β-ADRENOCEPTOR
BLOCKING DRUGS
For many years the prevailing
view was that β-blockers are contraindicated in CHF. The physiological
rationale for not using β-blockers in heart failure was certainly well founded.
Heart failure patients have a decrease in cardiac output. Since cardiac output
is a function of stroke volume times heart rate (CO = SV x HR), an in-creased
heart rate would be necessary to maintain an adequate cardiac output in the
presence of the rela-tively fixed decrease in stroke volume observed in CHF. A
rapid increase in heart rate does play an important role in the physiological
response to acute hemorrhage. Thus, a decrease in heart rate, along with a
depression in contractility produced by β-blockers, would be ex-pected to
precipitate catastrophic decompensation; and this certainly can happen in the
acute setting.
Several subsequent studies
have led to the incorpo-ration of β-blocker therapy, using either carvedilol or
metoprolol, into the standard of care for CHF. Patients already taking
digitalis, furosemide, and an ACE in-hibitor were prescribed a β-blocker in
these studies. Surprisingly, the long-term use of β-blockers in CHF improved
ventricular function and prolonged survival. The assumption that an increased
heart rate is neces- sary to maintain an adequate cardiac output in the face of
a reduced stroke volume is clearly not true in CHF.
The benefits of the use of β-blockade appear to ex-ceed
by far the risks of bronchospasm in patients diag-nosed with chronic
obstructive pulmonary disease (COPD) and/or suppression of hypoglycemic
responses in diabetics. COPD is very different from bronchospas-tic asthma.
Young people with asthma have highly reac-tive airways and can die within hours
of a broncho-spasm in response to an exposure to an external agent. This highly
reversible dynamic condition contrasts sharply with the destruction of
connective tissue in lung parenchyma and dead airway sacs that are not very
re-active. This is a very different phenomenon.
β-Blockers are adrenoceptor
antagonists that bind to the β-receptor at the same site as do endogenous β-adrenergic agonists, such as
norepinephrine. Norepi-nephrine binds to the adrenergic receptor, which
acti-vates a G protein, which participates in the conversion of ATP to cAMP via
adenylyl cyclase. cAMP activates pro-tein kinase A (protein kinase A, or PKA)
to phosphory-late proteins, such as the sarcolemmal L-type Ca++ chan-nel,
that subsequently increase calcium, increase heart rate, conduction, and
contraction. β-blockers bind to the same receptor as does norepinephrine but do
not facili-tate G protein coupling. Occupation of the binding site by the
β-blocker prevents norepinephrine from binding to it and stimulating cAMP
formation.
Circulating plasma
norepinephrine levels correlate inversely with survival in CHF; that is, higher
levels of norepinephrine are associated with a decrease in sur-vival. It
appears that norepinephrine levels are more than just markers of disease
severity: norepinephrine is actually directly toxic to cardiac myocytes, at
least in cul-ture. The addition of either an α- or β-blocker confers partial protection from
norepinephrine damage. Combined β- and α-blockade confers additive protec-tion. These
data from animal studies may be relevant to human heart failure, since they
suggest that both - and - adrenoceptor blockade may be beneficial in the man-
agement of CHF. This rationale favors the use of the combined nonselective α- and β-blocker carvedilol
over the relatively selective 1-antagonist metoprolol. In ad-dition,
in CHF the number of β1-receptors decreases while the number of β2-receptors increases, and the
ratio of β1- to β2-receptors changes. Thus, the 1-selectivity of
metoprolol may not confer any advantage over the less specific β-blocker carvedilol.
It is clear from clinical trial data that β-adrenoceptor blockers are not all the same.
Use of some has produced improvements in survival, and others have produced no
improvements at all. The mechanisms responsible for these benefits are not yet
established. Speculation includes up-regulation of β-adrenoceptors, improved
G-protein coupling, altered regulation of nitric oxide, and so on.
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