Cardiac Drugs

Overview of Modes of Action (A)
1. The pumping capacity of the heart is
regulated by sympathetic and parasympathetic
nerves. Drugs capable
of interfering with autonomic
nervous function therefore provide a
means of influencing cardiac performance.
Thus, anxiolytics of the benzodiazepine
type, such as diazepam,
can be employed in myocardial infarction
to suppress sympathoactivation
due to life-threatening distress.
Under the influence of antiadrenergic
agents, used to lower an elevated
blood pressure, cardiac work is decreased.
Ganglionic blockers
are used in managing hypertensive
emergencies. Parasympatholytics
and !-blockers prevent the
transmission of autonomic nerve impulses
to heart muscle cells by blocking
the respective receptors.
2. An isolated mammalian heart
whose extrinsic nervous connections
have been severed will beat spontaneously
for hours if it is supplied with a
nutrient medium via the aortic trunk
and coronary arteries (Langendorff
preparation). In such a preparation, only
those drugs that act directly on cardiomyocytes
will alter contractile force and
beating rate.
Parasympathomimetics and sympathomimetics
act at membrane receptors
for visceromotor neurotransmitters.
The plasmalemma also harbors
the sites of action of cardiac glycosides
(the Na/K-ATPases), of Ca2+ antagonists
(Ca2+ channels ), and of
agents that block Na+ channels (local
anesthetics). An intracellular
site is the target for phosphodiesterase
inhibitors (e.g., amrinone).
3. Mention should also be made of
the possibility of affecting cardiac function
in angina pectoris or congestive
heart failure by reducing
venous return, peripheral resistance,
or both, with the aid of vasodilators;
and by reducing sympathetic drive
applying !-blockers.
Events Underlying Contraction and
Relaxation (B)
The signal triggering contraction is a
propagated action potential (AP) generated
in the sinoatrial node. Depolarization
of the plasmalemma leads to a rapid
rise in cytosolic Ca2+ levels, which
causes the contractile filaments to
shorten (electromechanical coupling).
The level of Ca2+ concentration attained
determines the degree of shortening,
i.e., the force of contraction. Sources of
Ca2+ are: a) extracellular Ca2+ entering
the cell through voltage-gated Ca2+
channels; b) Ca2+ stored in membranous
sacs of the sarcoplasmic reticulum (SR);
c) Ca2+ bound to the inside of the plasmalemma.
The plasmalemma of cardiomyocytes
extends into the cell interior
in the form of tubular invaginations
(transverse tubuli).
The trigger signal for relaxation is
the return of the membrane potential to
its resting level. During repolarization,
Ca2+ levels fall below the threshold for
activation of the myofilaments (3 10–7
M), as the plasmalemmal binding sites
regain their binding capacity; the SR
pumps Ca2+ into its interior; and Ca2+
that entered the cytosol during systole
is again extruded by plasmalemmal
Ca2+-ATPases with expenditure of energy.
In addition, a carrier (antiporter),
utilizing the transmembrane Na+ gradient
as energy source, transports Ca2+ out
of the cell in exchange for Na+ moving
down its transmembrane gradient
(Na+/Ca2+ exchange).


Cardiac Glycosides
Diverse plants (A) are sources of sugarcontaining
compounds (glycosides) that
also contain a steroid ring (structural
formulas ) and augment the contractile
force of heart muscle (B): cardiotonic
glycosides. cardiosteroids, or “digitalis.”
If the inotropic, “therapeutic” dose
is exceeded by a small increment, signs
of poisoning appear: arrhythmia and
contracture (B). The narrow therapeutic
margin can be explained by the mechanism
of action.
Cardiac glycosides (CG) bind to the
extracellular side of Na+/K+-ATPases of
cardiomyocytes and inhibit enzyme activity.
The Na+/K+-ATPases operate to
pump out Na+ leaked into the cell and to
retrieve K+ leaked from the cell. In this
manner, they maintain the transmembrane
gradients for K+ and Na+, the negative
resting membrane potential, and
the normal electrical excitability of the
cell membrane. When part of the enzyme
is occupied and inhibited by CG,
the unoccupied remainder can increase
its level of activity and maintain Na+ and
K+ transport. The effective stimulus is a
small elevation of intracellular Na+ concentration
(normally approx. 7 mM).
Concomitantly, the amount of Ca2+ mobilized
during systole and, thus, contractile
force, increases. It is generally
thought that the underlying cause is the
decrease in the Na+ transmembrane
gradient, i.e., the driving force for the
Na+/Ca2+ exchange (p. 128), allowing the
intracellular Ca2+ level to rise. When too
many ATPases are blocked, K+ and Na+
homeostasis is deranged; the membrane
potential falls, arrhythmias occur.
Flooding with Ca2+ prevents relaxation
during diastole, resulting in contracture.
The CNS effects of CG (C) are also
due to binding to Na+/K+-ATPases. Enhanced
vagal nerve activity causes a decrease
in sinoatrial beating rate and velocity
of atrioventricular conduction. In
patients with heart failure, improved
circulation also contributes to the reduction
in heart rate. Stimulation of the
area postrema leads to nausea and vomiting.
Disturbances in color vision are
evident.
Indications for CG are: (1) chronic
congestive heart failure; and (2) atrial
fibrillation or flutter, where inhibition of
AV conduction protects the ventricles
from excessive atrial impulse activity
and thereby improves cardiac performance
(D). Occasionally, sinus rhythm
is restored.
Signs of intoxication are: (1) cardiac
arrhythmias, which under certain
circumstances are life-threatening, e.g.,
sinus bradycardia, AV-block, ventricular
extrasystoles, ventricular fibrillation
(ECG); (2) CNS disturbances — altered
color vision (xanthopsia), agitation,
confusion, nightmares, hallucinations;
(3) gastrointestinal — anorexia, nausea,
vomiting, diarrhea; (4) renal — loss of
electrolytes and water, which must be
differentiated from mobilization of accumulated
edema fluid that occurs with
therapeutic dosage.
Therapy of intoxication: administration
of K+, which inter alia reduces
binding of CG, but may impair AV-conduction;
administration of antiarrhythmics,
such as phenytoin or lidocaine
; oral administration of colestyramine
for binding and preventing
absorption of digitoxin present
in the intestines (enterohepatic cycle);
injection of antibody (Fab) fragments
that bind and inactivate digitoxin and
digoxin. Compared with full antibodies,
fragments have superior tissue penetrability,
more rapid renal elimination,
and lower antigenicity.


The pharmacokinetics of cardiac
glycosides (A) are dictated by their polarity,
i.e., the number of hydroxyl
groups. Membrane penetrability is virtually
nil in ouabain, high in digoxin,
and very high in digitoxin. Ouabain (gstrophanthin)
does not penetrate into
cells, be they intestinal epithelium, renal
tubular, or hepatic cells. At best, it is
suitable for acute intravenous induction
of glycoside therapy.
The absorption of digoxin depends
on the kind of galenical preparation
used and on absorptive conditions in
the intestine. Preparations are now of
such quality that the derivatives methyldigoxin
and acetyldigoxin no longer offer
any advantage. Renal reabsorption is incomplete;
approx. 30% of the total
amount present in the body (s.c. full
“digitalizing” dose) is eliminated per
day. When renal function is impaired,
there is a risk of accumulation. Digitoxin
undergoes virtually complete reabsorption
in gut and kidneys. There is
active hepatic biotransformation: cleavage
of sugar moieties, hydroxylation at
C12 (yielding digoxin), and conjugation
to glucuronic acid. Conjugates secreted
with bile are subject to enterohepatic
cycling; conjugates reaching the
blood are renally eliminated. In renal insufficiency,
there is no appreciable accumulation.
When digitoxin is withdrawn
following overdosage, its effect
decays more slowly than does that of digoxin.
Other positive inotropic drugs.
The phosphodiesterase inhibitor amrinone
(cAMP elevation ) can be
administered only parenterally for a
maximum of 14 d because it is poorly
tolerated. A closely related compound is
milrinone. In terms of their positive inotropic
effect, !-sympathomimetics,
unlike dopamine, are of little
therapeutic use; they are also arrhythmogenic
and the sensitivity of the !-receptor
system declines during continuous
stimulation.
Treatment Principles in Chronic Heart
Failure
Myocardial insufficiency leads to a decrease
in stroke volume and venous
congestion with formation of edema.
Administration of (thiazide) diuretics
offers a therapeutic approach of
proven efficacy that is brought about by
a decrease in circulating blood volume
(decreased venous return) and peripheral
resistance, i.e., afterload. A similar
approach is intended with ACE-inhibitors,
which act by preventing the synthesis
of angiotensin II (!vasoconstriction)
and reducing the secretion of aldosterone
(! fluid retention). In severe
cases of myocardial insufficiency, cardiac
glycosides may be added to augment
cardiac force and to relieve the
symptoms of insufficiency.
In more recent times !-blocker on a
long term were found to improve cardiac
performance — particularly in idiopathic
dilating cardiomyopathy — probably
by preventing sympathetic overdrive.

Antiarrhythmic Drugs

The electrical impulse for contraction
(propagated action potential)
originates in pacemaker cells of the sinoatrial
node and spreads through the
atria, atrioventricular (AV) node, and
adjoining parts of the His-Purkinje fiber
system to the ventricles (A). Irregularities
of heart rhythm can interfere dangerously
with cardiac pumping function.
I. Drugs for selective control of sinoatrial
and AV nodes. In some forms
of arrhythmia, certain drugs can be used
that are capable of selectively facilitating
and inhibiting (green and red arrows,
respectively) the pacemaker function
of sinoatrial or atrioventricular
cells.
Sinus bradycardia. An abnormally
low sinoatrial impulse rate (<60/min)
can be raised by parasympatholytics.
The quaternary ipratropium is preferable
to atropine, because it lacks CNS
penetrability. Sympathomimetics
also exert a positive chronotropic action;
they have the disadvantage of increasing
myocardial excitability (and
automaticity) and, thus, promoting ectopic
impulse generation (tendency to
extrasystolic beats). In cardiac arrest
epinephrine can be used to reinitiate
heart beat.
Sinus tachycardia (resting rate
>100 beats/min). !-Blockers eliminate
sympathoexcitation and decrease cardiac
rate.
Atrial flutter or fibrillation. An excessive
ventricular rate can be decreased
by verapamil or cardiac
glycosides. These drugs inhibit
impulse propagation through the AV
node, so that fewer impulses reach the
ventricles.
II. Nonspecific drug actions on
impulse generation and propagation.
Impulses originating at loci outside the
sinus node are seen in supraventricular
or ventricular extrasystoles, tachycardia,
atrial or ventricular flutter, and fibrillation.
In these forms of rhythm disorders,
antiarrhythmics of the local anesthetic,
Na+-channel blocking type (B) are
used for both prophylaxis and therapy.
Local anesthetics inhibit electrical excitation
of nociceptive nerve fibers
; concomitant cardiac inhibition
(cardiodepression) is an unwanted effect.
However, in certain types of arrhythmias
(see above), this effect is useful.
Local anesthetics are readily cleaved
(arrows) and unsuitable for oral administration
(procaine, lidocaine). Given judiciously,
intravenous lidocaine is an effective
antiarrhythmic. Procainamide
and mexiletine, congeners endowed
with greater metabolic stability, are examples
of orally effective antiarrhythmics.
The desired and undesired effects
are inseparable. Thus, these antiarrhythmics
not only depress electrical
excitability of cardiomyocytes (negative
bathmotropism, membrane stabilization),
but also lower sinoatrial rate (neg.
chronotropism), AV conduction (neg.
dromotropism), and force of contraction
(neg. inotropism). Interference with normal
electrical activity can, not too paradoxically,
also induce cardiac arrhythmias–
arrhythmogenic action.
Inhibition of CNS neurons is the
underlying cause of neurological effects
such as vertigo, confusion, sensory disturbances,
and motor disturbances
(tremor, giddiness, ataxia, convulsions).


Electrophysiological Actions of
Antiarrhythmics of the Na+-Channel
Blocking Type
Action potential and ionic currents.
The transmembrane electrical potential
of cardiomyocytes can be recorded
through an intracellular microelectrode.
Upon electrical excitation, a characteristic
change occurs in membrane potential—
the action potential (AP). Its underlying
cause is a sequence of transient
ionic currents. During rapid depolarization
(Phase 0), there is a short-lived influx
of Na+ through the membrane. A
subsequent transient influx of Ca2+ (as
well as of Na+) maintains the depolarization
(Phase 2, plateau of AP). A delayed
efflux of K+ returns the membrane
potential (Phase 3, repolarization) to its
resting value (Phase 4). The velocity of
depolarization determines the speed at
which the AP propagates through the
myocardial syncytium.
Transmembrane ionic currents involve
proteinaceous membrane pores:
Na+, Ca2+, and K+ channels. In A, the
phasic change in the functional state of
Na+ channels during an action potential
is illustrated.
Effects of antiarrhythmics. Antiarrhythmics
of the Na+-channel blocking
type reduce the probability that Na+
channels will open upon membrane depolarization
(“membrane stabilization”).
The potential consequences are
(A, bottom): 1) a reduction in the velocity
of depolarization and a decrease in
the speed of impulse propagation; aberrant
impulse propagation is impeded. 2)
Depolarization is entirely absent; pathological
impulse generation, e.g., in the
marginal zone of an infarction, is suppressed.
3) The time required until a
new depolarization can be elicited, i.e.,
the refractory period, is increased; prolongation
of the AP (see below) contributes
to the increase in refractory period.
Consequently, premature excitation
with risk of fibrillation is prevented.
Mechanism of action. Na+-channel
blocking antiarrhythmics resemble
most local anesthetics in being cationic
amphiphilic molecules ( exception:
phenytoin). Possible molecular
mechanisms of their inhibitory effects
are outlined in more detail.
Their low structural specificity is
reflected by a low selectivity towards
different cation channels. Besides the
Na+ channel, Ca2+ and K+ channels are also
likely to be blocked. Accordingly, cationic
amphiphilic antiarrhythmics affect
both the depolarization and repolarization
phases. Depending on the substance,
AP duration can be increased
(Class IA), decreased (Class IB), or remain
the same (Class IC).
Antiarrhythmics representative
of these categories include: Class IA—
quinidine, procainamide, ajmaline, disopyramide,
propafenone; Class IB—lidocaine,
mexiletine, tocainide, as well as
phenytoin; Class IC—flecainide.
Note: With respect to classification,
!-blockers have been assigned to Class
II, and the Ca2+-channel blockers verapamil
and diltiazem to Class IV.
Commonly listed under a separate
rubric (Class III) are amiodarone and the
!-blocking agent sotalol, which both inhibit
K+-channels and which both cause
marked prolongation of the AP with a
lesser effect on Phase 0 rate of rise.
Therapeutic uses. Because of their
narrow therapeutic margin, these antiarrhythmics
are only employed when
rhythm disturbances are of such severity
as to impair the pumping action of
the heart, or when there is a threat of
other complications. The choice of drug
is empirical. If the desired effect is not
achieved, another drug is tried. Combinations
of antiarrhythmics are not customary.
Amiodarone is reserved for special
cases.