DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

838 Pharmacologic Effects. Digitalis glycosides exert positive
inotropic effects and are used in heart failure
(Chapter 28). Their inotropic action results from increased
intracellular Ca 2+ (Smith, 1988), which also forms the
basis for arrhythmias related to cardiac glycoside intoxication.
Cardiac glycosides increase phase 4 slope (i.e.,
increase the rate of automaticity), especially if [K] o
is
low. These drugs (e.g., digoxin) also exert prominent
vagotonic actions, resulting in inhibition of Ca 2+ currents
in the AV node and activation of acetylcholinemediated
K + currents in the atrium. Thus, the major
“indirect” electrophysiologic effects of cardiac glycosides
are hyperpolarization, shortening of atrial action
potentials, and increases in AV nodal refractoriness. The
latter action accounts for the utility of digoxin in terminating
re-entrant arrhythmias involving the AV node and
in controlling ventricular response in patients with atrial
fibrillation. Cardiac glycosides may be especially useful
in the latter situation because many such patients have
heart failure, which can be exacerbated by other AV
nodal blocking drugs such as Ca 2+ channel blockers or
β adrenergic receptor antagonists. However, sympathetic
drive is increased markedly in many patients with
advanced heart failure, so digitalis is not very effective
in decreasing the rate; on the other hand, even a modest
decrease in rate can ameliorate heart failure.
Similarly, in other conditions in which high sympathetic
tone drives rapid AV conduction (e.g., chronic
lung disease, thyrotoxicosis), digitalis therapy may be
only marginally effective in slowing the rate. In heart
transplant patients, in whom innervation has been
ablated, cardiac glycosides are ineffective for rate control.
Increased sympathetic activity and hypoxia can
potentiate digitalis-induced changes in automaticity and
DADs, thus increasing the risk of digitalis toxicity. A
further complicating feature in thyrotoxicosis is
increased digoxin clearance. The major ECG effects of
cardiac glycosides are PR prolongation and a nonspecific
alteration in ventricular repolarization (manifested
by depression of the ST segment), whose underlying
mechanism is not well understood.
Adverse Effects. Because of the low therapeutic index of cardiac
glycosides, their toxicity is a common clinical problem (Chapter 28).
Arrhythmias, nausea, disturbances of cognitive function, and
blurred or yellow vision are the usual manifestations. Elevated
serum concentrations of digitalis, hypoxia (e.g., owing to chronic
lung disease), and electrolyte abnormalities (e.g., hypokalemia,
hypomagnesemia, hypercalcemia) predispose patients to digitalisinduced
arrhythmias. Although digitalis intoxication can cause
virtually any arrhythmia, certain types of arrhythmias are characteristic.
Arrhythmias that should raise a strong suspicion of digitalis
intoxication are those in which DAD-related tachycardias occur
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
along with impairment of sinus node or AV nodal function. Atrial
tachycardia with AV block is classic, but ventricular bigeminy
(sinus beats alternating with beats of ventricular origin), “bidirectional”
ventricular tachycardia (a very rare entity), AV junctional
tachycardias, and various degrees of AV block also can occur. With
severe intoxication (e.g., with suicidal ingestion), severe hyperkalemia
owing to poisoning of Na + ,K + -ATPase and profound bradyarrhythmias,
which may be unresponsive to pacing therapy, are
seen. In patients with elevated serum digitalis levels, the risk of
precipitating VF by DC cardioversion probably is increased; in
those with therapeutic blood levels, DC cardioversion can be used
safely.
Minor forms of cardiac glycoside intoxication may require
no specific therapy beyond monitoring cardiac rhythm until symptoms
and signs of toxicity resolve. Sinus bradycardia and AV block
often respond to intravenous atropine, but the effect is transient.
Mg 2+ has been used successfully in some cases of digitalis-induced
tachycardia. Any serious arrhythmia should be treated with
antidigoxin Fab fragments (DIGIBIND, DIGIFAB), which are highly
effective in binding digoxin and digitoxin and greatly enhance their
renal excretion (Chapter 28). Serum glycoside concentrations rise
markedly with antidigitalis antibodies, but these represent bound
(pharmacologically inactive) drug. Temporary cardiac pacing may
be required for advanced sinus node or AV node dysfunction.
Digitalis exerts direct arterial vasoconstrictor effects, which can be
especially deleterious in patients with advanced atherosclerosis who
receive intravenous drug; mesenteric and coronary ischemia have
been reported.
Clinical Pharmacokinetics. The only digitalis glycoside used in the
U.S. is digoxin (LANOXIN). Digitoxin (various generic preparations)
also is used for chronic oral therapy outside the U.S. Digoxin tablets
are incompletely (75%) bioavailable. In some patients, intestinal
microflora may metabolize digoxin, markedly reducing bioavailability.
In these patients, higher than usual doses are required for clinical
efficacy; toxicity is a serious risk if antibiotics that destroy
intestinal microflora are administered. Inhibition of P-glycoprotein
(see “Adverse effects and Drug Interactions” under “Dronaderone”)
also may play a role in cases of toxicity. Digoxin is 20-30% protein
bound. The anti-arrhythmic effects of digoxin can be achieved with
intravenous or oral therapy. However, digoxin undergoes relatively
slow distribution to effector site(s); therefore, even with intravenous
therapy, there is a lag of several hours between drug administration
and the development of measurable anti-arrhythmic effects such as
PR-interval prolongation or slowing of the ventricular rate in atrial
fibrillation. To avoid intoxication, a loading dose of ~0.6-1 mg
digoxin is administered over 24 hours. Measurement of postdistribution
serum digoxin concentration and adjustment of the daily dose
(0.0625-0.5 mg) to maintain concentrations of 0.5-2 ng/mL are useful
during chronic digoxin therapy (Table 29–5). Some patients may
require and tolerate higher concentrations but with an increased risk
of adverse effects.
The elimination t 1/2
of digoxin ordinarily is ~36 hours, so
maintenance doses are administered once daily. Renal elimination
of unchanged drug accounts for less than 80% of digoxin elimination.
Digoxin doses should be reduced (or dosing interval
increased) and serum concentrations monitored closely in patients
with impaired excretion owing to renal failure or in patients who