CARDIAC GLYCOSIDES

Digitalis glycosides are no longer considered first-line drugs in the

treatment of heart failure. However, because they are not discussed
elsewhere in this book, we begin our discussion with this group.
A. Prototypes and Pharmacokinetics
All cardiac glycosides include a steroid nucleus and a lactone ring;
most also have one or more sugar residues. The cardiac glycosides
are often called digitalis! because several come from the digitalis
"fo#glove$ plant. Digoxin is the prototype agent and the only one
commonly used in the %nited &tates. A very similar molecule,
digito#in, which also comes from the fo#glove, is no longer available
in the %nited &tates. Digo#in has an oral bioavailability of
'()*+,, and a half-life of -').( h. /limination is by renal e#cretion
"about '(,$ and hepatic metabolism ".(,$.
. !echanism o" Action
0nhibition of 1a2342 AT5ase of the cell membrane by digitalis is
well documented and is considered to be the primary biochemical
mechanism of action "6igure 7-)-$. 0nhibition of 1a2342 AT5ase
results in a small increase in intracellular sodium. The increased
sodium alters the driving force for sodium-calcium e#change by
the e#changer, 189, so that less calcium is removed from the cell.
The increased intracellular calcium is stored in the sarcoplasmic
reticulum and upon release increases contractile force. :ther
mechanisms of action for digitalis have been proposed, but they
are probably not as important as inhibition of the AT5ase. The
conse;uences of 1a2342 AT5ase inhibition are seen in both the
mechanical and the electrical function of the heart. Digitalis also
modifies autonomic outflow, and this action has effects on the
electrical properties of the heart.
C. Cardiac E""ects
#. !echanica$ e""ects%The increase in contractility evoked
by digitalis results in increased ventricular e<ection, decreased
end-systolic and end-diastolic si=e, increased cardiac output,
and increased renal perfusion. These beneficial effects permit a
decrease in the compensatory sympathetic and renal responses
previously described. The decrease in sympathetic tone is especially
beneficial> reduced heart rate, preload, and afterload permit
the heart to function more efficiently "point 8 in 6igure 7-)7
may approach point A as the function curve approaches normal$.
&. E$ectrica$ e""ects%/lectrical effects include early cardiac
parasympathomimetic responses and later arrhythmogenic
actions. They are summari=ed in Table 7-)7.
a. Early responses0ncreased 5? interval, caused by the
decrease in atrioventricular "A@$ conduction velocity, and flattening
of the T wave are common electrocardiogram "/8A$ effects.
The effects on the atria and A@ node are largely parasympathetic
"mediated by the vagus nerve$ and can be partially blocked
by atropine. The increase in the A@ nodal refractory period is
particularly important when atrial flutter or fibrillation is present
because the refractoriness of the A@ node determines the
ventricular rate in these arrhythmias. The effect of digitalis is to slow
ventricular rate. &hortened BT, inversion of the T, and &T depression
may occur later.
b. Toxic responses0ncreased automaticity, caused by intracellular
calcium overload, is the most important manifestation of
digitalis to#icity. 0ntracellular calcium overload results in delayed
afterdepolari=ations, which may evoke e#trasystoles, tachycardia,
or fibrillation in any part of the heart. 0n the ventricles, the e#trasystoles
are recogni=ed as premature ventricular beats "5@Cs$.
Dhen 5@Cs are coupled to normal beats in a 7>7 fashion, the
rhythm is called bigeminy "6igure 7-).$.
D. C$inica$ 'ses
#. Congesti(e heart "ai$)re%Digitalis is the traditional
positive inotropic agent used in the treatment of chronic heart
failure. However, careful clinical studies indicate that while digitalis
may improve functional status "reducing symptoms$, it does
not prolong life. :ther agents "diuretics, A8/ inhibitors, vasodilators$
may be e;ually effective and less to#ic, and some of these
alternative therapies do prolong life "see later discussion$. Cecause
the half-lives of cardiac glycosides are long, the drugs accumulate
significantly in the body, and dosing regimens must be carefully
designed and monitored
&. Atria$ "i*ri$$ation%0n atrial flutter and fibrillation, it is
desirable to reduce the conduction velocity or increase the refractory
period of the A@ node so that ventricular rate is controlled
within a range compatible with efficient filling and e<ection.
The parasympathomimetic action of digitalis often accomplishes
this therapeutic ob<ective, although high doses may be re;uired.
Alternative drugs for rate control include E blockers and calcium
channel blockers, but these drugs have negative inotropic effects.
E. Interactions
Buinidine causes a well-documented reduction in digo#in clearance
and can increase the serum digo#in level if digo#in dosage is not
ad<usted. &everal other drugs have the same effect "amiodarone,
verapamil, others$, but the interactions with these drugs are not
clinically significant. Digitalis to#icity, especially arrhythmogenesis,
is increased by hypokalemia, hypomagnesemia, and hypercalcemia
Foop diuretics and thia=ides, which are always included in the
treatment of heart failure, may significantly reduce serum potassium
and thus precipitate digitalis to#icity. Digitalis-induced
vomiting may deplete serum magnesium and similarly facilitate
to#icity. These ion interactions are important in treating digitalis
to#icity.
+. Digita$is ,oxicity
The ma<or signs of digitalis to#icity are arrhythmias, nausea, vomiting,
and diarrhea. ?arely, confusion or hallucinations and visual or
endocrine aberrations may occur. Arrhythmias are common and
dangerous. 8hronic into#ication is an e#tension of the therapeutic
effect of the drug and is caused by e#cessive calcium accumulation
in cardiac cells "calcium overload$. This overload triggers abnormal
automaticity and the arrhythmias noted in Table 7-)7.
&evere, acute into#ication caused by suicidal or accidental
e#treme overdose results in cardiac depression leading to cardiac
arrest rather than tachycardia or fibrillation.
Treatment of digitalis to#icity includes several steps, as follows.
Correction o" potassi)m or magnesi)m de"iciency
8orrection of potassium deficiency "caused, eg, by diuretic use$ is
useful in chronic digitalis into#ication. Gild to#icity may often be
managed by omitting 7 or H doses of digitalis and giving oral or parenteral 42 supplements. &evere
acute into#ication "as in suicidal overdoses$ usually causes marked hyperkalemia and should not be
treated with supplemental potassium.
&. Antiarrhythmic dr)gs%Antiarrhythmic drugs may be useful
if increased automaticity is prominent and does not respond to normali=ation
of serum potassium. Agents that do not severely impair
cardiac contractility "eg, lidocaine or phenytoin$ are favored, but
drugs such as propranolol have also been used successfully. &evere
acute digitalis overdose usually causes marked inhibition of all
cardiac pacemakers, and an electronic pacemaker may be re;uired.
Antiarrhythmic drugs are dangerous in such patients.
-. Digoxin anti*odies%Digo#in antibodies "6ab fragments;
Digibind$ are e#tremely effective and should always be used if
other therapies appear to be failing. They are effective for poisoning
with many cardiac glycosides in addition to digo#in and may
save patients who would otherwise die.