiodarone concentration. Contrasting with the picture created by case reports, a meta-
analysis of placebo-controlled trials by Ruzieh et al. in 2019
[53] showed only a modest increase in hepatotoxicity
from a baseline rate of 0.25% per patient-year in the placebo group up to 0.52% per patient-year in the active
treatment group, 100 times below some estimates in the literature.
Guidance from comprehensive reviews of amiodarone hepatotoxicity remains quite limited. As of January 31,
2021, a search of PubMed/Medline for the MESH Term “amiodarone” yields 4851 publications without the off
topic “dronedarone” in the title. Intersection with the MESH Terms “hepatotoxicity” OR “hepatic toxicity” OR
“liver toxicity” OR “liver disease” yields only 111 citations. Of these, only three analyzed prospective patient
data
[22,43,116] and only one was a comprehensive focused review of the English language literature [4].
How toxic is amiodarone to the liver?
How a clinician approaches assessment of possible toxicity is highly influenced by perception of risk. Reliable
estimation of amiodarone hepatotoxicity risk is somewhat difficult because most early prospective randomized-
controlled trials (RCT) were designed to evaluate efficacy, not to estimate risk
[103]. Attempts to identify para-
meters indicating amiodarone toxicity have come up short, including increased liver density on radiographic
imaging (simple iodine accumulation)
[117,118] and presence of MLB inclusions in tissues from patients being
43Part 1: amiodarone
I. Liver and heart
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