Timolol Eye Drops Research Articles

Pharmacogenetic Explanation for Excessive β-Blockade Following Timolol Eye Drops

To determine whether the effects of topically administered timolol in an individual would be dependent on the presence or absence in that individual of the P-450 enzyme CYP2D6 and whether the effects of topically administered timolol would be increased and its metabolism decreased by the oral administration of quinidine, a known inhibitor of CYP2D6. Single-blind randomized crossover comparison of topical timolol, placebo, and the effects of inhibition of timolol metabolism by oral quinidine. Clinical research center of an academic medical center. Eight male extensive metabolizers (EMs) and five male poor metabolizers (PMs) of debrisoquin. Two drops of 0.5% timolol or artificial tears were administered into each nostril in random order, and placebo or 50 mg of quinidine was administered orally to the EMs in random order, followed 30 minutes later by either the timolol or placebo drops. Plasma timolol concentrations were measured by high-pressure liquid chromatography, while the extent of beta-blockade was determined by the suppression of exercise-induced rise in heart rate. The exercise heart rate was reduced following timolol eye drops compared with placebo in both EMs (P < .001) and PMs (P < .001) with significantly greater heart rate reduction (P = .01) and higher plasma timolol concentration in PMs compared with EMs (P = .03). Administration of quinidine with timolol eye drops to EMs resulted in a further significant reduction in heart rate (P = .02) and increase in plasma timolol concentration (P = .04). An individual's debrisoquin phenotype is an important determinant of beta-blockade following timolol eye drops, and metabolism of timolol is inhibited and beta-blockade increased by coadministration of oral quinidine. Clinicians should be aware of the potential for drug interactions that occur when orally administered drugs inhibit the metabolism of a topically administered drug.

Pharmacogenetic explanation for excessive beta-blockade following timolol eye drops. Potential for oral-ophthalmic drug interaction

Pharmacogenetic explanation for excessive beta-blockade following timolol eye drops. Potential for oral-ophthalmic drug interaction

Determination of low plasma timolol concentrations following topical application of timolol eye drops in humans by high-performance liquid chromatography with electrochemical detection

A simple and sensitive high-performance liquid chromatographic assay was developed for determination of timolol in human plasma following administration of two drops of a 5% timolol ophthalmic solution. A 4% butyl alcohol—hexane extract of an alkalized sample of plasma was chromatographed on a reversed-phase column and the components in the column effluent were monitored by coulometric detection. The extraction efficiency of timolol was 69.02 ± 4.16% (mean ± S.D.) and its detection limit was 107.2 pg/ml. The effect of mobile phase pH, buffer concentration and the working potential of the detector on column performance and the electrochemical response are described.

Diurnal variation in pulsatile ocular blood flow in normal and glaucomatous eyes

Ocular blood flow, in particular to the optic nerve head, is considered important in determining the extent of glaucomatous damage. The 24-hour variation in the pulsatile component of ocular blood flow (POBF) was measured using a pneumotonometer linked to the Langham Ocular Blood Flow System ®. Intraocular pressure (IOP), ocular pulse amplitude, POBF, systemic blood pressure and heart rate were recorded at three-hourly intervals over a 24-hour period in 10 ocular hypertensives, eight patients with primary open angle glaucoma (POAG) treated with timolol eyedrops (G timolol 0.25%), and eight ocular normotensive control subjects. The POAG subjects were readmitted for a second set of 24-hour measurements after temporarily discontinuing G timolol for two weeks. The POBF showed no significant diurnal variation in any of the patient groups, the POAG values being taken from the “off treatment” period. By contrast, there were overnight falls in IOP, ocular pulse amplitude, blood pressure and heart rate, which reached significance in some groups. This suggests that overall there are compensatory changes in IOP, blood pressure, heart rate, and perhaps ocular vascular resistance, to preserve POBF overnight. Within all groups there was much individual variation, with some subjects showing an overnight fall in POBF, suggesting a lack of autoregulation in these cases who might prove to be at greater risk of developing nocturnal glaucomatous damage. When timolol was withdrawn from POAG subjects, there was no change in POBF despite an increase in IOP, implying that timolol, though effective as ocular hypotensive, did not alter POBF.

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.

Theoretical corneal permeation model for ionizable drugs.

The primary route into the eye for many drugs is transcorneal permeation. A better understanding of the mechanisms involved in transcorneal permeation could lead to improvements in drug dosage forms or the development of drug delivery devices which enhance the ocular bioavailability of drugs. A corneal permeation model has been developed which can be used to study the mechanisms involved in corneal permeation. The model uses five compartments in series to simulate the tear film, epithelium, stroma, endothelium and aqueous humour. These tissues were assumed to be adequately represented by plane sheet barriers of physiological thickness. The tear film was assumed to be perfectly mixed and the stroma completely stagnant. Due to inadequate knowledge of the hydrodynamics of the aqueous humour, both stagnant and perfectly mixed extremes were studied. The four routes of drug loss which were considered the most significant and therefore included in the model were lacrimal drainage, conjunctival absorption, aqueous drainage and iris-ciliary body absorption. The equilibrium that can exist between the ionic and non-ionic forms of a drug was found to be an important step in the mechanism of transcorneal permeation. Including the equilibrium condition in the model resulted in aqueous humour drug levels that were over 50 times higher than the levels predicted by a model which did not use the equilibrium mechanism. A relationship between the lipophilicity of each of the two drug forms and its permeability in each layer of the cornea was used in the model. The model was used to predict aqueous humour drug concentrations resulting from a constant release of timolol into the tear film or from the application of timolol, levobunolol and pilocarpine eyedrops. The model produced transient aqueous humour drug levels that closely followed experimental in vivo data from literature. Using the model, it was also possible to predict the amount of instilled drug that is lost through each of the four elimination routes of the eye.

Pharmacokinetic simulation reveals in vivo deviations from in vitro release of timolol from polymer matrices

In some glaucoma patients timolol eye drops may cause severe cardiovascular and respiratory side-effects due to systemic absorption. Administration of timolol in controlled release devices reduces the harmful systemic absorption of the drug, however, as in the case of many drug delivery systems, the in vivo release rate relative to the in vitro rate is not known. In the present investigation, the concentrations of timolol in lacrimal fluid and plasma after administration into rabbit eyes in different matrices of monoisopropyi ester of poly(vinyl methyl ether-maleic anhydride) (PVM-MA) was analysed using STELLA® simulation software. In the model, in vitro release rates of timolol were used as input values and preocular and systemic kinetic parameters from literature were included. The simulation model calculated predicted drug concentration profiles in tear fluid and plasma. The simulations showed that drug release in vivo in tear fluid was decreased compared to the in vitro experiments in the case of the unbuffered and phosphate buffered matrices. Differences in the conjunctival permeability of timolol after administration of various matrix types were revealed by the simulations where measured concentrations in tear fluid were used as input values. The phosphate buffered matrix showed similar tear fluid — plasma transfer of timolol in simulations and experimentally. Sodium acetate buffer in the matrix reduced the permeability of timolol in the conjunctival epithelium, thus decreasing the systemic absorption of the drug. In the case of the unbuffered matrix, probably a decrease in the pH of tear fluid close to the matrix may reduce the transport of timolol through the conjunctiva. STELLA® simulations proved useful in the in vitro — in vivo comparisons of ophthalmic timolol.

Beeinflussung der Tränenfilmaufreißzeit (BUT) durch Betablocker-Augentropfen ohne Konservierungsstoffe

Traditional beta-blocking eye drops preserved with benzalkonium chloride show an adverse effect on the precorneal tear film, which can be measured by checking the break-up-time (BUT). To decide, whether this adverse effect is caused more by the beta-blocking drug or the preservative, we tested the influence of timolol eye drops without preservative in single dose units Timosine) on the BUT in a prospective, open study. These eyedrops caused no significant shortening of the BUT in persons, which where untreated before. Patients using preserved beta-blocking eye drops and having irritations of their eyes showed significant prolongation of the BUT after changing the therapy to Timosine. Preservative-free beta-blocking eye drops are a real improvement in the therapy of glaucoma patients with irritated eyes.

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.

Effects of Epinephrine Pretreatment and Solution DH on Ocular and Systemic Absorption of Ocularly Applied Timolol in Rabbits

The ratio between ocular and systemic drug concentrations describes the relative safety of ophthalmic dosage forms of the same drug in terms of its systemic side effects. In this study, we evaluated the effects of epinephrine pretreatment and solution pH on the aqueous humor:plasma and iris‐ciliary body:plasma ratios of peak timolol concentrations after ocular application of timolol. Timolol eyedrops (5 mg/mL, 25 μL) were applied ocularly in pigmented rabbits. Raising pH of the eyedrops from 6.2 to 7.5 did not affect the ratio between ocular and systemic peak drug concentrations, since both ocular and systemic concentrations of timolol were increased. Administration of epinephrine (20 mg/mL, 50 μL) 5min prior to timolol eyedrop administration reduced the peak timolol concentrations in plasma 65–80%. Epinephrine did not affect the ocular concentrations of timolol. The decreased peak concentrations in plasma were due to the conjunctival and nasal vasoconstricting effects of epinephrine and to the subsequent slower absorption of timolol. Our study demonstrates that compared with currently available eyedrops (pH 6.9), the ocular:systemic concentration ratio of ophthalmic timolol can be improved four‐ to sixfold in rabbits by combining epinephrine‐induced conjunctival and nasal vasoconstriction and improved ocular absorption from pH 7.5 eyedrops.

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.

Cardiovascular responses to metipranolol and timolol eyedrops in healthy volunteers.

1. Intraocular pressure and cardiovascular responses to metipranolol 0.1% and 0.3% and timolol 0.25% eyedrops were measured in a balanced single dose placebo-controlled crossover study in eight healthy volunteers aged 34-58 years. 2. Timolol 0.25% and metipranolol 0.3% reduced intraocular pressure throughout the 6 h period of observation to a similar extent. Metipranolol 0.1% was marginally less effective, significantly reducing pressure up to 4 h only. 3. No drug treatment significantly altered resting heart rate or blood pressure. Timolol 0.25% significantly reduced exercise tachycardia (P less than 0.05), an effect which was not shown by metipranolol 0.1 or 0.3%. Exertional pain in the legs occurred more frequently after timolol 0.25% and metipranolol 0.3% than after metipranolol 0.1% or placebo eyedrops. 4. Octan-1-ol/pH 7.4 buffer distribution coefficients at 37 degrees C were found to be: metipranolol 5.19, timolol 0.84, indicating that metipranolol has an approximately 6-fold greater lipid solubility. 5. It is concluded that, by comparison with timolol, metipranolol in eyedrop concentrations up to 0.3%, despite its greater lipid solubility, reaches concentrations in the systemic circulation which are less likely to affect the heart.

Accidents systémiques des bêta-bloquants en collyres

Six cases of systemic reactions to topical treatment with beta-blocking eyedrops are reported, bradycardia and faintness due to an overdosage of ophthalmic timolol; decompensated heart failure one month after the prescription of carteolol eyedrops: bronchospasm after two weeks of treatment with metipranolol eyedrops; crippling Raynaud's phenomenon of otherwise unknown origin, which had begun with timolol eyedrops, continued with carteolol eyedrops and regressed after discontinuation of ophthalmic beta-blockers; aggravation of an anaphylactoid shock in a patient treated with ophthalmic timolol, and myocardial infarction possibly due to the abrupt withdrawal of timolol eyedrops. It cannot be overstressed that the rules governing the prescription of oral beta-blockers also apply to ophthalmic preparations of these drugs: respect of contra-indications, strict adherence to the dosage recommended, gradual drug withdrawal and regular supervision. Only controlled studies and long-term follow-up will be able to demonstrate differences in safety between the five beta-blockers commercialized as eyedrops in this country.

L 714 465: appears to have no safety advantage over timolol eyedrops for the treatment of glaucoma patients with asthma

L 714 465: appears to have no safety advantage over timolol eyedrops for the treatment of glaucoma patients with asthma

Drug interactions with timolol eye drops

Drug interactions with timolol eye drops

Prospective study of intraocular pressure 2 1/2 years after intracapsular cataract extraction and implantation of a semiflexible anterior chamber lens

Fifty-one patients available for a 2 1/2 year follow-up after intracapsular cataract extraction and implantation of the semiflexible McGhan/3M, style 70 anterior chamber lens were evaluated for intraocular pressure (IOP). No significant change in the IOP could be demonstrated despite progression of iris-like tissue adhesions between the iris and lens haptics at or close to the trabecular meshwork. Four eyes (7.8%) had IOPs ≥ 22 mm Hg without medication, and four other eyes used timolol eyedrops with subsequent IOPs ≤ 18 mm Hg. Eight eyes (15.7%) demonstrated an IOP increase ≥ 25% over baseline pressures.

▾ New topical β-blockers for glaucoma

The introduction in 1979 of timolol eyedrops (Timoptol - MSD) was an important advance in the treatment of chronic open-angle glaucoma. Timolol’s relative lack of ocular unwanted effects,1 and its twice daily administration, makes it more acceptable than other eyedrops such as pilocarpine or adrenaline.2,3 But because it is absorbed through the nasal mucosa it can occasionally cause bradycardia and bronchospasm4 which may be fatal. It is also expensive. Carteolol (Teoptic) and betaxolol (Betoptic) are new ophthalmic β-blockers claimed to have a lower incidence of unwanted systemic effects. This is not claimed for metipranolol (Glauline) which is notably cheaper.

Prevention of IOP-rise following Nd-YAG laser capsulotomy with pre-operative timolol eye-drops and 1 tablet acetazolamide 250 mg systematically.

Short-term observation following Nd-YAG laser capsulotomy indicates that serious elevation of intra-ocular pressure may occur, unrelated to the amount of energy used. In this study the IOP in 3 groups of 10 pseudophakic patients undergoing Nd-YAG laser posterior capsulotomy was measured before capsulotomy and 2 and 4 hours afterwards, using the fellow-eye as control. The first group received no medication, the second received timolol 1/2% eyedrops preoperatively, the third group a combination of timolol 1/2% and 1 tablet of acetazolamide 250 mg systemically. Pretreatment with timolol 0.5% minimizes IOP-rise but does not give complete protection. The combination of timolol 0.5% with 1 tablet of acetazolamide 250 mg proves to be a safe procedure for the prevention of IOP-rise after YAG laser capsulotomy. To prevent other complications it is advisable to make a small capsulotomy of 2-3 mm diameter using as little energy as possible. Also a defocussing system in the laser is a great advantage. Indomethacin drops during a period of 6 weeks after Nd-YAG laser capsulotomy should prevent cystoid macular edema.

Sinus arrest due to timolol eye drops

International Journal of Clinical PracticeVolume 40, Issue 6 p. 256-258 Case Report Sinus arrest due to timolol eye drops A S Treseder DCH, MRCP(UK), A S Treseder DCH, MRCP(UK) Senior Registrar in Geriatric Medicine, Consultant Physician in Geriatric Medicine West Wales General Hospital, CarmarthenSearch for more papers by this authorT P L Thomas MRCP(UK), T P L Thomas MRCP(UK) Consultant Physician in Geriatric Medicine Bryntirion Hospital, LlanelliSearch for more papers by this author A S Treseder DCH, MRCP(UK), A S Treseder DCH, MRCP(UK) Senior Registrar in Geriatric Medicine, Consultant Physician in Geriatric Medicine West Wales General Hospital, CarmarthenSearch for more papers by this authorT P L Thomas MRCP(UK), T P L Thomas MRCP(UK) Consultant Physician in Geriatric Medicine Bryntirion Hospital, LlanelliSearch for more papers by this author First published: 01 June 1986 https://doi.org/10.1111/j.1742-1241.1986.tb07970.xRead the full textAboutRelatedInformationPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessClose modalShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume40, Issue6June 1986Pages 256-258 RelatedInformation RecommendedTimolol/pilocarpine combination eye drops in open angle glaucoma and in ocular hypertensionGunnar Høvding M.D., Henry Aasved, Acta OphthalmologicaShort‐term effect of latanoprost and timolol eye drops on tear fluid and the ocular surface in patients with primary open‐angle glaucoma and ocular hypertensionJ. Thygesen, K. Aaen, F. Theodorsen, S. V. Kessing, J. U. Prause, Acta Ophthalmologica ScandinavicaTwelve‐hour IOP control obtained by a single dose of timolol/pilocarpine combination eye dropsKjell T. Løfors, Gunnar Høvding, Lars Viksmoen, Henry Aasved, Bjørn Bergaust, Tore Bulie, Acta OphthalmologicaGLAUCOMA TREATMENT WITH TIMOLOLEMILIA KERTY M.D, IVAR HØRVEN, Acta Ophthalmologica

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