- 17 Downloads
Betaxolol is a lipophilic β-adrenoceptor antagonist relatively selective for β1-adrenoceptors with only weak β2-blocking activity. Used topically in glaucoma and ocular hypertension, betaxolol 0.5% solution produces a reduction in intraocular pressure of between 13 and 30%, an effect comparable with that of ocular timolol. It may usefully be combined with other types of anti-glaucoma agents. The most notable feature of its adverse effect profile is transient local stinging or irritation, occurring in 25 to 40% of patients. Following ocular administration, betaxolol appears to be largely devoid of adverse bronchopulmonary or cardiac effects, in comparison with nonselective ocular β-adrenoceptor antagonists, which may be more likely to exert systemic effects. Betaxolol has negligible local anaesthetic activity, so that corneal desensitisation does not occur with its use. Thus, betaxolol is an alternative therapeutic option available to the physician for the management of chronic open-angle glaucoma and ocular hypertension. Its apparently lower propensity to affect the cardiopulmonary system represents a significant advantage over other ocular β-adreno-ceptor antagonists.
Betaxolol is a lipid-soluble (lipophilic) β-adrenoceptor antagonist which is relatively cardioselective, with no intrinsic sympathomimetic activity and little or no membrane stabilising activity. In common with other ocular β-adrenoceptor antagonists, the mechanism of the reduction in intraocular pressure observed with betaxolol is generally considered to be decreased production of aqueous humour by the ciliary body, with no apparent effect on aqueous outflow. The precise mechanism of this effect remains to be elucidated. Retinal and ciliary perfusion pressures in patients have been reported to be unaltered by betaxolol treatment. Betaxolol 0.5% was less toxic to regenerating corneal epithelium in rabbits than was timolol 0.5% or levobunolol 0.5%. Similarly, corneal healing rates were faster with betaxolol (and levobunolol) than with timolol.
Although ocularly administered betaxolol may be absorbed from the nasopharyngeal and conjunctival mucosa into the systemic circulation, betaxolol appears to possess minimal systemic β-blocking activity — approximately 5% that of timolol in 1 radioreceptor assay in rabbits. Ocular betaxolol also failed to antagonise the isoprenaline-induced increase in heart rate in monkeys, an index of systemic β-blockade.
Betaxolol appears to have less propensity for adverse effects on pulmonary function than nonselective ocular β-adrenoceptor antagonists. In studies in patients with respiratory disease or timolol-induced bronchoconstriction, betaxolol has not had any effect on FEV1, forced vital capacity, or relative forced expiratory volume. However, in an investigation in 85 patients followed for up to 2 years, symptomatic pulmonary obstruction was apparent in 5 patients after 1 to 554 days’ betaxolol treatment. All patients had glaucoma and chronic obstructive pulmonary disease, asthma, or timolol-induced bronchoconstriction at baseline. In 1 study, no statistically significant difference was apparent between betaxolol and placebo in the histamine concentration necessary to produce a 15 to 20% reduction in FEV1.
Despite its cardioselectivity, betaxolol has had minimal effects on resting or exercise heart rate, blood pressure or double product, after ocular administration, in several placebo-controlled studies. This is in contrast to timolol, which effects significant reductions in these parameters. In 1 study in healthy volunteers, the incidence of CNS effects, including insomnia, depression, hypochondriasis and hysteria, tended to be less with betaxolol than with timolol. In 2 further studies, 16 of 18, and 5 of 7 patients experiencing CNS effects while receiving timolol improved after betaxolol treatment.
There are no published data detailing the pharmacokinetic properties of betaxolol following ocular administration in humans; such information is important to assess the extent of systemic availability.
The bioavailability of oral betaxolol is 80 to 90% - it does not undergo extensive first pass metabolism. Excretion is mainly via O-dealkylation followed by aliphatic hydroxylation, yielding 2 major inactive metabolites. Betaxolol and its metabolites are excreted renally with an elimination half-life of between 14 and 22 hours, which is prolonged in neonates and the elderly. Total body clearance does not appear to be affected by liver disease but is reduced in patients with severe renal failure.
In comparisons with placebo, betaxolol has proven superior in reducing intraocular pressure. Mean reductions have ranged between 13 and 27% with betaxolol compared with about 2 to 13% with placebo. Trials comparing betaxolol with timolol reported reductions in intraocular pressure at the end of 6 months’ treatment of between 26 and 36% with betaxolol, and between 29 and 37% with timolol. These 3 trials involved a total of 101 patients.
In a noncomparative trial a reduction of intraocular pressure was obtained within several hours of instillation of betaxolol 0.25%, was maximal at 2 weeks, at 30 to 35%, and was sustained for the duration of the study ( 1 year). In a second noncomparative trial, patients previously administered pilocarpine showed a nonsignificant reduction in intraocular pressure of 8.4% following substitution with betaxolol; in newly diagnosed patients, mean diurnal intraocular pressure was significantly reduced with betaxolol by 17%. In 17 of 20 patients with open-angle glaucoma or ocular hypertension receiving betaxolol 0.5% alone (n=15) or in combination with pilocarpine (n=5), who had been treated with timolol, an additional mean reduction in intraocular pressure of 2.4mm Hg was apparent after 2 weeks, and was maintained for the 12 weeks of study. In specific investigations of combination use, betaxolol therapy resulted in small incremental reductions in intraocular pressure over those obtained with other monotherapies.
After 2 weeks’ treatment with dipivefrine 0.1% alone, intraocular pressure was reduced by 12%, and addition of betaxolol resulted in a total reduction of 15% at 4 weeks. Betaxolol 0.5% twice daily added to oral acetazolamide resulted in an incremental reduction in outflow pressure (intraocular pressure minus an episcleral venous pressure assumed to be 10mm Hg) of 17.6%. With acetazolamide alone the reduction was 42.5%. With betaxolol alone the reduction was 27.3% below baseline, decreased by an additional 35.1% with acetazolamide.
The most frequent adverse effect of topical betaxolol treatment is transient local irritation, which occurs in 25 to 40% of patients. A double-blind comparison indicated a higher incidence of ocular symptoms with betaxolol (89%), than with timolol (48%). Ocular symptoms reported include burning, stinging or irritation, pruritus, hyphaemia, vitreous separation and blurred vision. As a cardioselective agent, betaxolol is less likely to be associated with adverse respiratory effects than nonselective β-adrenoceptor antagonists. While adverse respiratory effects have been observed in a small number of patients with underlying respiratory disease followed for up to 2 years on betaxolol, their relationship to treatment is uncertain. Of a total of 56 spontaneous reports of adverse drug experience attributed to betaxolol during its first year of marketing in the US, postmarketing surveillance identified 11 cases of asthma, 8 requiring hospitalisation.
During a clinical trial in 101 patients treated with betaxolol for up to 2 years, cardiac arrhythmia and shortness of breath occurred in 1 patient and bundle branch block in a second. There are case reports describing myocardial infarction, sinus arrest, and congestive heart failure in association with ocular betaxolol. Of the 56 spontaneous reports mentioned above, there were 4 instances of bradycardia, 1 with syncope, and 1 of cardiac arrhythmia. Other adverse effects reported in association with ocular betaxolol include depression, disorientation, vertigo and sleepwalking; and rhinitis, dysuria, alopecia, and prolonged prothrombin time.
Dosage and Administration
The recommended dosage of ocular betaxolol in glaucoma or ocular hypertension is one drop of 0.5% solution in each eye twice daily.
KeywordsGlaucoma Intraocular Pressure Aqueous Humour Timolol Pilocarpine
Unable to display preview. Download preview PDF.
- Bianchetti G, Padovani P, Thiercelin J, Thenot J, Morselli P. Pharmacokinetic studies of betaxolol — evaluation of the effects of age, hypertension, presence of food, and concomitant administration of hydrochlorothiazide on the disposition of the drug. In Morselli et al. (Eds) LERS Monograph Series, Vol. 1, pp. 123–131, Raven Press, New York, 1983Google Scholar
- Bleckmann H, Dorow P. Betaxolol vs placebo in ten patients with glaucoma and reactive airway disease. New Trends in Ophthalmology 2: 114–123, 1987Google Scholar
- Bloom E, Richmond C, Alvarado J, Polansky J. Betaxolol vs timolol: plasma radio-receptor assays to evaluate systemic complications of beta blocker therapy for glaucoma. Investigative Ophthalmology and Visual Science 26 (Suppl): 125–129, 1986Google Scholar
- Boudot J, Cavero I, Fenard S, Lefèvre-Borg F, et al. Preliminary studies on SL 75212, a new potent cardioselective beta-adrenoceptor antagonist. British Journal of Pharmacology 66: 445P, 1979Google Scholar
- Boutroy M, Vert P, Bianchetti G, Morselli P. Betaxolol: pharmacokinetics and pharmacodynamic effects of a new cardioselective beta-blocker in pregnant women. Abstract no. 565. II World Conference on Clinical Pharmacology and Therapeutics, Washington DC, July 31–August 5, 1983Google Scholar
- Brogliatti B, Rolle T, Franzone M. Effects of topical betaxolol on ocular hypertensive or glaucomatous eyes. New Trends in Ophthalmology 2: 87–94, 1987Google Scholar
- Cavero I, Lefèvre-Borg F. Antihypertensive activity of betaxolol in conscious spontaneously hypertensive rats. British Journal of Pharmacology 78 (Suppl.): 28P, 1983aGoogle Scholar
- Cavero I, Lefèvre-Borg F. Studies on the mechanism of the anti-hypertensive action of betaxolol, a beta 1 adrenoceptor antagonist, in spontaneously hypertensive rats. Ricerca Scientifica ed Educazione Permanente (Suppl. 33), 1983bGoogle Scholar
- DeSantis L, Polansky JR, Bruce L. Relative differences in beta receptor activity between the cardioselective beta blocker, betaxolol, and nonselective beta blockers. Proceedings of the XXVth International Congress of Ophthalmology, Rome, pp. 1501–1505, May 4–10, 1986, Khugler & Ghedini, Amsterdam, 1987Google Scholar
- Ferrandes B, Durand A, André-Fraisse J, Thénot J, Hermann P. Pharmacokinetics and metabolism of betaxolol in various animal species and man. In Morselli et al. (Eds) LERS Monograph Series, Vol. 1, pp. 51–64, Raven Press, New York, 1983Google Scholar
- Ganansia J, Bianchetti G, Bouchet JL, Allen J, Morselli P. Protein binding of betaxolol in healthy volunteers and in patients with renal or hepatic disease. In Aiache and Hirtz (Eds) Proceedings of the 2nd European Congress of Biopharmaceutics and Pharmacokinetics, pp. 440–447, Vol. III, Clinical Pharmacokinetics, 24–27 April, Salamanca, Spain, 1984Google Scholar
- Gillet G, Bianchetti G, Ferrandes B, Morselli P. Kinetics of the distribution of betaxolol and metoprolol in various tissues in the rat. In Aiache and Hirtz (Eds) Proceedings of 2nd European Congress of Biopharmaceutics and Pharmacokinetics, pp. 529–535, Vol. II, Experimental Pharmacokinetics, 24–27 April, Salamanca, Spain, 1984Google Scholar
- Hermann P, Thenot J, Warrington S, Ganansia J, Morselli P. Metabolism of betaxolol in man. Abstract no. 272. 8th European Workshop on Drug Metabolism, Sart Tilman, Belgium, September 5–9, 1982Google Scholar
- Kitazawa Y, Azuma I, Araie M. Clinical evaluation of betaxolol hydrochloride in the treatment of primary open angle glaucoma and ocular hypertension: multicentre double-masked study in comparison with timolol. Rinsho Hyoka 17: 243–274, 1989Google Scholar
- Le Jeunne C, Munera Y, Hugues FC. Systemic effects of 3 beta-blocker eyedrops: comparison in healthy volunteers of gb1 and β2 adrenoceptor inhibition. Clinical Pharmacology and Therapeutics, in press, 1990Google Scholar
- Levy NS, Boone LR. Effects of 0.25% betaxolol vs placebo. Glaucoma 5: 230, 1983Google Scholar
- Levy NS, Boone L, Ellis E. A controlled comparison of betaxolol and timolol with long-term evaluation of safety and efficacy. Glaucoma 7: 54–62, 1985Google Scholar
- Manoury P. Betaxolol: chemistry and biological profile in relation to its physicochemical properties. In Morselli et al. (Eds) LERS Monograph Series, Vol. 1, pp. 13–19, Raven Press, New York, 1983Google Scholar
- Mekki QA, Davies IB, Sinclair AJ, Turner P. Effect ofβ2 -selective adrenoceptor blockers on intraocular pressure in man. Abstract. British Journal of Clinical Pharmacology 21: 596P-597P, 1985Google Scholar
- Merte HI, Schnarr KD. Ophthalmic betaxolol: a twelve-week study in glaucoma patients. New Trends in Ophthalmology 2: 98–108, 1987Google Scholar
- Morselli PL, Thiercelin JF, Padovani P, Bianchetti G, Fries D, et al. Comparative pharmacokinetics of several beta-blockers in renal and hepatic insufficiency. In Morselli et al. (Eds) LERS Monograph Series, Vol. 1, pp. 233–241, Raven Press, New York, 1983Google Scholar
- Ryan M, Jain AK, Ryan JR, McMahon FG, Richards J. Relative ocular tolerance of ophthalmic solutions of timolol and betaxolol in normal volunteers. Clinical Pharmacology and Therapeutics 41: 193, 1987Google Scholar
- Shanks RG. Clinical pharmacology of beta-adrenoceptor blocking drugs. In Morselli et al. (Eds) LERS Monograph Series, Vol. 1, pp. 73–88, Raven Press, New York, 1983Google Scholar
- Thiercelin J, Bianchetti G, Larribaud J, Ganansia J, Deves C, et al. Effects of meal and its composition on the bioavailability of betaxolol administered orally to healthy subjects. In Debrey (Ed.) World review of nutrition and dietetics, Vol. 33, pp. 183–186, Karger, Basel, 1984Google Scholar
- Vukich JA, Leef DL, Allen RC. Betaxolol in patients with coexistent chronic open angle glaucoma and pulmonary disease. Investigative Ophthalmology and Visual Science 26 (Suppl): 227, 1986Google Scholar
- Wright S, Edgar DF, Stewart-Jones JH, Turner P. Comparison of topical betaxolol, carteolol, metipranolol and saline on intraocular pressure in normal volunteers. British Journal of Clinical Pharmacology 27: 696P-697P, 1988Google Scholar