β-Adrenergic receptor antagonists (β-blockers) are medications used in the treatment of various cardiovascular, neurologic, endocrine, ophthalmologic, and psychiatric disorders. Among all drug-related fatalities reported to poison control centers nationwide in 2016, β-blockers were involved in 8% of all cases and were responsible for 2% of single-agent fatal exposures.1
The β-adrenergic receptors are membrane glycoproteins present as three subtypes in various tissues (Table 194-1). These receptors play a critical role in cardiovascular physiology by modulating cardiac activity and vascular tone.
TABLE 194-1Location and Activity of β-Adrenergic Receptors ||Download (.pdf) TABLE 194-1 Location and Activity of β-Adrenergic Receptors
|β-Receptor Type ||Location ||Agonism ||Antagonism |
|β1 ||Myocardium ||Increases inotropy ||Decreases inotropy |
| ||Increases chronotropy ||Decreases chronotropy |
|Kidney ||Stimulates renin release ||Inhibits renin release |
|Eye ||Stimulates aqueous humor production ||Inhibits aqueous humor production |
|β2 ||Bronchial smooth muscle ||Causes bronchodilation ||Causes bronchospasm |
|Visceral smooth muscle ||Relaxes uterus ||— |
| ||Causes ileus || |
|Skeletal muscle ||Increases force of contraction ||— |
| ||Stimulates glycogenolysis || |
|Liver ||Stimulates glycogenolysis and gluconeogenesis ||Inhibits glycogenolysis and gluconeogenesis |
|Vascular ||Vasodilation ||Minimal vasoconstriction |
|β3 ||Adipose tissue ||Stimulates lipolysis ||Inhibits lipolysis |
|Skeletal muscle ||Stimulates thermogenesis ||Inhibits thermogenesis |
During times of stress (i.e., catecholamine release), β-adrenergic receptor stimulation increases myocardial and vascular smooth muscle cell activity through a sequence of intracellular events (Figure 194-1).2,3
Cardiac myocyte β1-receptor and calcium signaling. Following myocyte depolarization, extracellular calcium (Ca2+) enters the cell via the L-type or voltage-gated calcium channel (L-VDCC) and binds to the ryanodine receptor (RyR) in the sarcoplasmic reticulum, causing an efflux of sequestered Ca2+ out of the sarcoplasmic reticulum into the cytosol. Free Ca2+ binds to troponin that allows the myosin and actin interaction, resulting in contraction of the cardiac myocyte. Binding of a β-agonist to the β1-adrenergic receptor (B1) on the cell surface activates the Gs protein. The Gs protein then activates adenylate cyclase (AC), which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). The increased cAMP activates protein kinase A (PKA). Activated PKA serves as further stimulus for the L-VDCC opening. Glucagon independently activates adenylate cyclase. cAMP is metabolized by phosphodiesterase (PDE) into inactive adenosine 5’-monophosphate (5’AMP).
The β-receptor is coupled to a stimulatory Gs protein. This Gs protein stimulates adenylate cyclase, which in turn catalyzes the formation of cyclic adenosine monophosphate (cAMP), the so-called intracellular second messenger. Increased cAMP ultimately phosphorylates the L-type calcium channel, which leads to channel opening and calcium entry into the cell. This increase in cytosolic calcium acts at the ryanodine receptor, a calcium channel on the sarcoplasmic reticulum, causing it to release its stored calcium into the cytosol. This process is termed calcium-induced calcium release. Stored calcium becomes available to ...