In recent years the role of beta-blockers as a primary tool to treat hypertension has come under question. These drugs have shown disappointing results when used as antihypertensive therapy in patients without heart disease, ie, when used as primary prevention. At the same time, beta-blockers clearly reduce the risk of future cardiovascular events in patients who already have heart disease, eg, who already have had a myocardial infarction or who have congestive heart failure.
Several meta-analyses and a few clinical trials have shown that beta-blockers may have no advantage over other antihypertensive drugs, and in fact may not reduce the risk of stroke as effectively as other classes of blood pressure medications.
Why should this be? Is it that the patients in the antihypertensive trials were mostly older, and that beta-blockers do not work as well in older patients as in younger ones? Or does it have to do with the fact that atenolol (Tenormin) was the drug most often used in the trials? Would newer, different beta-blockers be better?
Hypertension experts currently disagree on how to interpret the available data, and this has led to conflict and confusion among clinicians as to the role of beta-blockers in managing hypertension. Current evidence suggests that older beta-blockers may not be the preferred first-line antihypertensive drugs for hypertensive patients who have no compelling indications for them (eg, heart failure, myocardial infarction, diabetes, high risk of coronary heart disease). However, newer beta-blockers with vasodilatory properties should be considered in cases of uncontrolled or resistant hypertension, especially in younger patients.
Further, while controversy and debate continue over the benefits and adverse effects of one class of antihypertensive drugs vs another, it is indisputable that controlling arterial blood pressure to the recommended goal offers major protection against cardiovascular and renal events in patients with hypertension.1,2
MECHANISM OF ACTION OF BETA-BLOCKERS
Beta-blockers effectively reduce blood pressure in both systolic-diastolic hypertension and isolated systolic hypertension.3–5 Exactly how is not known, but it has been proposed that they may do so by:
Reducing the heart rate and cardiac output. When catecholamines activate beta-1 receptors in the heart, the heart rate and myocardial contractility increase. By blocking beta-1 receptors, beta-blockers reduce the heart rate and myocardial contractility, thus lowering cardiac output and arterial blood pressure.6
Inhibiting renin release. Activation of the renin-angiotensin system is another major pathway that can lead to elevated arterial blood pressure. Renin release is mediated through the sympathetic nervous system via beta-1 receptors on the juxtaglomerular cells of the kidney. Beta-blockers can therefore lower blood pressure by inhibiting renin release.7
Inhibiting central nervous sympathetic outflow, thereby inducing presynaptic blockade, which in turn reduces the release of catecholamines.
Reducing venous return and plasma volume.
Generating nitric oxide, thus reducing peripheral vascular resistance (some agents).8
Reducing vasomotor tone.
Reducing vascular tone.
Improving vascular compliance.
Resetting baroreceptor levels.
Attenuating the pressor response to catecholamines with exercise and stress.
HETEROGENEITY OF BETA-BLOCKERS
Beta-blockers are not all the same. They can be classified into three categories.
Nonselective beta-blockers block both beta-1 and beta-2 adrenergic receptors. It is generally accepted that beta-blockers exert their primary antihypertensive effect by blocking beta-1 adrenergic receptors.6 Of interest, nonselective beta-blockers inhibit beta-2 receptors on arteries and thus cause an unopposed alpha-adrenergic effect, leading to increased peripheral vascular resistance.9 Examples of this category:
- Nadolol (Corgard)
- Pindolol (Visken)
- Propranolol (Inderal)
- Timolol (Blocadren).
Selective beta-blockers specifically block beta-1 receptors alone, although they are known to be nonselective at higher doses. Examples:
- Atenolol (Tenormin)
- Betaxolol (Kerlone)
- Bisoprolol (Zebeta)
- Esmolol (Brevibloc)
- Metoprolol (Lopressor, Toprol).
Beta-blockers with peripheral vasodilatatory effects act either via antagonism of the alpha-1 receptor, as with labetolol (Normodyne) and carvedilol (Coreg),10 or via enhanced release of nitric oxide, as with nebivolol (Bystolic).8
Lipid and water solubility
The lipid solubility and water solubility of each beta-blocker determine its bioavailability and side-effect profile.
Lipid solubility determines the degree to which a beta-blocker penetrates the blood-brain barrier and thereby leads to central nervous system side effects such as lethargy, nightmares, confusion, and depression. Propranolol is highly lipid-soluble; metoprolol and labetalol are moderately so.
Water-soluble beta-blockers such as atenolol have less tissue permeation, have a longer half-life, and cause fewer central nervous system effects and symptoms.11
Routes of elimination
Beta-blockers also differ in their route of elimination.
Atenolol and nadolol are eliminated by the kidney and require dose adjustment in patients with impaired renal function.12,13
On the other hand, propranolol, metoprolol, labetalol, carvedilol, and nebivolol are excreted primarily via hepatic metabolism.13