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investigated for toxicity [87,91,119]. Both these finding fail to differentiate between mere exposure to amiodarone
in patients who remain well and actual toxicity.
For decades, unbl inded observational series, lacking control groups and case reports have largely been the
source of estimates of hepatotoxicity
[20,32]. Although published guidance quotes broad, high ranges for the inci-
dence of hepatotoxicity ranging from 5% to 25%
[23,32,105110], when reliable data are examined systematically,
the incidence is found to be much lower. This is clear from Ruzieh et al.’s. examination of prospective placebo-
controlled RCT involving 5792 patients receiving amiodarone versus 5603 given placebos. This meta-analysis
found only a twofold difference in hepatic complications between those receiving amiodarone compared to those
receiving placebo (54 vs 25; RR 2.27, P 5 0.01). Thus, while clearly real, the risk of hepatotoxicity more likely
,1% per year of patient exposure to amiodarone
[53]. Because the increase in drug exposure stabilizes in the sec-
ond year, it is reasonable to expect that those who have not exceeded their threshold for toxicity by 2 years do
not face an ever-increasing risk of toxicity implied by an often-cited relationship to TCD.
Amiodarone: effects on hepatic metabolism and other drugs
Since orally administered drugs are absorbed via the portal system and pass through the liver, their ability to
produce effective concentrations is largely determined by the liver. Membrane transport proteins and the cyto-
chrome P450 (CYP) enzyme families both play major roles in drug metabolism and pharmacokinetics. The
amount of drug reaching the systemic circulation depends on speed of absorption (determined by transport pro-
teins and blood flow) and rapidity of first-pass metabolism in the intestinal and hepatic vessel walls (determined
by cytochrome enzymes and blood flow). Drugs that compete for transport or metabolic capacity inhibit the pro-
cessing of other drugs. Since amiodarone and DEA are persistent molecules inhibiting both P-glycoprotein (ATP-
binding cassette subfamily B member 1 or ABCB1) and the CYP enzymes, amiodarone is a frequent participant
in drugdrug interactions, even at normal therapeutic concentrations. Removal of an ethyl group from amiodar-
one by CYP3A4 and CYP2C8 enzymes in the liver and intestines
[120], produces its active metabolite, DEA.
Induction of metabolic enzyme activity has not be observed with amiodarone in clinical use
[121].
At least 638 drugs are known to interact with amiodarone. However, most interactions are not clinically
important. Both the magnitude of interaction and the time frame over which it occurs must be considered in
deciding if corrective action is required. A pharmacokinetic interaction that changes drug concentrations by
,20%, or lasts for only a short period, should not have a clinically important effect. For example, if amiodarone
caused the concentration of an antibiotic with safety margin to triple, that antibiotic would be no less effective
and yet remain safe. More concerning would be amiodarone causing a 50% reduction in the elimination of a
drug with a 12-hour half-life and a low therapeutic index. Within 60 hours (5 half-lives), the concentrations of the
affected drug would double. The likelihood of a drug causing clinically important changes in amiodarone con-
centration is much lower. A drug causing a 50% inhibition of amiodarone elimination would have to be coadmi-
nistered for 6 to 10 months (35 half-lives) for doubling of amiodarone concentration to occur. This gives an
observant clinician plenty of time to recognize and correct the interaction.
Tables 4.1 and 4.2 list important pharmacokinetic and pharmacodynamic drug interactions of concern involv-
ing amiodarone. These occur most frequently when coadministered with other medication used in the chronic
treatment atrial fibrillation. Initiating amiodarone in patients already receiving stable doses of a drug whose elim-
ination will be rapidly reduced are at the greatest risk. Drugs such as digoxin or warfarin have a half-life short
enough to allow their steady-state concentration to double within days after exposure to amiodarone. To avoid
digoxin-induced conduction issues, or dangerous INR elevation, their previous doses should be reduced by 50%
as soon as amiodarone is introduced and then titrated back to optimum as necessary. In contract, the reverse situ-
ation is less dangerous. When digoxin or warfarin is introduced to a patient already stabilized on amiodarone,
standard slow upward titration from an initial low dose works without extra precautions.
Computerized drug interaction databases will often flag amiodarone as having pharmacodynamic interactions
with other QT-prolonging drugs, especially quinoline and macrolide antibiotics, and azole antifungal agents.
However, coadministration of these medications is usually of limited duration and the multimodal antiarrhyth-
mic effects of amiodarone make Torsade de Pointes extremely rare in these patients
[123]. Pharmacodynamic
interaction with beta-blockers is of interest to clinicians treating both cardiac and hepatic failure. However, it is
reassuring that a review of large trials in which beta-blockers were coadministered with amiodarone found no
signal for harm and it was recommended that beta-blocker therapy should be continued unadjusted in patients
requiring both medications
[124].
44 4. Drugs at the crossroads of heart and liver
I. Liver and heart
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Amiodarone hepatotoxicity: the challenge of attribution
Being asked to identify if a patient has amiodarone hepatotoxicity presents a challenge to the Hepatologist.
It is an important challenge because the answer has potentially lifestyle altering consequences for the patient.
The low incidence of hepatotoxicity in randomized trials
[53], suggests that outside blinded trials, amiodarone
hepatotoxicity is more often assumed than proven as a diagnosis. Experimentally, a strongly lipophilic com-
pound, like amiodarone, partitions preferentially into high-adipose tissues such as the liver, where it can cause
alterations to normal lipid physiology
[125]. Therefore amiodarone is always in the differential for hepatotoxic-
ity when it occurs in a patient receiving the drug, but the probability of causality is proportional to the concen-
tration to which the patient is exposed. Drug-toxicity is most likely the diagnosis when sufficient drug
exposure can be demonstrated in addition to ruling out o ther causes. The single most cost-effective assessment
tool is measurement of a serum concentration to determinethepatient’sdegreeofexposuretoamiodarone.Yet
this tool is not promoted by clinical laboratories and must be sought out by the practitioner. Diagnosis is also
greatly aided by an understanding of the pharmacokinetic/ pharmacodynamic attributes of amiodarone,
wherein discussion with a Clinical Pharmacologist will greatly leverage the value of a concentration
measurement.
The decision to iodinate the amiodarone molecule during its development brought increased efficacy. Yet its
effect of prolonging half-life makes dosing choices more complex and its influence on thyroid function makes
some patients more difficult to treat. Both these factors have contributed to its bad reputation. Without a gold-
standard test for attribution of amiodarone toxicity, extra effort must be made to investigate the differential diag-
noses. Diagnostic guidance from history and physical is limited, as patients experience nonspecific symptoms of
fatigue, malaise, anorexia, nausea, vomiting and hepatomegaly indistinguishable from nondrug-induced hepatic
disease. Careful consideration of alternate causes of toxicity is especially important to avoid being biased by the
drug’s reputation when assessing possible amiodarone hepatotoxicity.
In the future, given its bad reputation and continued widespread use, the number of consultations regarding
possible amiodarone-associated liver toxicity will only increase. Above all, it is important to remember that amio-
darone is never prescribed for frivolous reasons. When amiodarone is sto pped in the face of probable toxicity, it
benefits the patient, but when amiodarone is stopped because of liver abnormalities misattributed to drug toxic-
ity, the overall management of the patient is harmed. Not only does the latter situation delay finding the actual
hepatic pathology, but it also subjects patients to trials of other antiarrhythmic drugs of lesser efficacy that have
other possible toxicities.
TABLE 4.1 Common pharmacokinetic drugdrug interactions with amiodarone.
Cytochrome Drug affected by amiodarone
CYP3A4 cyclosporine A, simvastatin
CYP2C9 S-warfarin
CYP2D6 Procainamide, flecainide, metoprolol, opiates, antidepressants
CYP1A2 Lidocaine, caffeine, theophylline
Effects on CYP1A1 and CYP2A6 have no clinical examples
[122].
TABLE 4.2 Common pharmacodynamic drugdrug interactions with amiodarone.
Pharmacodynamic effect Drug interacting with amiodarone
QT prolongation Azole antifungals
Macrolide antibiotics
Fluoroquinolones
Sinus and atrioventricular node suppression Beta-blockers
Nondihydropyridine calcium channel blockers (high doses may cause sinus
bradycardia or AV block)
45Part 1: amiodarone
I. Liver and heart
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Monitoring hepatic function in patients receiving amiodarone
Its low cost, excellent antiarrhythmic efficacy, and minimal proarrhythmic potential, along with the low eco-
nomic incentive to develop a replacement, mean that amiodarone will continue to be the dominant antiarrhyth-
mic agent worldwide. This leaves health care providers with little choice but to improve their management of
amiodarone therapy.
One strategy is a structured monitoring plan to reduce the potential for adverse events, especially because
amiodarone’s unusual pharmacokinetic profile makes it difficult to adjust on the fly. Systematic monitoring helps
avoid missing effects that are occurring later than would be expected with more familiar drugs. However, the lit-
erature regarding hepatic monitoring lacks consensus and the clinical application of recommendations remains
inconsistent. In a review of 52 articles mentioning amiodarone monitoring, only 15 laid out specific recommenda-
tions
[126]. The majority advised establishing baseline values for liver chemistry with repeat testing at either 3-
or 6-monthly intervals. None explicitly compared outcomes of patients managed with different monitoring regi-
mens or to no monitoring at all.
To explore which hepatic indices should be monitored and at what intervals, multiyear data was prospec-
tively collected in a cohort of 50 patients
[22]. Six parameters were recorded at baseline and 1, 2, 3, 4, 6, 9, 12,
18, and 24 m onths. Only ALT and AST varied in relation to amiodarone therapy. Changes observed in LDH,
alkaline phosphatase, total bilirubin, and albumin were small and random in nature. The minimal change
observed in parameters reflecting canalicular function and protein synthesis is consistent with the paucity of
reports involving these parameters in patients receiving oral amiodarone. Gamma-glutamyl t ranspeptidase
(GGT) elevation has only been reported once in a patient with normal cardiac function exposed to amiodar-
one
[100].
Although the evidence underlying Guidelines for amiodarone follow-up from the North American Society of
Pacing and Electro physiology (NASPE) is not explained, they recommend baseline monitoring of liver chemistry
with only 6-monthly follow-ups. Surprisingly, they also advocate for drug discontinuation in patients when ALT
surpasses $ 2x ULN
[36]. Given that transient elevations of ALT $ 2x ULN occur in the absence of amiodarone
in many patients with undiagnosed NASH, it is surprising that no further investigation is suggested.
Furthermore, no strategy is outlined for the reintroduction amiodarone should ALT elevations prove to be tran-
sient. These guidelines exemplify a low threshold for the attribution of hepatotoxicity. Although adopting a low
threshold for drug discontinuation would surely eliminate the occurrence of hepatotoxicity, it would also lead to
many patients being den ied effective therapy because of clinically unimportant enzyme elevations from etiologies
as simple as gastroenteritis
[127].
Baseline liver chemistry values are integral to preventing misattribution of preexisting abnormalities to amio-
darone. Yet, in prevailing institutional practice, baseline monitoring is patchy, performed in as few as 44% of
patients, with follow-up testing performed as infrequently as 41%
[128]. Serial monitoring of ALT will most
closely reflect exposure to amiodarone. After 1 month of therapy, having a normal ALT value rules out idiosyn-
cratic hypersensitivity to amiodarone. Three-monthly monitoring then allows for detection of hepatic sensitivity
to rising serum amiodarone concentration prior to steady state. Once it can be assumed that steady state has
been attained, 6 months after initiation of a stable maintenance dose, semiannual checks should suffice
[44].
Because changes in AST were observed to correlate so closely to ALT, routine measurement of AST is unlikely to
provide independent predictive data
[22]. Once other parameters of liver function are documented at baseline,
they need only be reassessed should concerns arise through detection of an ALT elevated to .3x ULN, or clinical
changes suggest liver dysfunction.
Screening for unexpectedly low or high se rum amiodarone concentrations is not widely practiced.
However, such screening can guide adjustment of a patent’s maintenance dose in order to avoid develop-
ment of concentrations associated with inefficacy, ,0.7 mg/L, or toxicity, that is, .2.5 mg/L
[23,129].
Current lack of acceptance of TDM practice stems from frustrations enco untered in early stud ies of insuffi-
cient duration (mean follow-up , 1 y) to gather enough post steady state data to correlate drug effects with
steady-state serum concentrations
[38]. Congruence b etween conc entration and effect is much more appar-
entinmodelingofdatafrompatients exposed to amiodarone for 2 years
[22]. The distribution of concen-
trations produced by fixed dosing can be narrowed by increasing the maintenance dose in patients found
to have low concentrations and reducing doses in patients with higher concentrations. The clinical rele-
vance of such a dose adjustment strategy was demonstrated in population modeling, where .6% of
patients in whom plasma concentrations were .2.5 mg/L d eveloped an ALT of .3timesULN,compared
to virtually none with concentrations ,1.5 mg/L
[22].
46 4. Drugs at the crossroads of heart and liver
I. Liver and heart
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Although DEA is similar in efficacy and toxicity to amiodarone, once steady state is attained, DEA exists in
fixed proportion to amiodarone. Because DEA is minimally affected by acute dosing of amiodarone, concentra-
tions follow more dampened swings, when dosing rates are altered
[111]. This means that prior to steady state
DEA is a more accurate gauge of a patient’s deep compartment exposure to the drug.
A simplified approach to pre-steady-state TDM is to check drug concentration after one month of dosing to
verify that “standard” dosing is producing a reasonable serum concentration, not so low as to suggest inadequate
absorption, and not so high as to indicate accumulation will exceed steady-state targets. A normal serum ALT at
that time provides reassurance that amiodarone concentration is being tolerated. At this point, the prescriber can
make an early adjustment to daily dosing based on a rough assessment of whether the patient’s ability to absorb
amiodarone is: too low, about average, or dangerously high. Verification that serum concentrations are approach-
ing desirable steady-state values of 0.71.5 mg/L (1.02.2 μmol/L) need only be done after 23 half-lives (46
months) of dosing and after initiation and each change in the dosing rate. This interval provides enough time for
the peripheral tissues to approach equilibrium with serum concentrations when dosing rate is changed.
Assessment of drug concentration and ALT annually (every 6 typical half-lives) can confirm lack of hepatic
effects that might indirectly point to long-term accumulation of drug and can be done sooner if there a clinical
indication.
Liver biopsy, obviously impractical as a monitoring tool, is also difficult to interpret in the absence of
amiodarone-specific pathognomonic signs, making it much more useful as a tool for ruling out other etiologies
than screening for early amiodarone hepatotoxicity. Similarly, periodic Compu ted Tomography (CT) imaging,
would be neither practical nor diagnostic. The characteristic hyperdense CT appearance of iodine deposited in
the liver roughly correlates with the degree of serum drug exposure, but does not signal toxicity
[130]. Thus,
patients with low hepatic density on CT have accumulate d less amiodarone-derived iodine and are found to
have lower probability of toxicity
[117,131,132]. Given the rarity of serious liver toxicity reported amongst the
millions of patients treated with amiodarone, it appears appropriate to forego liver biopsy and ionizing radiation
of CT, except in the most perplexing cases.
Therapy for hepatotoxicity
There remains no specific treatment for amiodarone-associated hepatotoxicity. Because it takes weeks after an
interruption in amiodarone dosing for rhythm management to lapse, it makes sense to stop dosing whenever a
question of amiodarone toxicity requires investigation. If another diagnosis is found, dosing can be effectively
resumed. If toxicity is diagnosed, an early start on lowering exposure below the threshold of toxicity has already
been made. Often once half the drug is eliminated about 2 months following suspended dosing, the issues
resolve. Thus, stopping dosing is usually the biggest contributor to resolving any drug-toxicity. Unless initial
deterioration was fulminant other nonspecific supportive measures, including corticosteroids are usually not
required.
Corticosteroids have variably been suggested to improve hepatotoxicity, but without strong evidence. As with
many drug-related toxicities, artificial laboratory models have shown reduction of toxicity with the use of many
antioxidants. N-acetyl choline has been proposed to help in acute toxicity
[133,134]. Silymarin, given to increase
glutathione stores, glutathione peroxidase, and superoxide dismutase activity, has moderated the extent of injury
in cultured human liver cell models
[135]. Alpha-tocopherol shows dose-dependent protection in cultured fibro-
blasts exposed to amiodarone, reducing both cumulative drug uptake and the accumulation of cellular phospho-
lipids
[136]. However, in the clinical setting, achieving delivery of antioxidants to the affected parenchyma
remains a challenge. No specific therapies have been systematically tested in patients with amiodarone-
associated liver injuries.
Amiodarone: principles of clinical pharmacology
The following three “Pollak Principles of Clinical Pharmacology” can help in the clinical approach problems
encountered with medication prescribing:
1. Indication: A justifiable therapeutic indication should be identified, as drug administration for the wron g
indication has little potential for benefit, but all the potential for adverse effects.
2. Concentration: The goal of therapy is producing optimum drug concentrations in each patient, remembering
that dose is merely the tool that is individually adjusted to achieve that concentration.
47Part 1: amiodarone
I. Liver and heart
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3. Optimization: A therapeutic titration cycle should follow initial dosing, using organi zed monitoring for
beneficial and adverse effects to adjust and confirm the best dose for each patient.
In the case of amiodarone, this translates to:
1. There must be an expectation of benefit from rhythm or rate control. If so, factors suggesting that amiodarone
has a clinical indication might include the patient being intolerant of other therapeutic options or at more risk
with other agents because of reduced ejection fraction.
2. One-dose-fits-all is not appropriate. Optimal dosing in the population will cluster around the typical dose of
200 mg/d, but each patient’s dose should be individually verified. Informed application of TDM is the surest
way to provide the optimum dose. Patience is essential to the observation of any effects related to an
amiodarone dose change, as several months may be required before all effects become apparent.
3. A therapeutic cycle starts with prescribing the dose most likely to be optimal, then assessing response for
beneficial and adverse effects, and finally adjusting the dose using available tools, including occasional serum
concentration, if available. Awareness of the drug’s timeline is imperative. ALT is the best single parameter to
monitor for adverse liver effects
[22].
Although amiodarone has traditionally been supplied only as a 200 mg tablet, it is still highly titratable,
because it does not need to be dosed daily. With only 2% eliminated per day, even weekly dosing is frequent
compared to most other cardiac medications that are dosed once each half- life. Therefore it is quite justifiable to
calculate dosing in terms of grams per week and divide dosing as practical. The “standard” 200 mg/d dose is
1400 mg/wk divided evenly, but a 20% increase is easily achieved at 1700 mg/wk or 8.5 tablets distributed over
the week. Titration by half tablets per week is equivalent to amiodarone titration by superfine intervals of
15 mg/d.
Conclusions
During its more than 50 years of clinical use, amiodarone has slowly become better understood. Yet, prospec-
tive trials of amiodarone therapy designed to examine efficacy and adverse effects in relation to degree of drug
exposure (serum concentration) remain virtually absent. Most clinical trials were done before the implications of
amiodarone’s unusual pharmacokinetics were understood and thus did not include measurement of drug con-
centrations. New trials are unlikely to be funded for an old drug. While estimates of hepatotoxicity are lowest in
larger well-controlled studies, concerns surrounding potential liver toxicity remain widespread and create nega-
tive bias when making decisions about amiodarone. Studies in whole animals and cell cultures support that tox-
icity is proportional to drug concentration, as predicted by the science of pharmacology. Therefore it is not
surprising that over the last two decades, as patients have been exposed to lower doses of amiodarone, rates of
toxicity have been decreasing. However, while simply lowering the dosing rate for all patients lowers
population-wide rates of toxicity, it also lowers efficacy. The optimum balance between efficacy and toxicity is
best achieved by identify those patients with atypical pharmacokinetics and adjusting their dosi ng rates to lower
their risk of adverse outcomes. This is relatively easy using a few properly timed measurements of serum drug
concentration and a basic understanding of pharmacokinetics.
Acute toxicity reported with early administration of intravenous amiodarone appears to occur by a different
mechanism than the delayed toxicity that follows oral dosing and perhaps is related to the intravenous vehicle.
The histology of liver lesions resembles that of alcoholic hepatitis, but even patients remaining perfectly healthy
while receiving amiodarone will have their exposure to amiodarone identified on histology by the presence of
lamellar inclusion bodies, signifying a mild degree of phospholipidosis.
Persistent ALT elevation appears to be the best indicator of amiodarone hepatic effects. Recording liver chem-
istry values at baseline is essential. Monitoring of ALT at baseline, 1, 3, and 6 months and then semi-annually
appears to be sufficiently frequent for a drug with this half-life. However, opinion varies widely as to what
degree of ALT increase constitutes toxicity and what course of action to take when toxicity is suspected. Since
liver injury appears to be related to degree of drug exposure, and serum amiodarone concentrations are in equi-
librium with tissue concentrations at steady state, there is logic in recommending TDM to avoid overexposure
[22]. However, the groundwork clinically supporting the use of TDM will require larger trials before it is widely
accepted.
48 4. Drugs at the crossroads of heart and liver
I. Liver and heart
https://t.me/medicina_free
Inhibition of p-glycoprotein reduces the elimination of digoxin, potentially leading to accumulation and toxic-
ity. CYP2C9 inhibition causes warfarin concentrations to increase leading to over anticoagulation. Inhibition of
the transport protein that moves statins into the liver can increase the concentrations of atorvastatin, leading to
muscle toxicity. A transplant patient taking cyclosporin should have their cyclosporin dose lowered and TDM
intensified to avoid renal toxicity at the time amiodarone is introduced. As amiodarone is both an inhibitor of sil-
denafil elimination and a vasodilator, coadministration of sildenafil without dose reduction can cause headache.
Inhibition of CYP2D6 by amiodarone will produce higher concentrations of SSRI antidepressant drugs.
Amiodarone hepatotoxicity is not excessively frequent, and its incidence can be further reduced by systematic
monitoring. However, diagnosis of amiodarone hepatotoxicity with absolute certainty continues to remain a chal-
lenge frequently confronted at the interface between Cardiology and Hepatology.
Part 2: beta-blockers
In Part 2, the pharmacology of beta-blockers is explored, focusing on therapy of cirrhosis with attention to
their effects on portal hypertension.
Introduction
Nonselective beta-blockers (NSBBs) have been the mainstay of treatment for portal hypertension in cirrhosis
since the early 1980s, and are still the only drug class cu rrently recommended for the long-term therapy of portal
hypertension
[137]. The key event leading to the introduction of NSBBs for the treatment of cirrhosis was the
understanding that portal hypertension is not only the result of an increased resistance to portal blood flow by
the cirrhotic liver, but that there is also a major contribution from increased portal blood inflow, that becomes
more relevant as cirrhosis progresses. The contribution of an increase in blood inflow to portal hypertension, ini-
tially demonstrated in the 1970s by Roberto Groszmann and Jay Cohn
[138,139], was later translated into a thera-
peutic concept by Didier Lebrec, who proposed for the first time the use of beta-blockers for the treatment of
portal hypertension and varices in cirrhosis
[140,141]. Since then, successively, propranolol, nadolol, and carvedi-
lol have shown to improve clinical outcomes in different indications in cirrhosis.
Pathophysiology of portal hypertension and cirrhosis stages
In the initial phases of cirrhosis, portal hypertension mainly develops as consequence of increased resistance
to portal blood flow. However, as disease advances, there is a progressive splanchnic vasodilation leading to an
increase in portal inflow, which further aggravates portal hypertension despite the development of collateral cir-
culation (
Fig. 4.7). Splanchnic vasodilation leads to a progressive arterial underfilling, leading the activation of
neurohumoral systems (sympathetic nervous system, the reninangiotensinaldosterone system, and the
arginine-vasopressin system). The consequence is sodium and water retention promoting an increase in plasma
volume. Altogether, this results in an increased cardiac output (CO) that initially compensates for the progressive
vasodilation
[142], maintaining an adequate blood pressure to guarantee kidney perfusion. When the increase in
CO is insufficient to compensate for vasodilation, the neurohumoral systems become maximally activated, lead-
ing to a state of severe circulatory dysfunction with refractory ascites, hyponatremia and to decreased renal per-
fusion in addition to functional kidney impairment (hepatorenal syndrome).
Clinical pharmacology of nonselective beta-blockers in portal hypertension related to cirrhosis
NSBBs have a dual mechanism of action in managing portal hypertension: β1 blockade decreases CO while β2
blockade leads to unopposed α1 activity in the splanchnic circulation, resulting in splanchnic vasoconstriction, with
ensuing decrease in portal inflow and porto-collateral blood flow and reduction in portal pressure and variceal pres-
sure
[143].Bothβ1andβ2 effects are relevant for the treatment of portal hypertension. Selective β1 beta-blockers are
less effective decreasing portal pressure than NSBBs
[144] [145]. There is limited experimental data with β2 selective
blockers
[146] and they never progressed to clinical evaluation due to concerns with adverse effects.
49Part 2: beta-blockers
I. Liver and heart
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An important concept concerning portal hypertension in cirrhosis is that, with disease progression, the contri-
bution of the increased blood flow (as compared to the increase d hepatic resistance) becomes more relevant
(
Fig. 4.8) [147,148]. As a consequence, in the initial stages of cirrhosis, when portal hypertension depends mostly
on increased intrahepatic resistance, NSBBs have only a mild portal hypotensive effect
[147], that has not trans-
lated in clinical benefits in randomized trials
[149]. In more advanced stages (i.e., as the portal pressure gradient
reaches 10 mmHg), when the hyperdynamic state is more developed, the effect of NSBBs on portal pressure is
greater
[150] and is associated with relevant benefits on clinical outcomes [151,152].
Several observational studies have shown that patients showing a hemodynamic response to NSBBs (defined
as decrease in portal pressure to values ,12 mmHg or a decrease by .20% from baseline) have better prognosis
that patients not achieving these hemodynamic targets
[153]. This response, achieved by only 40%50% of
patients started on NSBBs, is associated with a decreased risk of all complications of cirrhosis and improved sur-
vival
[154]. In patients with compensated cirrhosis, reductions in HVPG . 10% from baseline have been also asso-
ciated with a reduction in variceal development
[149], first variceal hemorrhage and death [155]. On the other
hand, it is important to note that even patients classified as hemodynamic nonresponders have better outcomes
than untreated patients, showing that the proportion of clinical responders is much higher than the proportion of
FIGURE 4.7 Summary of the pathophysiology of portal hypertension. The increase in hepatic resistance leads to an increase in portal
pressure. This leads to a cascade of disturbances in the splanchnic and systemic circulation, characterized by vasodilation, sodium and water
retention, and plasma volume expansion. Additionally, these alterations lead to an increase in portal blood inflow, which contributes to main-
taining and aggravating portal hypertension. Another characteristic feature is the development of porto-systemic collaterals, which are respon-
sible for complications, such as variceal bleeding and hepatic encephalopathy (CO: cardiac output; Na: sodium). Source: Drawing courtesy
Alexandra Mason.
50 4. Drugs at the crossroads of heart and liver
I. Liver and heart
https://t.me/medicina_free
hemodynamic responders [156]. This might be, in part, related to nonhemodynamic effects of NSBBs [157], such as
decreased bacterial translocation with decreased systemic inflammation
[158].
Currently, there are no noninvasive methods to measure HVPG response and NSBBs are empirically titrated.
Methods of titration in trials have been to target a heart rate decrease of 20%25%, or to target the maximum tolerated
dose (provided that heart rate does not decrease below 5560 bpm and systolic blood pressure below 90 mmHg)
[137].
Lebrec explained that he initially proposed to target a 20%25% decrease in heart rate, since while in cardiology the
dose of propranolol was the dose which reduces heart rate to 5060 bpm, that would have been difficult for patients
with cirrhosis, since they have different baseline heart rate than noncirrhotics
[159].Lateron,itwasshownthatthe
higher the dose of NSBBs, the higher the effect on portal pressure
[154,160] and hence the strategy in some trials to
target the maximum tolerated dose. Even though heart rate response does not predict portal pressure response
[161], in RCTs using heart rate for titration have demonstrated a clinical benefit, so this empirical strategy is
evidence-based. Most importantly, the large corpus of randomized clinical trials assessing the effects of NSBBs have
not used HVPG response to guide therapy, and lack of availability of HVPG measurements should not deter from
the use of NSBBs as first-choice therapy
[137]. Finally, recent data suggest that variability in HVPG measurements
might be too high to allow using HVPG monitoring to guide clinical decision making
[162].
A key concept in the use of NSBBs in cirrhosis is that cautious dose up-titration and down-titration is a key
factor for the efficacy and safety of these drugs
[5,163]. Nurse-run titration clinics are an efficient way of monitor-
ing treatment
[164]. Titration is especially important to avoid significant hypotension that might place the patient
at risk of developing prerenal kidney dysfunction. As discussed earlier, a key compensatory mechanism for
maintaining blood pressure in advanced cirrhosis is an increase in CO
[29], which is in part reliant on sympa-
thetic activation, especially in advances stages such as in re fractory ascites [165]. NSBBs might interfere with this
mechanism (
Fig. 4.7). This might be particularly important during a situation of increased physiologic stress,
such as sepsis, which is a frequent event in cirrhosis.
In addition, propranolol is mainly metabolized by the liver and, therefore, as liver function deteriorates, its
bioavailability can increase significantly
[166], whereas nadolol is excreted unchanged in urine, and its
FIGURE 4.8 Differing contributions of increased hepatic resistance and increased portal blood inflow to portal hypertension at differ-
ent stages of cirrhosis and response to nonselective beta-blockers (NSBBs). A. Initially the increase in portal pressure is mainly determined by
an increase in hepatic resistance. Progressively, the contribution of increased portal blood inflow becomes more prominent. B. The hepatic venous
pressure gradient (HVPG) response to propranolol is greater in patients with clinically significant portal hypertension (HVPG $ 10 mmHg) than in
patients with an HVPG ,10 mmHg. Source: With data from Villanueva C, Albillos A, Genesca J, Abraldes JG, Calleja JL, Aracil C, et al. Development
of hyperdynamic circulation and response to beta-blockers in compensated cirrhosis with portal hypertension. Hepatology 2016;63(1):197206.
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bioavailability increases with kidney dysfunction [167]. For all these reasons, doses of NSBBs need to be re-
evaluated on a frequent basis.
More recently, carvedilol, an NSBB with intrinsic α-1-adrenergic antagonist activity, has been introduced in
the management of portal hypertension
[168,169]. In addition to being a NSBB, the α1 receptor blockade in the
liver circulation decreases intrahepatic vascular resistance, further decreasing portal pressure
[168]. Carvedilol
has a greater effect on portal pressure than traditional beta-blockers and has been shown to “rescue” nonrespon-
ders to propranolol
[170], making them hemodynamic responders.
Carvedilol has two enantiomers: the R(1) and the S(2). The former has alpha-1-antagonism, whereas the latter
has both, alpha-1 and beta-antagonism. Carvedilol undergoes a stereoselective first-pass metabolism in the liver,
with selectivity for the S(2) enantiomer. As liver function worsens, the stereoselectivity is lost, resulting in a
lower R-to-S ratio. Therefore lower doses of carvedilol may be associated with a more pronounced beta-blockade
and greater decrease in heart rate in patients with advanced liver disease
[168,171]. Carvedilol is, in addition, a
highly protein-bound drug, and with progressive hypoalbuminemia related to advanced liver disease, unbound
concentration of carvedilol increases. In advanced stages lower doses may achieve the same pharmacodynamic
effect
[172]. Due to its α-1-adrenergic antagonist activity carvedilol induces a greater decrease in arterial pressure
than traditional NSBBs
[173] and, in studies using high doses ($25 mg/d) it was associated with fluid retention
and worsening ascites (reflected by the need for increasing doses of diuretics)
[168].
Up to 15% of patients with cirrhosis may have a relative/absolute contraindication to NSBBs, the most fre-
quent being peripheral arterial insufficiency, chronic obstructive pulmonary disease, asthma, insulin-dependent
diabetes mellitus and atrioventricular block. In addition, up to 15% of the patients will develop adverse effects
leading to their discontinuation. The most frequent reasons for discontinuation are orthostatic symptoms, fatigue,
shortness of breath and impotence. Although these are rarely life-threatening, they might considerably limit the
quality of life of the patients
[152,174,175]. In case NSBBs are discontinued, an alternative treatment when indi-
cated (such as variceal ligation) should be considered
[176].
Table 4.3 summarizes the recommended doses for propranolol, nadolol, and carvedilol.
Clinical contexts for the use of nonselective beta-blockers
Until very recently, clinical trials assessing NSBBs in cirrhosis have focused on esophageal varices, either for the
prevention of the development of varices, for preventing first bleeding or for recurrent variceal bleeding. There is
scarce data on the effects of NSBBs on other complications of cirrhosis. A systematic search published in 2016
[177]
did not find enough evidence to support an effect of NSBBs on other complications (beyond varices) in patients with
decompensatedcirrhosis.Tworecenttrials,however,might expand the indications for NSBBs. These evaluated beta-
blockers for the prevention of first decompensation of cirrhosis, and for improving survival in patients with acute on
chronic liver failure
[178]. These clinical contexts, summarized in Table 4.4, are discussed in the following sections.
TABLE 4.3 Doses and titration strategies for propranolol, nadolol, and carvedilol.
Therapy Dose Goals of therapy Maintenance/follow-up/notes
Propranolol
• 20 mg orally twice a day
• Adjust every 23 days until treatment goal
is achieved
• Maximal daily dose should not exceed
320 mg in patients without ascites and
160 mg in patients with ascites
• Maximum tolerated dose targeting
heart rate 5560 bpm or decrease in
heart rate by 20%25%
• At every outpatient visit make sure
that patient is appropriately beta-
blocked
• Continue indefinitely.
• Liver elimination: might need to
decrease dose with progressive
liver dysfunction
Nadolol
• 40 mg orally once a day
• Adjust every
• 23 days until treatment goal is achieved
• Maximal daily dose should not exceed
160 mg in patients without ascites or 80 mg
in patients with ascites
As for propranolol
• As for propranolol
• Kidney elimination. Dose might
need to be reviewed or held in case
of kidney dysfunction
Carvedilol • Start with 6.25 mg once a day
• After 3 days increase to 12.5 mg
• Maximal dose should not exceed 25 mg/d
Systolic arterial blood pressure should
not decrease ,90 mmHg
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Prevention of the development of varices
Only one RCT has compared NSBBs (in this case, timolol) with placebo in the prevention of the development
of varices, with negative results
[149]. Timolol is a NSBB with higher affinity than propranolol or nadolol for
beta-adrenergic rece ptors, especially for beta-2
[184]. The study included patients with compensated cirrhosis
and no varices. The main endpoint was the development of varices that occurred in 39% and 40% of the patients
on timolol and placebo, respectively. Interestingly, timolol did not achieve a significant decrease in HVPG as
compared with placebo, which probably explains the negative effect of the trial. Although it cannot be ruled out
that the lack of effect on portal pressure was due to the pharmacological specificities of timolol (as compared to
propranolol, nadolol, or carvedilol), a likely explanation is that these patients were too early in the natural history
of portal hypertension, with small degree of splanchnic vasodilation and hyperdynamic circulation, which is the
pathophysiological target for NSBBs.
Prevention of decompensation
A subsequent multicenter randomized trial (the PREDESCI or “PREvention of DE(S)compensation in
CIrrhosis” trial)
[151] tried to address the factors that were thought to underlie the ‘timolol trial” failure. First,
the new trial recognized that the most relevant endpoint in compensated cirrhosis, rather than the development
of varices, is the development of decompensation, and therefore beta-blockers (or placebo ) were given until
decompensation developed, whereas in the “timolol trial” NSBBs (or placebo) were discontinued upon the devel-
opment of varices. Second, only patients with clinically significant portal hypertension were selected (HVPG
$ 10 mmHg). These patients have a more developed splanchnic vasodilation and hype rdynamic circulation
[147]
and are therefore more likely to respond to NSBBs. Third, the NSBBs arm was either propranolo l (in patients
showing $ 10% acute decrease to i.v. propranolol) or carvedilol (in patients not achieving a 10% response to i.v.
propranolol). Therefore the HVPG response to NSBBs was optimized and indeed, contrary to the “timolol trial,”
where timolol did not significantly decrease portal pressure, there was a 12% mean decrease in HVPG in the
NSBBs arm.
The trial randomized 201 patients to NSBBs or placebo. The rate of decompensation was significantly lower in
the NSBBs arm (16%) than in the placebo arm (27%). The main effect was on a reduction in the incidence of asci-
tes (the most frequent first decompensation in cirrhosis). There was also a consistent reduction in other secondary
events (such as progression of varices and death).
Taking into account the safety of NSBBs, the consistent benefits in different settings of cirrhosis, the consi stent
effects on primary and secondary endpoints, the low cost and the immediate availability without specific regula-
tory approval, it seems reasonable to start NSBBs in patients with compensated cirrhosis and suspected clinically
significant portal hypertension, independently of the presence of varices.
TABLE 4.4 Evidence from randomized trials comparing nonselective beta-blockers with placebo on clinical outcomes.
Clinical context Evidence
Prevention of first decompensation Evidence from a single randomized trial
[151]
Prevention of first variceal bleeding • Evidence from metaanalysis [152]
•
Individual patient metaanalysis did not show differential
effect in patients with or without ascites, though the effect
wasgreater(inabsoluteterms)inthosewithascites
[179]
•
A subsequent RCT [180] showed again that the
benefit of NSBBs were more marked in patients with ascites or
Child B/C
Prevention of variceal rebreeding
• Evidence from metaanalysis [181]
•
Individual patient metaanalysis shows more marked
effect in patients Child B/C
[182]
Prevention of bleeding-related death in patients without previous
bleeding
Evidence from metaanalysis [179]
Prevention of death in patients with previous variceal bleeding Evidence from metaanalysis [181]
Prevention of death in patients with ACLF Evidence from one RCT (carvedilol) [178]
Prevention of rebleeding from portal hypertensive gastropathy Evidence from one RCT [183]
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