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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