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Mydriatic Effect of Phenylephrine Hydrochloride
MYDRIATIC E F F E C T O F P H E N Y L E P H R I N E HYDROCHLORIDE N I C K I E J. HADDAD, M.D.,
NORMA J. MOYER, R.N.,
FENWICK C. RILEY, JR.,
AND
M.D.
Rochester, Minnesota Phenylephrine HC1 is a direct-acting sympathomimetic amine commonly employed clinically in a 10% concentration to produce mydriasis. Two observations have suggested that this drug may have a deleterious effect on the iris and in particular the dilator mus cle. Mitsui and Takagi, 1 using a 5% solution of phenylephrine, observed pigment floaters in the aqueous humor in 4.6% of subjects following pupillary dilation. These floaters appeared within 30 to 40 minutes after in stillation of the drug, reached a maximum in one to four hours, and disappeared within 12 to 24 hours. This phenomenon occurred pre dominantly in older subjects and the floaters were found to be pigment granules having the same characteristics as melanin from the pigment epithelium of the iris. With other mydriatics, only an occasional pigment gran ule was present in the aqueous humor. The authors postulated that the direct-acting sympathomimetic drug caused rupture of the pigment epithelial cells of the iris, thus re leasing pigment granules. While studying the mydriatic effect of phenylephrine, Loewenfeld2 noted the oc currence of rebound miosis in some older subjects (that is, anisocoria developing after mydriasis, with the drug-treated pupil being smaller than the normal pupil on the follow ing day). She also found that the subsequent instillation of phenylephrine produced less mydriasis in these subjects than did the ini tial instillation. The present study was undertaken to de termine the dose-response curve for phenylFrom the Pupillography Laboratory, Department of Ophthalmology, Mayo Clinic and Mayo Founda tion, Rochester, Minnesota. This investigation was supported in part by USPHS, NIH Research Grant EY-439. Reprint requests to Fenwick C. Riley, M.D., Mayo Clinic, Rochester, Minnesota 55901. 729
ephrine HC1 in a group of young, normal subjects and to evaluate the mydriatic effect of this drug in a group of older subjects in order to better characterize the effects of this drug on the iris. Effects on accommodation and intraocular pressure were also studied. METHOD
Pupillary size was recorded in dim back ground illumination by means of an infrared electronic pupillograph with a one-second light stimulus approximately five log units above threshold. The results are expressed as the degree of mydriasis, that is, the difference in pupillary diameter of the two eyes at maxi mal constriction produced by light stimula tion.3 After a base-line tracing was made, two drops of the drug solution being evalu ated were instilled into the right eye of the subject. Group 1—In the first phase of this study, eight normal subjects ranging in age from 21 to 53 years were studied. Six were 20 to 30 years of age, one was 43, and the eighth was S3. Of the eight subjects, three had blue, three had brown, and two had hazel irides. Fresh aqueous solutions of phenylephrine HC1 were prepared in concentrations of 0.1, 0.25, 0.5, 1, 5, and 10% ; and a commercially available 10% solution was used for compar ison. All subjects were tested with each con centration; at least seven days elapsed be tween recordings when a solution stronger than 1% was used. Pupillary size and re sponse to the standard light stimulus were recorded at 15-minute intervals for 90 min utes and then hourly until recovery from mydriasis had occurred. The tracing was re peated at 24 hours after instillation of the drug. Each subject was examined with the slit lamp before and after drops were in stilled. In this group, accommodation was
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AMERICAN JOURNAL OF OPHTHALMOLOGY
measured by near point of accommodation using a 14/21-size letter viewed through a 3-mm artificial pupil. Results of accommoda tive measurement represented an average of three measurements per eye. Group 2—In the second phase of the study, 24 subjects over age 50 with no known eye disease were divided into two subgroups of 12 each. One subgroup re ceived 1% aqueous phenylephrine solution while the other received the commercial 10% solution. The drug was instilled after an ini tial tracing, and a repeat tracing was re corded at 75 minutes, the average time for maximal mydriasis to occur as determined in Group 1. Pupillary size and reactivity were again recorded at 24 hours after initial instil lation of the drug; the same drug solution was then instilled and a final tracing ob tained 75 minutes later. Applanation ten sions were determined and the aqueous hu mor was examined for pigment floaters prior to and 75 minutes after each instillation of the drug. RESULT
Figure 1 shows the maximal mydriasis produced in Group 1 by each concentration of the drug, expressed as degree of mydria sis (that is, difference in constricted size be
NOVEMBER, 1970
tween the control and the treated pupil in re sponse to a standard light stimulus). As ex pected, mydriasis increases as the concentra tion of phenylephrine HCl increases, with a plateau developing as stronger concentra tions are used. The commercial 10% solution was found to be equivalent in effect to a 2.25% aqueous solution even though freshly obtained bottles of the drug were utilized. Significant differences in degree of my driasis occur with variations in iris pigmen tation. Of our subjects, those with hazel in des consistently developed the least mydria sis, while those with blue irides developed the greatest. No difference in latency prior to the onset of mydriasis or in time required for develop ment of maximal mydriasis was noted among the seven concentrations of phenyl ephrine HCl. Maximal mydriasis occurred with all solutions in 60 to 90 minutes (mean 75). As the strength of the solution in creased, however, a corresponding increase in the degree of mydriasis and a prolonga tion of the half-time for recovery from my driasis occurred. Data on the half-time for recovery from mydriasis produced by the five strongest drug concentrations are given in Table 1. Half-time could not be deter mined accurately for the two weakest solu-
Fig. 1 (Haddad, Moyer, and Riley). Dose-response curve for phenylephrine HCl mydriasis in Group 1 (mean ± SE). Percent of concentration of phenylephrine HCl is shown across bottom. Lower point at 10% concentration represents commercially available solution.
VOL. 70, NO. 5
PHENYLEPHRINE-INDUCED MYDRIASIS TABLE 1
HALF-TIME FOR RECOVERY FROM MYDRIASIS AS RELATED TO CONCENTRATION OF PHENYLEPHRINE HCL IN GROUP 1
Concentration of Drug 0.5% 1.0% 5.0% 10.0% 10.0%
aqueous aqueous aqueous aqueous commercial
Half-Time for Recovery in Hours (mean + SE) 2.48±0.50 2.6610.28 2.97±0.21 3.44 + 0.24 2.86 + 0.37
tions because of insignificant mydriasis in the majority of subjects. The results again illustrate that the commercial 10% solution produced a degree of mydriasis intermediate between those of the freshly prepared 1% and 5% aqueous solutions of phenylephrine HC1. The younger group of subjects studied with all seven concentrations of phenyleph rine HC1 showed no evidence of rebound miosis following instillation of any concen trations of the drug, except the one subject over age 50. Table 2 demonstrates that in Group 2 re bound miosis was present 24 hours after ini tial instillation of phenylephrine HC1, and a diminished mydriatic response occurred with the drug on subsequent use. These differ ences are statistically significant (p < 0.001 for rebound miosis and p < 0.01 for reduced mydriasis). The commercial 10% solution and the 1% aqueous solutions produced sim ilar degrees of rebound miosis and decreased mydriasis. It is apparent from these results that the degree of mydriasis is exaggerated by light stimulation. The light reflex re corded on the pupillographic tracings during the period of rebound miosis appeared nor mal except for a slight depression in the ac tive phase of redilation due to contraction of the dilator muscle. This was apparent as a flattening of this phase on many of the re cordings. In three subjects of Group 2 simultaneous
731
instillation of 10% phenylephrine HC1 and 1% tropicamide solution did not prevent de velopment of a similar degree of rebound miosis and decreased mydriasis. In three other subjects from Group 2, the use of 1% cyclopentolate to induce mydriasis did not re sult in rebound miosis or in decreased my driasis. In Group 1, slit-lamp examination demon strated occasional pigment floaters in the one subject over age 50 ; rarely a pigment gran ule was noted in the 43-year-old subject and in one brown-eyed subject 30 years of age. In Group 2 subjects over the age of 50 years, 65% of those receiving commercial 10% phenylephrine HC1 solution showed oc casional to Grade 2 pigment floaters in the aqueous humor 75 minutes after instillation of the drug, with 36% rated as Grade 2 float ers. In the group receiving 1% aqueous so lution, 7 1 % showed some evidence of pig ment granules in the anterior chamber and 36% of these were rated as Grade 1 or 2. In the entire group of older subjects, seven of eight who had no floaters had blue irides, while three of four with Grade 2 floaters had brown irides. No significant accommodative effect was demonstrated by measuring the near point of accommodation and no significant difference in the intraocular pressures prior to or after instillation of phenylephrine HC1 was noted. COMMENT
The mydriatic dose-response curve of phenylephrine HC1 in aqueous solution rises rapidly as the extent of mydriasis increases with the initial increases of the drug concen tration. But the curve becomes a plateau as higher concentrations are reached, the ex tent of mydriasis changes less than 0.5 mm as the concentration is increased from 5% to 10%. Disparity in the degree of mydriasis resulting from the freshly prepared solution of 10% phenylephrine HC1, and the com mercially available preparation might be re lated to differences in pH, use of preserva tives in the commercial solution, or instabil-
AMERICAN JOURNAL OF OPHTHALMOLOGY
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NOVEMBER, 1970
TABLE 2 REBOUND MIOSIS AND REDUCED MYDRIASIS IN GROUP 2 OCCURRING WITH PHENYLEPHRINE HCL EXPRESSED AS DEGREE OF MYDRIASIS*
Mydriasis (in mm) Time
10% Commercial Solution Unstimulated
Before drug After drug: 75 minutes 24 hours 25 hours and 15 minutes
Stimulated
1% Aqueous Solution Unstimulated
Stimulated
-0.02+0.13
0.07±0.14
- 0 . 1 3 + 0.13
0.06±0.05
2.08±0.14 -0.73±0.10 1.51±0.19
3.57±0.02 -0.53 + 0.08 2.41+0.27
1.97 + 0.20 -0.78±0.11 1.6Ü0.21
3.40±0.35 -0.56±0.09 2.65+0.31
* Denned as size of treated pupil minus size of control pupil.
ity of the drug during storage. We have not found reference to the phe nomenon of rebound miosis and reduction in the degree of mydriasis when phenylephrine H Q is used subsequently to induce mydria sis. This appears to be an age-related phe nomenon, best explained as a direct effect of the drug on the dilator muscle fibers. The al teration in the active phase of pupillary redilation found by pupillography appears to substantiate this hypothesis. Cyclopentolate did not produce a similar effect in the same subjects, and simultaneous administration of tropicamide did not prevent the occurrence of rebound miosis. Weaker concentrations of phenylephrine HCl did not appear to prevent the develop ment of this phenomenon. There is no ap parent relation between rebound miosis and the release of pigment granules, for subjects who had no pigment floaters developed re bound miosis. The phenomenon of rebound miosis and reduced mydriasis is of clinical importance, for the pupils of older subjects are fre quently dilated with this agent for examina tion prior to retinal detachment or cataract surgery, and the subsequent use of phenyl ephrine may result in reduced mydriasis that impairs visibility of the fundus or makes round-pupil cataract extraction difficult. Ac cording to the results measured in this study, the decrease of mydriasis on the second day
would leave the maximal pupillary area 30 to 40% smaller than on the first day. The results suggest that release of pig ment granules into aqueous humor during phenylephrine hydrochloride mydriasis is related to age of subject and color of iris, oc curring more commonly in older subjects with pigmented irides. Selection of predomi nantly older subjects for this study presum ably accounts for the higher incidence of pigment floaters than that reported by Mitsui and Takagi. 1 Comparing the size of pigment granules in aqueous aspirates with those found in stromal melanocytes and pigment epithelium of the iris, Mitsui and Takagi 1 postulated that the floaters originate from pigment epithelial cells which rupture during contraction of the dilator muscle. Embryologically the dilator muscle develops from pigment epithelium, and pigment granules that would be expected to have dimensions similar to those of the pigmented epithelium persist in cells of this muscle. The pupillographic findings during rebound miosis sug gest damage to the dilator muscle, and this might also contribute to the phenomenon of pigmented aqueous floaters. Pigment gran ules are released into aqueous humor from epithelial cells in the process of aging, and settle on various tissues in the anterior seg ment of the globe. Mobilization of these granules might occur during mydriasis, al though a specific relationship to sympatho-
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PHENYLEPHRINE-INDUCED MYDRIASIS
733
SUMMARY mimetics would not be anticipated in this The dose-response curve for phenyleph case. The variation of mydriatic response in re rine HCl mydriasis was studied in a group lationship to iris pigmentation is consistent of young subjects with concentrations rang ing from 0.1% to 10%. No associated change with previous reports.3'* Biggs and associates5 measured an early in intraocular pressure or in accommodation transient change in accommodation after in was found to occur with phenylephrine my stillation of eight drops of 10% phenyleph driasis. Pigment granules were found in the rine HCl, but Roth 6 was unable to demon aqueous humor of older subjects and seemed strate anything more than a random and sta to be related to age and iris pigmentation. In tistically insignificant variation in the refrac the older subjects rebound miosis and reduced tive state of human eyes following instilla mydriasis occurred with the subsequent use tion of two drops of 10% solution of this of phenylephrine HCl to induce mydriasis. drug. Using a relatively unsophisticated This finding is significant in relation to clini measurement of accommodative change, we cal ophthalmology. were unable to demonstrate any significant ACKNOWLEDGEMENT variation of accommodation during the We thank Irene E. Loewenfeld, Ph.D., for her development of phenylephrine mydriasis. helpful comments and encouragement The failure of intraocular pressure to rise REFERENCES after phenylephrine mydriasis is consistent 1. Mitsui, Y., and Takagi, Y. : Nature of aqueous with previous reports. 7 · 8 In studying cyclo- floaters due to sympathomimetic mydriatics. Arch. plegic-induced elevation of intraocular pres Ophth. 65:626, 1961. 2. Loewenfeld, I. E. : Personal communication. sure, Harris 8 was unable to demonstrate an 3. Gambill, H. D., Ogle, K. N., and Kearns, elevation following the use of phenylephrine T. P. : Mydriatic effect of four drugs determined HCl and weak cycloplegics, whereas strong with pupillograph. Arch. Ophth. 77:740, 1967. 4. Barbee, R. F., and Smith, W. O., Jr. : A com cycloplegics such as cyclopentolate ( 1% ) and parative study of mydriatic and cycloplegic agents: atropine caused elevation of intraocular pres In human subjects without eye disease. Am. J. sure without angle closure in 3 % of his nor Ophth. 44:617,19S7. 5. Biggs, R. D., Alpern, M., and Bennett, D. R. : mal subj'ects and in 27% of his glucomatous The effect of sympathomimetic drugs upon the am patients. This difference has been attributed plitude of accommodation. Am. J. Ophth. 48:169, to the lack of effect of phenylephrine on the 1959. 6. Roth, N. : Refractive state after instillation of ciliary muscle, which is suggested by its lack paredrine and neosynephrine. Brit. J. Ophth. 52 : of effect on accommodation. In general, it 763,1968. 7. Becker, B., Gage, T., Kolker, A. E., and Gay, seems that phenylephrine rarely raises intra J. : The effect of phenylephrine hydrochloride on ocular pressure when used as a mydriatic. A. the miotic-treated eye. Am. J. Ophth. 48:313, 19S9. 9 10 However, Lee and Hill have both reported 8. Harris, L. S.: Cycloplegic-induced intraocular a significant rise of intraocular pressure with pressure elevations—A study of normal and openglaucomatous eyes. Arch. Ophth. 79:242, out angle closure in a few patients after phe angle 1968. nylephrine mydriasis. We have recently had 9. Lee, P. F. : The influence of epinephrine and occasion to study a similar patient in whom an phenylephrine on intraocular pressure. Arch. Ophth. 1958. anomalous rise of pressure occurred with 60:863, 10. Hill, K.: What's the angle on mydriasis? phenylephrine mydriasis. Arch. Ophth. 79:804, 1968.
NORMA J. MOYER, R.N.,
FENWICK C. RILEY, JR.,
AND
M.D.
Rochester, Minnesota Phenylephrine HC1 is a direct-acting sympathomimetic amine commonly employed clinically in a 10% concentration to produce mydriasis. Two observations have suggested that this drug may have a deleterious effect on the iris and in particular the dilator mus cle. Mitsui and Takagi, 1 using a 5% solution of phenylephrine, observed pigment floaters in the aqueous humor in 4.6% of subjects following pupillary dilation. These floaters appeared within 30 to 40 minutes after in stillation of the drug, reached a maximum in one to four hours, and disappeared within 12 to 24 hours. This phenomenon occurred pre dominantly in older subjects and the floaters were found to be pigment granules having the same characteristics as melanin from the pigment epithelium of the iris. With other mydriatics, only an occasional pigment gran ule was present in the aqueous humor. The authors postulated that the direct-acting sympathomimetic drug caused rupture of the pigment epithelial cells of the iris, thus re leasing pigment granules. While studying the mydriatic effect of phenylephrine, Loewenfeld2 noted the oc currence of rebound miosis in some older subjects (that is, anisocoria developing after mydriasis, with the drug-treated pupil being smaller than the normal pupil on the follow ing day). She also found that the subsequent instillation of phenylephrine produced less mydriasis in these subjects than did the ini tial instillation. The present study was undertaken to de termine the dose-response curve for phenylFrom the Pupillography Laboratory, Department of Ophthalmology, Mayo Clinic and Mayo Founda tion, Rochester, Minnesota. This investigation was supported in part by USPHS, NIH Research Grant EY-439. Reprint requests to Fenwick C. Riley, M.D., Mayo Clinic, Rochester, Minnesota 55901. 729
ephrine HC1 in a group of young, normal subjects and to evaluate the mydriatic effect of this drug in a group of older subjects in order to better characterize the effects of this drug on the iris. Effects on accommodation and intraocular pressure were also studied. METHOD
Pupillary size was recorded in dim back ground illumination by means of an infrared electronic pupillograph with a one-second light stimulus approximately five log units above threshold. The results are expressed as the degree of mydriasis, that is, the difference in pupillary diameter of the two eyes at maxi mal constriction produced by light stimula tion.3 After a base-line tracing was made, two drops of the drug solution being evalu ated were instilled into the right eye of the subject. Group 1—In the first phase of this study, eight normal subjects ranging in age from 21 to 53 years were studied. Six were 20 to 30 years of age, one was 43, and the eighth was S3. Of the eight subjects, three had blue, three had brown, and two had hazel irides. Fresh aqueous solutions of phenylephrine HC1 were prepared in concentrations of 0.1, 0.25, 0.5, 1, 5, and 10% ; and a commercially available 10% solution was used for compar ison. All subjects were tested with each con centration; at least seven days elapsed be tween recordings when a solution stronger than 1% was used. Pupillary size and re sponse to the standard light stimulus were recorded at 15-minute intervals for 90 min utes and then hourly until recovery from mydriasis had occurred. The tracing was re peated at 24 hours after instillation of the drug. Each subject was examined with the slit lamp before and after drops were in stilled. In this group, accommodation was
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AMERICAN JOURNAL OF OPHTHALMOLOGY
measured by near point of accommodation using a 14/21-size letter viewed through a 3-mm artificial pupil. Results of accommoda tive measurement represented an average of three measurements per eye. Group 2—In the second phase of the study, 24 subjects over age 50 with no known eye disease were divided into two subgroups of 12 each. One subgroup re ceived 1% aqueous phenylephrine solution while the other received the commercial 10% solution. The drug was instilled after an ini tial tracing, and a repeat tracing was re corded at 75 minutes, the average time for maximal mydriasis to occur as determined in Group 1. Pupillary size and reactivity were again recorded at 24 hours after initial instil lation of the drug; the same drug solution was then instilled and a final tracing ob tained 75 minutes later. Applanation ten sions were determined and the aqueous hu mor was examined for pigment floaters prior to and 75 minutes after each instillation of the drug. RESULT
Figure 1 shows the maximal mydriasis produced in Group 1 by each concentration of the drug, expressed as degree of mydria sis (that is, difference in constricted size be
NOVEMBER, 1970
tween the control and the treated pupil in re sponse to a standard light stimulus). As ex pected, mydriasis increases as the concentra tion of phenylephrine HCl increases, with a plateau developing as stronger concentra tions are used. The commercial 10% solution was found to be equivalent in effect to a 2.25% aqueous solution even though freshly obtained bottles of the drug were utilized. Significant differences in degree of my driasis occur with variations in iris pigmen tation. Of our subjects, those with hazel in des consistently developed the least mydria sis, while those with blue irides developed the greatest. No difference in latency prior to the onset of mydriasis or in time required for develop ment of maximal mydriasis was noted among the seven concentrations of phenyl ephrine HCl. Maximal mydriasis occurred with all solutions in 60 to 90 minutes (mean 75). As the strength of the solution in creased, however, a corresponding increase in the degree of mydriasis and a prolonga tion of the half-time for recovery from my driasis occurred. Data on the half-time for recovery from mydriasis produced by the five strongest drug concentrations are given in Table 1. Half-time could not be deter mined accurately for the two weakest solu-
Fig. 1 (Haddad, Moyer, and Riley). Dose-response curve for phenylephrine HCl mydriasis in Group 1 (mean ± SE). Percent of concentration of phenylephrine HCl is shown across bottom. Lower point at 10% concentration represents commercially available solution.
VOL. 70, NO. 5
PHENYLEPHRINE-INDUCED MYDRIASIS TABLE 1
HALF-TIME FOR RECOVERY FROM MYDRIASIS AS RELATED TO CONCENTRATION OF PHENYLEPHRINE HCL IN GROUP 1
Concentration of Drug 0.5% 1.0% 5.0% 10.0% 10.0%
aqueous aqueous aqueous aqueous commercial
Half-Time for Recovery in Hours (mean + SE) 2.48±0.50 2.6610.28 2.97±0.21 3.44 + 0.24 2.86 + 0.37
tions because of insignificant mydriasis in the majority of subjects. The results again illustrate that the commercial 10% solution produced a degree of mydriasis intermediate between those of the freshly prepared 1% and 5% aqueous solutions of phenylephrine HC1. The younger group of subjects studied with all seven concentrations of phenyleph rine HC1 showed no evidence of rebound miosis following instillation of any concen trations of the drug, except the one subject over age 50. Table 2 demonstrates that in Group 2 re bound miosis was present 24 hours after ini tial instillation of phenylephrine HC1, and a diminished mydriatic response occurred with the drug on subsequent use. These differ ences are statistically significant (p < 0.001 for rebound miosis and p < 0.01 for reduced mydriasis). The commercial 10% solution and the 1% aqueous solutions produced sim ilar degrees of rebound miosis and decreased mydriasis. It is apparent from these results that the degree of mydriasis is exaggerated by light stimulation. The light reflex re corded on the pupillographic tracings during the period of rebound miosis appeared nor mal except for a slight depression in the ac tive phase of redilation due to contraction of the dilator muscle. This was apparent as a flattening of this phase on many of the re cordings. In three subjects of Group 2 simultaneous
731
instillation of 10% phenylephrine HC1 and 1% tropicamide solution did not prevent de velopment of a similar degree of rebound miosis and decreased mydriasis. In three other subjects from Group 2, the use of 1% cyclopentolate to induce mydriasis did not re sult in rebound miosis or in decreased my driasis. In Group 1, slit-lamp examination demon strated occasional pigment floaters in the one subject over age 50 ; rarely a pigment gran ule was noted in the 43-year-old subject and in one brown-eyed subject 30 years of age. In Group 2 subjects over the age of 50 years, 65% of those receiving commercial 10% phenylephrine HC1 solution showed oc casional to Grade 2 pigment floaters in the aqueous humor 75 minutes after instillation of the drug, with 36% rated as Grade 2 float ers. In the group receiving 1% aqueous so lution, 7 1 % showed some evidence of pig ment granules in the anterior chamber and 36% of these were rated as Grade 1 or 2. In the entire group of older subjects, seven of eight who had no floaters had blue irides, while three of four with Grade 2 floaters had brown irides. No significant accommodative effect was demonstrated by measuring the near point of accommodation and no significant difference in the intraocular pressures prior to or after instillation of phenylephrine HC1 was noted. COMMENT
The mydriatic dose-response curve of phenylephrine HC1 in aqueous solution rises rapidly as the extent of mydriasis increases with the initial increases of the drug concen tration. But the curve becomes a plateau as higher concentrations are reached, the ex tent of mydriasis changes less than 0.5 mm as the concentration is increased from 5% to 10%. Disparity in the degree of mydriasis resulting from the freshly prepared solution of 10% phenylephrine HC1, and the com mercially available preparation might be re lated to differences in pH, use of preserva tives in the commercial solution, or instabil-
AMERICAN JOURNAL OF OPHTHALMOLOGY
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NOVEMBER, 1970
TABLE 2 REBOUND MIOSIS AND REDUCED MYDRIASIS IN GROUP 2 OCCURRING WITH PHENYLEPHRINE HCL EXPRESSED AS DEGREE OF MYDRIASIS*
Mydriasis (in mm) Time
10% Commercial Solution Unstimulated
Before drug After drug: 75 minutes 24 hours 25 hours and 15 minutes
Stimulated
1% Aqueous Solution Unstimulated
Stimulated
-0.02+0.13
0.07±0.14
- 0 . 1 3 + 0.13
0.06±0.05
2.08±0.14 -0.73±0.10 1.51±0.19
3.57±0.02 -0.53 + 0.08 2.41+0.27
1.97 + 0.20 -0.78±0.11 1.6Ü0.21
3.40±0.35 -0.56±0.09 2.65+0.31
* Denned as size of treated pupil minus size of control pupil.
ity of the drug during storage. We have not found reference to the phe nomenon of rebound miosis and reduction in the degree of mydriasis when phenylephrine H Q is used subsequently to induce mydria sis. This appears to be an age-related phe nomenon, best explained as a direct effect of the drug on the dilator muscle fibers. The al teration in the active phase of pupillary redilation found by pupillography appears to substantiate this hypothesis. Cyclopentolate did not produce a similar effect in the same subjects, and simultaneous administration of tropicamide did not prevent the occurrence of rebound miosis. Weaker concentrations of phenylephrine HCl did not appear to prevent the develop ment of this phenomenon. There is no ap parent relation between rebound miosis and the release of pigment granules, for subjects who had no pigment floaters developed re bound miosis. The phenomenon of rebound miosis and reduced mydriasis is of clinical importance, for the pupils of older subjects are fre quently dilated with this agent for examina tion prior to retinal detachment or cataract surgery, and the subsequent use of phenyl ephrine may result in reduced mydriasis that impairs visibility of the fundus or makes round-pupil cataract extraction difficult. Ac cording to the results measured in this study, the decrease of mydriasis on the second day
would leave the maximal pupillary area 30 to 40% smaller than on the first day. The results suggest that release of pig ment granules into aqueous humor during phenylephrine hydrochloride mydriasis is related to age of subject and color of iris, oc curring more commonly in older subjects with pigmented irides. Selection of predomi nantly older subjects for this study presum ably accounts for the higher incidence of pigment floaters than that reported by Mitsui and Takagi. 1 Comparing the size of pigment granules in aqueous aspirates with those found in stromal melanocytes and pigment epithelium of the iris, Mitsui and Takagi 1 postulated that the floaters originate from pigment epithelial cells which rupture during contraction of the dilator muscle. Embryologically the dilator muscle develops from pigment epithelium, and pigment granules that would be expected to have dimensions similar to those of the pigmented epithelium persist in cells of this muscle. The pupillographic findings during rebound miosis sug gest damage to the dilator muscle, and this might also contribute to the phenomenon of pigmented aqueous floaters. Pigment gran ules are released into aqueous humor from epithelial cells in the process of aging, and settle on various tissues in the anterior seg ment of the globe. Mobilization of these granules might occur during mydriasis, al though a specific relationship to sympatho-
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PHENYLEPHRINE-INDUCED MYDRIASIS
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SUMMARY mimetics would not be anticipated in this The dose-response curve for phenyleph case. The variation of mydriatic response in re rine HCl mydriasis was studied in a group lationship to iris pigmentation is consistent of young subjects with concentrations rang ing from 0.1% to 10%. No associated change with previous reports.3'* Biggs and associates5 measured an early in intraocular pressure or in accommodation transient change in accommodation after in was found to occur with phenylephrine my stillation of eight drops of 10% phenyleph driasis. Pigment granules were found in the rine HCl, but Roth 6 was unable to demon aqueous humor of older subjects and seemed strate anything more than a random and sta to be related to age and iris pigmentation. In tistically insignificant variation in the refrac the older subjects rebound miosis and reduced tive state of human eyes following instilla mydriasis occurred with the subsequent use tion of two drops of 10% solution of this of phenylephrine HCl to induce mydriasis. drug. Using a relatively unsophisticated This finding is significant in relation to clini measurement of accommodative change, we cal ophthalmology. were unable to demonstrate any significant ACKNOWLEDGEMENT variation of accommodation during the We thank Irene E. Loewenfeld, Ph.D., for her development of phenylephrine mydriasis. helpful comments and encouragement The failure of intraocular pressure to rise REFERENCES after phenylephrine mydriasis is consistent 1. Mitsui, Y., and Takagi, Y. : Nature of aqueous with previous reports. 7 · 8 In studying cyclo- floaters due to sympathomimetic mydriatics. Arch. plegic-induced elevation of intraocular pres Ophth. 65:626, 1961. 2. Loewenfeld, I. E. : Personal communication. sure, Harris 8 was unable to demonstrate an 3. Gambill, H. D., Ogle, K. N., and Kearns, elevation following the use of phenylephrine T. P. : Mydriatic effect of four drugs determined HCl and weak cycloplegics, whereas strong with pupillograph. Arch. Ophth. 77:740, 1967. 4. Barbee, R. F., and Smith, W. O., Jr. : A com cycloplegics such as cyclopentolate ( 1% ) and parative study of mydriatic and cycloplegic agents: atropine caused elevation of intraocular pres In human subjects without eye disease. Am. J. sure without angle closure in 3 % of his nor Ophth. 44:617,19S7. 5. Biggs, R. D., Alpern, M., and Bennett, D. R. : mal subj'ects and in 27% of his glucomatous The effect of sympathomimetic drugs upon the am patients. This difference has been attributed plitude of accommodation. Am. J. Ophth. 48:169, to the lack of effect of phenylephrine on the 1959. 6. Roth, N. : Refractive state after instillation of ciliary muscle, which is suggested by its lack paredrine and neosynephrine. Brit. J. Ophth. 52 : of effect on accommodation. In general, it 763,1968. 7. Becker, B., Gage, T., Kolker, A. E., and Gay, seems that phenylephrine rarely raises intra J. : The effect of phenylephrine hydrochloride on ocular pressure when used as a mydriatic. A. the miotic-treated eye. Am. J. Ophth. 48:313, 19S9. 9 10 However, Lee and Hill have both reported 8. Harris, L. S.: Cycloplegic-induced intraocular a significant rise of intraocular pressure with pressure elevations—A study of normal and openglaucomatous eyes. Arch. Ophth. 79:242, out angle closure in a few patients after phe angle 1968. nylephrine mydriasis. We have recently had 9. Lee, P. F. : The influence of epinephrine and occasion to study a similar patient in whom an phenylephrine on intraocular pressure. Arch. Ophth. 1958. anomalous rise of pressure occurred with 60:863, 10. Hill, K.: What's the angle on mydriasis? phenylephrine mydriasis. Arch. Ophth. 79:804, 1968.