A Textbook of Clinical Pharmacology and Therapeutics

therapeutic plasma concentration can be obtained more rap-
idly by administering a loading dose (Chapter 3).

Mechanism of action

Digoxin inhibits Na/Kadenosine triphosphatase (Na/K
ATPase). This causes accumulation of intracellular Naand
increased intracellular [Ca^2 ] concentrations via reduced
Na/Ca^2 exchange. The rise in availability of intracellular Ca^2 
accounts for the positive inotropic effect of digoxin. Excessive
inhibition of Na/KATPase causes numerous non-cardiac as
well as cardiac (dysrhythmogenic) toxic effects. Ventricular
slowing results from increased vagal activity on the AV node.
Slowing of ventricular rate improves cardiac output in patients
with atrial fibrillation by improving ventricular filling during
diastole. Clinical progress is assessed by measuring heart rate (at
the apex): apical rates of 70–80 per minute can be achieved at
rest. Unfortunately, since vagal activity is suppressed during
exercise (when heart rate is controlled by sympathetic acti-
vation), control of rate during exercise is not usually achievable.

Pharmacokinetics

Approximately 80% is excreted unchanged in the urine
in patients with normal renal function with a half-life of
30–48 hours. It is eliminated mainly by glomerular filtration,
although small amounts are secreted and reabsorbed. A small
amount (5–10%) undergoes metabolism to inactive products or
excretion via the bile and elimination in faeces. The proportion
eliminated by these non-renal clearance mechanisms increases
in patients with renal impairment, being 100% in anephric
patients, in whom the half-life is approximately 4.5 days.
Blood for digoxinconcentration determination should be
sampled more than six hours after an oral dose or immedi-
ately before the next dose is due (trough level) to allow its tis-
sue distribution to be complete. The usual therapeutic range is
1–2 ng/mL, although toxicity can occur at concentrations of
less than 1.5 ng/mL in some individuals.

Drug interactions

Digoxinhas a steep dose–response curve and a narrow thera-
peutic range, and clinically important interactions are com-
mon (see Chapters 13 and 32). Pharmacokinetic interactions
withdigoxininclude combined pharmacokinetic effects involv-
ing displacement from tissue-binding sites and reduced renal
elimination (e.g. digoxintoxicity due to concurrent treatment
withamiodaroneorquinidine).
Pharmacodynamic interactions are also important. In
particular, drugs that cause hypokalaemia (e.g. diuretics,
β-agonists, glucocorticoids) predispose to digoxintoxicity by
increasing its binding to (and effect on) Na/KATPase.

OTHER POSITIVE INOTROPES

Positive inotropes for intravenous infusion (e.g. adrenaline)
have a place in treating acute shock, but not for chronic heart
failure. Orally active positive inotropes other than digoxin
include phosphodiesterase inhibitors, e.g. milrinone. These
increase cardiac output and may bring some symptomatic
benefit, but they worsen survival.

DRUGS FORHEARTFAILURE 215

Key points

Heart failure: pathophysiology and principles of

therapeutics

• Heart failure has diverse aetiologies; ischaemic and
  idiopathic cardiomyopathy are especially important.


• Neurohumoral activation (e.g. of sympathetic and
  renin–angiotensin systems) may have adverse
  consequences.


• Treatment is sometimes specific (e.g. valve
  replacement), but is also directed generally at:
  
  
  • reducing preload (diuretics, nitrates, ACE inhibitors
    and sartans);
  
  
  • reducing afterload (ACE inhibitors and hydralazine);
  
  
  • increasing contractility (digoxin);
  
  
  • reducing heart rate (rapid rates do not permit
    optimal filling; rapid atrial fibrillation is slowed by
    digoxin).
    Treatment of chronic heart failure
  
  
  
  


• Dietary salt should be restricted.


• Drugs that improve survival usually reduce preload,
  afterload or heart rate by interrupting counter-
  regulatory hormonal mechanisms. They comprise:
  
  
  • diuretics (e.g. furosemide);
  
  
  • ACEI (e.g. captopril acutely, then ramipril,
    trolandopril);
  
  
  • sartans (e.g. candesartan);
  
  
  • β-adrenoceptor antagonists (e.g. bisoprolol,
    carvedilol);
  
  
  • aldosterone antagonists (e.g. spironolactone);
  
  
  • hydralazine plus an organic nitrate in African-
    American patients.
  
  
  
  


• Digoxin does not influence survival, but can improve
  symptoms.


• Other positive inotropes (e.g. phosphodiesterase
  inhibitors, milrinone) worsen survival.

Case history

A 62-year-old physician has developed symptoms of chronic

congestive cardiac failure in the setting of treated essential

hypertension. He had had an angioplasty to an isolated

atheromatous lesion in the left anterior descending coron-

ary artery two years previously, since when he had not had

angina. He also has a past history of gout. He is taking ben-

droflumethiazide for his hypertension and takes meclofena-

mate regularly to prevent recurrences of his gout. He

disregarded his cardiologist’s advice to take aspirin because

he was already taking another cyclo-oxygenase inhibitor (in

the form of the meclofenamate). On examination, he has a

regular pulse of 88 beats/minute, blood pressure of 160/98

mmHg, a 4–5 cm raised jugular venous pressure, mild pretib-

ial oedema and cardiomegaly. Routine biochemistry tests are

unremarkable except for a serum urate level of 0.76 mmol/L,

a total cholesterol concentration of 6.5 mmol/L, a trigly-

ceride concentration of 5.2 mmol/L and γ-glutamyltranspep-

tidase twice the upper limit of normal. An echocardiogram

shows a diffusely poorly contracting myocardium.

Question

Decide whether each of the following would be appropri-

ate as immediate measures.

(a)Digitalization

(b)Intravenous furosemide