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(CL

int

), which is a function of the activity of hepatic drug-metabolizing enzymes and transporters. These three

parameters may be significantly altered in patients with CHF.

Hepatic blood flow, hepatic intrinsic clearance

The liver receives approximately 25% of cardiac output, that is 1500 mL/min in a healthy 70 kg adult, via

two inflows: the portal vein and the hepatic artery

[46]. The portal vein, which drains the blood from the capil-

lary system of the intestine, spleen, pancreas, omentum, and gallbladder, contributes approximately 75%80%

to the liver’s blood supply. The remaining 20%25% of the liver’s blood supply is delivered by the hepatic

artery. H epatic blood flow is reduced in severe CHF

[47]. In addition, changes in liver hemodynamics due to

moderate and severe right-sided heart failure can result in congestive hepatopathy. Chronic hepatic congestion

leads to decreased hepatic oxygenation, atrophy of hepatocytes, distention of sinusoids, and centrizonal fibro-

sis, which can progress to cirrhosis

[12]. Consequently, besides the reduced drug delivery to the liver due to

impaired liver blood flow, hepatic co ngestion may cause hepatocellular damage with decreased activity of

drug-metabolizing enzymes

[4851]. In additi on, patients with heart failure have high circulating levels of the

proinflammatory cytokines tumor necrosis factor-α (TNF-α)andinterleukin-6(IL-6)

[52,53].BothTNF-α and

IL-6 are well known to negatively regulate cytochrome P450 (CYP) enzyme activity

[48,51,54].Fryeetal.

showed that by using the CYP cocktail approach, i n 16 patients with heart failure, plasma levels of TNF- α and

IL-6 were inversely related to CYP2C19 and CYP1A2 activity

[48]. The activities of CYP2D6 and CYP2E1 did

notshowasignificantcorrelationwithTNF-α and IL-6 plasma levels. The results of this study indicate that

CYP-mediated drug metabolism may be differentially impaired in patients with heart failure. In addition,

congestive hepatopathy is associated with cholestasis, which would interfere with the biliary excretion of drugs

and/or drug metabolites

[55,56].

Plasma protein binding

Hypoalbuminemia is a common condition in patients with heart failure

[12]. It is most often related to malnu-

trition, liver dysfunction, and protein-losing enteropathy, a condition characterized by gastrointestinal loss

of proteins

[57]. Patients with CHF have elevated plasma concentrations of cytokines indicating the presence of

inflammatory processes

[58]. As a result, patients with CHF have been shown to have elevated plasma levels of

-acid glycoprotein, an acute-phase protein, to which many weak basic drugs are reversibly bound [33,59].

Changes in the binding of drugs in plasma or blood can affect the blood (plasma) clearance and may also lead to

changes in the drug’s volume of distribution

[60,61].

Loop diuretics, the mainstay of diuretic therapy in patients with heart failure, act by blocking the luminal

NaK2Cl transporter in the ascending limb of the loop of Henle

[14]. Furosemide, bumetamide, and torse-

mide are tightly bound to albumin and their binding in plasma is 95%99% and, as a result, their glomerular

filtration is very low

[62]. They reach their intraluminal site of action by active tubular secretion mediated by

organic anion transporters, which “strip” these diuretics from the plasma albu min to transport them across the

tubular cells

[14]. The volume of distribution of the loop diuretics is low but will be substantially increased in

patients with severe hypoalbuminemia. It has, therefore been suggested that the diuretic effectiveness of loop

diuretics may be impaired in severe hypoalbuminemia owing to decreased delivery to the kidney, and that

albumin coadministration might overcome diuretic resistance in hypoalbuminemic patients

[63]. However, a

meta-analysis of clinical studies investigating the effect of coadministratio n of furosemide and albumin as a

strategy to overcome diuretic resistance in patients with hypoalbuminemia (nephrotic syndrome, cirrhosis with

ascites, chronic kidney disease), concluded that there is no justification for albumin coadministration to overcome

diuretic resistance in hypoalbuminemic patients

[64]. A recent study in heart patients with or without hypoalbumi-

nemia and treated with bumetanide and torsemide showed that plasma albumin levels do not meaningfully influ-

ence diuretic response

[65].

Intravenous administration of high hepatic extraction ratio drugs

For drugs, mainly eliminated by the liver, and having a high extraction ratio (E

. 0.7), the systemic clear-

ance following intravenous administration will be approximated by hepatic blood flow (see

Table 3.2) [16,66]. For

example, the intravenous clearance of lidocaine, a drug with a high hepatic extraction ratio, is reduced in

advanced CHF and this reduction correlates with cardiac output

[67]. On the contrary, the intravenous clearance

of felodipine, a calcium channel antagonist, which is mostly eliminated by hepatic metabolism and has a high

24 3. Pathophysiologic changes in chronic heart failure affecting drug pharmacokinetics

I. Liver and heart

https://t.me/medicina_free

hepatic extraction ratio, was not significantly altered in patients with chronic congestive heart failure (NYHA III)

and no significant correlation was found between felodipine’s clearance and cardiac output

[68,69]. These con-

trasting results for two drugs having a high hepatic extraction ratio may have been due to differences in the clini-

cal characteristics of the CHF patients who participated in these studies. Based on a comprehensive review of the

existing literature, Ogawa et al. concluded that the pharmacokinetics of many intravenously administered drugs

do not seem to be significantly altered, especially in patients with asymptomatic or compensated CHF with no

concurrent hepatic dysfunction

[66].

Oral administration

Following oral administration of drugs that are mainly eliminated by the liver, first of all, the effect of CHF on

bioavailability should be considered. The oral bioavailability is determined by the intestinal permeability (F

), the

gut wall, and hepatic first-pass effects. As pointed out above, little information is available on the effect of CHF

on the intestinal permeability of drugs. The same is true for the effect of CHF on gut wall metabolism. Although

theoretically, the changes occurring in the gastrointestinal tract in CHF may affect the metabolic activity of the

gut wall, no studies are available to support this hypothesis. On the contrary, several studies have shown a

reduction in the activity of hepatic drug-metabolizing enzymes in patients with CHF

[4851]. This decrease in

hepatic intrinsic clearance can lead to a significant increase in the fraction of the orally administered drug escap-

ing hepatic first-pass effect that is F

[see Eq. (3.5)], leading to a significant increase in the patient’s systemic

exposure to the drug. For example, the oral bioavailability of felodipine is low that is 15%, due to extensive

hepatic and, to a lesser extent, gut wall presystemic metabolism

[30,68,70,71]. The oral bioavailability of felodi-

pine in 11 patients with CHF (NYHA III; mean age: 62 years) after 8 weeks of oral therapy was 29% (range 12%

74%) and significantly correlated with cardiac output

[69]. The mean oral bioavailability of felodipine in these

CHF patients (i.e., 29%) was not only approximately twice as high as in healthy controls (i.e., 15%), but also

showed a very high (sixfold) interpatient variability. The oral pharmacokinetic parameters of felodipine in these

11 patients with CHF were similar to those reported for elderly patients with hypertension (mean age: 74 years)

[69]. In patients with CHF and concurrent hepatic cirrhosis, the hepatic and intestinal first-pass effects may be

substantially decreased resulting in a several-fold increase in oral bioavailability of drugs such as carvedilol,

nisoldipine, and midazolam

[72].

For drugs that are mostly eliminated by hepatic mechanisms but having a low hepatic extraction ratio, the

first-pass effect is small or even negligible, and systemic exposure (AUC) following oral administration is mostly

determined by fu

3 CL

int

. Both these parameters, that is the fraction unbound in blood and the hepatic intrinsic

clearance may be affected by CHF. To correctly assess the effect of changes in plasma protein binding on drug

pharmacokinetics, drugs are best classified as having a low (,90%) or high ($90%) binding

[73]. For drugs with

high binding, a relatively small change in the percentage of drug bound will have a large effect on fu

, the

parameter driving the drug’s blood (plasma) clearance following oral administration (see

Table 3.2).

Tolbutamide, a drug with a low hepatic extraction ratio, is highly bound to plasma proteins (approximately

95%), mainly albumin

[74]. In five patients with acute viral hepatitis, the unbound fraction of tolbutamide in

plasma was shown to be on average 0.087 and slightly, but significantly, decreased to 0.068 after the patients had

recovered

[75]. The decreased binding during the acute phase of the disease was at least partly due to the

increased plasma levels of bilirubin. Bilirubin is highly bound to albumin and is known to compete with numer-

ous drugs for the same binding site on albumin

[76]. This moderate increase (128%) in fu during the acute phase

of the disease resulted in a significant increase in the plasma clearance of tolbutamide: 26 mL/h/kg during the

acute phase versus 18 mL/h/kg after recovery. The increased plasma clearance of tolbutamide would lead to

lower total steady-state plasma concentrations of tolbutamide during the acute phase of the disease [see

Eq. (3.2)]. The unbound concentrations of tolbutamide in plasma, however, do not change because of the

increased fraction of drug unbound in plasma. Because pharmacologic effect is more directly related to unbound

rather than total plasma concentrations, the increase in unbound fraction of tolbutamide during the acute phase

of the disease has no clinical consequences. Since hyperbilirubinemia is common in patients with CHF, a

decreased binding of weak acid drugs, which like bilirubin have a high binding affin ity for albumin, can be

expected in CHF

[6,8].

As discussed above, in congestive hepatopathy the activity of hepatic drug-metabolizing enzymes may be

impaired. Hence, in these patients, it is possible that an increase in the unbound drug fraction in plasma, due to

hyperbilirubinemia, may coexist with a decrease in the hepatic intrinsic clearance of the drug, thus keeping the

25Pathophysiological changes affecting pharmacokinetics in patients with chronic heart failure

I. Liver and heart

https://t.me/medicina_free

plasma clearance of the drug, that is fu 3 CL

int

, relatively constant. Consequently, total plasma concentrations

may be unaffected but the unbound, pharmacologically active, plasma concentrations will increase:

u;ss

5 fu 3 C

p;ss

5 fu 3

F 3 D

τ 3 fu 3 CL

int

ð3:15Þ

where C

u,ss

is the steady-state plasma concentration of unbound drug, and fu is the unbound fraction of drug in

plasma. This particular situation has been described for naproxen in patients with hepatic cirrhosis in whom the

total plasma concentrations of naproxen are not affected but the unbound, active, naproxen plasma concentra-

tions may be twofold to threefold higher than in patients with normal hepatic function

[72,77]. Needless to say

that in such a situation unbound plasma concentrations have to be measured for a correct interpretation of the

changes found in the pharmacokinetic parameters.

Basic drugs often bind with high affinity to α

-acid glycoprotein, a plasma protein whose concentrations are

increased in disease states associated with inflammation like CHF. As a result, the fraction unbound drug in

plasma may be decreased in heart failure patients with elevated α

-acid glycoprotein plasma levels, which may

lead to a dec rease in the drug’s distribution volume and plasma clearance

[78,79].

Renal clearance

Although in general the majority of drugs are eliminated by the liver, a number of drugs used to treat congestive

heart failure are eliminated to a relatively large extent in unchanged form by the kidneys, for example, lisinopril,

enalaprilat (the active metabolite of enalapril), candesartan (the active metabolite of candesartan cilexetil), digoxin,

furosemide, and others

[66]. Even though renal blood flow is relatively well maintained in the early stages of the

disease, approximately half the patients with congestive heart failure have chronic kidney disease defined as a cre-

atinine clearance (CL

) of less than 60 mL/min [8082]. Bumetanide is a loop diuretic with the following pharma-

cokinetics characteristics: F

oral

: . 80%, fe: 0.65, fu: D 0.01, CL: 2.6 mL/min/kg [83].Cooketal.studiedthe

pharmacokinetics of bumetanide in healthy controls (CL

: 118 mL/min) and in patients with congestive heart fail-

ure (NYHA III or IV; CL

:45mL/min)[84]. Following oral administration, only the renal clearance of bumetanide

was significantly lower in patients with CHF (1.03 mL/min/kg) compared with healthy controls (1.83 mL/min/kg).

All the other pharmacokinetics parameters that are oral bioavailability, fraction unbound in plasma, and half-life

were not significantly different in patients with CHF. The reduction in renal clearance is predictable based on

the decreased kidney function in the patients with CHF. It is clear that for drugs used in CHF and which are pre-

dominantly eliminated in unchanged form by the kidneys that are fe . 0.5, CL

or GFR is a good predictor of the

risk of excessive systemic accumulation of the drug. This principle is applied to predict the plasma clearance of

digoxin, a drug whose fraction excreted unchanged in urine is 0.65, in a patient with CHF:

digoxin

5 0:33 ml=min=kg 3 TBW 1 0:9CL

where CL

digoxin

is the plasma clearance of digoxin, and TBW is total body weight [85].

Volume of distribution

The volume of distribution depends on the phy sicochemical characteristics of the drug, reversible binding to

plasma proteins and tissue macromolecules, blood flow to and diffusion/partitioning into organs and tissues.

Pathophysiological changes in CHF may lead to increased, decreased, or unaltered volume of distribution of

drugs

[86]. For example, in patients with congestive heart failure, the volume of distribution of lidocaine was

shown to be reduced by one-third compared to healthy controls: 1.32 L/kg versus 0.88 L/kg

[67]. Lidocai ne is a

weak base with a large volume of distribution. The decrease in volume of distribution of a drug like lidocaine in

patients with CHF could be explained by the reduced perfusion of tissues and/or altered partitioning of lido-

caine between blood and tissue macromolecules.

One of the most common signs of congestive heart failure is peripheral edema

[87]. Studies in untreated symp-

tomatic heart failure patients demonstrated that the volumes of both the interstitial and intravascular compart-

ments are 33%35% ab ove normal volumes

[88]. This means that drugs whose distribution volume is mostly

restricted to the extracellular space that is having a V , 20 L may have a significantly larger volume of distribu-

tion in patients with CHF. For example, the results of several studies on the pharmacokinetics of theophylline

have shown that the volume of distribution is significantly decreased (on average approximately 50%) in patients

26 3. Pathophysiologic changes in chronic heart failure affecting drug pharmacokinetics

I. Liver and heart

https://t.me/medicina_free

with heart failure [8994]. Unlike lidocaine, theophylline has a much smaller volume of distribution (0.5 L/kg)

and as a result of peripheral edema , concentrations of theophylline in plasma are lower and its volume of distri-

bution is larger in patients with heart failure. Significant changes in the volume of distribution in patients with

CHF will have to be taken into account in case a loading dose has to be administered to rapidly achieve thera -

peutic blood (plasma) concentrations of the drug.

Pharmacotherapeutic implications: general recommendations

The pharmacotherapeutic management of CHF, a common disease sta te predominantly affecting the older

population, is particularly challenging because of the large interpatient variability in the severity of the syn-

drome, the dynamic nature of the condition, and the presence of various comorbidities. During the last decade,

several review articles have summarized the existing information regarding the effect of heart failure on the

pharmacokinetics of both cardiac and noncardiac therapeutic agents

[36,66,86,95,96]. The following important

comments/recommendations and perspectives for future research can be made:

1. When studying the effect of CHF on drug pharmacokinetics it is very important to provide all relevant

information regarding the participating study subjects, which may have an impact on the results: NHYA

functional class, age, frailty, sex, concomitant medications (potential drug-drug interactions), indicators of

renal and hepatic function, and phenotype/genotype of the drug’s relevant metabolizing enzymes and/or

transporters.

2. Even though pathophysiological changes occurring in patients with CHF could potentially affect the

absorption, distribution, and elimination of drugs, it seems that for most drugs studied the effect is rather

limited in patients with NYHA class II and III heart failure except when the patient has concurrent

compromised renal or hepatic dysfunction. Obviously for drugs with a narrow therapeutic window even

relatively small changes in pharmacokinetics may have significant therapeutic implications.

3. Although relatively few studies have been conducted to investigate the effects of chronic and advanced heart

failure on the pharmacokinetics of orally administered drugs, significant pharmacokinetic changes have been

documented for some drugs in patients with NYHA class IV heart failure. However, extensive interpatient

and intrapatient variability may preclude extrapolating the results to individual patients, thus necessitating

careful monitoring on an individual basis.

4. Drugs whose elimination is mostly via renal excretion in unchanged form (fe $ 0.5) will accumulate in a

rather predictable way in CHF patients with reduced kidney function. Dosage adjustment should be

implemented based on the patient’s estimated CL

or GFR [97].

5. The pharmacokinetics of drugs that are mostly eliminated by the liver (metabolism, biliary excretion) is

less well predictable mainly because a simple functional parameter to assess the capacity of the liver to

eliminate drugs, like CL

or GFR to estimate kidney function, does not exist. The current dosing

recommendations in patients with liver dysfunction are mostly based on the ChildPugh classification.

However, this three-class score has a very low resolution to estimate the degree of liver dysfunction in a

specific patient

[72]. A more objective, quantitative, and precise estimator of hepatic dysfunction for

dosing adjustment purposes should be developed

[98].

6. When studying the pharmacokinetics of a drug with a high plasma protein binding, that is $ 90% bound, in

patients with CHF, the unbound fraction should always be measured to correctly interpret the effect of the

syndrome on the drug’s pharmacokinetics. In that case, the focus should be on to what extent the plasma

concentrations of the unbound drug that is the pharmacologically active concentrations are affected by CHF.

7. Pharmaceutical regulatory authorities like the United States Food and Drug Administration (USFDA) and

the European Medicines Agency (EMA) recommend/require the pharmacokinetics for new investigational

drugs to be studied in special patient populations like those with kidney or hepatic dysfunction, elderly,

and sometimes pediatric patients. Heart failure is a major and growing health concern and its prevalence is

expected to rise dramatically because of the aging population and improvements in treatment. Especially in

patients with advanced CHF substantial changes in pharmacokinetics are expected. Therefore we would like

to recommend to investigate the pharmacokinetics (and pharmacodynamics) of investigational new drugs

during the drug development in patients with CHF, especially those drug candidates that are intended to be

used to treat heart failure, so that rational prescription guidelines have been established at the time the drug

will be marketed.

27Pharmacotherapeutic implications: general recommendations

I. Liver and heart

https://t.me/medicina_free

Conclusion

Congestive heart failure is a complex clinical syndrome interfering with the normal functioning of organs that

play an important role in the absorption, distribution, and elimination of drugs. A critical review of pharmacoki-

netic studies carried out in this complex patient population shows many gaps in the current knowledge. More

research is needed to better understand and predict the pharmacokinetics of drugs in patients with CHF in order

to provide robust, evidence-based recommendations for dosage adjustment in this complex patient population.

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30 3. Pathophysiologic changes in chronic heart failure affecting drug pharmacokinetics

I. Liver and heart

https://t.me/medicina_free

CHAPTER

Drugs at the crossroads of heart and liver

P. Timothy Pollak

and Juan Gonzalez Abraldes

Department of Medicine and Cardiac Sciences, Amiodarone Monitoring Clinic, University of Calgary, Calgary, AB,

Canada

Liver Unit, Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada

Introduction

Therapeutics is a vital component of all branches of medicine. Its practice is based on pharmacology, a relatively

young science developed from concepts first proposed only in the 20th century. A brief review of the clinical impli-

cations of pharmacologic science is an excellent beginning for any discussion of drugs and disease.

Modern therapeutics is based on the construct that stimulus of receptors is the basis for the effect of drugs, a

concept not proven experimentally until 1937

[1]. Ideally, truly personalized medicine would produce optimal

receptor stimulation achieved by individualized dose adjustment. Receptor stimulation is proportional to incidence

of occupation by drugs, the sum of dynamic interactions in which each molecule stimulates a micro-response from

its target receptor and then moves on. The strength of the total response is dependent on the frequency at which

further molecular interactions take place. This in turn is a probabilistic function of: drug concentration; concentra-

tion of other molecules competing for occupation of the receptor sites; and the number of receptors available. Our

understanding of how to achieve the optimum drug concentration at the therapeutic receptor site has expanded

rapidly over the last 80 years, but is often overlooked in therapeutic decisions. Differences between patients man-

date a spectrum of dose adjustment. Thus one cannot know the “right” dose of a drug, as it is merely a flexible tool

by which to achieve an effective concentration when personally adjusted for each patient to avoid poor outcomes

in the inevitable outliers

[2].

Both liver and heart are therapeutic targets for drugs. However, both also play central roles in the presentation

of drugs to the tissues where they exert their effects. Once absorbed from the GI tract, orally administered medi-

cations pass through the portal system and the liver parenchyma, prior to bein g diluted into the systemic circula-

tion through the hepatic vein. This means the hepatic parenchyma is not only the first tissue exposed to

incoming foreign molecules, but is also the tissue exposed to their highest concentrations. Thus, in addition to

being a major determinant of initial xenobiotic concentrations seen in the body, the liver parenchyma is some-

what of a “Canary in the Coal Mine,” as the tissue most likely to exhibit adverse effects to exogenous com-

pounds. The heart is equally important to drug absorption, a process dependent on the heart’s capacity to pump

blood efficiently to the intestinal mucosa, circulate absorbed substances to effect sites, and return the molecules

back to the liver for further metabolic proce ssing. Furthermore, hepatic function is dependent on the heart’s abil-

ity to decompress the portal circulation

[3]. Thus the liver and heart work in concert determining both the magni-

tude and the time frame over wh ich pharmacologic targets are exposed to drugs.

The interplay of medication in the cardio-hepatic realm is vast. However, this chapter will focus on two medica-

tions that share a special place at the boundary between Cardiology and Hepatology. To provide a comprehensive

discussion of two clinically representative examples of this interplay, the chapter is divided into two parts: Part (1)

amiodarone, an antiarrhythmic agent widely used in Cardiology, yet having a reputation for hepatotoxicity that

makes it a frequent subject of consultations to Hepatology

[4]; and Part (2) adrenergic beta-receptor-blocking agents

(beta-blockers), a class of drugs widely used in Cardiology to protect the cardiovascular system from over stimulus

by the sympathetic nervous system, but also a proven tool in Hepatology for modulating portal blood flow and

Cardio-Hepatology.

DOI:

https://t.me/medicina_free

pressure [5]. Consequently, beta-blockers not only improve hemodynamics in advanced hepatic failure but can also

affect hepatic metabolic processing of other medications.

Part 1: amiodarone

Amiodarone plays little role in the treatment of hepatology patients, other than occasional use in management

of hepatic leishmaniasis

[6]. Of course, amiodarone can indirectly improve hepatic function by suppressing

hemodynamically significant arrhythmias that can exacerbate the negative effect of cardiac failure on organ per-

fusion

[7]. However, what inevitably brings amiodarone to the attention of Hepatology is its widespread reputa-

tion for causing adverse liver effects, coupled with its broad use in Cardiology

[8].

One might reasonably ask why such a “dangerous” drug has not simply been discontinued. The abbreviated

answer is twofold. First, as the most effective rhythm control medication available, amiodarone currently has no

clinical equivalent. Second, in clinical practice, amiodarone does not measure up its reputation for toxicity

[9,10].

In a monitored clinical setting, most patients have few adverse effects. However, in an under monitored patient,

inadvertently overexposed to amiodarone, the observed toxicity can be spectacular fodder for case reports

[11].

Some knowledge of the history of amiodarone is useful to place its reputation in context, and familiarity with its

pharmacokinetic quirks helps appreciate how best to approach suspected amiodarone hepatotoxicity

[12].Inaddi-

tion, clinicians assessing a patient receiving amiodarone should keep in mind that inhibition of P450 isozymes and

drug transporters causes amiodarone to have a major influence on the hepatic elimination of other medications.

Historical perspective

Following its clinical introduction as an antianginal agent in the 1960s, amiodarone enjoyed a benign reputa-

tion for over a decade. Its name is derived from the traditional remedy Ammi visnaga, the source of the khellin

moiety to which iodine was added to improve its antianginal activity

[13]. Its iodine moieties also slowed hepatic

elimination drug, similar to the effect of fluorine

[14]. Only after patients receiving amiodarone were observed to

experience fewer arrhythmias

[15], was it formally investigated as an antiarrhythmic agent [16].

In 1969 a review of its effects on hepatic indices in patients taking amiodarone for angina raised no concerns

of toxicity

[17] and through the 1970s, its efficacy as a safe antiarrhythmic became regarded as almost ideal

[18,19]. However, as amiodarone was introduced to North America, its slow onset of effect ran contrary to clini-

cal urgency to control life-threatening ventricular arrhythmias. To address this, loading rates in the order of 400-

mg QID became common. Consequently, neurological and gastrointestinal effects came to the forefront, and

many patients experienced a wide array of adverse effects associated with the high concentrations produced dur-

ing aggressive loading (

Fig. 4.1). Prior to its long half-life being documented, the awkward lag between dosing

changes and observable effects made attempts to avoid toxicity by dose titration a source of frustration.

Amiodarone quickly gained a bad reputation for toxicity through hundreds of case reports without documented

drug concentrations. Only when chromatographic analysis was adapted to measuring serum amiodarone concen-

trations, was the impact of its extraordinarily long half-life fully recognized

[20,21]. Of note, older publications

reported concentrations in weight-based units (mg/L), while newer ones report them as number of molecules

per volume (μmol/L). Magnitudes of weight based units are smaller such that amiodarone concentration in

mg/L 5 0.645 • μmol/L and desethylamiodarone (DEA) in mg/L 5 0.617 • μmol/L.

In the 1980s, rapid development of newer, more easily dosed antiarrhythmic agents caused amiodarone to lose

prominence. However, with the publication of the Cardiac Arrhythmia Suppression Trial (CAST) at the end of

the decade, the mortality implications of using sodium-channel blocking agents in ischemic patients became clear

[24] and amiodarone, with its low propensity for pro-arrhythmia in ischemia, found new favor [25,26]. Efforts to

find equally efficacious alternate therapies failed, particularly disappointing examples being the pro arrhythmic

effects of sotalol and the failure of dronedarone to match the efficacy of amiodarone, despite having been specifi-

cally patterned after the amiodarone molecule

[2729].

Why amiodarone has not been replaced

Development of dronedarone held out great hope as a replacement for amiodarone, being designed as an amio-

darone variant maintaining its broad mechanism of action, while being safer and having a much shorter onset of

32 4. Drugs at the crossroads of heart and liver

I. Liver and heart

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effect. Eliminating iodine from the structure did avoid untoward thyroid effects and shortened its elimination half-

life. Unfortunately, the unanticipated penalty for this modification was a sharp decline in clinical efficacy compared

to amiodarone. Although the months-long delay to full onset and offset of steady-state effects after each amiodar-

one dosing change is frustrating, requiring initial aggressive loading protocols, its slow elimination also restricts the

daily fluctuation in serum concentrations to ,2%. This steady concentration exposure contributes to round-the-

clock consistency of drug effect, making amiodarone generally twice as effective as other agents. In comparison,

most other antiarrhythmic agents have a .50% fluctuation in serum concentrations between doses, associated with

much-reduced efficacy. Dealing with the complexity of the much longer half-life of amiodarone requires dose-

management strategies based on an understanding of its pharmacokinetics and where possible assisted by

Therapeutic Drug Monitoring (TDM) using measurement of serum drug concentration.

While Cardiology might hope for an amiodarone replacement, the current pharmaceutical landscape provides

limited prospects for the arrival of better antiarrhythmic agents. Development costs are high and the market size

small and further shrunk by availability of implantable defibrillating devices and arrhythmia ablation proce-

dures. The financial losses associated with dronedarone may well have ended the future of antiarrhythmic devel-

opment. Even if a better agent already existed in the pipeline, the protracted drug development timeline means

that amiodarone would continue to occupy its essential role for at least the next decade

[30,31]. The bottom line

for Hepatology and Cardiology is that consultation regarding potential amiodarone hepatotoxicity will continue

for the foreseeable future.

FIGURE 4.1 Pharmacokinetics of amiodarone, time course of typical serum drug concentration accumulation, and variability in the

patient population during dosing and elimination. Amiodarone demonstrates a pattern of slow accumulation in a large Volume of

Distribution (Vd) made up of two compartments. Measurement of drug concentrations is most practical in blood sampled from the central

(vascular) compartment. The distribution half-life for movement between the small central and the much larger peripheral compartment is

only 17 h. However, the typical half-life of elimination from the body is about 80 times longer, at 1320 h (55 days). This means that prior to 10

months of dosing (five elimination half-lives), when steady state is attained, many grams of amiodarone have been sequestered in the periph-

eral compartment before saturation. In chronic atrial fibrillation therapy, serum concentrations ideally remain within the target range associ-

ated with effective therapy (Yellow Band on the plots). The upper limit of the Yellow Band denotes the threshold below which elevations of

ALT are seldom observed

[22]. The Horizontal Red Line denotes the threshold generally accepted to be associated with high frequency of clin-

ically important toxicity

[23]. (A) Serum amiodarone accumulation over 1 year, demonstrating the concentration relationship between fixed

doses ranging from 100 to 1200 mg/d. Without loading doses, a patient with typical pharmacokinetics receiving 200 mg/d will attain efficacy

(Yellow Band) at 90 days. A patient receiving 200 mg/d, who has half the typical fractional drug absorption, will follow the same concentra-

tion curve as a typical patient receiving 100 mg/d and would not achieve the target concentration without a higher dose. Conversely, a patient

with twice the typical fractional drug absorption would achieve concentrations higher than the target zone, making them more susceptible to

hepatic effects unless their maintenance dose is reduced. Dashed Blue Line depicts concentration decrement after discontinuation of dosing.

(B) Modeled amiodarone concentrations over 18 months as produced by oral loading regimens and fixed maintenance doses and followed for

12 months after dosing is ceased. Red curve demonstrates maximally aggressive loading strategy recommended for rapid control of life-

threatening ventricular tachycardia in the 1980s product monograph. This was 1600 mg/d for 21 days, followed by 800 mg/d for 28 days, fol-

lowed by a maintenance dose of 600 mg/d. Given that 50% of the population will achieve steady-state concentrations higher than the typical

patient, many patients would clearly be above the threshold for toxicity. Blue curve illustrates a more moderate contemporary loading strategy

of 800 mg/d for 7 days, moving to 400 mg/d for 28 days, followed by a high maintenance of 400 mg/d. Green curve illustrates the same load-

ing dose, followed by the commonly used 200 mg/d maintenance dose. Gray lines demonstrate the wide inter-individual variation on the

same dosing regimen found in 77 patients using mixed-effects population modeling

[2].

33Part 1: amiodarone

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