Normal Heart Rhythm.docx

Normal Heart Rhythm
Normal heart rhythm is generated and driven by the spontaneous firing of pacemakers cells of the
sinoatrial (SA) node located in the posterior wall of the right atrium. These cells have an intrinsic firing
rate of 100-110 depolarizations per second. However, this intrinsic rate is under the control of
autonomic nerves, which may either increase or decrease this rate. At rest, the sinoatrial rate, and
therefore heart rate when the heart is in sinus rhythm (i.e., controlled by SA node), may be in the
range of 60-80 beats/minutes (bpm), which is well below the intrinsic firing rate. This reduced resting
rhythm is due to vagal tone. Efferent vagus nerve fibers innervating the SA node normally have a high
level of activity under resting conditions. These nerves release acetylcholine, which binds to
muscarinic (M2) receptors on the SA nodal cells to cause the decrease in firing rate. (Click here for
additional detail). The SA node is also innervated by sympathetic fibers. These autonomic nerves
release norepinephrine, which binds principally to beta1-adrenoceptors located on SA nodal cells.
When the activity of sympathetic efferent nerves is increased, the SA node firing rate increases. (Click
here for additional detail). Normally, there is a reciprocal relationship between the parasympathetic
(vagal) and sympathethic influences acting on the SA node so that a reduction in heart rate is brought
about by increased vagal activity and decreased sympathetic activity. The opposite changes produces
an increase in heart rate.
In normal sinus rhythm, the impulses generated by the SA node travel through the atria and converge
at the atrioventricular (AV) node where the speed of conduction is reduced to give the atria sufficient
time to contract and empty their contents into the ventricles prior to ventricular contraction. Impulses
from the AV node travel into the ventricles via the Bundle of His, and then branch into the left and
right bundle branches, the terminal Purkinje fibers, and finally are conducted to the ventricular
myocytes. Because of this spread of electrical activity from the atria to the ventricles, every atrial
depolarization and contraction is normally followed by ventricular depolarization and contraction. In
other words, there is normally a one-to-one correspondence between atrial and ventricular
depolarization and contraction.
ypes of Arrhythmias
Arrhythmias can be divided into three categories: altered rate, premature beats and altered
conduction.
Altered Rate
Normal resting heart rates are between 60 and 100 bpm. A rate lower than 60 bpm is called
bradycardia and a rate greater than 100 bpm is called tachycardia. There are subcategories of altered
rate such as sinus tachycardia or bradycardia (rate is determined by SA node), atrial tachycardia or
bradycardia (rate governed by atrial pacemaker site), supraventricular tachycardia, and ventricular
tachycardia (rhythm originating from within ventricles). Atrial tachycardias having a rate of 250-350
bpm (>200 bpm in ventricles) are call flutter, and can be either atrial or ventricular in origin.
Fibrillation occurs (either atrial or ventricular) when the frequency is so high and irregular that the
rate cannot be determined.

Premature Beats
Sometimes a cell within the atria or ventricles that is not normally a pacemaker cell (called an ectopic
foci) spontaneously fires off an action potential. When this occurs, it can cause what is called a
premature beat. If this occurs in the atria the impulse will generally be conducted to the ventricles
and produce an early depolarization and contraction of the atria and ventricles. If the premature beat
originates from a ventricular ectopic foci, this will lead to an early depolarization and contraction in
the ventricles without affecting the atrial rhythm.
Altered Conduction
Delays in the conduction of electrical impulses within the heart produce abnormal electrical activation
of the heart that are termed conduction defects. These most commonly occur at the AV node. Less
severe conduction delays at the AV node will only delay the time it takes for the impulse to reach the
ventricles (called a first degree AV block). However, if AV nodal conduction is depressed sufficiently,
only some of the impulses may be able to travel into the ventricles leading to a loss of the one-to-one
correspondence between the atria and ventricles (called a second degree AV block). If the AV node (or
Bundle of His) become completely blocked, the atrial will depolarize normally, but ventricular
depolarization will no longer be triggered by atrial impulses. When this occurs, pacemaker sites within
the ventricle will drive ventricular rate, although at a much lower rate (30-40 bpm) than normal sinus
rate (>60 bpm). This is called a third degree AV block. Conduction blocks can also occur in the
ventricular bundle branches. These blocks do not normally alter the ventricular rhythm, although they
will alter ventricular activation leading to an increase in the QRS duration and abnormal QRS shape;
abnormal activation of the ventricles will depress ventricular mechanical function. Special types of
partial conduction blocks, sometimes in conjunction with abnormal conduction pathways (e.g., Wolff-
Parkinson-White syndrome), can lead to reentry pathways that produce tachycardia.
Specific Arrhythmias - definitions:
 Sinus bradycardia - low sinus rate <60 beats/min.
 Sinus tachycardia - high sinus rate of 100-180 beats/min as occurs during exercise or other
conditions that lead to increased SA nodal firing rate.
 Sick sinus syndrome - a disturbance of SA nodal function that results in a markedly variable
rhythm (cycles of bradycardia and tachycardia).
 Atrial tachycardia - a series of 3 or more consecutive atrial premature beats occurring at a
frequency >100/min; usually due to abnormal focus within the atria and paroxysmal in
nature. This type of rhythm includes paroxysmal atrial tachycardia (PAT).
 Atrial flutter - sinus rate of 250-350 beats/min.
 Atrial fibrillation - uncoordinated atrial depolarizations.

 Junctional escape rhythm - SA node suppression can result in AV node-generated rhythm of
40-60 beats/min (not preceded by P wave).
 Supraventricular tachycardia (SVT) - usually caused by reentry currents within the atria or
between ventricles and atria producing high heart rates of 140-250.
 Ventricular premature beats (VPBs) - caused by ectopic ventricular foci; characterized by
widened QRS.
 Ventricular tachycardia (VT) - high ventricular rate caused by aberrant ventricular
automaticity or by intraventricular reentry; can be sustained or non-sustained (paroxysmal);
characterized by widened QRS with similar appearance (monomorphic) or dissimilar
appearance (polymorphic) resulting from multiple triggering foci; rates of 100 to 200
beats/min; life-threatening.
 Ventricular flutter - ventricular depolarizations >200/min.
 Ventricular fibrillation - uncoordinated ventricular depolarizations.
 AV blocks - a conduction block within the AV node (or occasionally in the bundle of His) that
impairs impulse conduction from the atria to the ventricles.
First-degree AV nodal block - the conduction velocity is slowed so that the PR interval is increased to
greater than 0.2 seconds. Can be caused by enhanced vagal tone, digitalis, beta-blockers, calcium
channel blockers, or ischemic damage.
Second-degree AV nodal block - the conduction velocity is slowed to the point where some impulses
from the atria cannot pass through the AV node. This can result in P waves that are not followed by
QRS complexes. With a Mobitz type I block, the PR interval gradually increases until a QRS is dropped.

Therefore, the atrial rate will be greater than the ventricular rate. When there is a Mobitz type II
block, the PR interval is usually normal (<0.2 msec), but there may be 2 or 3 P waves before one is
followed by a QRS (as shown in the figure). In this type of block, the ventricular rhythm is less than the
sinus rhythm.
Third-degree AV nodal block - conduction through the AV node is completely blocked so that no
impulses are able to be transmitted from the atria to the ventricles. QRS complexes will still occur
(escape rhythm), but they will originate from within the AV node, bundle of His, or other ventricular
regions. Therefore, QRS complexes will not be preceded by P waves. Furthermore, there will be
complete asynchrony between the P wave and QRS complexes. Atrial rhythm may be completely
normal, but ventricular rhythm will be greatly reduced depending upon the location of the site
generating the ventricular impulse. Ventricular rate typically range from 30 to 40 beats/min.
Causes of Arrhythmias
Bradycardia
Sinus bradycardia results from reduced SA nodal firing rate. This can occur because of excessive vagal
stimulation (e.g., during fainting) or because of damage to the SA node (e.g., damage caused by
ischemia or disease). Ventricular bradycardia usually occurs as a result of AV block, which leads to the
expression of a pacemaker site within the ventricles that fires at a slow rate (30-40 beats/min).
Tachycardia
Sinus tachycardia most commonly results from excessive sympathetic nerve stimulation of the SA
node or high circulating levels of catecholamines (e.g., pheochromocytoma). Sinus tachycardia that
occurs during exercise, for example, is physiologic and normal. However, sinus tachycardia at rest is
not normal. Atrial (non-sinus) tachycardia can occur due to either an ectopic foci firing at a high
frequency or to reentry mechanisms within the atria. Both of these mechanisms may be stimulated by
ischemia or increased sympathetic activity. Supraventricular tachycardia caused by global reentry
involves an abnormal conduction pathway. For example, accessory pathways between the right
atrium and right ventricle (Bundle of Kent) can cause Wolff-Parkinson-White syndrome. Reentry
within the AV node can also precipitate a supraventricular tachycardia. These reentry mediated
tachycardias can be triggered by elevated sympathetic activity, which alters conduction velocity
within the cardiac tissue and the effective refractory period of action potentials. In some forms of
heart disease, ventricular and or atrial dilation occurs, which can lead to tachyarrhythmias or
premature beats. Fibrillation is usually caused by diseased ischemic myocardium.
Premature Beats
Atrial and ventricular premature beats are seen as premature atrial complexes (PAC) or premature
ventricular complexes (PVC) on the electrocardiogram. These premature beats can be caused by
disturbances that increase the excitability of cardiac cells. Stretching of the tissue and ischemia are

common causes. Increased sympathetic activity and circulating catecholamines can also precipitate
premature beats.
Conduction Blocks
AV conduction blocks can occur during excessive vagal stimulation or removal of normal sympathetic
influences on the AV node, which tips the autonomic balance toward a more dominant vagal
influence. This can occur, for example, as a consequence of beta1-adrenoceptor blockade. The most
common cause of AV conduction blocks is changes in the electrophysiological properties of the
specialized cells within the AV node and Bundle of His. Ischemia, damage caused by trauma, infection
or inflammation, or degenerative changes caused by age or disease can lead to AV conduction blocks.
These same mechanisms (except for vagal) can cause conduction blocks in other regions of the
conduction system, such as the bundle branches.
Therapeutic Use and Rationale
The ultimate goal of antiarrhythmic drug therapy is to restore normal rhythm and conduction. When it
is not possible to revert to normal sinus rhythm, drugs may be used to prevent more serious and
possibly lethal arrhythmias from occurring. Antiarrhythmic drugs are used to:
 decrease or increase conduction velocity
 alter the excitability of cardiac cells by changing the duration of the effective refractory period
 suppress abnormal automaticity
All antiarrhythmic drugs directly or indirectly alter membrane ion conductances, which in turn alters
the physical characteristics of cardiac action potentials. For example, some drugs are used to block
fast sodium channels. These channels determine how fast the membrane depolarizes (phase 0) during
an action potential. Since conduction velocity is related to how fast the membrane depolarizes,
sodium channel blockers reduce conduction velocity. Decreasing conduction velocity can help to
abolish tachyarrhythmias caused by reentry circuits. Other types of antiarrhythmic drugs affect the
duration of action potentials, and especially the effective refractory period. By prolonging the
effective refractory period, reentry tachycardias can often be abolished. These drugs typically affect
potassium channels and delay repolarization of action potentials (phase 3). Drugs that block slow
inward calcium channels are used to reduce pacemaker firing rate by slowing the rate of rise of
depolarizing pacemaker potentials (phase 4 depolarization). These drugs also reduce conduction
velocity at the AV node, because those cells, like SA nodal cells, depend on the inward movement of
calcium ions to depolarize.
Because sympathetic activity can precipitate arrhythmias, drugs that block beta1-adrenoceptors are
used to inhibit sympathetic effects on the heart. Because beta-adrenoceptors are coupled to ion

channels through defined signal transduction pathways, beta-blockers indirectly alter membrane ion
conductance, particularly calcium and potassium conductance.
In the case of AV block, drugs that block vagal influences (e.g., atropine, a muscarinic receptor
antagonist) are sometimes used. AV block can occur during beta-blocker treatment and therefore
simply removing a beta-blocker in patients being treated with such drugs may normalize AV
conduction.
Sometimes ventricular rate is excessively high because it is being driven by atrial flutter or fibrillation.
Because it is very important to reverse ventricular tachycardia, drugs are often used to slow AV nodal
conduction. Calcium channel blockers and beta-blockers are useful for this indication. Digitalis,
because of its ability to activate the vagus nerve (parasympathomimetic effect), can also be used to
reduce AV conduction velocity in an attempt to normalize ventricular rate during atrial flutter or
fibrillation.
Classes of Drugs Used to Treat Arrhythmias
Classes of drugs used in the treatment of arrhythmias are given below. Clicking on the drug class will
link you to the page describing the pharmacology of that drug class and specific drugs. Please note
that many of the drugs comprising the first five listed classes have considerable overlap in their
pharmacologic properties.
Antiarrhythmic drug classes:
 Class I - Sodium-channel blockers
 Class II - Beta-blockers
 Class III - Potassium-channel blockers
 Class IV - Calcium-channel blockers
 Miscellaneous - adenosine
- electrolyte supplement (magnesium and potassium salts)
- digitalis compounds (cardiac glycosides)
- atropine (muscarinic receptor antagonist)
The following table summarizes which antiarrhythmic drugs may be used to treat different types
of arrhythmias. It is important to note that for a given condition a particular drug may not be
efficacious, and in fact, it may precipitate other arrhythmias or adverse cardiovascular effects
(e.g., cardiac depression, hypotension). Therefore, drug efficacy and safety must be carefully
evaluated and individualized to the patient when treating arrhythmias.
Condition Drug Comments
Sinus tachycardia Class II, IV Other underlying causes may need treatment

Atrial fibrillation/flutter
Class IA, IC, II,
III, IV
digitalis
adenosine
Ventricular rate control is important goal;
anticoagulation required
Paroxysmal supraventricular
tachycardia
Class IA, IC, II,
III, IV
adenosine
AV block atropine Acute reversal
Ventricular tachycardia Class I, II, III
Premature ventricular
complexes
Class II, IV
Mg++
salts
PVCs are often benign and not treated
Digitalis toxicity
Class IB
Mg++
salts;
KCl
General Pharmacology
Effects on depolarization
Sodium-channel blockers comprise the Class I antiarrhythmic compounds according to the Vaughan-
Williams classification scheme. These drugs bind to and block the fast sodium channels that are
responsible for the rapid depolarization (phase 0) of fast-response cardiac action potentials. This type of
action potential is found in non-nodal, cardiomyocytes (e.g., atrial and ventricular myocytes; purkinje
tissue). Because the slope of phase 0 depends on the activation of fast sodium-channels and the rapid

entry of sodium ions into the cell (Figure: Na+
in), blocking these channels decreases the slope of phase
0, which also leads to a decrease in the amplitude of the action potential. In contrast, nodal tissue action
potentials (sinoatrial and atrioventricular nodes) do not depend on fast sodium channels for
depolarization; instead, phase 0 depolarization is carried by calcium currents. Therefore, sodium-
channel blockers have no direct effect on nodal tissue, at least through the blockade of fast sodium-
channels.
The principal effect of reducing the rate and magnitude of depolarization by blocking sodium channels is
a decrease in conduction velocity in non-nodal tissue (atrial and ventricular muscle, purkinje conducting
system). The faster a cell depolarizes, the more rapidly adjacent cells will become depolarized, leading
to a more rapid regeneration and transmission of action potentials between cells. Therefore, blocking
sodium channels reduces the velocity of action potential transmission within the heart (reduced
conduction velocity; negative dromotropy). This can serve as an important mechanism for suppressing
tachycardias that are caused by abnormal conduction (e.g., reentry mechanisms). By depressing
abnormal conduction, reentry mechanisms can be interrupted.
Effects on repolarization
Besides affecting phase 0 of action potentials, sodium-channel blockers may also alter the action
potential duration (APD) and effective refractory period (ERP). Because some sodium-channel blockers
increase the ERP (Class IA), while others decrease the ERP (Class IB) or have no effect on ERP (Class IC),
the Vaughan-Williams classification recognizes these differences as subclasses of Class I antiarrhythmic

drugs. These effects on ERP are not directly related to sodium channel blockade, but instead are related
to drug actions on potassium channels involved in phase 3 repolarization of action potentials. These
channels regulate potassium efflux from the cell (K+
out), and therefore repolarization. The drugs in
these subclasses also differ in their efficacy for reducing the slope of phase 0, with IC drugs having the
greatest and IB drugs having the smallest effect on phase 0 (IA drugs are intermediate in their effect on
phase 0). The following summarize these differences:
Sodium-channel blockade:
IC > IA > IB
Increasing the ERP:
IA > IC > IB (decreases)
Increasing or decreasing the APD and ERP can either increase or decrease arrhythmogenesis, depending
on the underlying cause of the arrhythmia. Increasing the ERP, for example, can interrupt tachycardia
caused by reentry mechanisms by prolonging the duration that normal tissue is unexcitable (its
refractory period). This can prevent reentry currents from re-exciting the tissue. On the other hand,
increasing the APD can precipitate torsades de pointes, a type of ventricular tachycardia caused by
afterdepolarizations.
Effects on automaticity
By mechanisms not understood and unrelated to blocking fast sodium channels, Class I antiarrhythmics
can suppress abnormal automaticity by decreasing the slope of phase 4, which is generated by
pacemaker currents.
Indirect vagal effects
The direct effect of Class IA antiarrhythmic drugs on action potentials is significantly modified by their
anticholinergic actions. Inhibiting vagal activity can lead to both an increase in sinoatrial rate and
atrioventricular conduction, which can offset the direct effects of the drugs on these tissues. Although a
IA drug may effectively depress atrial rate during flutter, it can lead to an increase in ventricular rate
because of an increase in the number of impulses conducted through the atrioventricular node
(anticholinergic effect), thereby requiring concomitant treatment with a beta-blocker or calcium-
channel blocker to slow AV nodal conduction. These anticholinergic actions are most prominent at the
sinoatrial and atrioventricular nodes because they are extensively innervated by vagal efferent nerves.
Different drugs within the IA subclass differ in their anticholinergic actions (see table below).
Specific Drugs and Therapeutic Indications
The following table summarizes Class I compounds in terms of their therapeutic use and some special or
distinguishing characteristics. More detailed information on specific drugs can be found at
www.rxlist.com.

Class IA: atrial fibrillation, flutter; supraventricular & ventricular tachyarrhythmias
quinidine* anticholinergic (moderate)
cinchonism (blurred vision, tinnitus, headache, psychosis);
cramping and nausea; enhances digitalis toxicity
procainamide
anticholinergic (weak);
relatively short half-life
lupus-like syndrome in 25-30% of patients
disopryamide anticholinergic (strong) negative inotropic effect
Class IB: ventricular tachyarrhythmias (VT)
lidocaine* IV only; VT and PVCs good efficacy in ischemic myocardium
tocainide orally active lidocaine analog can cause pulmonary fibrosis
mexiletine orally active lidocaine analog good efficacy in ischemic myocardium
Class IC: life-threatening supraventricular tachyarrhythmias (SVT) and ventricular tachyarrhythmias
(VT)
flecainide* SVT can induce life-threatening VT
propafenone SVT & VT;
β-blocking and Ca++
-channel blocking activity can worsen
heart failure
moricizine VT; IB activity
* prototypical drug
Abbreviations: IV, intravenous; PVC, premature ventricular complex.
Side Effects and Contraindications
The anticholinergic effects of IA drugs can produce tachycardia, dry mouth, urinary retention, blurred
vision and constipation. Diarrhea, nausea, headache and dizziness are also common side effects of many
Class I drugs. Quinidine enhances digitalis toxicity, especially if hypokalemia is present. Quinidine, by
delaying repolarization, can precipitate torsades de pointes (especially in patients with long-QT
syndrome), a ventricular tachyarrhythmia caused by afterdepolarizations. Disopyramide is
contraindicated for patients with uncompensated heart failure because of its negative inotropic actions;
propafenone can also depress inotropy. IC compounds can cause increased risk of sudden death in
patients with a prior history of myocardial infarction or sustained ventricular arrhythmias.

Beta-blockers are drugs that bind to beta-adrenoceptors and thereby block the binding of
norepinephrine and epinephrine to these receptors. This inhibits normal sympathetic effects that act
through these receptors. Therefore, beta-blockers are sympatholytic drugs. Some beta-blockers, when
they bind to the beta-adrenoceptor, partially activate the receptor while preventing norepinephrine
from binding to the receptor. These partial agonists therefore provide some "background" of
sympathetic activity while preventing normal and enhanced sympathetic activity. These particular beta-
blockers (partial agonists) are said to possess intrinsic sympathomimetic activity (ISA). Some beta-
blockers also possess what is referred to as membrane stabilizing activity (MSA). This effect is similar to
the membrane stabilizing activity of sodium-channels blockers that represent Class I antiarrhythmics.
The first generation of beta-blockers were non-selective, meaning that they blocked both beta-1 (β1)
and beta-2 (β2) adrenoceptors. Second generation beta-blockers are more cardioselective in that they
are relatively selective for β1 adrenoceptors. Note that this relative selectivity can be lost at higher drug
doses. Finally, the third generation beta-blockers are drugs that also possess vasodilator actions through
blockade of vascular alpha-adrenoceptors.

Heart
Beta-blockers bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system, and
contracting myocytes. The heart has both β1 and β2 adrenoceptors, although the predominant receptor
type in number and function is β1. These receptors primarily bind norepinephrine that is released from
sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that circulate in
the blood. Beta-blockers prevent the normal ligand (norepinephrine or epinephrine) from binding to the
beta-adrenoceptor by competing for the binding site.
Beta-adrenoceptors are coupled to a Gs-proteins, which activate adenylyl cyclase to form cAMP from
ATP. Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that phosphorylates L-type
calcium channels, which causes increased calcium entry into the cell. Increased calcium entry during
action potentials leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart; these
actions increase inotropy (contractility). Gs-protein activation also increases heart rate (chronotropy).
PK-A also phosphorylates sites on the sarcoplasmic reticulum, which lead to enhanced release of
calcium through the ryanodine receptors (ryanodine-sensitive, calcium-release channels) associated
with the sarcoplasmic reticulum. This provides more calcium for binding the troponin-C, which enhances
inotropy. Finally, PK-A can phosphorylate myosin light chains, which may contribute to the positive
inotropic effect of beta-adrenoceptor stimulation.
Because there is generally some level of sympathetic tone on the heart, beta-blockers are able to reduce
sympathetic influences that normally stimulate chronotropy (heart rate), inotropy (contractility),
dromotropy (electrical conduction) and lusitropy (relaxation). Therefore, beta-blockers cause decreases

in heart rate, contractility, conduction velocity, and relaxation rate. These drugs have an even greater
effect when there is elevated sympathetic activity.
Blood vessels
Vascular smooth muscle has β2-adrenoceptors that are normally activated by norepinephrine released
by sympathetic adrenergic nerves or by circulating epinephrine. These receptors, like those in the heart,
are coupled to a Gs-protein, which stimulates the formation of cAMP. Although increased cAMP
enhances cardiac myocyte contraction (see above), in vascular smooth muscle an increase in cAMP leads
to smooth muscle relaxation. The reason for this is that cAMP inhibits myosin light chain kinase that is
responsible for phosphorylating smooth muscle myosin. Therefore, increases in intracellular cAMP
caused by β2-agonists inhibit myosin light chain kinase thereby producing less contractile force (i.e.,
promoting relaxation).
Compared to their effects in the heart, beta-blockers have relatively little direct vascular effect because
β2-adrenoceptors have only a small modulatory role on basal vascular tone. Nevertheless, blockade of
β2-adrenoceptors is associated with a small degree of vasoconstriction in many vascular beds. This
occurs because beta-blockers remove a small β2-adrenoceptor vasodilator influence that is normally
opposing the more dominant alpha-adrenoceptor mediated vasoconstrictor influence.
Therapeutic Indications
Beta-Blockers
Cardiac Effects
 Decrease contractility
(negative intropy)
 Decrease relaxation rate
(negative lusitropy)

 Decrease heart rate
(negative chronotropy)
 Decrease conduction velocity
(negative dromotropy)
Vascular Effects
 Smooth muscle contraction
(mild vasoconstriction)
Beta-blockers are used for treating hypertension, angina, myocardial infarction, arrhythmias and heart
failure.
Hypertension
Beta-blockers decrease arterial blood pressure by reducing cardiac output. Many forms of hypertension
are associated with an increase in blood volume and cardiac output. Therefore, reducing cardiac output
by beta-blockade can be an effective treatment for hypertension, especially when used in conjunction
with a diuretic. Acute treatment with a beta-blocker is not very effective in reducing arterial pressure
because of a compensatory increase in systemic vascular resistance. This may occur because of
baroreceptor reflexes working in conjunction with the removal of β2 vasodilatory influences that
normally offset, to a small degree, alpha-adrenergic mediated vascular tone. Chronic treatment with
beta-blockers lowers arterial pressure more than acute treatment possibly because of reduced renin
release and effects of beta-blockade on central and peripheral nervous systems. Beta-blockers have an
additional benefit as a treatment for hypertension in that they inhibit the release of renin by the kidneys
(the release of which is partly regulated by β1-adrenoceptors in the kidney). Decreasing circulating
plasma renin leads to a decrease in angiotensin II and aldosterone, which enhances renal loss of sodium
and water and further diminishes arterial pressure.
Hypertension in some patients is caused by emotional stress, which causes enhanced sympathetic
activity. Beta-blockers can be very effective in these patients.
Beta-blockers are used in the preoperative management of hypertension caused by a
pheochromocytoma, which results in elevated circulating catecholamines. When used for this condition,
the blood pressure is first controlled using an alpha-blocker such as phenoxybenzamine, and then a
beta-blocker can be carefully administered to reduce the excessive cardiac stimulation by the
catecholamines. It is important that a beta-blocker is administered only after adequate blockade of
vascular alpha-adrenoceptors so that a hypertensive crisis does not occur as a result of unopposed
alpha-adrenoceptor stimulation.
Angina and myocardial infarction
Therapeutic Use of
Beta-Blockers

 Hypertension
 Angina
 Myocardial infarction
 Arrhythmias
 Heart failure
The antianginal effects of beta-blockers are attributed to their cardiodepressant and hypotensive
actions. By reducing heart rate, contractility, and arterial pressure, beta-blockers reduce the work of the
heart and the oxygen demand of the heart. Reducing oxygen demand improves the oxygen
supply/demand ratio, which can relieve a patient of anginal pain that is caused by a reduction in the
oxygen supply/demand ratio due to coronary artery disease. Furthermore, beta-blockers have been
found to be very important in the treatment of myocardial infarction in that they have been shown to
decrease mortality. Their benefit is derived not only from improving the oxygen supply/demand ratio
and reducing arrhythmias, but also from their ability to inhibit subsequent cardiac remodeling.
Arrhythmias
The antiarrhythmic properties beta-blockers (Class II antiarrhythmic) are related to their ability to inhibit
sympathetic influences on cardiac electrical activity. Sympathetic nerves increase sinoatrial node
automaticity by increasing the pacemaker currents, which increases sinus rate. Sympathetic activation
also increases conduction velocity (particularly at the atrioventricular node), and stimulates aberrant
pacemaker activity (ectopic foci). These sympathetic influences are mediated primarily through β1-
adrenoceptors. Therefore, beta-blockers can attenuate these sympathetic effects and thereby decrease
sinus rate, decrease conduction velocity (which can block reentry mechanisms), and inhibit aberrant
pacemaker activity. Beta-blockers also affect non-pacemaker action potentials by increasing action
potential duration and the effective refractory period. This effect can play a major role in blocking
arrhythmias caused by reentry.
Heart failure
The majority of patients in heart failure have a form that is called systolic dysfunction, which means that
the contractile function of the heart is depressed (loss of inotropy). Although it seems counterintuitive
that cardioinhibitory drugs such as beta-blockers would be used in cases of systolic dysfunction, clinical
studies have shown quite conclusively that some specific beta-blockers actually improve cardiac
function and reduce mortality. Furthermore, they have been shown to reduce deleterious cardiac
remodeling that occurs in chronic heart failure. Although the exact mechanism by which beta-blockers
confer their benefit to heart failure patients is poorly understood, it may be related to blockade of
excessive, chronic sympathetic influences on the heart, which are known to be harmful to the failing
heart. Note in the table of drugs that based upon clinical trials only three beta-blockers are FDA
approved for use in heart failure - carvedilol, metoprolol and bisoprolol.

Different Classes of Beta-Blockers and Specific Drugs
Beta-blockers that are used clinically can be divided into two classes: 1) non-selective blockers (block
both β1and β2 receptors), or 2) relatively selective β1 blockers ("cardioselective" beta-blockers). Some
beta-blockers have additional mechanisms besides beta-blockade that contribute to their unique
pharmacologic profile. The two classes of beta-blockers along with specific compounds are listed in the
following table. Additional details for each drug may be found at www.rxlist.com. The clinical uses
indicated in the table represent both on and off-label uses of beta-blockers. For example, a given beta-
blocker may only be approved by the FDA for treatment of hypertension; however, physicians
sometimes elect to prescribe the drug for angina because of the class-action benefit that beta-blockers
have for angina.
Clinical Uses
Class/Drug HTN Angina Arrhy MI CHF Comments
Non-selective
β1/β2
carteolol X ISA; long acting; also used for glaucoma
carvedilol X X α-blocking activity
labetalol X X ISA; α-blocking activity
nadolol X X X X long acting
penbutolol X X ISA
pindolol X X ISA; MSA
propranolol X X X X MSA; prototypical beta-blocker
sotalol X several other significant mechanisms
timolol X X X X primarily used for glaucoma
β1-selective
acebutolol X X X ISA
atenolol X X X X
betaxolol X X X MSA

bisoprolol X X X X
esmolol X X ultra-short acting; intra or postoperative HTN
metoprolol X X X X X MSA
nebivolol X
relatively selective in most patients; vasodilating (NO
release)
Abbreviations: HTN, hypertension; Arrhy, arrhythmias; MI, myocardial infarction; CHF, congestive heart
failure; ISA, intrinsic sympathomimetic activity.
Cardiovascular side effects
Many of the side effects of beta-blockers are related to their cardiac mechanisms and include
bradycardia, reduced exercise capacity, heart failure, hypotension, and atrioventricular (AV) nodal
conduction block. Beta-blockers are therefore contraindicated in patients with sinus bradycardia and
partial AV block. The side effects listed above result from excessive blockade of normal sympathetic
influences on the heart. Considerable care needs to be exercised if a beta-blocker is given in conjunction
with cardiac selective calcium-channel blockers (e.g., verapamil) because of their additive effects in
producing electrical and mechanical depression. Although this may change with future clinical trials on
safety and efficacy of beta-blockers in heart failure, at present only carvedilol and metoprolol have been
approved by the FDA for this indication.
Other side effects
Bronchoconstriction can occur, especially when non-selective beta-blockers are administered to
asthmatic patients. Therefore, non-selective beta-blockers are contraindicated in patients with asthma
or chronic obstructive pulmonary disease. Bronchoconstriction occurs because sympathetic nerves
innervating the bronchioles normally activate β2-adrenoceptors that promote bronchodilation. Beta-
blockers can also mask the tachycardia that serves as a warning sign for insulin-induced hypoglycemia in
diabetic patients; therefore, beta-blockers should be used cautiously in diabetics.
Potassium-Channel Blockers (Class III Antiarrhythmics)

Effects on action potentials
The primary role of potassium channels in cardiac action potentials is cell repolarization. In non-nodal
tissue (see figure), action potentials are initiated when a cell is depolarized to a threshold potential by
an adjacent cell. This leads rapid opening of fast sodium channels and a slower opening of L-type
calcium channels that permit calcium to enter the cell (phase 0 and 2, respectively). As these channels
become inactivated, potassium channels open permitting potassium ions to leave the cell (Figure: K+
out), which causes repolarization of the membrane potential (phase 3). Potassium channels remain
open until the next action potential is triggered. There are also different potassium channels that are
responsible for the initial repolarization (phase 1) that occurs as the fast sodium channels become
inactivated. Potassium channels are also responsible for repolarizing slow-response action potentials in
the sinoatrial and atrioventricular nodes.
Potassium-channel blockers comprise the Class III antiarrhythmic compounds according to the Vaughan-
Williams classification scheme. These drugs bind to and block the potassium channels that are
responsible for phase 3 repolarization. Therefore, blocking these channels slows (delays) repolarization,
which leads to an increase in action potential duration and an increase in the effective refractory period
(ERP).
On the electrocardiogram, this increases the Q-T interval. This is the common effect of all Class III
antiarrhythmic drugs. The electrophysiological changes prolong the period of time that the cell is
unexcitable (refractory) and therefore make the cell less excitable.

By increasing the ERP, these drugs are very useful in suppressing tachyarrhythmias caused by reentry
mechanisms. Reentry occurs when an action potential reemerges into normal tissue when that tissue is
no longer refractory. When this happens, a new action potential is generated prematurely (before
normal activation) and a circular, repeating pattern of early activation can develop, which leads to a
tachycardia. If the ERP of the normal tissue is lengthened, then the reemerging action potential may find
the normal tissue refractory and premature activation will not occur.
The following table summarizes Class III compounds in terms of their therapeutic use and some special
or distinguishing characteristics. More detailed information on specific drugs can be found at
www.rxlist.com.
Drug Therapeutic Uses Comments
amiodarone
ventricular tachycardia,
includuing ventricular
fibrillation; atrial
fibrillation and flutter
(off-label use)
very long half-life (25-60 days); Class I, II, III & IV actions and
therefore decreases phase 4 slope and conduction velocity;
potentially serious side effects (e.g., pulmonary fibrosis;
hypothyroidism)
dronedarone
atrial fibrillation (non-
permanent) and flutter
structurally related to amiodarone, but has a much smaller
volume of distribution and shorter elimination half-life (13-19
hr); Class I, II, III & IV actions; containdicated in severe or
recently decompensated, symptomatic heart failure; based on
results from the PALLAS trial in 2011, the FDA has concluded
there are concerns regarding increased risk for severe liver
injury and serious cardiovascular adverse events in patients
with permanent atrial fibrillation, and therefore, this drug
should be used only in patients in sinus rhythm with a history of

non-permanent atrial fibrillation
bretylium
life-threatening
ventricular tachycardia
and fibrillation
IV only; initial sympathomimetic effect (norepinephrine
release) followed by inhibition, which can lead to hypotension
sotalol
ventricular tachycardia;
atrial flutter and
fibrillation
also has Class II activity
ibutilide
atrial flutter and
fibrillation
slow inward Na+
activator, which delays repolarization; –
inhibits Na+
-channel inactivation, which increases ERP; IV only;
can cause life-threatening ventricular arrhythmias
dofetilide
atrial flutter and
fibrillation
very selective K+
-channel blocker; can cause life-threatening
ventricular arrhythmias
Abbreviations: IV, intravenous.
All of these compounds, like Class I compounds, are proarrhythmic as well as being antiarrhythmic. For
example, the increase in action potential duration can produce torsades de pointes (a type of ventricular
tachycardia), especially in patients with long-QT syndrome. Amiodarone, because of its Class IV effects,
can cause bradycardia and atrioventricular block, and therefore is contraindicated in patients with heart
block, or sinoatrial node dysfunction.
Calcium-Channel Blockers (CCBs)
Currently approved calcium-channel blockers (CCBs) bind to L-type calcium channels located on the
vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular
nodes). These channels are responsible for regulating the influx of calcium into muscle cells, which in
turn stimulates smooth muscle contraction and cardiac myocyte contraction. In cardiac nodal tissue, L-

type calcium channels play an important role in pacemaker currents and in phase 0 of the action
potentials. Therefore, by blocking calcium entry into the cell, CCBs cause vascular smooth muscle
relaxation (vasodilation), decreased myocardial force generation (negative inotropy), decreased heart
rate (negative chronotropy), and decreased conduction velocity within the heart (negative dromotropy),
particularly at the atrioventricular node.
Therapeutic Indications
CCBs are used to treat hypertension, angina and arrhythmias.
Hypertension
Therapeutic Use of
Calcium-Channel Blockers
 Hypertension
(systemic & pulmonary)
 Angina
 Arrhythmias
By causing vascular smooth muscle relaxation, CCBs decrease systemic vascular resistance, which lowers
arterial blood pressure. These drugs primarily affect arterial resistance vessels, with only minimal effects
on venous capacitance vessels.
Angina
The anti-anginal effects of CCBs are derived from their vasodilator and cardiodepressant actions.
Systemic vasodilation reduces arterial pressure, which reduces ventricular afterload (wall stress) thereby
decreasing oxygen demand. The more cardioselective CCBs (verapamil and diltiazem) decrease heart
rate and contractility, which leads to a reduction in myocardial oxygen demand, which makes them
excellent antianginal drugs. CCBs can also dilate coronary arteries and prevent or reverse coronary
vasospasm (as occurs in Printzmetal's variant angina), thereby increasing oxygen supply to the
myocardium.
Arrhythmias
The antiarrhythmic properties (Class IV antiarrhythmics) of CCBs are related to their ability to decrease
the firing rate of aberrant pacemaker sites within the heart, but more importantly are related to their
ability to decrease conduction velocity and prolong repolarization, especially at the atrioventricular
node. This latter action at the atrioventricular node helps to block reentry mechanisms, which can cause
supraventricular tachycardia.
Different Classes of Calcium-Channel Blockers

There are three chemical classes of CCBs. They differ not only in their basic chemical structure, but also
in their relative selectivity toward cardiac versus vascular L-type calcium channels. The most smooth
muscle selective class of CCBs are the dihydropyridines. Because of their high vascular selectivity, these
drugs are primarily used to reduce systemic vascular resistance and arterial pressure, and therefore are
used to treat hypertension. Extended release formulations or long-acting compounds are used to treat
angina and are particularly effecting for vasospastic angina; however, their powerful systemic
vasodilator and pressure lowering effects can lead to reflex cardiac stimulation (tachycardia and
increased inotropy), which can offset the beneficial effects of afterload reduction on myocardial oxygen
demand. Note that dihydropyridines are easy to recognize because the drug name ends in "pine."
Dihydropyridines include the following specific drugs: (Go to www.rxlist.com for specific drug
information)
 amlodipine
 felodipine
 isradipine
 nicardipine
 nifedipine
 nimodipine
 nitrendipine
Non-dihydropyridines, of which there are only two currently used clinically, comprise the other two
classes of CCBs. Verapamil (phenylalkylamine class), is relatively selective for the myocardium, and is
less effective as a systemic vasodilator drug. This drug has a very important role in treating angina (by
reducing myocardial oxygen demand and reversing coronary vasospasm) and arrhythmias. Diltiazem
(benzothiazepine class) is intermediate between verapamil and dihydropyridines in its selectivity for
vascular calcium channels. By having both cardiac depressant and vasodilator actions, diltiazem is able
to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by
dihydropyridines.
Dihydropyridine CCBs can cause flushing, headache, excessive hypotension, edema and reflex
tachycardia. Baroreceptor reflex activation of sympathetic nerves and lack of direct negative cardiac
effects can make dihydropyridines a less desirable choice for stable angina than diltiazem, verapamil or
beta-blockers. Long-acting dihydropyridines (e.g., extended release nifedipine, amlodipine) have been
shown to be safer anti-hypertensive drugs, in part, because of reduced reflex responses. This
characteristic also makes them more suitable for angina than short-acting dihydropyridines. The cardiac
selective, non-dihydropyridine CCBs can cause excessive bradycardia, impaired electrical conduction

(e.g., atrioventricular nodal block), and depressed contractility. Therefore, patients having preexistent
bradycardia, conduction defects, or heart failure caused by systolic dysfunction should not be given
CCBs, especially the cardiac selective, non-dihydropyridines. CCBs, especially non-dihydropyridines,
should not be administered to patients being treated with a beta-blocker because beta-blockers also
depress cardiac electrical and mechanical activity and therefore the addition of a CCB augments the
effects of beta-blockade.
Adenosine
Adenosine is a naturally occurring purine nucleoside that forms from the breakdown of adenosine
triphosphate (ATP). ATP is the primary energy source in cells for transport systems and many enzymes.
Most ATP is hydrolyzed to ADP, which can be further dephosphorylated to AMP. Most ADP and AMP

that form in the cell is rephosphorylated in the mitochondria by enzymatic reactions requiring oxygen. If
there are large amounts of ATP hydrolyzed, and especially if there is insufficient oxygen available (i.e.,
hypoxia), then some of the AMP can be further dephosphorylated to adenosine by the cell membrane
associated enzyme, 5'-nucleotidase.
Adenosine can bind to purinergic receptors in different cell types where it can produce a number of
different physiological actions. One important action is vascular smooth muscle relaxation, which leads
to vasodilation. This is a particularly important mechanism for matching coronary blood flow to the
metabolic needs of the heart. In coronary vascular smooth muscle, adenosine binds to adenosine type
2A (A2A) receptors, which are coupled to the Gs-protein. Activation of this G-protein stimulates adenylyl
cyclase (AC in figure), increases cAMP and causes protein kinase activation. This stimulates KATP
channels, which hyperpolarizes the smooth muscle, causing relaxation. Increased cAMP also causes
smooth muscle relaxation by inhibiting myosin light chain kinase, which leads to decreased myosin
phosphorylation and a decrease in contractile force. There is also evidence that adenosine inhibits
calcium entry into the cell through L-type calcium channels. Since calcium regulates smooth muscle
contraction, reduced intracellular calcium causes relaxation. In some types of blood vessels, there is
evidence that adenosine produces vasodilation through increases in cGMP, which leads to inhibition of
calcium entry into the cells as well as opening of potassium channels.
In cardiac tissue, adenosine binds to type 1 (A1) receptors, which are coupled to Gi-proteins. Activation
of this pathway opens potassium channels, which hyperpolarizes the cell. Activation of the Gi-protein
also decreases cAMP, which inhibits L-type calcium channels and therefore calcium entry into the cell. In
cardiac pacemaker cells located in the sinoatrial node, adenosine acting through A1 receptors inhibits
the pacemaker current (If), which decreases the slope of phase 4 of the pacemaker action potential
thereby decreasing its spontaneous firing rate (negative chronotropy). Inhibition of L-type calcium

channels also decreases conduction velocity (negative dromotropic effect) particularly at the
atrioventricular (AV) nodes. Finally, adenosine by acting on presynaptic purinergic receptors located on
sympathetic nerve terminals inhibits the release of norepinephrine. In terms of its electrical effects in
the heart, adenosine decreases heart rate and reduces conduction velocity, especially at the AV node,
which can produce atrioventricular block. Note, however, that when adenosine is infused into humans,
heart rate increases because of baroreceptor reflexes caused by systemic vasodilation and hypotension.
Adenosine has a very short half-life. In human blood, its half-life is less than 10 seconds. There are two
important metabolic fates for adenosine.
1. Most importantly, adenosine is rapidly transported into red blood cells (and other cell types)
where it is rapidly deaminated by adenosine deaminase to inosine, which is further broken
down to hypoxanthine, xanthine and uric acid, which is excreted by the kidneys. Adenosine
deamination also occurs in the plasma, but at a lower rate than that which occurs within cells.
Dipyridamole is a vasodilator drug that blocks adenosine uptake by cells, thereby reducing the
metabolism of adenosine. Therefore, one important mechanism for dipyridamole-induced
vasodilation is its potentiation of extracellular adenosine.
2. Adenosine can be acted on by adenosine kinase and rephosphorylated to AMP. This salvage
pathway helps maintain the adenine nucleotide pool in cells.
Therapeutic and Diagnostic Use and Rationale
Although adenosine is a powerful vasodilator, especially in the coronary circulation, it is not used as a
vasodilator for the treatment of coronary artery disease. The reason is that it is very short acting, limited
to intravascular administration, and in the heart it can produce coronary vascular steal. When
administered by intravenous infusion, it can produce hypotension and atrioventricular block.
Adenosine's unique vasodilator properties, however, are utilized in cardiac imaging during stress tests,
to determine coronary fractional flow reserve (a measure of severity of coronary stenosis), and to assess
pulmonary vasodilatory responses in patients with pulmonary hypertension.
The major therapeutic use of adenosine is as an antiarrhythmic drug for the rapid treatment of
supraventricular tachycardias. Its supression of atrioventricular conduction makes it very useful in
treating paroxysmal supraventricular tachycardia in which the AV node is part of the reentry pathway
(as in Wolff-Parkinson-White Syndrome). For these indications, adenosine is administered either as
bolus intravenous injection or as an intravenous infusion.
Adenosine is not effective for atrial flutter or fibrillation.
Most of adenosine's side effects are related to its vasodilatory properties. Patients can experience
flushing and headache, both of which are related to vasodilation. Adenosine can produce rapid arterial
hypotension; however, this is reversed shortly after stopping the infusion of adenosine. Coronary

vascular steal is of theoretical concern in some patients with coronary artery disease, although there is
no clinical evidence supporting this adverse effect. Methylxanthines such as caffeine and theophylline
competitively antagonize the binding of adenosine at its purinergic receptor. Finally, adenosine may
produce undesirable AV block; however, this is usually rapidly corrected by stopping adenosine
administration. Therefore, adenosine is contraindicated in patients with preexisting second or third
degree AV block.
Electrolyte Supplements (Magnesium and
Potassium)
Magnesium is an important ion in many enzymatic reactions, including cardiac Na+
-K+
-ATPase.
Hypomagnesemia can inhibit this vital ion transport system and lead to cellular depolarization.
Potassium ion plays an important role in membrane potentials, particularly in the resting membrane
potential. It is also very important in the repolarization phase of cardiac pacemaker and non-pacemaker
action potentials (phase 3).
Therefore, hypomagnesemia (serum concentration <1.5 mg/dl) and hypokalemia (serum concentration
<3.5 mg/dl; severe hypokalemia, <2.5 mg/dl) can precipitate cardiac arrhythmias, which include
ventricular tachycardia and fibrillation, premature ventricular complexes, supraventricular tachycardias
(e.g., Wolff-Parkinson-White Syndrome), atrial tachycardias, including flutter and fibrillation, and
arrhythmias associated with digitalis toxicity.
For treating hypomagnesemia-associated arrhythmias, magnesium sulfate may by administered
intravenously. Oral magnesium supplementation can be administered using magnesium gluconate,
oxide or hydroxide salts. Potassium chloride may be administered intravenously or orally.
Cardiac Glycosides (Digitalis Compounds)
Cardiac glycosides represent a family of compounds that are derived from the foxglove plant (Digitalis
purpurea). The therapeutic benefits of digitalis were first described by William Withering in 1785.
Initially, digitalis was used to treat dropsy, which is an old term for edema. Subsequent investigations
found that digitalis was most useful for edema that was caused by a weakened heart (i.e., heart failure).

Mechanisms of action
Digitalis compounds are potent inhibitors of cellular Na+
/K+
-ATPase. This ion transport system moves
sodium ions out of the cell and brings potassium ions into the cell. This transport function is necessary
for cell survival because sodium diffusion into the cell and potassium diffusion out of the cell down their
concentration gradients would reduce their concentration differences (gradients) across the cell
membrane over time. Loss of these ion gradients would lead to cellular depolarization and loss of the
negative membrane potential that is required for normal cell function. The Na+
/K+
-ATPase also plays an
active role in the membrane potential. this pump is electrogenic because it transports 3 sodium ions out
of the cell for every 2 potassium ions that enter the cell. This can add several negative millivolts to the
membrane potential depending on the activity of the pump.
Cardiac myocytes, as well as many other cells, have a Na+
-Ca++
exchanger (not an active energy-requiring
pump) that is essential for maintaining sodium and calcium homeostasis. The exact mechanism by which
this exchanger works is unclear. It is known that calcium and sodium can move in either direction across
the sarcolemma. Furthermore, three sodium ions are exchanged for each calcium, therefore an
electrogenic potential is generated by this exchanger. The direction of movement of these ions (either
inward or outward) depends upon the membrane potential and the chemical gradient for the ions. We
also know that an increase in intracellular sodium concentration competes for calcium through this
exchange mechanism leading to an increase in intracellular calcium concentration. As intracellular
sodium increases, the concentration gradient driving sodium into the cell across the exchanger is
reduced, thereby reducing the activity of the exchanger, which decreases the movement of calcium out
of the cell. Therefore, mechanisms that lead to an accumulation of intracellular sodium cause a
subsequent accumulation of intracellular calcium because of decreased exchange pump activity.
By inhibiting the Na+
/K+
-ATPase, cardiac glycosides cause intracellular sodium concentration to increase.
This then leads to an accumulation of intracellular calcium via the Na+
-Ca++
exchange system. In the
heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum,
thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy).
Inhibition of the Na+
/K+
-ATPase in vascular smooth muscle causes depolarization, which causes smooth
muscle contraction and vasoconstriction.

By mechanisms that are not fully understood, digitalis compounds also increase vagal efferent activity to
the heart. This parasympathomimetic action of digitalis reduces sinoatrial firing rate (decreases heart
rate; negative chronotropy) and reduces conduction velocity of electrical impulses through the
atrioventricular node (negative dromotropy).
Pharmacokinetics and toxicity
The long half-life of digitalis compounds necessitates special considerations when dosing. With a half-life
of 40 hours, digoxin would require several days of constant dosing to reach steady-state, therapeutic
plasma levels (digitoxin with a half-life of 160 hours, would require almost a month!). Therefore, when
initiating treatment, a special dosing regimen involving "loading doses" is used to rapidly increase
digoxin plasma levels. This process is termed "digitalization." For digoxin, the therapeutic plasma
concentration range is 0.5 - 1.5 ng/ml. It is very important that therapeutic plasma levels are not
exceeded because digitalis compounds have a relatively narrow therapeutic safety window. Plasma
concentrations above 2.0 ng/ml can lead to digitalis toxicity, which is manifested as arrhythmias, some
of which may be life-threatening. If toxicity occurs with digoxin, it may take several days for the plasma
concentrations to fall to safe levels because of the long half-life. There is available for digoxin toxicity an
immune Fab (Digibind) that can be used to rapidly reduce plasma digoxin levels. Potassium
supplementation can also reverse the toxic effects of digoxin if the toxicity is related to hypokalemia
(see below).
Drug Interactions
Many commonly used drugs interact with digitalis compounds. The Class IA antiarrhythmic, quinidine,
competes with digoxin for binding sites and depresses renal clearance of digoxin. These effects increase
digoxin levels and can produce toxicity. Similar interactions occur with calcium-channel blockers and
nonsteroidal anti-inflammatory drugs. Other drugs that interact with digitalis compounds are
amiodarone (Class III antiarrhythmic) and beta-blockers. Diuretics can indirectly interact with digoxin
because of their potential for decreasing plasma potassium levels (i.e., producing hypokalemia).
Hypokalemia results in increased digoxin binding to the Na+
/K+
-ATPase (possibly through
increased phosphorylation of the enzyme) and thereby enhances digoxin's therapeutic and toxic effects.
Hypercalcemia enhances digitalis-induced increases in intracellular calcium, which can lead to calcium
overload and increased susceptibility to digitalis-induced arrhythmias. Hypomagnesemia also sensitizes
the heart to digitalis-induced arrhythmias.
Therapeutic Uses
Therapeutic Uses of
Digitalis Compounds
Heart Failure
 ↑ inotropy

 ↑ ejection fraction
 ↓ preload
 ↓ pulmonary congestion/edema
Arrhythmias
 ↓ AV nodal conduction
(parasympathomimetic effect)
 ↓ ventricular rate in atrial flutter
and fibrillation
Heart failure
Digitalis compounds have historically been used in the treatment of chronic heart failure owing to their
cardiotonic effect. Although newer and more efficacious treatments for heart failure are available,
digitalis compounds are still widely used. Clinical studies in heart failure patients have shown that
digoxin, when used in conjunction with diuretics and vasodilators, improves cardiac output and ejection
fraction, and reduces filling pressures and pulmonary capillary wedge pressure (this reduces pulmonary
congestion and edema); heart rate changes very little. These effects are to be expected for a drug that
increases inotropy. Although the direct effect of digoxin on blood vessels is vasoconstriction, when given
to patients in heart failure, the systemic vascular resistance falls. This most likely results from the
improvement in cardiac output, which leads to withdrawal of compensatory vasoconstrictor
mechanisms (e.g., sympathetic adrenergic activity and angiotensin II influences). Digitalis compounds
have a small direct diuretic effect on the kidneys, which is beneficial in heart failure patients.
Atrial fibrillation and flutter
Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to
decreased filling time) and reduce cardiac output. Furthermore, chronic ventricular tachycardia can lead
to heart failure. Digitalis compounds, such as digoxin, are useful for reducing ventricular rate when it is
being driven by a high atrial rate. The mechanism of this beneficial effect of digoxin is its ability to
activate vagal efferent nerves to the heart (parasympathomimetic effect). Vagal activation can reduce
the conduction of electrical impulses within the atrioventricular node to the point where some of the
impulses will be blocked. When this occurs, fewer impulses reach the ventricles and ventricular rate
falls. Digoxin also increases the effective refractory period within the atrioventricular node.
Specific Drugs
Three different digitalis compounds (cardiac glycosides) are listed in the table below. The compound
most commonly used in the U.S. is digoxin. Ouabain is used primarily as a research tool. (See
www.rxlist.com for more details on digoxin).

Drug Oral Availability* Half-life (hours) Elimination
Digoxin 75% 40 kidneys
Digitoxin >90% 160 liver
Ouabain 0% 20 kidneys
* percent absorption
Side Effects, Contraindications and Warnings
The major side effect of digitalis compounds is cardiac arrhythmia, especially atrial tachycardias and
atrioventricular block. Digitalis compounds are contraindicated in patients who are hypokalemic, or who
have atrioventricular block or Wolff-Parkinson-White (WPW) syndrome. Impaired renal function leads to
enhanced plasma levels of digoxin because digoxin is eliminated by the kidneys. Lean, elderly patients
are more susceptible to digitalis toxicity because they often have reduced renal function, and their
reduced muscle mass increases plasma digoxin levels at a given dose because muscle Na+
/K+
-ATPase acts
as a large binding reservoir for digitalis. A 2012 analysis of the AFFIRM trial determined that digoxin
significantly increased all-cause mortality in patients with atrial fibrillation. This calls into question the
practice of using digoxin for lowering ventricular rate in patients with atrial fibrillation.
Atropine (Muscarinic Receptor Antagonist)

The vagus (parasympathetic) nerves that innervate the heart release acetylcholine (ACh) as their
primary neurotransmitter. ACh binds to muscarinic receptors (M2) that are found principally on cells
comprising the sinoatrial (SA) and atrioventricular (AV) nodes. Muscarinic receptors are coupled to the
Gi-protein; therefore, vagal activation decreases cAMP. Gi-protein activation also leads to the activation
of KACh channels that increase potassium efflux and hyperpolarizes the cells.
Increases in vagal activity to the SA node decreases the firing rate of the pacemaker cells by decreasing
the slope of the pacemaker potential (phase 4 of the action potential); this decreases heart rate
(negative chronotropy). The change in phase 4 slope results from alterations in potassium and calcium
currents, as well as the slow-inward sodium current that is thought to be responsible for the pacemaker
current (If). By hyperpolarizing the cells, vagal activation increases the cell's threshold for firing, which
contributes to the reduction the firing rate. Similar electrophysiological effects also occur at the AV
node; however, in this tissue, these changes are manifested as a reduction in impulse conduction
velocity through the AV node (negative dromotropy). In the resting state, there is a large degree of vagal
tone on the heart, which is responsible for low resting heart rates.
There is also some vagal innervation of the atrial muscle, and to a much lesser extent, the ventricular
muscle. Vagus activation, therefore, results in modest reductions in atrial contractility (inotropy) and
even smaller decreases in ventricular contractility.
Muscarinic receptor antagonists bind to muscarinic receptors thereby preventing ACh from binding to
and activating the receptor. By blocking the actions of ACh, muscarinic receptor antagonists very
effectively block the effects of vagal nerve activity on the heart. By doing so, they increase heart rate
and conduction velocity.

Atropine is a muscarinic receptor antagonist that is used to inhibit the effects of excessive vagal
activation on the heart, which is manifested as sinus bradycardia and AV nodal block. Therefore,
atropine can temporarily revert sinus bradycardia to normal sinus rhythm and reverse AV nodal blocks
by removing vagal influences.
The anticholinergic effects of atropine can produce tachycardia, pupil dilation, dry mouth, urinary
retention, inhibition of sweating (anhidrosis), blurred vision and constipation. However, most of these
side effects are only manifested with excessive dosing or with repeated dosing. Atropine is
contraindicated in patients with glaucoma.
Revised 03/15/07

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