Effects of the topically applied calcium-channel blocker flunarizine on intraocular pressure in clinically normal dogs

Andrew L. Greller Eye Care for Animals, 2316 W Northern Ave, Phoenix, AZ 85021.

Search for other papers by Andrew L. Greller in
Current site
Google Scholar
PubMed
Close
 VMD
,
Allison R. Hoffman Eye Care for Animals, 150 N San Gabriel, Pasadena, CA 91107.

Search for other papers by Allison R. Hoffman in
Current site
Google Scholar
PubMed
Close
 DVM
,
Chengcheng Liu Department of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Search for other papers by Chengcheng Liu in
Current site
Google Scholar
PubMed
Close
 MS
,
Gui-shuang Ying Department of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Search for other papers by Gui-shuang Ying in
Current site
Google Scholar
PubMed
Close
 PhD
,
Daljit K. Vudathala Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Search for other papers by Daljit K. Vudathala in
Current site
Google Scholar
PubMed
Close
 PhD
,
Gregory M. Acland James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

Search for other papers by Gregory M. Acland in
Current site
Google Scholar
PubMed
Close
 BVSc
, and
András M. Komáromy Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Search for other papers by András M. Komáromy in
Current site
Google Scholar
PubMed
Close
 DrMedVet, PhD

Abstract

Objective—To determine effects of the topically applied calcium-channel blocker flunarizine on intraocular pressure (IOP) in clinically normal dogs.

Animals—20 dogs.

Procedures—Baseline diurnal IOPs were determined by use of a rebound tonometer on 2 consecutive days. Subsequently, 1 randomly chosen eye of each dog was treated topically twice daily for 5 days with 0.5% flunarizine. During this treatment period, diurnal IOPs were measured. In addition, pupillary diameter and mean arterial blood pressure (MAP) were evaluated. Serum flunarizine concentrations were measured on treatment day 5. Intraday fluctuation of IOP was analyzed by use of an ANOVA for repeated measures and a trend test. Changes in IOP from baseline values were assessed and compared with IOPs for the days of treatment. Values were also compared between treated and untreated eyes.

Results—A significant intraday fluctuation in baseline IOP was detected, which was highest in the morning (mean ± SE, 15.8 ± 0.63 mm Hg) and lowest at night (12.9 ± 0.61 mm Hg). After 2 days of treatment, there was a significant decrease in IOP from baseline values in treated (0.93 ± 0.35 mm Hg) and untreated (0.95 ± 0.34 mm Hg) eyes. There was no significant treatment effect on pupillary diameter or MAP. Flunarizine was detected in serum samples of all dogs (mean ± SD, 3.89 ± 6.36 μg/L).

Conclusions and Clinical Relevance—Topically applied flunarizine decreased IOP in dogs after 2 days of twice-daily application. This calcium-channel blocker could be effective in the treatment of dogs with glaucoma.

Abstract

Objective—To determine effects of the topically applied calcium-channel blocker flunarizine on intraocular pressure (IOP) in clinically normal dogs.

Animals—20 dogs.

Procedures—Baseline diurnal IOPs were determined by use of a rebound tonometer on 2 consecutive days. Subsequently, 1 randomly chosen eye of each dog was treated topically twice daily for 5 days with 0.5% flunarizine. During this treatment period, diurnal IOPs were measured. In addition, pupillary diameter and mean arterial blood pressure (MAP) were evaluated. Serum flunarizine concentrations were measured on treatment day 5. Intraday fluctuation of IOP was analyzed by use of an ANOVA for repeated measures and a trend test. Changes in IOP from baseline values were assessed and compared with IOPs for the days of treatment. Values were also compared between treated and untreated eyes.

Results—A significant intraday fluctuation in baseline IOP was detected, which was highest in the morning (mean ± SE, 15.8 ± 0.63 mm Hg) and lowest at night (12.9 ± 0.61 mm Hg). After 2 days of treatment, there was a significant decrease in IOP from baseline values in treated (0.93 ± 0.35 mm Hg) and untreated (0.95 ± 0.34 mm Hg) eyes. There was no significant treatment effect on pupillary diameter or MAP. Flunarizine was detected in serum samples of all dogs (mean ± SD, 3.89 ± 6.36 μg/L).

Conclusions and Clinical Relevance—Topically applied flunarizine decreased IOP in dogs after 2 days of twice-daily application. This calcium-channel blocker could be effective in the treatment of dogs with glaucoma.

Contributor Notes

Dr. Greller's present address is the Eye Care for Animals, 6651-F Backlick Rd, Springfield, VA 22150.

Supported by the National Institutes of Health, National Eye Institute (EY006855, K12 EY015398, and P30 EY001583), and Foundation Fighting Blindness.

Presented in part at the American College of Veterinary Ophthalmologists Annual Meeting, San Antonio, Tex, November 2006.

The authors thank Amanda Nickle, Gerri Antonini, Alice Eidsen, and Tracy Greiner for technical assistance.

Address correspondence to Dr. Komáromy.
  • 1.

    Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90:253254.

  • 2.

    Gelatt KN, MacKay EO. Prevalence of the breed-related glaucomas in pure-bred dogs in North America. Vet Ophthalmol 2004;7:97111.

  • 3.

    Fechtner RD, Weinreb RN. Mechanisms of optic nerve damage in primary open angle glaucoma. Surv Ophthalmol 1994;39:2342.

  • 4.

    Flammer J, Orgül S. Optic nerve blood-flow abnormalities in glaucoma. Prog Retin Eye Res 1998;17:267289.

  • 5.

    Gelatt KN, Miyabayashi T, Gelatt-Nicholson KJ, et al. Progressive changes in ophthalmic blood velocities in Beagles with primary open angle glaucoma. Vet Ophthalmol 2003;6:7784.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Brooks DE, Garcia GA, Dreyer EB, et al. Vitreous body glutamate concentration in dogs with glaucoma. Am J Vet Res 1997;58:864867.

  • 7.

    Schwartz M. Neurodegeneration and neuroprotection in glaucoma: development of a therapeutic neuroprotective vaccine—the Friedenwald lecture. Invest Ophthalmol Vis Sci 2003;44:14071411.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet 2004;363:17111720.

  • 9.

    Netland PA, Chaturvedi N, Dreyer EB. Calcium channel blockers in the management of low-tension and open-angle glaucoma. Am J Ophthalmol 1993;115:608613.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Takahashi K, Lam TT, Edward DP, et al. Protective effects of flunarizine on ischemic injury in the rat retina. Arch Ophthalmol 1992;110:862870.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Saito S, Ohashi M, Naito A, et al. Neuroprotective effect of the novel Na+/Ca2+ channel blocker NS-7 on rat retinal ganglion cells. Jpn J Ophthalmol 2005;49:371376.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Ishii K, Fukaya Y, Araie M, et al. Topical administration of iganidipine, a new water-soluble Ca2+ antagonist, increases ipsilateral optic nerve head circulation in rabbits and cynomolgus monkeys. Curr Eye Res 2004;29:6773.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Maltese A, Bucolo C. Pharmacokinetic profile of topical flunarizine in rabbit eye and plasma. J Ocul Pharmacol Ther 2003;19:171179.

  • 14.

    Campana G, Bucolo C, Murari G, et al. Ocular hypotensive action of topical flunarizine in the rabbit: role of sigma 1 recognition sites. J Pharmacol Exp Ther 2002;303:10861094.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Beatty JF, Krupin T, Nichols PF, et al. Elevation of intraocular pressure by calcium channel blockers. Arch Ophthalmol 1984;102:10721076.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Melena J, Santafe J, Segarra J. The effect of topical diltiazem on the intraocular pressure in betamethasone-induced ocular hypertensive rabbits. J Pharmacol Exp Ther 1998;284:278282.

    • Search Google Scholar
    • Export Citation
  • 17.

    Osborne NN, Wood JP, Cupido A, et al. Topical flunarizine reduces IOP and protects the retina against ischemia-excitotoxicity. Invest Ophthalmol Vis Sci 2002;43:14561464.

    • Search Google Scholar
    • Export Citation
  • 18.

    Segarra J, Santafe J, Garrido M, et al. The topical application of verapamil and nifedipine lowers intraocular pressure in conscious rabbits. Gen Pharmacol 1993;24:11631171.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Tamaki Y, Araie M, Fukaya Y, et al. Effects of lomerizine, a calcium channel antagonist, on retinal and optic nerve head circulation in rabbits and humans. Invest Ophthalmol Vis Sci 2003;44:48644871.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Tamaki Y, Araie M, Tomita K, et al. Time change of nicardipine effect on choroidal circulation in rabbit eyes. Curr Eye Res 1996;15:543548.

  • 21.

    Harino S, Riva CE, Petrig BL. Intravenous nicardipine in cats increases optic nerve head but not retinal blood flow. Invest Ophthalmol Vis Sci 1992;33:28852890.

    • Search Google Scholar
    • Export Citation
  • 22.

    Källberg ME, Brooks DE, Komaromy AM, et al. The effect of an L-type calcium channel blocker on the hemodynamics of orbital arteries in dogs. Vet Ophthalmol 2003;6:141146.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Siegner SW, Netland PA, Schroeder A, et al. Effect of calcium channel blockers alone and in combination with antiglaucoma medications on intraocular pressure in the primate eye. J Glaucoma 2000;9:334339.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Netland PA, Grosskreutz CL, Feke GT, et al. Color Doppler ultrasound analysis of ocular circulation after topical calcium channel blocker. Am J Ophthalmol 1995;119:694700.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Osborne NN, Ugarte M, Chao M, et al. Neuroprotection in relation to retinal ischemia and relevance to glaucoma. Surv Ophthalmol 1999;43 (suppl 1):S102S128.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Cellini M, Possati GL, Caramazza N, et al. The use of flunarizine in the management of low-tension glaucoma: a color Doppler study. Acta Ophthalmol Scand Suppl 1997;224:5758.

    • Search Google Scholar
    • Export Citation
  • 27.

    Munger RJ. Veterinary ophthalmology in laboratory animal studies. Vet Ophthalmol 2002;5:167175.

  • 28.

    Knollinger AM, La Croix NC, Barrett PM, et al. Evaluation of a rebound tonometer for measuring intraocular pressure in dogs and horses. J Am Vet Med Assoc 2005;227:244248.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Leiva M, Naranjo C, Pena MT. Comparison of the rebound tonometer (ICare) to the applanation tonometer (Tonopen XL) in normotensive dogs. Vet Ophthalmol 2006;9:1721.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Gelatt KN, Gum GG, Barrie KP, et al. Diurnal variations in intraocular pressure in normotensive and glaucomatous Beagles. J Glaucoma 1981;3:121124.

    • Search Google Scholar
    • Export Citation
  • 31.

    Wilkie DA, Latimer CA. Effects of topical administration of timolol maleate on intraocular pressure and pupil size in dogs. Am J Vet Res 1991;52:432435.

    • Search Google Scholar
    • Export Citation
  • 32.

    Skorobohach BJ, Ward DA, Hendrix DV. Effects of oral administration of methazolamide on intraocular pressure and aqueous humor flow rate in clinically normal dogs. Am J Vet Res 2003;64:183187.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Abelson MB, Gilbert CM, Smith LM. Sustained reduction of intraocular pressure in humans with the calcium channel blocker verapamil. Am J Ophthalmol 1988;105:155159.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Colasanti BK, Brown RE, Craig CR. Ocular hypotension, ocular toxicity, and neurotoxicity in response to marihuana extract and cannabidiol. Gen Pharmacol 1984;15:479484.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Gelatt KN, MacKay EO. Effect of different dose schedules of latanoprost on intraocular pressure and pupil size in the glaucomatous Beagle. Vet Ophthalmol 2001;4:283288.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Gelatt KN, Mackay EO, Gelatt JK, et al. Effects on intraocular pressure and pupil size in glaucomatous beagles after topical pilocarpine instilled with standard (pH 5) and buffer-tip (pH 7) droptainers. J Ocul Pharmacol Ther 1997;13:95104.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Holmes B, Brogden RN, Heel RC, et al. Flunarizine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use. Drugs 1984;27:644.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Pauwels PJ, Leysen JE, Janssen PA. Ca2+ and Na+ channels involved in neuronal cell death. Protection by flunarizine. Life Sci 1991;48:18811893.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Weizman R, Getslev V, Pankova IA, et al. Pharmacological interaction of the calcium channel blockers verapamil and flunarizine with the opioid system. Brain Res 1999;818:187195.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    Mito T, Delamere NA, Coca-Prados M. Calcium-dependent regulation of cation transport in cultured human nonpigmented ciliary epithelial cells. Am J Physiol 1993;264:C519C526.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Lepple-Wienhues A, Rauch R, Clark AF, et al. Electrophysiological properties of cultured human trabecular meshwork cells. Exp Eye Res 1994;59:305311.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42.

    Lepple-Wienhues A, Stahl F, Wiederholt M. Differential smooth muscle-like contractile properties of trabecular meshwork and ciliary muscle. Exp Eye Res 1991;53:3338.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    Erickson KA, Schroeder A, Netland PA. Verapamil increases outflow facility in the human eye. Exp Eye Res 1995;61:565567.

Advertisement