BETA BLOCKERS: MECHANISMS OF ACTION

 

β-adrenergic receptors are found in many different tissues (vascular, cardiac, pulmonary, and ocular). The receptors in the heart and blood vessels are primarily β1, whereas those in the lung are primarily β2.

Agents that block both β1- and β2-receptors are classified as nonselective, whereas agents that primarily block β1-receptors are classified as cardio-selective or simply as selective β1. Blockade of β1-receptors in the heart can induce or exacerbate heart block, bradycardia, and cardiac failure. Blockade of β2-receptors can precipitate bronchospasm, dyspnea, and respiratory failure, especially in patients with asthma or chronic obstructive pulmonary disease.

β-adrenergic antagonists competitively (reversibly) inhibit the binding of catecholamines at the β-adrenoreceptor.

In the eye, the sites for receptor interaction of these drugs are suggested to be β-adrenergic receptors in the iris and ciliary body.

The highest density of receptors was reported in the ciliary processes (180 fmol/mg of protein), whereas the density of receptors in the iris (98 fmol/mg of protein) and ciliary body (42 fmol/mg of protein) is notably lower.

Most of the β-adrenergic receptors in the human iris-ciliary body are of the β2 subtype. β2-adrenergic receptors have also been detected in cultured human trabecular cells and in the human trabecular meshwork.

The most commonly accepted theory of the mechanism of IOP reduction by topical β-adrenergic antagonists is that by blocking the β-receptors in the ciliary epithelium, aqueous production is suppressed, thereby lowering IOP.

It has been suggested by Mishima that β-adrenergic antagonists lowered IOP by reducing aqueous humor formation.

Timolol does not appear to be effective in sleeping human participants during which time the aqueous flow is normally less than half the daytime flow rate. However, timolol does lower aqueous flow at night in humans receiving systemic epinephrine. Based on these clinical observations in certain diseases known to affect the sympathetic nervous system and normal physiologic conditions, the precise mechanisms by which the sympathetic system regulates aqueous humor dynamics is complex and not fully understood.

Although the outflow facility is not apparently affected by beta-blockers there is a school of thought which points to the presence of β-receptors in the trabecular meshwork which could play a role in enhancing aqueous outflow through the conventional pathway.

A histologic study of the outflow apparatus in human eyes treated with timolol before enucleation for malignant melanoma revealed no morphologic changes suggestive of a pressure-lowering action by the drug. However, the trabecular meshwork in primates after long-term timolol therapy revealed degeneration of the trabecular cells, partial destruction of the beams, rarefaction of the meshwork, and disconnection of the trabecular lamellae from the ciliary muscle fibers.

In experiments conducted by Neufeld, topically applied timolol did not increase cyclic adenosine monophosphate (cAMP) levels in the aqueous humor of rabbit eyes or stimulate cyclic AMP formation by ocular tissues, indicating that the drug has no intrinsic β-adrenergic agonistic activity. He postulated that timolol may cause vasoconstriction of blood flow to the ciliary body, thus decreasing aqueous humor production.

The possible effect of ß-blockers on ocular blood flow is complex and involves consideration of the various vascular beds, including the ciliary, retinal, choroidal, and retrobulbar vessels located within their respective tissues. There are conflicting effects of the topical ß-blockers on ciliary systolic perfusion pressure.

Van Buskirk experimentally confirmed that topical β-blockers, namely timolol maleate and betaxolol hydrochloride, cause substantial, localized constriction in the arterioles that supply the ciliary processes. However, Millar and Wilson found no change in vascular resistance in arterially perfused bovine eyes after administration of timolol.

Experiments by Crook and Riese showed that Timolol, propranolol, and betaxolol inhibited the cotransport of the ions in ciliary epithelial cells, suggesting that aqueous humor production decreases due to the inhibition of Na+/K+/Cl- cotransport. Inhibition of Na+/K+/Cl- cotransport also inhibits cAMP formation, indicating that β-adrenergic antagonists may inhibit cAMP formation in ciliary epithelial cells.

Maren did confirm that aqueous humor production was reduced with timolol, but did not find similar reduction of sodium transport from plasma to aqueous humor as seen with carbonic anhydrase inhibitors.

Kiland et al. studied the mechanisms of timolol on aqueous suppression and ultrafiltration and confirmed that timolol does decrease the formation of aqueous humor, but does not enhance filtration or increase the outflow facility of aqueous humor through the trabecular meshwork. Kiland found that timolol does not affect levels of ascorbate in the aqueous humor indicating that timolol may not inhibit the Na+/glucose transporter.