Ocular Timolol Research Articles

Considerations of prescribers and pharmacists for the use of non-selective β-blockers in asthma and COPD patients: An explorative study.

Rationale, aims, and objectivesDespite recommendations in prevailing guidelines to avoid the use of non‐selective (NS) β‐blockers in patients with asthma or COPD, on average, 10 patients per community pharmacy receive NS β‐blockers monthly. The aim of our study was to identify the reasons of prescribers and pharmacists to treat asthma and COPD patients with NS β‐blockers.MethodsFifty‐three community pharmacists in the Netherlands selected patients with actual concurrent use of inhalation medication and NS β‐blockers. For at least 5 patients, each pharmacist screened all medication surveillance signals and actions taken at first dispensing. Each pharmacist selected 3 different initial prescribers for a short interview to explore their awareness of the co‐morbidity and reasons to apply NS β‐blockers.ResultsPharmacists identified 827 asthma/COPD patients with actual use of NS β‐blockers. From these, 153 NS β‐blocker prescribers were selected and interviewed (64 general practitioners, 45 ophthalmologists, 24 cardiologists, and 20 other prescribers). One hundred seven prescribers were aware of the drug‐disease interaction of the asthma or COPD co‐morbidity when initiating the NS β‐blocker, and 46 were not. From these, 40 prescribers did not consider the contraindication to be relevant.For 299 patients, medication surveillance signals and actions at first dispensing were retrieved. Patients used predominantly ocular timolol (39.8%), and the oral preparations propranolol (30.8%) and carvedilol (15.1%). In 154 cases, the pharmacy system generated a warning alert.ConclusionsA substantial number of prescribers was unaware of the co‐morbidity or did not regard NS β‐blockers contraindicated, despite prevailing clinical guidelines. Improvement programs should target prescribers' awareness and knowledge of NS β‐blockers in patients with asthma or COPD.

Formulation and In-vitro Characterization of Sustained Release Matrix Type Ocular Timolol Maleate Mini-Tablet.

The purpose of this study was preparation and evaluation of sustained release matrix type ocular mini-tablets of timolol maleate, as a potential formulation for the treatment of glaucoma. Following the initial studies on timolol maleate powder, it was formulated into ocular mini-tablets. The polymers investigated in this study included cellulose derivatives (HEC, CMC, EC) and Carbopol 971P. Mannitol was used as the solubilizing agent and magnesium stearate as the lubricant. Mini-tablets were prepared by through mixing of the ingredients, followed by direct compression. All the prepared formulations were evaluated in terms of physicochemical tests, including uniformity of weight, thickness, crushing strength, friability and in-vitro drug release. Four groups of formulations were prepared. The presence of different amounts of cellulose derivatives or Carbopol 971P, alone, was studied in group A formulations. In group B formulations, the effect of adding Carbopol 971P alongside different cellulose derivatives was investigated. Group C formulations were made by including mannitol as the solubilizing agent, alongside Carbopol 971P and a cellulose derivative. In group D formulations, mini-tablets were made using Carbopol 971P, alongside two different cellulose derivative. The selected formulation (C1) contained ethyl cellulose, Carbopol 971P, mannitol and magnesium stearate, which showed almost 100% drug release over 5 h. Based on kinetic studies, this formulation was found to best fit the zero-order model of drug release. However, the Higuchi and Hixson -Crowell models also showed a good fit. Hence, overall, formulation C1 was chosen as the best formulation.

β-Adrenoceptor antagonist activities and binding affinities of timolol enantiomers in rat atria

S-Timolol is an effective anti-glaucoma drug, but has potentially hazardous side effects. Recently, R-timolol, also, has been reported to be effective in lowering elevated intraocular pressure. In the present study, the beta-adrenoceptor antagonist activities and binding of R- and S-enantiomers of timolol have been examined on rat atrial preparations. The beta-antagonistic activities were investigated using spontaneously beating rat heart atria. Both timolol enantiomers inhibited (-)-isoprenaline-induced chronotropic action competitively. S-Timolol was about 54 times more potent than R-timolol. The apparent binding affinities of timolol enantiomers to beta 1- and beta 2-adrenoceptors were determined by a radioligand binding assay using (-)-[125I]iodocyanopindolol (ICYP) as a marker and CGP 20712 A as a beta 1- and ICI 118,551 as a beta 2-adrenoceptor antagonist. Both enantiomers of timolol inhibited ICYP binding in nanomolar concentrations with Hill coefficients near unity. Neither enantiomer showed selectivity between beta 1- and beta 2-adrenoceptors, but R-timolol was approximately 30 times less active than S-timolol. It is concluded that R-timolol is a relatively potent non-selective beta-adrenoceptor blocking agent, but may possibly exert a more localized beta-adrenoceptor action in the eye than S-timolol, thus improving the safety of ocular timolol therapy.

Improved pharmacodynamics of timolol maleate from a mucoadhesive niosomal ophthalmic drug delivery system

In the present study chitosan (REVTMbio1) or Carbopol (REVTMbio2 and 3) coated niosomal timolol maleate (0.25%) formulations were prepared by reverse phase evaporation (REV) and compared to timolol solution (TMS; 0.25%) in terms of in vitro release and IOP lowering pharmacodynamic effect. The in vitro release phase of timolol (91% release in 2 h) was extended significantly by its incorporation into niosomes and further by the polymer coating (40–43% release upto 10 h). The developed formulations were evaluated for their pharmacodynamics in albino rabbits, by measuring intraocular pressure (IOP) using a non-contact pneumatonometer, and were compared to a marketed in situ gel forming solution of timolol (Timolet GFS, 0.5%; Sun Pharma). REVTMbio1 formulation showed a more sustained effect of upto 8 h (vis a vis 6 h for carbopol-coated niosomes). TMS in comparison showed effect for only 2 h though the peak effect was slightly more (14%). Lowering of IOP in the contralateral eye (20–40% as compared to 100% in case of TMS), considerably reduces with REV and REVbio formulations indicating lesser systemic side effects. Moreover, the results of REVTMbio1formulation containing 0.25% of timolol maleate compared well with the 0.5% marketed gel formulation, indicating our formulation to be significantly better considering that similar effect is obtained at half the concentration. The later becomes especially important in context to the cardiovascular side effects associated with ocular timolol maleate therapy.

Tensioactivity and supramolecular organization of the palmitoyl prodrug of timolol.

To improve the bioavailability of the ocular drug timolol by facilitating its transport through the cornea, an amphiphilic prodrug was synthesized via the addition of a palmitic chain by esterification. The present study was undertaken to investigate the physicochemical and tensioactive properties of the prodrug. The amphiphilic properties of the prodrug were firstly investigated by the Wilhelmy plate method. The textures generated by the supramolecular organizations of the ester were visualized by optical microscopy. The prodrug clearly decreased the surface tension. Optical microscopy provided excellent evidence for the existence of lyotropic liquid crystalline phases: two isotropic but organized phases and a birefringent lamellar phase. The results from the ensemble of studies undertaken to determine the amphiphilic properties of the prodrug were all in accord with its ability to form liquid crystalline phases. The liquid crystalline state of the prodrug is believed to introduce a delay in the drug pharmacological effect.

Basis for dosing time-dependent changes in the ocular and systemic absorption of topically applied timolol.

The objective of the present study was to determine the basis for dosing time-dependent changes in the ocular and systemic absorption of topically applied timolol in pigmented rabbits. The gamma scintigraphic technique was used to monitor the changes in precorneal solution retention following instillation. Changes in timolol concentration in the plasma over 120 min and in various anterior segment eye tissues at 30 min following the topical instillation of 25 microliters of 0.65% timolol maleate solutions at various dosing times were monitored using reversed phase HPLC. Corneal and conjunctival permeability at various dosing times was evaluated in the modified Ussing chamber. The results indicated that precorneal solution drainage was slowest at noon. Suppressing tear production by anesthesia led to an increase in ocular timolol absorption at 6 a.m. but not at other dosing times, in spite of the lowest corneal permeability then. There was no statistically significant dosing time influence on systemic timolol absorption following nasal or conjunctival dosing. In conclusion, possible diurnal changes in precorneal solution clearance may be the main factor underlying the diurnal changes in ocular as well as systemic timolol absorption in rabbits. In addition, diurnal changes in corneal permeability may also contribute to diurnal changes in ocular timolol absorption.

Plasma kinetics and antagonist activity of topical ocular timolol in elderly patients.

Systemic adverse effects of ocular timolol therapy are due to absorption of the drug from the eye into the systemic circulation. Elderly patients are frequently more susceptible to side effects than younger patients. This study was conducted to evaluate the plasma kinetics and antagonist activity of ocular timolol in elderly patients. Plasma kinetics and antagonist activity of timolol were studied in 12 patients scheduled for extracapsular cataract extraction and intraocular lens implantation. The patients received 40 microliters of 0.25% timolol into the lower cul-de-sacs of each eye. Blood samples were collected over a period of 12 h and plasma concentrations of timolol were analyzed using a radioreceptor assay. The corresponding ex vivo beta 1- and beta 2-receptor occupancies were calculated using radioligand binding techniques. Timolol was absorbed rapidly into the systemic circulation and occupied on average up to 68% of beta 1-receptors and up to 87% of beta 2-receptors. The beta 1- and beta 2-receptor occupancy decreased slowly and was on average 38% and 64%, respectively, 12 h after the single dose. The calculated mean area under concentration-time curve of timolol in plasma was 10.28 ng/ml per hour and the mean half-life was 4.8 h. Both values were about twice as high as those found in healthy young volunteers following an intravenous 0.25-mg dose of timolol. In elderly patients the beta-receptor antagonist effect of ocular timolol after a single dose is strong and long-lasting. This finding may explain the frequent reported systemic side effects of ophthalmic timolol.

Controlled ocular timolol delivery: systemic absorption and intraocular pressure effects in humans.

Timolol eyedrops may cause systemic side-effects in glaucoma patients due to absorption of the drug into systemic circulation. In a previous study, timolol concentrations in plasma were reduced if timolol was administered in ocular inserts instead of eyedrops. We compared the intraocular pressure lowering effect and systemic absorption of timolol inserts to those of 0.5% timolol eyedrops in humans. Inserts of silicone tubing released 90.3 +/- 13.9 micrograms of timolol in 24 hours in vivo. Timolol inserts afforded similar decreases in intraocular pressure in open-angle glaucoma patients as did b.i.d. eyedrops, but produced lower peak timolol concentrations in plasma, 0.70 +/- 0.10 ng/ml and 0.24 +/- 0.05 ng/ml, respectively. After eyedrops, peak concentrations were achieved at 15.0 +/- 2.2 min, while application of an insert resulted in a delayed peak (tmax = 623 +/- 195 min). The insert resulted in a higher systemically absorbed fraction of the timolol dose than the eyedrop, but the peak timolol concentration and daily absorbed amount of timolol were decreased. The release rate of timolol from the inserts in vivo was only slightly less than that in vitro. Silicone devices are useful for clinical testing of controlled delivery properties of ocular drugs.

Absorption of ocular timolol: drug concentrations and ß‐receptor binding activity in the aqueous humour of the treated and contralateral eye

We studied the ocular and systemic absorption of 40 microliters of topical 0.5% timolol in 57 patients using radioligand binding techniques. The mean concentration of timolol in aqueous humour of the treated eye was 1.9 +/- 0.8 micrograms/ml 74 minutes after instillation of the drug. About 18 h after drug instillation the aqueous humour concentration of timolol was 105.5 +/- 60.9 ng/ml. Timolol was found in 15 (42%) contralateral eyes. Concentration of timolol in the contralateral eye increased from 0.04 +/- 0.08 ng/ml at 50 min to 0.3 +/- 0.2 ng/ml at 134 min and was 0.2 +/- 0.4 ng/ml at 18 h after instillation. Timolol concentrations in the aqueous humour of the treated eye appeared to be high enough to occupy beta 1- and beta 2-receptors completely (100%) at 74 min and at 18 h after drug instillation. Timolol concentrations in the contralateral eye were high enough to occupy up to 33.0 +/- 24.7% of the beta 2-receptors and up to 51.7 +/- 35.1% of beta 2-receptors. High drug concentrations and complete beta-receptor occupancy in the aqueous humour of the treated eye after topical timolol are in agreement with the long-lasting ocular hypotensive effects. The low drug concentrations and partial receptor occupancy in the contralateral eye may also be of some clinical significance.

Light-dark variations in ocular timolol concentrations following topical solution installation in the pigmented rabbit

The objective of this study was to determine whether ocular absorption of topically applied timolol in the pigmented rabbit varied with the time of drop installation. Twenty-five microliters of a 0.65% timolol maleate solution were instilled in the pigmented rabbit eye at 0600, 0900, 1200, 1500, 1800, 2100, 2400, or 0300 hr. Timolol concentrations in the conjunctiva, sclera, corneal epithelium, corneal stroma, aqueous humor, and iris-ciliary body at 15 and 30 min post-dosing were monitored using reversed phase HPLC. Ocular timotol concentrations were higher when the drug was administered during the light period (0900–1800 hr) than when it was administered during the dark period (1800-0600 hr). There exist, therefore, light-dark variations in the ocular absorption of topically applied timolol.

Systemic Absorption of Ocular Timolol in Poor and Extensive Metabolizers of Debrisoquine

The oxidation of timolol exhibits genetic polymorphism of debrisoquine type. After oral administration, poor metabolizers have high timolol concentrations in plasma and show an intensified systemic beta-blockade. Since the contribution of debrisoquine metabolizer status on timolol eyedrop therapy is not known we determined the systemic absorption of ocularly applied timolol in healthy subjects classified either extensive or poor metabolizers. Unlike after oral timolol ocular drug administration caused higher peak drug concentrations in plasma in extensive metabolizers. The variation in the systemic absorption of ocular timolol contributed more than the debrisoquine oxidation phenotype to timolol plasma levels after a single ocular timolol application.

Ocular Betaxolol

Betaxolol is a lipophilic beta-adrenoceptor antagonist relatively selective for beta 1-adrenoceptors with only weak beta 2-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 beta-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 beta-adrenoceptor antagonists.

Controlled drug delivery devices for experimental ocular studies with timolol 2. Ocular and systemic absorption in rabbits

Controlled drug delivery was tested as a means to decrease the potentially dangerous systemic drug concentrations which are associated with timolol eyedrop therapy. l-Tumolol (125 μg) was administered in 0.5% eyedrops (25 μl, pH 6.86) and in controlled release silicone tubing devices (dose 57.6 μ;g; release rate 7.2 μg h for 8 h) in the eyes of pigmented rabbits. [ 3H]Timolol tracer was used in ocular absorption studies and unlabeled timolol dosage forms in systemic absorption studies. [ 3H]Timolol concentrations were determined in ocular tissues and tear fluid. Beta blocking activity in plasma was determined using a radioreceptor assay. Comparable timolol concentrations were achieved in the iris-ciliary body with silicone tubing devices (57.6 μg) and with eyedrops (125 μg). The relative ocular timolol bioavailability after controlled drug delivery was about 2-fold greater than from eyedrops. In plasma, peak beta-blocking activity was much higher after eyedrop administration (17.16 ± 2.40 ng/ml) than during controlled timolol delivery (< 1.0 ng ml ). The results indicate that controlled drug delivery is a viable alternative in improving the therapeutic index of glaucoma therapy with timolol.

Review: Systemic Absorption of Topically Applied Ocular Drugs in Humans

Literature on human plasma concentrations after instillation of ocular timolol, levobunolol, atropine, cyclopentolate, scopolamine, phenylephrine, betamethasone and technetium Tc 99m and theories of lacrimal drainage were reviewed. In all studies the eyedrops absorbed rapidly into the systemic circulation. Like the kinetics of the tracer substances in lacrimal scintigraphy, the plasma drug levels showed interindividual variations. Plasma levels of ocular drugs were lower when punctal occlusion was applied, the mechanism, however, could not be explained. Since an early and a late plasma peak was occasionally registered in some subjects in timolol and cyclopentolate studies, it is suggested that systemic absorption of ocular drugs is low during the nasolacrimal passage but occurs during conjunctival and nasal contact.

Effect of Coenzyme Q10 on Hemodynamic Response to Ocular Timolol

Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial membrane and plays an important role in the maintenance of normal cardiac function. To evaluate the effects of ocular timolol on the cardiovascular system and determine the protective effect of CoQ10, 16 patients with glaucoma were studied using impedance cardiography. Following instillation of 1 mg timolol maleate in each eye, heart rate (HR) and stroke index (SI) decreased, and total peripheral resistance index (TPRI) increased significantly. Reexamination was performed after 6 weeks of 90 mg oral CoQ10. Despite decreases in HR, percent changes in HR were significantly less after CoQ10 at 120 min. Stroke index showed an initial increase which was not observed without CoQ10. These data suggest that CoQ10 delayed the appearance of inotropic blockade of timolol and hastened the disappearance of chronotropic blockade. Additional study of six normal volunteers with 6 weeks of oral CoQ10 showed a similar decrease of intraocular pressure after timolol instillation as compared to those without CoQ10. Thus, administration of oral CoQ10 in patients receiving ocular timolol may be useful in mitigating cardiovascular side effects without affecting intraocular pressure in the treatment of glaucoma.

Ocular levobunolol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.

Levobunolol is a potent non-selective beta-adrenoceptor blocking agent used for the topical treatment of increased intraocular pressure in patients with chronic open angle glaucoma or ocular hypertension. In comparative studies of up to 2 years' duration levobunolol 0.5 to 1% reduced intraocular pressures by about 30% and adequately controlled intraocular hypertension in 50 to 85% of those treated. These results were significantly superior to those produced by placebo and comparable to the responses achieved with ocular timolol in double-blind controlled trials. Levobunolol has been well tolerated, producing only minor changes in objective and subjective ophthalmic and systemic parameters. Adverse reactions resulted in approximately 5% of patients withdrawing from treatment with levobunolol which was equivalent to that observed with timolol. Thus, ocular levobunolol is a well-tolerated and effective therapy for the management of raised intraocular pressure, and is a suitable alternative to ocular timolol in patients with chronic open angle glaucoma or ocular hypertension.

Psychiatric Side Effects from Topical Ocular Timolol, a Beta-Adrenergic Blocker

Neuropsychiatric side effects have been reported with various systemic betablockers. Data submitted to the National Registry of Drug-Induced Ocular Side Effects appear to indicate similar adverse reactions secondary to topical ophthalmic timolol. One hundred sixty-three of 369 central nervous system cases (44%) reported depression, psychosis, confusion, and hallucinations following topical ophthalmic timolol administration. The psychiatric community should be aware that sudden changes in mental status or onset of common psychiatric conditions, such as depression, may be due to topical ocular timolol. Withdrawal of the drug usually results in disappearance of these effects in 1 to 7 days.

The pharmacokinetics of ocularly applied timolol in rabbits

[3H]timolol derived radioactivity and beta-antagonistic activity in the aqueous humour, iris, ciliary body and blood in rabbits were analyzed by liquid scintillation counting (LSC) and radioreceptor assay (RRA) after ocular timolol. After ocular application of tracer labelled timolol, the radioactivity decreased slowly in the iris (Kel = 0.05 h-1) and ciliary body (Kel = 0.02 h-1). In the aqueous humour the elimination rate was faster (Kel = 0.57 h-1). The beta-antagonistic activities of the aqueous humour and plasma decreased rapidly when compared to LSC values. The ethanol extractable pool of the beta-antagonistic activity from the iris and ciliary body was only a few percent of the corresponding LSC estimates. The kinetics of beta-antagonistic activity extractable from iris and ciliary body was identical with that in the aqueous humour. Timolol concentrations in the untreated rabbit eye were sufficiently high to lower the intraocular pressure.

Ocular ß-Blockers and Systemic Effects

As pointed out by Swenson, 1 there can be drug-induced systemic effects from topical ophthalmic application of a β-adrenergic antagonist. Over the past eight years, the National Registry of Drug-Induced Ocular Side Effects in the Department of Ophthalmology at the Oregon Health Sciences University, Portland, has been monitoring this medication. It is evident that some patients who receive topical ocular timolol maleate obtain therapeutic plasma timolol levels. 2,3 Of the 1,900 cases of possible adverse reactions secondary to ophthalmic timolol reported to the Registry, 63% are systemic side effects. One reason why systemic blood levels of this drug may occur is the order pass effect. Essentially, this means that when timolol is administered orally, the drug first passes through the liver where most of it is metabolized before being exposed to the target organs. However, timolol eyedrops drain through the nasolacrimal system rapidly, and an estimated 80% of the drug may

Sexual Dysfunction and Ocular Timolol

<h3>To the Editor.—</h3> The letter from Dr F. T. Fraunfelder and S. Martha Meyer¹states that the National Registry of Drug Induced Ocular Side Effects has received reports of 28 complaints of various sexual dysfunctions in 25 patients following usual doses of topical ocular timolol. Impotence was reported in 18 patients, decreased libido in nine patients, and decreased ejaculate volume in one patient. In a subsequent issue of<i>JAMA</i>, Curb et al²reviewed the results of the Hypertension Detection and Followup Program clinical trial in a cohort of 5,485 patients. According to the authors, this is the largest cohort to date from which detailed data on antihypertensive drug surveillance are available. Sexually related side effects of oral antihypertensive drugs are often a major concern, and in the Hypertension Detection and Follow-up Program study, discontinuation of oral antihypertensive drug treatment in 8.3% of the male patients resulted from these side