Beta blocker selectivity: beta-1, ISA and alpha blockade

The case: a heart drug, cold fingers and a wheeze

A man with high blood pressure starts a beta blocker for his heart. A month later his fingers are cold and he wheezes on the stairs. A heart drug, so why the hands and the chest?

The answer is beta blocker selectivity. This lesson sorts beta blockers by selectivity, partial agonism and alpha blockade, and uses those three properties to predict what each drug does.

Beta-1 and beta-2 receptors: what every beta blocker does

Beta-1 receptors sit in the heart and in the kidney's renin-releasing cells. Beta-2 receptors sit in airway smooth muscle and in vessels, including those in skeletal muscle.^[1][2][11]

Every beta blocker blocks beta-1. Heart rate, force of contraction and renin fall, so blood pressure and myocardial oxygen demand fall.^[1][3][7]

Three questions sort every beta blocker

1. Is it selective for beta-1?Nonselective drugs block beta-1 and beta-2; selective drugs mainly block beta-1.
2. Does it have intrinsic sympathomimetic activity (ISA)?A partial agonist blocks the receptor but also stimulates it a little.
3. Does it also block alpha-1?Alpha-1 blockade adds vasodilation.

Beta blockers differ in these three properties, and some vasodilate by other routes, such as nitric oxide release. The differences explain their different side effects.^[3][4]

Question 1: beta blocker selectivity and the A-to-M trick

A trick: the selective names mostly run A to M, the nonselective ones N to Z. There are three exceptions: labetalol and carvedilol are nonselective and also block alpha-1, and nebivolol is selective. The rule is a memory device, not a pharmacological law.^[2][3][4]

Selectivity is relative, and it fades with dose. In the laboratory, bisoprolol's affinity for beta-1 is 13.5 times its affinity for beta-2; for metoprolol it is 2.3. At higher doses, any selective drug starts to block beta-2.^[2][6] The costs of blocking beta-2, plus one shared by all beta blockers:

• Bronchospasm in people with asthma, because airway beta-2 relaxation is lost.^[2][3][6]
• Cold extremities, because vessels lose their beta-2 dilation and the alpha-1 squeeze goes unopposed.^[3]
• Masked hypoglycemia: beta blockade can hide the racing heart that warns a person with diabetes that glucose is falling.^[1][12]

This is the mechanism behind the opening case: a nonselective drug tightened his airways and the vessels in his fingers. A beta-1 selective drug, such as atenolol, would have spared more of them, until the dose rises.^[2][3][6]

Question 2: intrinsic sympathomimetic activity (ISA)

Pindolol and acebutolol are partial agonists: they block the receptor but also stimulate it a little. That limits the fall in resting heart rate and cardiac output.^[2][3]

ISA has shown no clinical benefit in coronary disease or heart failure.^[2]

Question 3: alpha-1 blockade and nitric oxide vasodilation

Labetalol and carvedilol also block alpha-1, so they dilate vessels and lower blood pressure without raising the heart rate.^[1][3][5]

Nebivolol is beta-1 selective and adds nitric oxide mediated vasodilation, a mechanism distinct from alpha-1 blockade.^[3][5]

Putting the three questions together

Same class, same effect on the heart, different side effects. Nonselective drugs add bronchospasm and cold extremities; selective drugs spare more, until the dose rises.^[2][3][6] Any beta blocker can blunt the racing heart that warns of hypoglycemia.^[1][12] ISA means less resting bradycardia; alpha-1 blockade or nitric oxide means vasodilation.^[2][3][5]