|Year : 1996 | Volume
| Issue : 2 | Page : 87-89
A comparative evaluation of pilocarpine 1% and clonidine 0.125% versus timolol 0.5%
R Sihota, HC Agarwal, YL Rajashekar
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, A.I.I.M.S. New Dehi, India
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, A.I.I.M.S. New Dehi
Source of Support: None, Conflict of Interest: None
All the presently available antiglaucoma medications have either local or systemic adverse effects. Combinations of drugs are being used not only to increase the effectivity and compliance but also to decrease the incidence and magnitude of side effects.
The single dose response of open angle glaucoma eyes to pilocarpine 1%, clonidine 0.125%, a combination of pilocarpine 1% and clonidine 0.125%, and timolol 0.5% was studied in a double blind, masked, cross over study.
Over a period of twelve hours the effectivity of the combination of pilocarpine 1% and clonidine 0.125% was significantly more than that of either drug alone and was found to be similar to that of timolol 0.5%. No local or systemic adverse effects were seen.
Keywords: Pilocarpine - Clonidine - Timolol - Combination therapy.
|How to cite this article:|
Sihota R, Agarwal H C, Rajashekar Y L. A comparative evaluation of pilocarpine 1% and clonidine 0.125% versus timolol 0.5%. Indian J Ophthalmol 1996;44:87-9
|How to cite this URL:|
Sihota R, Agarwal H C, Rajashekar Y L. A comparative evaluation of pilocarpine 1% and clonidine 0.125% versus timolol 0.5%. Indian J Ophthalmol [serial online] 1996 [cited 2019 Dec 13];44:87-9. Available from: http://www.ijo.in/text.asp?1996/44/2/87/24594
Control of intraocular pressure still remains the mainstay of therapy for glaucoma. The range of topical medications available has increased in the last two decades, but each has its own limitations, due to local as well as systemic problems. Combinations of drugs are used to increase individual effectivity, compliance and to decrease the dosage of drugs thereby decreasing the incidence of any side effects. Two drugs acting at different points on the aqueous pathway can have a greater ocular hypotensive effect than either drug alone. Cairns suggested that a combination of pilocarpine and clonidine may form an ideal antiglaucoma therapy.
Experimental studies have shown that topical clonidine is adequately absorbed into the anterior chamber with low systemic concentrations. Clinical evaluation in humans has led to contradictory claims about its efficacy, duration of action, effect on the fellow eye and systemic hypotension. Pilocarpine 1% has a signficant hypotensive effect, without the attendant, problems of brow ache and extreme miosis. There is no available information on the effectivity of a combination of pilocarpine 1 % and clonidine.
We studied the ocular hypotensive effect of a single dose of pilocarpine 1%, clonidine 0.125%, combination of pilocarpine and clonidine and timolol 0.5% in a double blind, masked, cross over study.
| Materials and methods|| |
Ten consecutive patients with ocular hypertension or early open angle glaucoma with symmetric intraocular pressures (a difference of ± 3 mm Hg), were enrolled in this study after informed consent. Early open angle glaucoma was considered to be one with a field defect upto only a single arcuate scotoma and a cup-disc ratio of ± 0.7. All topical medications were withheld for two weeks to allow for an adequate washout of timolol maleate and acetazolamide was discontinued 48 hours prior to the study. Patients with other known ocular pathology, or cardiovascular, hepatic or renal disease were excluded from the study.
All patients had baseline diurnal intraocular pressures recorded. From the following day, at 72 hours intervals a single drop of one of the drugs - pilocarpine nitrate 1% (Group-I), clonidine hydrochloride 0.125% (Group-II), a combination of pilocarpine nitrate 1 % and clonidine hydrochloride 0.125% (piloclonidine) (Group-IIII), and timolol maleate 0.5% (Group-IV) was instilled in the right eye at the same time of the day.
Intraocular pressure was measured in both the eyes by applanation tonometry by a masked observer immediately prior to instillation of the drug and repeated 2, 4, 6, 8 and 12 hours later. The order in which the drugs were administered was randomized and was unknown to the patient and the observer.
Clonidine hydrochloride, obtained from Cipla Limited, Bombay was diluted in normal saline. The final pH was 4.61 and the osmolarity was 356 m Osm.
At each point the blood pressure, pulse rate, visual acuity and pupillary diameter were measured, so also were the patient's responses to the therapy.
One patient of group IV (timolol maleate) did not return for evaluation.
The results were analysed using the two sample 't' test on the basis of a percentage fall in intraocular pressure at each observation, for each patient, calculated as:
The power of the statistical test employed was almost 1.
| Results|| |
The mean age of the ten patients was 55 years (range 43 to 61 years). Seven patients were male and three were female. Four patients were newly diagnosed. Of the remaining six patients, two had been on timolol maleate and pilocarpine for less than a year; two patients had been on the same drug combination for 1.5 and 4 years respectively; and two patients on timolol alone for less than a year.
After withdrawing the topical medication for two weeks and acetazolamide for seventy two hours, the base line mean intraocular pressure was 26.1 mm Hg ± 2.90 mm Hg and 25.2 ± 1.51 mm Hg in the right and left eye respectively.
The reduction of IOP (mm Hg) from the baseline diurnal and as a percentage of the baseline diurnal intraocular pressure has been presented in [Table - 1]. One patient did not report for testing with the final instillation of timolol maleate 0.5%. The results of this group are therefore calculated for nine patients. Pilocarpine 1% produced a maximal IOP reduction of 17.1% at 2 hours, and clonidine 0.125% produced 24.9% reduction of IOP. The combination therapy caused the IOP to maximally reduce by 39.2% two hours after instillation. In contrast, the maximum activity of timolol maleate 0.5%, was seen at 4 hours and was 39.1%. There was statistical reduction of IOP by combination therapy of pilocarpine 1% and clonidine 0.125% compared to single therapy by either medications (two sample 't' test). There was no statistically significant difference in the effectivity of combination group and timolol maleate 0.5% [Table - 2].
Intraocular pressure changes in the fellow eye were minimal for pilocarpine 1%, clonidine 0.125% and combination therapy (-1.21 to +1.05%), while Timolol maleate caused a reduction in IOP 8.26 to 16.91% in the contralateral eye.
Blood pressure changes, both systolic and diastolic were insignificant as analysed by the paired students 't' test with pilocarpine 1%. Clonidine 0.125% produced a mean systolic pressure fall of 4.34% (SD ± 3.69) and a diastolic pressure fall of 4.13 ± 2.9% at two hours. In the combination group the systolic blood pressure reduced 4.21 ± 1.8% at two hours, and the diastolic pressure 3.16 ± 2.5%; and Timolol 0.5% produced a fall in systolic blood pressure of 2.79 ± 1.2% and diastolic change of 0.32 ± 0.4%. All these changes were statistically not significant. The pulse rate variations with all the drugs was also statistically not significant.
The mean pupil size with pilocarpine 1% was 1.85 ± 0.4 mm, with clonidine 0.125% it was 3.72±0.5 mm, with combination therapy it was 2.41 ± 0.3 mm and with timolol 0.5% it was 3.82 ± 0.5 mm. The miosis with both pilocarpine 1% and combination therapy was statistically significant (p < 0.001).
The visual acuity remained unchanged throughout the study in all groups and local or systemic side effects were not noted during the study period.
| Discussion|| |
Many new antiglaucoma drugs have been introduced in the last two decades, but they all have local or systemic adverse effects. Patient compliance with more than one medication is often suspect. There has been some interest to combine two medications inorder to overcome their known limitations and to increase patient compliance with the use of a single drop once or twice daily.,
The mechanism of action of clonidine has yet to be completely elucidated, but there are reservations to its use because of a possible fall in disc perfusion pressure., Clonidine in concentrations of 0.125%, has been found to produce no significant change in blood pressure or pulse rate.,, In a study by Sood et al(personal communication) clonidine 0.125% was found to be more effective than clonidine 0.06%, but did not produce any local or systemic adverse effects. Clonidine in a concentration of 0.125% is also probably at the top of the dose response curve. Pilocarpine is a time tested drug with associated problems of brow ache and miosis in the usual concentrations of 2% and above. Pilocarpine 1% in single dose application has been found to produce a reduction in intraocular pressure of 18.25% at ninety minutes, with insignificant side effects. The effectivity of pilocarpine increases further on regular use.
A seventy-two hour washout period was given between the drugs evaluated to allow for a return to baseline values. Timolol maleate has a half life of 1.2 hours in rabbit aqueous and clinical effectivity for upto twenty-four hours in human eyes. Preparatory to the study, we confirmed that one drop of Timolol maleate 0.5% had no clinical effect at the end of seventy-two hours in four patients. The sample size could also be considered small, but using the same eye of the same patients has given our statistical analysis an almost optimal power to detect a difference.
The combination of pilocarpine 1% and clonidine 0.125% was assessed in this study for effectivity and adverse reactions. Over twelve hours the effectivity of this therapy was found to be similar to that of timolol maleate 0.5% in the eye in which it was applied, and was significantly more than that of either drug alone. No clinically significant changes in blood pressure or pulse rate were recorded and there was no reduction in the intraocular pressure in the fellow eye, suggesting that the systemic absorption was subminimal. No local adverse effects were recorded.
This combination of pilocarpine 1% and clonidine 0.125% is effective, well tolerated and has no significant systemic effects. It could be used as an alternative or additive drug in glaucoma therapy.
| References|| |
Airaksinen PJ., Valkonen R., Stenorg T. et al. A double masked study of timolol and pilocarpine combined. Am J Ophthalmol 104:587-590, 1987.
Cairns JE. Glaucoma. New York, Grune and Stratton, 1986 pp.619.
Sihota R., Ganesh A., Bandopadhyaya GP. et al.Pharmacokinetics of topical clonidine. Ann Ophthalmol 27:4-8, 1995.
Harrison R., Kaufmann CS. Clonidine. Arch Ophthalmol 95:1368-1373, 1977.
Kreiglstein GK., Langham ME., Leydhecker W. The peripheral and central neural actions of clonidine in normal and glaucomatous eyes. Inv Ophthalmol 17:149-158, 1978.
Hodapp E., Kolker AE., Kass MA., Goldberg I. et al. The effect of topical clonidine on intraocular pressure. Arch Ophthalmol 99:1208-1311, 1981.
Lee DA., Topper JE., Brubaker RF. Effect of clonidine on aqueous humor flow in normal eyes. Exp Eye Res 38:239-246, 1984.
Mehta U., Agarwal HC., Sood NN. Clonidine in chronic simple glaucoma. Ind J Ophthalmol 33:15-17, 1985.
Harris LS., Galin MA. Dose response analysis of pilocarpine induced ocular hypotension. Arch Ophthalmol 84:605-608, 1979.
Morrison JC. and Robin AL. Adjunctive glaucoma therapy. Ophthalmology 96:3-7, 1989.
Schoenwald R. in Havener's Ocular pharmacology. Ed TF Manger, EL Craig. Mosby Year Book Inc, 1994, pg.30.
Zimmerman TJ, Kaufman HE. Timolol:Dose response and duration of action. Arch Ophthalmol 95:605-607, 1977.
[Figure - 1]
[Table - 1], [Table - 2]