The effects of antiglaucoma and systemic medications on ocular blood flow

doi:10.1016/S1350-9462(03)00064-8

Progress in Retinal and Eye Research

Volume 22, Issue 6, November 2003, Pages 769-805

https://doi.org/10.1016/S1350-9462(03)00064-8 Get rights and content

Abstract

Based on the body of evidence implicating ocular blood flow disturbances in the pathogenesis of glaucoma, there is great interest in the investigation of the effects of antiglaucoma drugs and systemic medications on the various ocular vascular beds. The primary aim of this article was to review the current data available on the effects of antiglaucoma drugs and systemic medications on ocular blood flow. We performed a literature search in November 2002, which consisted of a textword search in MEDLINE for the years 1968–2002. The results of this review suggest that there is a severe lack of well-designed long-term studies investigating the effects of antiglaucoma and systemic medications on ocular blood flow in glaucomatous patients. However, among the 136 articles dealing with the effect of antiglaucoma drugs on ocular blood flow, only 36 (26.5%) investigated the effects of medications on glaucoma patients. Among these 36 articles, only 3 (8.3%) were long-term studies, and only 16 (44.4%) were double-masked, randomized, prospective trials. Among the 33 articles describing the effects of systemic medications on ocular blood flow, only 11 (33.3%) investigated glaucoma patients, of which only one (9.1%) was a double-masked, randomized, prospective trial. Based on this preliminary data, we would intimate that few antiglaucoma medications have the potential to directly improve ocular blood flow. Unoprostone appears to have a reproducible antiendothelin-1 effect, betaxolol may exert a calcium-channel blocker action, apraclonidine consistently leads to anterior segment vasoconstriction, and carbonic anhydrase inhibitors seem to accelerate the retinal circulation. Longitudinal, prospective, randomized trials are needed to investigate the effects of vasoactive substances with no hypotensive effect on the progression of glaucoma.

Section snippets

Rationale for modulating ocular blood flow in the treatment of glaucoma

Glaucoma refers to a multifactorial disease characterized by a progressive optic neuropathy followed by gradual visual field loss. Elevated intraocular pressure (IOP), which previously was part of the definition of glaucoma, is now recognized as the major risk factor for the development of the disease. Years ago, adrenergic drugs, parasympathomimetics, beta-blockers and systemic carbonic anhydrase inhibitors (CAIs) were the only available drugs to treat glaucoma. Despite the change in concept

Ocular blood flow measurement techniques

In the last 30 years, the assessment of ocular circulation has evolved from a subjective description of visible vessels to direct quantitative measurement of ocular blood velocity and flow. Since no single technique provides a complete description of ocular hemodynamics, it is impossible to obtain a measurement from a single device and extrapolate a complete and accurate understanding of OBF. Therefore, a number of measurements are used to quantify the various vascular beds comprising the

Ocular penetration of topically applied antiglaucoma medications

Most glaucoma drugs are applied topically to the eye. A small fraction of the drug dosage is absorbed directly through the cornea, conjunctiva, and sclera, and a larger fraction is absorbed into the systemic circulation. Penetration across the cornea is proposed as the primary pathway by which drugs reach the anterior segment after topical administration, whereas the conjunctiva/scleral route is more important to allow the access to posterior tissues (Burstein and Anderson, 1985; Grass and

Literature search

We performed a literature search in November 2002 which consisted of a textword search in MEDLINE for the years 1968–2002. It used the combination of the terms blood flow and pilocarpine, timolol, betaxolol, levobunolol, carteolol, apraclonidine, brimonidine, dorzolamide, brinzolamide, acetazolamide, latanoprost, travoprost, bimatoprost, and unoprostone. Articles dealing with OBF were then selected and reviewed. This search retrieved 136 citations. Articles investigating the effects of systemic

Pilocarpine

Pilocarpine is a parasympathomimetic drug that promotes its effect directly at the neuromuscular junction. Cholinergic stimulation of the ciliary muscle by pilocarpine results in traction of the scleral spur, altering the configuration of the trabecular meshwork and leading to enhanced outflow and reduced IOP (Drance and Nash, 1971; Fellman and Starita, 1990). In general, parasympathomimetic drugs tend to induce vasodilation, although Stjernschantz (1990) suggested a colinergic-induced

The effects of systemic medications on ocular blood flow

The effects of systemic medications with vasoactive properties on OBF have also been evaluated, especially with regard to calcium channel blockers. There are other substances that could theoretically improve OBF and have also been included in the list of potentially useful drugs in the treatment of glaucoma.

Perspectives and conclusions

The results of this review suggest that there are very few well-designed studies investigating the long-term effects of antiglaucoma or systemic medications on the OBF of glaucomatous patients. Among the 136 articles dealing with the effect of antiglaucoma drugs on OBF, only 36 (26.5%) investigated the effects of medications on glaucomatous patients. Among these 36 articles, only 3 (8.3%) were long-term studies (duration of at least 3 months), and only 16 (44.4%) were double-masked, randomized,

References (375)

M.B. Abelson et al.
Sustained reduction in intraocular pressure in humans with the calcium channel blocker verapamil
Am. J. Ophthalmol.
(1988)
A. Alm et al.
Ocular and optic nerve blood flow at normal and increased intraocular pressures in monkeys (Macaca irus)a study with radioactively labelled microspheres including flow determinations in brain and some other tissues
Exp. Eye Res.
(1973)
A. Alm et al.
The effects of pilocarpine and neostigmine on the blood flow the anterior uvea in monkeys. A study with radioactively labells microspheres
Exp. Eye Res.
(1973)
M. Araie et al.
Effect of long-term topical betaxolol on tissue circulation in the iris and optic nerve head
Exp. Eye Res.
(1997)
G.E. Barnes et al.
Increased optic nerve head blood flow after 1 week of twice daily topical brinzolamide treatment in Dutch-belted rabbits
Surv. Ophthalmol.
(2000)
B. Becker
The effects of the carbonic anhydrase inhibitor, acetazolamide, on the composition of aqeuos humor
Am. J. Ophthalmol.
(1955)
B. Becker
Diabetes mellitus and primary open-angle glaucoma. The XXVII Edward Jackson Memorial Lecture
Am. J. Ophthalmol.
(1971)
A. Bhandari et al.
Effect of brimonidine on optic nerve blood flow in rabbits
Am. J. Ophthalmol.
(1999)
L. Bonomi et al.
Vascular risk factors for primary open angle glaucomathe Egna-Neumarkt Study
Ophthalmology
(2000)
M.E. Bosem et al.
Short-term effects of levobunolol on ocular pulsatile flow
Am. J. Ophthalmol.
(1992)

A.M. Carlsson et al.

The effect of brimonidine tartrate on retinal blood flow in patients with ocular hypertension

Am. J. Ophthalmol.

(2000)

K.G. Claridge et al.

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

Surv. Ophthalmol.

(1994)

C.M. Clineschmidt et al.

A randomized trial in patients inadequately controlled with timolol alone comparing the dorzolamide-timolol combination to monotherapy with timolol or dorzolamide. Dorzolamide-Timolol Combination Study Group

Ophthalmology

(1998)

W.H. Constad et al.

Use of angiotensin converting enzyme inhibitor in ocular hypertension and primary open-angle glaucoma

Am. J. Ophthalmol.

(1988)

C. Costagliola et al.

Effect of oral losartan potassium administration on intraocular pressure in normotensive and glaucomatous human subjects

Exp. Eye Res.

(2000)

D.N. Damon et al.

A comparison between mean blood velocities and center-line red-cell velocities as measured with a mechanical image streaking velocimeter

Microvasc. Res.

(1979)

L. DeSantis

Preclinical overview of brinzolamide

Surv. Ophthalmol.

(2000)

S.M. Drance et al.

Response of blood flow to warm and cold in normal and low-tension glaucoma patients

Am. J. Ophthalmol.

(1988)

O. Findl et al.

Assessment of optic disk blood flow in patients with open-angle glaucoma

Am. J. Ophthalmol.

(2000)

J. Flammer et al.

Vasospasm, its role in the pathogenesis of diseases with particular reference to the eye

Prog. Retin. Eye Res.

(2001)

J. Flammer et al.

The impact of ocular blood flow in glaucoma

Prog. Retin. Eye Res.

(2002)

A.A. Acheampong et al.

Comparison of concentration-time profiles of levobunolol and timolol in anterior and posterior ocular tissues of albino rabbits

J. Ocul. Pharmacol. Ther.

(1995)

A.A. Acheampong et al.

Distribution of brimonidine into anterior and posterior tissues of monkey, rabbit, and rat eyes

DMD

(2002)

A. Alm

Ocular circulation

Alder's Physiol. Eye

(1992)

S. Alonso et al.

Enhancement of the coronary vasodilator action of adenosine tri-phosphate by dipyridamole

Circ Res.

(1967)

R. Altan-Yaycioglu et al.

The effects of beta-blockers os ocular blood flow in patients with primary open angle glaucomaa color doppler imaging study

Eur. J. Ophthalmol.

(2001)

B.M. Altura et al.

Magnesium ı́ons and contraction of vascular smooth musclesrelationship to some vascular diseases

Fed. Proc.

(1981)

M. Araie et al.

Beta-adrenergic blockersocular penetration and binding to the uveal pigment

Jpn. J. Ophthalmol.

(1982)

O. Arend et al.

The acute effect of topical beta-adrenoreceptor blocking agent on retinal and optic nerve head circulation

Acta Ophthalmol. Scand.

(1998)

P. Ashton et al.

Formulation influence on conjunctival penetration of four beta blockers in the pigmented rabbita comparison with corneal penetration

Pharm. Res.

(1991)

M. Astin et al.

Role of nitric oxide in PGF2 alpha-induced ocular hyperemia

Exp. Eye Res.

(1994)

K. Auckland

Measurement of local blood flow with hydrogen gas

Circ Res.

(1964)

A.M. Avunduk et al.

The one-month effects of topical betaxolol, dorzolamide and apraclonidine on ocular blood flow velocities in patients with newly diagnosed primary open-angle glaucoma

Ophthalmologica

(2001)

M. Babiole et al.

In vitro corneal permeation of unoprostone isopropyl (UI) and its metabolism in the isolated pig eye

J. Ocul. Pharmacol. Ther.

(2001)

F. Beano et al.

An evaluation of the effect of unoprostone isopropyl 0.15% of ocular hemodynamics in normal-tension glaucoma patients

Graefes Arch. Clin. Exp. Ophthalmol.

(2001)

B. Becker

Decrease in intraocular pressure in man by a carbonic anhydrase inhibitor, Diamox

Am. J. Ophthalmo.l

(1954)

B. Bengtsson

The prevalence of glaucoma

Br. J. Ophthalmo.l

(1981)

I.C. Bergstrand et al.

Timolol increased retrobulbar flow velocities in untreated glaucoma eyes but not in ocular hypertension

Acta Ophthalmol. Scand.

(2001)

I.C. Bergstrand et al.

Dorzolamide and ocular blood flow in previously untreated glaucoma patientsa controlled double-masked study

Acta Ophthalmol. Scand.

(2002)

A.S. Bernd et al.

Ocular hemodynamics and visual field in glaucoma treated with dorzolamide

Ophthalmologe

(2001)

A.H. Bloom et al.

Effects of one week of levobunolol HCI 0.5% on the human retinal circulation

Curr. Eye Res.

(1997)

A. Boles-Carenini et al.

Differences in the longterm effect of timolol and betaxolol on the pulsatile ocular blood flow

Surv. Ophthalmol.

(1994)

E. Braunwald

Mechanisms of action of calcium channel blocking agents

N. Engl. J. Med.

(1982)

D.C. Broadway et al.

Glaucoma and vasospasm

Br. J. Ophthalmol.

(1998)

G. Brogiolo et al.

Latanoprost is a vasoconstrictor in isolated porcine ciliary arteries

Klin. Monatsbl. Augenheilkd.

(2001)

G. Brogiolo et al.

The β-blocker carteolol inhibits contractions induced by KCl in pig ciliary arteriesan effect modulated by extracellular Ca++

Klin. Monatsbl. Augenheilkd.

(2002)

R. Brubaker

Measurement of aqueous flow by fluorophotomerty

N.L. Burstein et al.

Corneal penetration and ocular availability of drugs

J. Ocular. Pharmacol.

(1985)

H.I. Bussey et al.

Promising uses of calcium channel blocking agents

Pharmacotherapy

(1984)

Z. Butt et al.

Reproducibility of pulsatile ocular blood flow measurements

J. Glaucoma

(1995)

Cited by (117)

Neuroprotection: A versatile approach to combat glaucoma
2020, European Journal of Pharmacology
In most retinal diseases, neuronal loss is the main cause of vision loss. Neuroprotection is the alteration of neurons and/or their environment to encourage the survival and function of the neurons, especially in environments that are deleterious to the neuronal health. The area of neuroprotection progresses with a therapeutically-based hope of improving vision and clinical outcomes for patients through the developments in neurotrophic therapy, antioxidative therapy, anti-excitotoxic, anti-ischemic, anti-inflammatory, and anti-apoptotic care. In this review, we summarize the various neuroprotection strategies for the treatment of glaucoma, genetics of glaucoma and the role of various nanoplatforms in the treatment of glaucoma.
Restoring retinal neurovascular health via substance P
2019, Experimental Cell Research
Regulation of vascular permeability plays a major role in the pathophysiology of visually threatening conditions such as retinal vein occlusion and diabetic retinopathy. Principally, several factors such as vascular endothelial growth factor (VEGF), are up-regulated or induced in response to hypoxia thus adversely affecting the blood-retinal barrier (BRB), resulting in retinal edema and neovascularisation. Furthermore, current evidence supports a dysregulation of the inner retinal neural-vascular integrity as a critical factor driving retinal ganglion cell (RGC) death and visual loss. The principal objective of this study was to interrogate whether Substance P (SP), a constitutive neurotransmitter of amacrine and ganglion cells, may protect against N-methyl-d-aspartate (NMDA)-induced excitotoxic apoptosis of ganglion cells and VEGF-induced vessel leakage in the retina. Tight junctional protein expression and a Vascular Permeability Image Assay were used to determine vascular integrity in vitro. The protective effect of SP on RGC was established in ex vivo retinal explants and in vivo murine models. After NMDA administration, a reduction in TUNEL+ cells and a maintained number of Brn-3a+ cells were found, indicating an inhibition of RGC apoptosis mediated by SP. Additionally, SP maintained endothelial tight junctions and decreased VEGF-induced vascular permeability. In conclusion, administration of SP protects against NMDA apoptosis of RGC and VEGF-induced endothelial barrier breakdown.
Sustained release timolol maleate loaded ocusert based on biopolymer composite
2018, International Journal of Biological Macromolecules
Citation Excerpt :
They also increase the contact time and thus bioavailability, prolonged drug release, reduce systemic side effects, reduce number of administration, accurate dose administration and possibility of incorporating various novel chemical technological approaches such as pro-drugs, micro particulates, salts acting as buffers [6]. The drug delivered into the cul-de-sac gets absorbed by corneal route which mainly depends on the anatomical structure of cornea that further depends on the solubility nature of drug.The epithelial layer within the route is the rate limiting barrier for transcorneal diffusion of hydrophilic drug [7]. Absorption of drug also occurs across the non-corneal route by penetrating across the sclera and conjunctiva into the intra ocular tissue [8].
In the present investigation, the effect of timolol maleate loaded ocuserts was studied as an alternative for conventional anti-glaucoma formulation. Ocuserts were prepared using natural polymer sodium alginate and ethyl cellulose. Physico-chemical properties along with drug entrapment efficiency (94–98%), content uniformity (93.1% ± 0.264–98.00% ± 0.321), in vitro drug release (83.42% ± 0.35 at end of 12 h), ex vivo permeation all showed satisfactory results, which was found to follow zero order kinetics. Ex vivo permeation studies showed better results, revealed that the permeability coefficient was dependent on polymer type. The sterility test accelerated stability studies and in vivo studies such as eye irritancy test, in vivo drug release of the optimized ocusert was determined. The anti-glaucoma activity was measured using Schiotz tonometer at different time interval. Significant reduction in Intra ocular pressure (IOP) within 3 days was observed in case of rabbits treated with ocusert in comparison to the rabbit treated with marketed eye drop formulation. Hence timolol maleate loaded ocuserts proved to be a promising and viable alternative over conventional eye formulation for the sustained and controlled ophthalmic drug delivery, targeting the drug within the ocular globe thus improving patient compliance for the treatment of glaucoma.
Ocular inserts based on chitosan and brimonidine tartrate: Development, characterization and biocompatibility
2016, Journal of Drug Delivery Science and Technology
The glaucoma is an ocular pathology characterized by the increase of intraocular pressure and possibility of retinal degeneration. The treatment is based on the administration of eye drops. However, they do not induce the permanence of drug in the eye, compromising its bioavailability. In this study, inserts based on chitosan and brimonidine tartrate were developed to treat the glaucoma by improving the drug bioavailability. Inserts were characterized using different analytical techniques FTIR, SEM, DSC and WAXS. The in vitro release profile of drug from inserts was evaluated. The in vitro biocompatibility against ARPE-19 and MIO-M1 cells was investigated. The in vivo biocompatibility using the chorioallantoic membrane was also demonstrated. Analytical techniques demonstrated that the amorphous drug was physically dispersed into the polymeric chains without chemical interactions. However, a portion of drug crystals was on the surface of systems. Inserts provided the controlled release of drug for 30 days without a burst effect. Inserts did not induce a deleterious effect to ocular cells, indicating their biocompatibility. They were also well tolerated in vivo, suggesting the absence of toxicity. These inserts could be potential delivery systems to reduce the intraocular pressure and to induce neuroprotective effects in glaucomatous patients.
Optical Coherence Tomography Angiography Assessment of the Optic Nerve Head in Patients Hospitalized Due to COVID-19 Bilateral Pneumonia
2024, Medicina (Lithuania)
Three Major Causes of Metabolic Retinal Degenerations and Three Ways to Avoid Them
2023, International Journal of Molecular Sciences

View all citing articles on Scopus

View full text