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152 Chapter 7 Arrhythmias and chronic heart failure
7.4 Chronic heart failure
Symptoms of breathlessness and fatigue and signs of
uid retention resulting in oedema1 alert doctors to the
possibility of chronic heart failure (also referred to as
congestive heart failure). While many conditions we
discuss in this book are underdiagnosed, it is likely that
chronic heart failure is overdiagnosed in the elderly. is
is because the symptom cluster associated with chronic
heart failure has many other possible causes, including
obesity, renal disease, and severe anaemia; these should
be eliminated rst. A chest X-ray and echocardiogram
are useful investigations to conrm diagnosis. An
enlarged heart in the absence of other possible causes
and reduced ventricular function with an ejection
fraction of less than 35% are consistent with a diagnosis
of chronic heart failure. (Ejection fraction is the amount
of blood pumped out of the ventricle in one stroke, as a
proportion of the volume held at the end of the lling
phase, the end-diastolic volume. In the healthy heart
this is a little over 50%; stroke volume is ~70 ml, and
end-diastolic volume (EDV) is ~120–140 ml.) e
symptoms of chronic heart failure are a direct
consequence of the failure to maintain an adequate
cardiac output.
Normal
Failure + digoxin
Failure
Figure 7.4 Left ventricular function curve in the failing
heart.
A ventricular function curve is also presented in Figure 5.5.
Here it is developed further to show the lowered response in the
failing heart, the partial restoration of which may be achieved
with digoxin. In a resting individual with a healthy heart,
adequate stroke volume (horizontal dotted line) is the result of an
end-diastolic volume a. In chronic heart failure, generating the
same stroke volume requires a much greater end-diastolic
volume b. The inotropic effect of digoxin (increases force of
contraction) partially restores function. Note that the target
stroke volume can now be achieved with an end-diastolic
volume between a and b.
Chronic heart failure is one of the main causes of poor
quality of life. It is a progressive condition with eects
which can be disastrous, and is a major cause of
mortality. At any one time about 1–2% of the population
is suering from this condition, with a high prevalence in
the elderly.
Chronic heart failure2 can be dened as a state where the
heart is unable to maintain an adequate circulation for
the needs of the body despite an adequate venous lling
pressure.
In chronic heart failure there is characteristically a raised
central venous pressure. In other words there is an
increased preload. In a healthy heart, this would lead to a
greater EDV, resulting in an increased force of contraction
and elevation of cardiac output (see Chapter 5). However,
it is a cardinal feature of chronic heart failure that higher
1 Oedema (edema in US spelling): the accumulation of uid in the
interstitial spaces often producing a swelling. In heart failure this is due to
a raised venous pressure, and is especially evident in lower limbs (e.g.
ankles). is is hydrostatic oedema, distinguishing it from the oedema
caused by a change in leakiness of blood vessels to protein, seen in
inammation (Part 3).
2 Here we are discussing only systolic, left ventricular heart failure.
central venous pressure cannot result in increased
cardiac output because the left ventricle can no longer
contract strongly enough (Figure 7.4). is means that
blood accumulates in the venous system (this is the
congestion referred to in the term ‘congestive heart
failure’). e raised venous pressure forces uid from the
blood vessels into the interstitial spaces as oedema (uid
retention). When the patient is upright, the uid tends to
accumulate in the lower parts of the limbs, visible as
swollen ankles and feet. On lying down, the uid
redistributes, and the extra uid is forced into the
interstitial spaces of the lung, or the alveoli themselves,
leading to night-time attacks of breathlessness
(orthopnoea).
Loss of contractile function in the left ventricle is
commonly associated with:
• hypertension
• ischaemic heart disease
• MI
• arrhythmias (>10% of people with chronic heart failure
also have AF)
• primary malfunction of the cardiac muscle cells.
7.5 Drugs used in heart failure 153
↓
↑
Escalating inadequate
Increased sympathetic
ββ
stimulation
Chronic overstimulation
of cardiac
Figure 7.5
Chronic sympathetic overstimulation of the failing heart cannot
restore adequate cardiac output. Instead, occurring over months
and years, it contributes to the long-term decline in function.
-adrenoceptors
1
cardiac output
Further loss of
contractile response
Desensitization of
-adrenoceptors
1
e inadequate cardiac output elicits a compensatory
increase in sympathetic stimulation which, because of the
loss of contractile function, sets in place a futile cycle
(Figure 7.5).
e role of the renin–angiotensin–aldosterone
system (RAAS) e diminished cardiac output also
leads to decreased blood ow to the kidneys, and to
increased sympathetic activity at the juxtaglomerular
apparatus; both of these lead to enhanced renin release
from the juxtaglomerular cells (see Chapter 5, Box 5.1,
for a detailed description of the RAAS). e consequent
increase in angiotensin II results, through the activation
of multiple mechanisms, in vasoconstriction and
increased plasma volume. In the compromised heart
this serves to exacerbate dysfunction (Figure 7.6), and
contribute to long-term progressive deterioration.
Included in the structural deterioration of the heart is
the diagnostic sign of cardiac hypertrophy
(enlarged heart).
e enlarged heart is a consequence of greater
stimulation (Figure 7.7). e stretch of the ventricles is
increased (because of the higher EDV), which leads to
both greater dilatation and enhanced muscle mass (i.e.
thicker ventricle walls).
Blood ow
↑ Aldosterone
↑ Blood volume
↑ Preload
↑ EDV
1. Increase in symptoms
2. Increases long-term deterioration of left
ventricular function
Figure 7.6 Changes in the renin–aldosterone–
angiotensin system following the onset of heart failure.
Increases in angiotensin II levels lead to increased afterload due
to arterial vasoconstriction. This will result in the heart needing to
increase its work to achieve the same cardiac output. But the
failing heart cannot increase its force of contraction, and so
cardiac output falls further. The aldosterone-mediated increase
in salt and water retention in the kidney leads to increased blood
volume, raising central venous pressure and further adding to
the cardiac workload.
↑ Mass of muscle
… hypertrophy
Figure 7.7 Cardiac hypertrophy in the failing heart.
In a patient with chronic heart failure there is increased stretch of
ventricles (due to changes in central venous pressure and
end-diastolic volume; see text) and greater stimulation of the
cardiac muscle cells (e.g. by chronic overactivity in the
sympathetic nervous system). The resulting enlargement of the
heart is a consequence of increases in both the size of the
chambers of the heart, and the thickness of their muscle walls.
↑ Renin →→→to kidney →
Stretch of ventricles
↑ Stimulation of myocytes
↑ Heart size
↑ Angiotensin II
↑ Vasoconstriction
↑ Afterload
↑ Cardiac work
↑ Dilatation of
ventricles
7.5 Drugs used in heart failure
Chronic heart failure decreases quality of life and increases
mortality. e objective of drug treatment is twofold:
a) to restore day-to-day function by increasing the
capacity for cardiac output
b) to interfere with the mechanisms contributing to
long-term deterioration identied above.
It is noteworthy that some treatments improve cardiac
function, but do not increase longevity. is can in part be
154 Chapter 7 Arrhythmias and chronic heart failure
understood by relating the mode of action of these
therapeutic agents to the mechanisms that establish
chronic heart failure as outlined above. In this way the
response of a patient such as Den in Workbook 4 can be
interpreted at the level of his cellular and physiological
responses to the drugs administered.
7.5.1 RAAS-modifying drugs
Angiotensin-converting enzyme (ACE) inhibitors are
rst-line drugs in the management of chronic heart failure.
ey inhibit the nal step in the synthesis of angiotensin II, as
explained in Chapter 5, where they are introduced as
antihypertensive agents. eir benecial action in chronic
heart failure can be explained by reference to Figure 7.6,
which illustrates the central role of angiotensin II in this
condition; decreasing the levels of this hormone will dilate
arteries and veins, and reduce blood volume. e benecial
eect of arterial vasodilatation is to lower the resistance
against which the heart is pumping (decreased afterload).
is reduces cardiac work and improves tissue perfusion.
Venous dilatation and reduction in blood volume lowers
venous congestion, oedema, and central venous pressure
(decreased preload). ACE inhibitors thereby bring shortterm benet in terms of improving cardiac output, and
decreasing symptoms such as uid retention, breathlessness,
and fatigue. ey also provide long-term benets by
interrupting the progression of left ventricular disease.
ACE inhibitors have been shown to prolong life in chronic
heart failure, and all patients should be considered for
ACE inhibitor therapy. Examples are the same as those
encountered for hypertension in Chapter 5 (e.g. lisinopril
and enalapril).
ACE inhibitors are generally well tolerated although, as
discussed in Section 5.2.1, a minority of patients develop an
intolerable cough. is is thought to result from a build-up
For such patients the angiotensin II receptor AT-1
antagonists (ARBs, A2RAs) are an alternative way of
downregulating the inuence of the RAAS. In the treatment
of chronic heart failure these drugs (e.g. candesartan) are
alternative rst-line options. (Combined therapy with ARBs
and ACE inhibitors has been shown in clinical trials to be
associated with increased adverse eects, whilst conferring
no additional benet in terms of longevity; these drugs are
therefore not given together.)
When rst given, ACE inhibitors lower aldosterone
levels due to the reduced stimulation by angiotensin II
of aldosterone secretion by the adrenal cortex. During
prolonged treatment, however, this inhibitory eect
dwindles, and aldosterone levels recover. In addition to
increasing plasma volume (see below), aldosterone also
has direct eects on the heart which may worsen
chronic heart failure, including promoting arrhythmias
and cardiac brosis. Inhibition of the eects of
aldosterone can be achieved with the aldosterone
antagonist spironolactone, which therefore has a
role to play in chronic heart failure.
Aldosterone is a mineralocorticoid steroid hormone (see
Chapter 2) which increases the expression of the proteins
involved in Na+ transport from the more distal portions of
the kidney tubules (distal convoluted tubule and cortical
collecting ducts). Its net eect is to promote Na+ and water
reabsorption, whilst favouring K+ excretion. erefore
antagonists acting at the aldosterone receptor inhibit
these processes, with Na+ and water being lost whilst K+ is
preserved; they are K+-sparing diuretics. eir diuretic
action is only weak when used alone. However, when
used in combination with another diuretic the eect is
enhanced. Importantly, their K+-sparing property makes
them useful in counteracting the K+ loss associated with
loop and thiazide diuretics (see below).
Spironolactone is mainly held in reserve for those
patients with moderate to severe heart failure who remain
symptomatic despite rst-line therapy. When combined
with ACE inhibitors, spironolactone has been shown to
signicantly reduce mortality.
Eplerenone is a newer aldosterone antagonist which can
be used for patients diagnosed with left ventricular failure
after an MI (see Section 6.4). It has fewer side eects than
spironolactone because of the reduced anity for
androgen and progesterone receptors which can result in
menstrual disorders, gynaecomastia (enlargement of
male breast tissue), and testicular atrophy. Predictably,
aldosterone antagonists can cause hyperkalaemia;
monitoring plasma K+ levels should accompany their use,
and they should not be given with K
+
supplements. e
risk of hyperkalaemia is increased by combination with
other K
-elevating drugs such as ACE inhibitors.
+
7.5.2 Diuretics
Diuretics should be routinely used for patients with
chronic heart failure where symptoms of congestion and
uid retention are seen. As well as relieving symptoms of
oedema, the reduction in central venous pressure
7.5 Drugs used in heart failure 155
A
ADP
B
brought about by a diuretic will help to slow disease
progression. iazide diuretics (e.g.
bendroumethiazide) may be benecial, but loop
diuretics, such as furosemide (frusemide), are usually
the drug of choice. ey are powerful diuretics, acting on
the thick ascending limb of the loop of Henle to inhibit
the Na+/K+/2Cl− carrier by binding to its Cl– binding site.
e ensuing loss of K+ can, as mentioned above, be
countered by combining with a K+-sparing diuretic such
as spironolactone; combined preparations are available
and may be useful if compliance is an issue.
Loop diuretics also have a therapeutically benecial
vasodilatatory eect which is independent of their
diuretic action.
e eects of loop diuretics are seen within 1 hour of oral
administration, and are complete within 6 hours.
Predictable side eects result from excessive loss of
electrolytes and water, and include hypokalaemia,
hypotension, and dehydration. e hypokalaemia
produced can increase the eect and toxicity of several
drugs. Included amongst these are several which may also
be prescribed for management of chronic heart failure
(e.g. digoxin), or of common coexisting conditions such as
the anti-arrhythmic drugs amiodarone and quinidine.
7.5.3 Positive inotropic drugs
A positive inotropic drug is one that increases the force of
contraction of the ventricle. e main drug of this type used
for long-term treatment of chronic heart failure is digoxin.
Digoxin
Digoxin has already been mentioned in the control of
arrhythmias, where it was shown to have two modes of
action: slowing atrioventricular (AV) conductance, and
inhibition of the Na+/K+ pump on cardiac myocytes. Only
the second mechanism will be discussed further here, as
this is the benecial action in the treatment of chronic
heart failure. It should be noted, however, that its dual
mode of action makes digoxin of particular benet for
chronic heart failure patients who additionally have AF;
the two conditions are commonly seen together.
Figure 7.8, panel A, illustrates the normal role of the
Na+/K+ ATPase (the Na+/K+ pump) in maintaining the Na
gradient across the cell membrane of cardiac myocytes.
e intracellular concentration of Na+ is kept low, relative
to the high extracellular Na+ concentration. is Na
+
gradient drives the Na+/Ca2+ exchanger, extruding Ca2+
from the cell to keep its intracellular concentration low, at
the expense of Na+ entering. Digoxin acts to block the
Na+/K+ pump, and so the driving force for removal of Ca
2+
from the cytosol is reduced and intracellular Ca2+ levels
rise. e result is that the sarcoplasmic reticulum
becomes more heavily loaded with Ca2+; more is available
for release during the action potential, giving rise to
greater contractility of the cardiac myocyte. is results in
an increased force of contraction, raising stroke volume
and cardiac output. e eect this has on the ventricular
function curve of a failing heart can be seen in Figure
7.4—digoxin is able to increase cardiac output for a given
+
+
+
ATP
K
Na
+ Digoxin
Na
+
pump
+
Na
[Na+]low
Exchanger
2+
Ca
[Ca2+]low
Cardiac myocyte
[Na+]raised
Ca
[Ca2+]raised
2+
Figure 7.8 Consequences of inhibition of the Na+/K+ pump by digoxin.
In a normally functioning cardiac myocyte (panel A) the Na+/K+ pump maintains a low intracellular Na+ level, creating a
gradient across the cell membrane. This gradient drives the Na+/Ca2+ exchanger: Na+ travelling down its gradient results in
the removal of Ca
the Na+/K+ pump, allowing the intracellular Na+ level to rise. This decreases the Na+ gradient across the membrane, and
thereby reduces the driving force for the extrusion of Ca2+ from the cytosol; so its intracellular concentration also rises.
2 +
in the opposite direction, out of the cell, keeping the intracellular Ca2+ concentration low. Digoxin inhibits
156 Chapter 7 Arrhythmias and chronic heart failure
end-diastolic volume, partially restoring function, and
resulting in an increase in quality of life for many patients.
Side eects of digoxin are common and can be serious;
pro-arrhythmic eects include bradycardia, AV block,
ectopic pacemaker activity, and conduction disturbances
giving rise to a range of dierent arrhythmias. Noncardiac eects include nausea, gastrointestinal
disturbances, dizziness, and visual disturbances. Digoxin
suers from a low therapeutic window/index, meaning
that the dose range where it is eective without causing
toxicity is limited. It is eliminated solely by the kidney in
its unchanged form, necessitating dose reduction in
patients with renal impairment. e rate of elimination is
decreased by a number of other clinically relevant drugs
including spironolactone, and the anti-arrhythmics
verapamil and amiodarone; plasma digoxin
concentrations and therefore risk of toxicity are increased
by concomitant use. Digoxin has a long half-life, of the
order of 36 hours. is is prolonged in elderly patients,
who may be particularly sensitive to its toxic eects. e
action of digoxin on the Na+/K+ pump is enhanced by low
plasma K+ levels; care must therefore be exercised when
combining with loop and thiazide diuretics. Lifethreatening toxicity can be treated with digoxin-specic
antibody fragments, or with lidocaine.
Other positive inotropic drugs
As discussed in Chapter 5, in a healthy heart an increased
force of contraction is achieved by stimulation of
1-adrenoceptors (e.g. by adrenaline). is eect is
mediated by an increase in the intracellular level of cyclic
AMP in the ventricular myocytes. Cyclic AMP is then
broken down inside the cells by phosphodiesterases.
ese comments provide the rationale for thinking that
two further classes of drug might be useful in increasing
cardiac output in the failing heart (Figure 7.9):
a) drugs that stimulate cardiac -adrenoceptors
b) drugs that inhibit phosphodiesterase activity.
It must be remembered, however, that part of the
long-term problem in heart failure is chronic
overstimulation of a heart that is unable to respond
eectively (Figure 7.5). Consequently, neither of these
drug types has a role in its long-term management.
Inotropic sympathomimetics, such as the 1-selective
adrenoceptor agonist dobutamine, are used
intravenously in the short-term treatment of acute, but
potentially reversible, heart failure (e.g. following heart
surgery or MI).
Activation
of β-
adrenoceptors
Stimulation
e.g. dobutamine
Figure 7.9 Elevation of cyclic AMP levels can be
achieved by stimulating synthesis or inhibiting
breakdown.
In the healthy heart, raising intracellular cyclic AMP in cardiac
myocytes through stimulation of 1-adrenoceptors will increase
cardiac output. The cyclic AMP level can be modified by drugs
acting in two ways: to stimulate the receptors (e.g. dobutamide),
or to prevent the breakdown of cyclic AMP by inhibiting
phosphodiesterase (e.g. milrinone). These drugs are not used in
the long-term management of heart failure, where chronic
overstimulation of these receptors already exists.
↑ Activity
adenylyl cyclase
of
↑ cyclic AMP
Inhibition
e.g. milrinone
Breakdown
by
phosphodiesterase
Elevation of intracellular cyclic AMP, using
phosphodiesterase inhibitors such as milrinone, may
bring about temporary improvement in severe heart
failure which is unresponsive to conventional therapy.
Such drugs are, however, rarely used since they have been
shown in clinical trials to be associated with increased
mortality, most likely as a result of inducing arrhythmias.
7.5.4 -Adrenoceptor antagonists
We have seen in Chapter 5 that -adrenoceptor
antagonists (-blockers) reduce cardiac output. It may
therefore seem odd to use drugs acting in this way to treat
a condition characterized by inadequate cardiac output.
Indeed, the administration of -adrenoceptor
antagonists to chronic heart failure patients has the
potential for short-term exacerbation of symptoms.
However, by reducing the chronic overstimulation of the
heart by the sympathetic nervous system (Figure 7.5),
blocking 1-adrenoceptors in the heart reduces longterm progression of the disease. Combined with ACE
inhibitors, -blockers form the basis of treatment for all
patients with heart failure due to left ventricular systolic
dysfunction.
Because of the possibility of short-term deterioration,
-adrenoceptor antagonists should be introduced at a
low dose for chronic heart failure, and only slowly
increased with careful monitoring. e 1-selective
adrenoceptor antagonists bisoprolol, metoprolol, and
7.5 Drugs used in heart failure 157
Diagnosis
Box 7.3
Treatment of chronic heart failure—an introduction
A strategy for treatment is shown in Figure c.
conrmed
With atrial
brillation
Digoxin Diuretic
Figure c A strategy for the treatment of chronic heart failure
due to left ventricular systolic dysfunction.
First-line treatment involves an ACE inhibitor (or if not tolerated, an
ARB), together with a cardioselective -adrenoceptor antagonist.
*These two drugs are titrated slowly up to a maximum tolerated dose.
(For some patients, one of the drugs may be started ahead of the
other. For instance if heart rate is slow and blood pressure is not
elevated, an ACE inhibitor may be initiated first.) If symptoms persist
after several weeks, the addition of an aldosterone antagonist (usually
spironolactone) is considered. A diuretic (most commonly a loop
diuretic) is taken where fluid retention is seen, and can be continued
throughout, to control symptoms.
ACE inhibitor
+ β-blocker*
If remains symptomatic
Spironolactone
Fluid retention
nebivolol, and the combined 1- and -adrenoceptor
blocker carvedilol are used as rst-line options. Most
other -blockers, including propranolol, should not be
used in chronic heart failure. e adverse eects of
these drugs and other considerations for their use,
including avoidance in asthma, are described in
Chapter 5.
Key references and suggested reading
Mattson-DiCecca A-A, Reynolds E. Update: a 60-year-old
woman with atrial brillation. JAMA 2009; 301: 1808.
Squire I. Evidence-based drug treatment of chronic heart
failure. Prescriber 2009; 20(3): 22–36.
7.5.5 Strategy in the management of
chronic heart failure
An introduction to drug strategy in chronic heart failure is
provided in Box 7.3, which indicates that therapy with
more than one drug is usually anticipated. e
management of coexisting arrhythmia and chronic heart
failure is illustrated in Den’s case in Workbook 4.
Taggar J, Lip G. Atrial brillation: current approaches to drug
therapy. Prescriber 2008; 19(7): 48–59.
SUMMARY OF DRUGS USED FOR ARRHYTHMIAS
158 Chapter 7 Arrhythmias and chronic heart failure
Therapeutic class Drugs Mechanism of action Common clinical uses Comments Common adverse
drug reactions
Class IA Disopyramide
Class 1B Lidocaine Use-dependent Na+ channel blocker with
Class IC Flecainide
Class II -adrenoceptor
antagonist
Class III Amiodarone Blocks myocyte K+ channels leading to
Quinidine
Procainamide
Encainide
Propranolol
Sotalol
Esmolol
Use-dependent Na+ channel blocker with
intermediate rate of association and
dissociation from channel
Also prolong repolarization (Class III
action)
fast association and dissociation
Affects only high frequency firing
Use-dependent Na+ channel blocker with
slow association and dissociation
reducing all excitations to achieve steady
state block
Antagonist at -adrenoceptors
Slow pacemaker potential and ventricular
rate by increasing delay at AV node
Negative inotropic effect
delayed repolarization
Extends myocyte action potential and
therefore the refractory period
Ventricular arrhythmia
(including after MI)
Prevention of recurrent
paroxysmal atrial fibrillation
Ventricular arrhythmias
(especially after MI)
Prevention of paroxysmal
atrial fibrillation
Ventricular arrhythmias
Arrhythmia—many types
including: Atrial fibrillation,
atrial flutter and some
ventricular arrhythmias
Anxiety-induced tachycardia
(propranolol)
Secondary prevention of MI
Angina
Chronic heart failure
Hypertension
Prophylaxis of migraine
Supraventricular and
ventricular tachyarrhythmias
including atrial fibrillation
Chronic heart failure
Disopyramide metabolized by hepatic
P450 enzymes, leading to numerous
drug interactions
Troublesome antimuscarinic side
effects
High hepatic first-pass metabolism
Given as intravenous injection or
infusion
Not used in patients with structural
damage to heart
Metabolized by hepatic P450
enzymes, leading to interactions
Avoid in asthma
Sotalol has additional Class III action
and is used for short-term
management of life-threatening
ventricular tachyarrhythmias
Esmolol has very short duration of
action so given intravenously only
Used only as last resort when other
therapeutic options are ineffective or
inappropriate
Use only under specialist supervision
Binds extensively to tissues, leading
to extremely long plasma half-life
(4–15 weeks)
Pro-arrhythmic effects
Constipation
Urinary retention
Blurred vision
Dry mouth
Dizziness
Paraesthesia (pins and
needles)
Confusion
Drowsiness
Bradycardia
Pro-arrhythmic effects
Oedema
Dyspnoea
Dizziness
Fatigue
Visual disturbance
Bronchospasm
Bradycardia
Heart failure
Conductance disorders
Fatigue
Headache
GI disturbance
Dyspnoea
Coldness of the
extremities
Sleep disturbance
Sexual dysfunction
Pro-arrhythmic effects
including: bradycardia,
AV block
Nausea
Pulmonary fibrosis
Photosensitivity
Peripheral neuropathy
Taste disturbances
Liver dysfunction
Hypo- or hyperthyroidism
Class IV Verapamil
Diltiazem
Block L-type voltage-sensitive Ca2+
channels
Decreases SA node activity and AV
conductance to slow ventricular rate
Negative inotropic effect
Supraventricular
tachycardias including atrial
fibrillation and atrial flutter
Not combined with Class II
(-blockers)
Not used in heart failure
Verapamil has greater
cardioselectivity than diltiazem
7.5 Drugs used in heart failure 159
Pro-arrhythmic effects
including: palpitations,
bradycardia, SA or AV
block
Constipation (particularly
verapamil)
Nausea
Vomiting
Flushing
Headache
Ankle oedema
Dizziness
Atypical antiarrhythmic drugs
Adenosine A1-adenosine receptor agonist
Activation leads to K+ channel
opening, causing hyperpolarization
and reduction in pacemaker slopes at
SA and AV nodes
Digoxin Reduces AV conduction by stimulating
vagal nerve (parasympathetic
innervation to heart) to slow ventricular
rate
See additional mechanism in heart
failure drug table below
AV, atrioventricular; GI. gastrointestinal; MI, myocardial infarction; SA, sinoatrial.
Supraventricular
arrhythmias
Supraventricular
arrhythmias particularly
persistent atrial fibrillation
and atrial flutter
Heart failure
Drug of choice for rapid termination
of many supraventricular
tachycardias
Given by intravenous injection
Rapid onset of action
Very short half-life (seconds)
Not used in asthmatics
Long half-life
Low therapeutic window
Signs of toxicity include nausea,
vomiting, and visual disturbance
Increased risk in elderly patients
and with renal impairment—reduce
dose
Risk of toxicity increased by
hypokalaemia (caution needed
with loop diuretics) and with
amiodarone, calcium channel
blockers, and spironolactone
Pro-arrhythmic effects
including: bradycardia,
sinus pause, AV block,
palpitation
Flushing
Headache
Angina
Dizziness
Shortness of breath
(dyspnoea)
Pro-arrhythmic
effects include severe
bradycardia, AV block,
ectopic pacemaker
activity
Nausea
Vomiting
Diarrhoea
Dizziness
Visual disturbances
SUMMARY OF DRUGS USED FOR HEART FAILURE
160 Chapter 7 Arrhythmias and chronic heart failure
Therapeutic class Drugs Mechanism of action Common clinical uses Comments Common adverse
Angiotensinconverting enzyme
(ACE) inhibitors
Angiotensin II
receptor antagonists
(ARBs, A2RAs)
Aldosterone
antagonists
Diuretics
1. Loop Furosemide
’pril drugs e.g.
Captopril
Enalapril
Fosinopril
Lisinopril
Ramipril
‘Sartans’ e.g.
Candesartan
Losartan
Olmesartan
Telmisartan
Valsartan
Spironolactone
Eplerenone
Bumetanide
Torasemide
See Drug summary table for Chapter 5
NB: ACE inhibitor (or if not tolerated, an ARB) is the first-line treatment for chronic heart failure
K+-sparing diuretic
Competitive antagonist at
aldosterone receptor, promotes
Na+ and water loss, but
preserves K
Block reabsorption of Na+, K+, and
Cl– (and therefore water) in thick
ascending limb of loop of Henle
Powerful diuretics
vasodilatatory effect
+
Oedema in heart failure
Refractory oedema
Chronic heart failure
Pulmonary oedema
Additional other
oedematous states
Resistant hypertension
Used in combination with loop
diuretics to counteract loss of K
Risk of hyperkalaemia if combined
with K+-elevating drugs or K+
supplements
Cause hypokalaemia which can
be counteracted by combining with
K+-sparing diuretics
Potential interaction with drugs
excreted by kidney
Quick onset of effect (within 1 h of
oral administration) and duration of
about 6 h
drug reactions
Hyperkalaemia
+
GI disturbance
Confusion
Dizziness
Hypotension
Nausea
Vomiting
Increased urinary
frequency
Hypotension
Dehydration
Mild GI disturbances
Low electrolyte states
e.g.
Hypokalaemia
Hypocalcaemia
Hyponatraemia
Pancreatitis
At high dose:
Hearing loss
Tinnitus
2. Thiazide and
thiazide-like
Bendroflumethiazide
Chlortalidone
Indapamide
Metolazone
Cardiac glycosides Digoxin
Selective
1-adrenoceptor
Bisoprolol
Metoprolol
antagonist
-adrenoceptor
antagonists
Carvedilol
Nebivolol
with additional
vasodilatatory action
Inotropic
Dobutamine
sympathomimetic
Other drugs for heart
failure
Milrinone
Amrinone
Inhibit reabsorption of Na+ in
the distal tubule of the kidney,
promoting loss of Na+ and water in
urine leading to decreased plasma
volume
Additional sustained vasodilatatory
action (mechanism poorly
understood)
Inhibits myocyte Na+/K+ pump to
indirectly reduce Ca2 + extrusion,
increasing force of contraction
Antagonist at 1-adrenoceptor
Reduces cardiac output and
secretion of renin
As above plus additional
vasodilatatory effect through
antagonism of 1-adrenoceptors
(carvedilol) or NO-potentiating
action (nebivolol)
Agonist at 1-adrenoceptor on
cardiac myocytes to increase force
of contraction
Phosphodiesterase inhibitor
Enhances cAMP levels inside cells,
leading to increased myocardial
contractility
Chronic heart failure
Oedema
Hypertension
Act within 1–2 h of oral
administration
Duration of action about 12 h
Can exacerbate gout and
diabetes.
See Drug summary table for arrhythmias above
Chronic heart failure Added to ACE inhibitor (or ARB)
once patient stabilized
Avoid in asthma
Short-term treatment of
acute heart failure, e.g.
Not used in long-term
management of heart failure
following surgery or MI
(intensive care setting only)
Short-term treatment of
severe chronic heart failure
Rarely used because of
increased risk of mortality
which is unresponsive to
conventional therapy
Acute heart failure
7.5 Drugs used in heart failure 161
Increased urinary
frequency
Mild GI disturbance
Postural hypotension
Hypokalaemia
Hyperglycaemia (risk of
diabetes)
Hyperuricaemia (risk of
gout)
Hypercalcaemia
Erectile dysfunction
Headache
Dizziness
Bronchospasm
Bradycardia
Heart failure
Conductance disorders
Fatigue
Headache
GI disturbance
Dyspnoea
Coldness of the
extremities
Sleep disturbance
Oedema (carvedilol and
nebivolol)
Postural hypotension
(carvedilol)
Arrhythmias
Nausea
Hypotension
Headache
Palpitations
Bronchospasm
Supraventricular and
ventricular arrhythmias
Hypotension
Headache
GI. gastrointestinal; MI, myocardial infarction; NO, nitric oxide.