Distribution of Propranolol in Periocular Tissues: A Comparison of Topical and Systemic Administration

Abstract

Purpose: Oral propranolol has become a promising treatment of capillary hemangiomas (CHs) despite concerns of side effects associated with systemic beta-blockers. The objective of this study was to investigate the distribution of propranolol in periocular tissues and in plasma after topical application of propranolol as compared with intravenous and oral administration of propranolol. Methods: Each rabbit received propranolol as ophthalmic solution (1%) in one eye (1.5 mg dose), intravenous injection (1.5 mg dose), or commercially available propranolol oral solution (5 mg dose). The periocular tissues (e.g., eyelids and extraocular muscles) and blood were collected and assayed for propranolol. Results: After topical instillation of 1.5 mg propranolol, high amounts of propranolol were rapidly delivered to the eyelids and extraocular muscles (4 -32 mg/g at 1 h after dosing). The drug in these tissues was slowly cleared, and significant amounts of the drug ( > 0.4 mg/g) were still present at 24 h after the topical application. After oral administration of a clinically relevant dose of 5 mg propranolol, the drug concentrations in the periocular tissues were relatively low ( < 0.4 mg/g) at 1 h after dosing and generally undetectable at 8 h after dosing. After an intravenous injection of 1.5 mg propranolol, the drug concentrations in the eyelids and extraocular muscles were in the range of 0.2 -1 mg/g at 1 h after dosing. The plasma concentration of the drug after the intravenous injection was significantly higher than that after topical application of the same dose. The higher drug concentrations in the periocular tissues of the treated eyes as compared with untreated eyes suggest direct penetration of the drug into the periocular tissues from the administration site after topical application. Conclusions: Topical administration can provide increased concentrations of propranolol in the periocular tissues and, thus, is superior to systemic administration for the treatment of periocular CH.

Ocular Safety of Intravitreal Propranolol and Its Efficacy in Attenuation of Choroidal Neovascularization

“…Furthermore, with IVP injection the side effects of systemic route may be minimized as demonstrated with eye drop delivery of propranolol for treatment of retinal neovascularization. 16,18 Intravitreal propranolol injection can provide a higher concentration of drug in the retina and choroid. In the study by Martini et al, 19 after subcutaneous administration of 20 mg/kg propranolol three times daily, the concentration of propranolol in the retina was 20.02 6 3.21 lg/g.…”

“…20 Thus, topical and intravitreal delivery of propranolol leads to significantly higher ocular levels, and its lower systemic levels may eliminate potential complications. [16][17][18]21,22 Previous studies have demonstrated various results regarding the possible role of different b-ARs in retinal angiogenesis. In a study by Martini et al, 19 b1 agonists do not affect angiogenic phenotype in human choroidal and retinal endothelial cells.…”

“…16 The higher systemic doses of propranolol may have adverse effects. 17 Therefore, we determined the impact of intravitreal delivery propranolol and its potential ocular toxicity in rabbits and mice.…”

Pharmacokinetics and local safety profile of propranolol eye drops in rabbits

“…More recently, a study demonstrated the ability of an ophthalmic solution with 1% propranolol to reach, in rabbits, periocular tissues as well as the anterior ocular segment, with a higher tissue/plasma ratio compared with oral or intravenous administration. Unfortunately, no data were reported about propranolol delivery to the posterior segment of the eye (13). In a recent study, we have demonstrated in mice with OIR that propranolol dissolved in commercially available eye drops (2% concentration) efficiently reaches the retina and promotes the recovery of OIR, suggesting that trans-corneal application of propranolol can lead to adequate penetration of the drug in the posterior segment of the eye (14).…”

“…Following these observations, two independent prospective pilot trials have demonstrated that oral propranolol administered to preterm newborns suffering from a precocious phase of ROP is effective in counteracting the progression of the disease (11,12), even though not sufficiently safe (11). The ability of propranolol to cross the cornea and reach the periocular tissues in rabbits (13) or the retina of Padrini et al…”