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

214 HEART FAILURE
Precautions in terms of first-dose hypotension and monitoring
creatinine and electrolytes are similar to those for ACEI.
β-ADRENOCEPTOR ANTAGONISTS
For more information, see Chapter 28 for use in hypertension,
Chapter 29 for use in ischaemic heart disease and Chapter 32 for
use as antidysrhythmic drugs.
Classification of β-adrenoceptor antagonists
Adrenoceptors are classified as α or β, with a further subdivision
of the latter into β 1 , mainly in the heart, β 2 which are present
in, for example, bronchioles and β 3 , which mediate metabolic
effects in brown fat.
Cardioselective beta-blockers (e.g. atenolol, metoprolol)
inhibit β 1 -receptors relatively selectively, but are nonetheless
hazardous for patients with asthma.
Some beta-blockers (e.g. oxprenolol) are partial agonists and
possess intrinsic sympathomimetic activity. This is seldom
important in practice.
Vasodilating beta-blockers include drugs (e.g. labetolol,
carvedilol) with additional α-blocking activity. Celiprolol has
additional agonist activity at β 2 -receptors. Nebivolol releases
endothelium-derived nitric oxide, as well as being a highly
selective β 1 -adrenoceptor blocker.
Use in heart failure
Beta-blockers are negative inotropes and so intuitively would
be expected to worsen heart failure. There is, however, a
rationale for their use in terms of antagonizing counterregulatory
sympathetic activation and several randomized
controlled trials have demonstrated improved survival when
a β-adrenoceptor antagonist is added to other drugs, including
an ACEI. Several β-adrenoceptor antagonists have been
shown to be of benefit including bisoprolol, metoprolol and
carvedilol. Bisoprolol and metoprolol are cardioselective β 1
antagonists, whereas carvedilol is non-selective and has additional
α antagonist properties. Carvedilol may be more effective
than bisoprolol in heart failure, but is less well tolerated
because of postural hypotension. Treatment is started with a
low dose when the patient is stable and the patient reviewed
regularly at short intervals (e.g. every two weeks or more frequently
if needed), often by a heart failure nurse, with dose
titration as tolerated.
Adverse effects
• Intolerance Fatigue and cold extremities are common and
dose related. Erectile dysfunction occurs, but is less
common than with thiazide diuretics. Central nervous
system (CNS) effects (e.g. vivid dreams) can occur.
• Airways obstruction β-adrenoceptor antagonists
predispose to severe airways obstruction in patients with
pre-existing obstructive airways disease, especially
asthma.
• Peripheral vascular disease and vasospasm β-adrenoceptor
antagonists worsen claudication in patients with
symptomatic atheromatous peripheral vascular disease
and worsen Raynaud’s phenomenon.
• Hypoglycaemia β-adrenoceptor antagonists mask
symptoms of hypoglycaemia, and slow the rate of
recovery from it, because adrenaline stimulates
gluconeogenesis via β 2 -adrenoceptors.
• Heart block.
ALDOSTERONE ANTAGONISTS
For more information, see Chapter 36.
Spironolactone (or the newer expensive agent, eplerenone),
when added to conventional therapy with loop diuretic, ACEI
and β-adrenoceptor antagonist, further improves survival.
Concerns regarding hyperkalaemia in such patients may have
been overstated, at least provided patients with appreciably
impaired renal function are excluded from such treatment.
COMBINED HYDRALAZINE WITH ORGANIC NITRATE
THERAPY
There is renewed interest in combined therapy with
hydralazine (Chapter 28) and a long-acting nitrate (Chapter 29).
The pharmacologic basis for investigating this was that
hydralazine reduced afterload and the nitrate reduced preload.
As mentioned above, this improved survival in one randomized
controlled trial, but performed less well overall in a
direct comparison with an ACEI. However, a subgroup analysis
suggested that African-American patients did better with
the hydralazine/nitrate combination, whereas Caucasians
did better with ACEI. This observation led to a further study
in African-Americans which confirmed the efficacy of
hydralazine–nitrate treatment. It is now often used for patients
of African origin. Hopefully, genetic testing will further improve
the targeting of appropriate therapy (‘personalized medicine’)
in future.
DIGOXIN
For more information on the use of digoxin, refer to Chapter 32.
William Withering described an extract of foxglove as a
‘cure’ for ‘dropsy’ (congestive cardiac failure) in 1785. Digoxin
remains useful for symptoms.
Use in heart failure
Rapid atrial fibrillation can worsen heart failure and digoxin
can be used to control the ventricular response, which it does
by stimulating vagal efferents to the heart (Chapter 32). Its
positive inotropic action is an added benefit. Heart failure
patients in sinus rhythm who remain symptomatic despite
optimal treatment with life-prolonging medications also benefit.
Addition of digoxin to diuretics and ACEI reduces hospitalization
and improves symptoms, without prolonging life. It
is usually given orally, but can be given i.v. if a rapid effect is
required. Since the half-life is approximately 30–48 hours,
repeated administration of a once-daily maintenance dose results
in a plateau concentration in about five to ten days. The dose
may be adjusted based on plasma concentration determinations
once steady state has been reached (Chapter 8). Such determinations
are also useful if toxicity is suspected (e.g. because of
nausea, bradycardia or ECG changes). In urgent situations, a