A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

DRUGS FOR HEART FAILURE 215
therapeutic plasma concentration can be obtained more rapidly
by administering a loading dose (Chapter 3).
Mechanism of action
Digoxin inhibits Na /K adenosine triphosphatase (Na /K
ATPase). This causes accumulation of intracellular Na and
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 /K ATPase 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 activation),
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 digoxin concentration determination should be
sampled more than six hours after an oral dose or immediately
before the next dose is due (trough level) to allow its tissue
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
Digoxin has a steep dose–response curve and a narrow therapeutic
range, and clinically important interactions are common
(see Chapters 13 and 32). Pharmacokinetic interactions
with digoxin include combined pharmacokinetic effects involving
displacement from tissue-binding sites and reduced renal
elimination (e.g. digoxin toxicity due to concurrent treatment
with amiodarone or quinidine).
Pharmacodynamic interactions are also important. In
particular, drugs that cause hypokalaemia (e.g. diuretics,
β-agonists, glucocorticoids) predispose to digoxin toxicity by
increasing its binding to (and effect on) Na /K ATPase.
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.
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 counterregulatory
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 coronary
artery two years previously, since when he had not had
angina. He also has a past history of gout. He is taking bendroflumethiazide
for his hypertension and takes meclofenamate
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 pretibial
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 triglyceride
concentration of 5.2 mmol/L and γ-glutamyltranspeptidase
twice the upper limit of normal. An echocardiogram
shows a diffusely poorly contracting myocardium.
Question
Decide whether each of the following would be appropriate
as immediate measures.
(a) Digitalization
(b) Intravenous furosemide