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

enhance myocardial contractility. Elevated extracellular
K + levels (i.e., hyperkalemia) cause dephosphorylation
of the ATPase α subunit, altering the site of action of the
most commonly used cardiac glycoside, digoxin, and
thereby reducing the drug’s binding and effect.
Electrophysiologic Actions. At therapeutic serum or plasma concentrations
(i.e., 1-2 ng/mL), digoxin decreases automaticity and
increases the maximal diastolic resting membrane potential in atrial
and atrioventricular (AV) nodal tissues. This occurs via increases in
vagal tone and sympathetic nervous system activity inhibition. In
addition, digoxin prolongs the effective refractory period and
decreases conduction velocity in AV nodal tissue. Collectively, these
may contribute to sinus bradycardia, sinus arrest, prolongation of
AV conduction, or high- grade AV block. At higher concentrations,
cardiac glycosides may increase sympathetic nervous system activity
that influences cardiac tissue automaticity, change associated with
the genesis of atrial and ventricular arrhythmias. Increased intracellular
Ca 2+ loading and sympathetic tone increases the spontaneous
(phase 4) rate of diastolic depolarization as well as promoting
delayed afterdepolarization; together, these decrease the threshold
for generation of a propagated action potential and predisposes to
malignant ventricular arrhythmias (see Chapter 29).
Regulation of Sympathetic Nervous System Activity. Sympathetic
nervous system overactivation in CHF occurs, in part, from aberrant
arterial baroreflex responses to low cardiac output. Specifically, a
decline in baroreflex response to blood pressure results in a decline
in baroreflex- mediated tonic suppression of CNS- directed sympathetic
activity. This cascade contributes to the sustained elevation in
plasma NE, renin, and vasopressin (Ferguson et al., 1989). Cardiac
glycosides favorably influence carotid baroreflex responsiveness to
changes in carotid sinus pressure (Wang et al., 1990). In patients
with moderate- to- advanced CHF, cardiac glycoside infusion
increases forearm blood flow and cardiac index and decreased heart
rate. There is clinical evidence to suggest that digoxin decreases centrally
mediated sympathetic nervous system tone, although the
mechanism to explain this is unresolved (Ferguson et al., 1989).
Pharmacokinetics. The elimination t 1/2
for digoxin is
36-48 hours in patients with normal or near- normal
renal function, permitting once- daily dosing. Near
steady- state blood levels are achieved ~7 days after initiation
of maintenance therapy. Digoxin is excreted by
the kidney, and increases in cardiac output or renal
blood flow from vasodilator therapy or sympathomimetic
agents may increase renal digoxin clearance,
necessitating adjustment of daily maintenance doses.
The volume of distribution and drug clearance rate are
both decreased in elderly patients.
Despite renal clearance, digoxin is not removed effectively by
hemodialysis due to the drug’s large (4-7 L/kg) volume of distribution.
The principal tissue reservoir is skeletal muscle and not adipose
tissue, and thus dosing should be based on estimated lean body mass.
Most digoxin tablets average 70-80% oral bioavailability; however,
~10% of the general population harbors the enteric bacterium
Eubacterium lentum, which inactivates digoxin and thus may account
for drug tolerance that is observed in some patients. Liquid- filled capsules
of digoxin (LANOXICAPS) have a higher bioavailability than do
tablets (LANOXIN); thus, the drug requires dosage adjustment if a
patient is switched from one delivery form to the other. Digoxin is
available for intravenous administration, and maintenance doses can
be given intravenously when oral dosing is inappropriate. Digoxin
administered intramuscularly is erratically absorbed, causes local discomfort,
and usually is unnecessary. A number of clinical conditions
may alter the pharmacokinetics of digoxin or patient susceptibility to
the toxic manifestations of this drug. For example, chronic renal failure
decreases the volume of distribution of digoxin and therefore
requires a decrease in maintenance dosage of the drug. In addition,
drug interactions that may influence circulating serum digoxin levels
include several commonly used cardiovascular medications such as
verapamil, amiodarone, propafenone, and spironolactone. The rapid
administration of Ca 2+ increases the risk of inducing malignant
arrhythmias in patients already treated with digoxin. Electrolyte disturbances,
especially hypokalemia, acid–base imbalances, and one’s
form of underlying heart disease also may alter a patient’s susceptibility
to digoxin side effects.
Maximal increase in LV contractility becomes apparent at
serum digoxin levels ~1.4 ng/mL (1.8 nmol) (Kelly and Smith,
1992). The neurohormonal benefits of digoxin, however, may occur
between 0.5-1 ng/mL. In turn, higher serum concentrations are not
associated with incrementally increased clinical benefit. Moreover,
there are data to suggest that the risk of death is greater with increasing
serum concentrations, even at values within the traditional therapeutic
range, and therefore many advocate maintaining digoxin
levels <1 ng/mL.
Clinical Use of Digoxin in Heart Failure. Data from contemporary
clinical trials have re- characterized the utility
of cardiac glycosides, once first- line agents, in CHF,
especially in patients with normal sinus rhythm (as
opposed to atrial fibrillation).
Digoxin discontinuation in clinically stable patients with
mild- to- moderate CHF from LV systolic dysfunction worsened
symptoms and decreased maximal treadmill exercise (Uretsky et al.,
1993; Packer et al., 1993). However, eventhough digoxin may decrease
CHF- associated hospitalizations in patients with severe forms of the
disease, drug use does not reduce all- cause mortality. Overall, digoxin
use usually is limited to CHF patients with LV systolic dysfunction in
atrial fibrillation or to patients in sinus rhythm who remain symptomatic
despite maximal therapy with ACE inhibitors and βadrenergic
receptor antagonists. The latter agents are viewed as first- line therapies
because of their proven mortality benefit.
Digoxin Toxicity. The incidence and severity of digoxin toxicity
have declined substantially in the past 2 decades as a
consequence of alternative drugs available for the treatment
of supraventricular arrhythmias in CHF, increased
understanding of digoxin pharmacokinetics, improved
serum digoxin level monitoring, and identification of
important interactions between digoxin and other
commonly co- administered drugs. Nevertheless, the
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CHAPTER 28
PHARMACOTHERAPY OF CONGESTIVE HEART FAILURE