Digoxin

Pharmacokinetics
Digoxin can be given orally or intravenously. Th e
average volume of distribution is approximately
7.3 L/kg; this is decreased in patients with renal
disease, hypothyroidism and in patients taking quinidine.
It is increased in thyrotoxicosis. Clearance
varies from individual to individual and is the result
of both renal and metabolic elimination mechanisms.
In healthy adults, the metabolic component
is of the order of 4060 mL/min per 70 kg, and the
renal component approximates creatinine clearance.
Metabolic clearance is reduced in congestive cardiac
failure. Clearance in any individual can be calculated
by the equations discussed elsewhere (Chapter 1). In
patients with normal renal function, the elimination
half-life is approximately 2 days. Th is is increased to
approximately 46 days in severe renal disease.

Adverse effects
Adverse eff ects are determined in part by plasma
concentration (>2.5 g/L for digoxin) and in part by
electrolyte balance. Digoxin and potassium compete
for cardiac receptor sites and hypokalaemia can precipitate
digitalis adverse eff ects. Hypercalcaemia also
potentiates toxicity.
Th e common extracardiac adverse eff ects are anorexia,
nausea, diarrhoea, vomiting, fatigue or weakness.
Less commonly, neurological symptoms occur,
including diffi culty in reading, confusion or even
psychosis. Abdominal pain is another less common
manifestation.
Th e cardiac adverse eff ects may include depression
of automaticity or conduction resulting in sinus
bradycardia, sinus arrest, junctional rhythm or various
degrees of AV block, including complete heart
block. Additionally, digoxin may produce excitatory
eff ects, resulting in ventricular ectopic beats, atrial
or ventricular tachycardia, or ventricular fi brillation.
Th e typical eff ects of digitalis glycosides on the ECG,
i.e. prolonged PR interval and ST segment depression,
do not indicate toxicity. Cardiac signs precede
extracardiac signs in about 50% of cases of toxicity.

Drug interactions
Digoxin absorption is decreased by drugs that
increase intestinal motility (e.g. metoclopramide),
and increased by drugs that decrease motility (e.g.
propantheline). Many antacids, particularly magnesium
trisilicate, reduce digoxin absorption.
Digoxin levels increase if quinidine or amiodarone is
co-administered and toxicity can occur. Th e potential
for toxicity is enhanced for all cardiac glycosides
when diuretics are co-administered because of
hypokalaemia.

Clinical use and doses

Th e principal use of digoxin is in the control of ventricular

rate in atrial fi brillation, particularly when a
return to sinus rhythm is not expected (e.g. chronic
mitral valve disease). Combination therapy with
verapamil or beta-blockers provides better control of
exercise heart rate with a lower risk of toxicity than
high-dose digoxin. Th e onset of action even after
intravenous administration is delayed for several

hours. Th us if clinical circumstances require urgent

control of ventricular rate, other approaches such
as cardioversion or intravenous amiodarone may
be more appropriate. Acute digitalisation has been
superseded by the use of intravenous adenosine or
verapamil in the termination of supraventricular
tachycardias. Th e use of digoxin in patients with heart
failure in sinus rhythm is discussed elsewhere.
Th e dosing schedule used with digoxin depends
not only on its pharmacokinetic properties, but
also on factors that determine individual susceptibility.
Th e loading dose is determined by the
volume of distribution and the desired plasma
concentration; the maintenance dose by clearance
(Chapter 1). Nomograms and simple equations are
available for dose calculation. However, these must
remain approximations and the patients clinical
response must infl uence long-term management. If
a maintenance dose is employed without a loading
dose, drug accumulation and activity develop slowly
because steady state is not reached for four to fi ve
half-lives. Th e major determinant of digoxin clearance
is renal function and the maintenance dose
must be reduced if renal function is impaired. Th e
average loading dose of digoxin is 1.01.5 mg orally,
or 0.31.0 mg intravenously. Th e usual oral maintenance
dose in the presence of normal renal function
is 0.1250.250 mg/day.
Th e use of drug monitoring of digoxin plasma levels
has been useful, particularly in renal impairment
and toxicity. Th e normal therapeutic range of digoxin
is 12 g/L. Venous sampling should be performed
34 hours after an intravenous dose or 68 hours after
an oral dose. If blood levels are low then compliance
should be checked, and possible causes of malabsorption
considered.