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Systemic Effects of the Topical Use of Ophthalmic Corticosteroid Preparations
CONJUNCTIVAL
29
AMYLOIDOSIS
13. Mathur, S. P., and Matliur, B. P . : Conjunctival amyloidosis. Brit. J . Ophth., 43:765, 1959. 14. Hameed, S., and Nath, K . : Bone formation in the tarsal plate. Am. J . Ophth., 49:814, 1960. 15. Guerry, O., and Weisinger, Η.: Amyloid disease of conjunctiva and tarsus. Am. 1. Ophth., 4 9 : 1413, 1960. 16. Mishra, R. K . : Amyloid degeneration of bulbar conjunctiva. J . All-Indian Ophth. Soc. 1 0 : 1 6 - 1 7 , 1962. 17. Scott, R. Α., and Berghorn, Β. Μ.: Results of therapy of localized amyloidosis using derminjected triamcinolone suspension. Arch. Dermat., 8 2 : 7 4 6 , 1960. 18. Kaufman, Η. E., and Thomas, L. B . : Vitreous opacities diagnostic of familial primary amyloido sis. New England J . Med., 2 6 1 -.1267, 1959.
SYSTEMIC
EFFECTS
OF
THE
TOPICAL
CORTICOSTEROID JOHN
F . NTJRSALL,
Torrance,
It is well recognized that solutions and suspensions for topical use in ophthalmology contain amounts of active principle far in excess of that used by oral or parenteral routes. The systemic reaction to atropine or homatropine from the application of a few drops in the conjunctival sac is but one ex ample of a potential danger. Other prepara tions are known to produce side-reactions of a more or less severe nature when used topically. For years ophthalmologists have used corticosteroid suspensions and solutions containing sufficient amounts of various drugs to give a systemic response if absorp tion takes place, either through the ocular membranes, the nasolacrimal passages or the gastrointestinal tract, when swallowed. Many patients do complain of the "taste" of their eyedrops draining into the nasolacrimal sys tem. A case is presented here illustrating at least one instance of an apparent systemic response to a corticosteroid solution applied to the eye topically. CASE REPORT On April 29, 1960, a 26-year-old Caucasiou woman was operated on for an exotropia.A recession of the right lateral rectus muscle and a resection of the right medial rectus muscle were done. Su tures of 5-0 mild chromic catgut were used to anchor the muscles. The conjunctival incision was closed with silk sutures, which were removed a week later. There was a good cosmetic and func tional result.
USE
OF
OPHTHALMIC
PREPARATIONS M.D.
California An inordinate amount of swelling and redness persisted in the region of the buried sutures. On May 27, 1960, 0.25-percent Neodeltacortcf ophthal mic suspension was begun, being used every three hours. Only a moderate local response was noted but the young woman reported that, although she had a known allergy to vitamin-C tablets, citrus fruits and juices, since using the drops in her eye she could again tolerate orange juice and citrus fruit without the usual skin rash, itching, nasal congestion and headache. When the eyedrops were not used skin rash, itching, nasal congestion and headache followed the consumption of citrus fruits and juices. An absolute eosinophil count was performed as a baseline. Citrus fruits were then eaten for three days until nasal congestion was marked, hives and headache appeared. Another eosinophil count was taken prior to the use of drops in the eye. After the drops were used three days, symptoms had sub sided and another eosinophil count was taken. The whole routine was repeated several times with the willing co-ooeration of the patient, who was a med ical technician and understood the theory we had in mind. No other medication was taken during the time of testing and observation. Normal values, by the method used, for an ab solute eosinophil count were 50 to 250 mm. To he considered as evidence of an effect on circulating eosinophils, a drug should produce a drop in the count of at least 50 percent. 3
COMMENT
The corticosteroid preparation used con tained 0.25-percent (2.5 mg.)/cc. predniso lone acetate. Rased on an average of 20 drops/cc, each drop would contain 0.125 mg. of the drug. Used four times daily, two drops would result in a total exposure of 1.0 mg. daily. The usual daily dose of the predniso-
30
JOHN
F.
NURSALL
TABLE
1
EXPOSURE POTENTIAL OF WELL-KNOWN DRUGS
Corticosteroid /cc. (20 drops/cc.)
Daily Total Exposure (2 d r o p s X 1 6 )
1. Prednisolone acetate 1 % (Prednefrin-forte)
10 mg./cc. (0.5 mg./drop)
16 mg.
2. Dexamethasone 0 . 1 % (Maxidex)
1.0 mg./cc. (0.05 mg./drop)
1.6 mg.
3. Prednisolone acetate 0.5% (Metimyd)
5.0 mg./cc. (0.25 mg./drop)
8.0 mg.
Drug & Trade Name
lone acetate for therapeutic regimens is given as 5.0 to 20 mg./day. In the case described, a syscemic effect was apparent with an exposure of one mg. daily. How much was absorbed cannot be said because facilities for accurate assays were not available. Consider the exposure potential with other topical corticosteroids for ophthalmic use. Many treatment regimens call for the use of two drops hourly, during a 16-hour day. Some are less frequent, others more frequent in dosage prescribed. As examples, using the two drops hourly for 16 hours, several wellknown preparations might result in the ex posure indicated in Table 1. Greater exposure would result from use in both eyes and less if less frequent dosage schedules were followed. Another important facet of the problem presents when pediatrics cases are considered, because of the weightfor-weight consideration. The problem of topical corticosteroid ab sorbed percutaneously is recognized in der matology.* No extensive study of the sys temic effect of topically applied ophthalmic corticosteroids had been reported to the date of this writing. CONCLUSIONS
While results of the tests do not lend themselves to graphs or tables because of the single individual involved and the ex* Scoggins, R. B.: Decrease of urinary corticos teroids following application of fluocinalone acetonide under an occlusive dressing. J. Invest. Dermat., 39:473-474, 1962.
pected variation in the count, observation did allow the following conclusions: 1. The use of the corticosteroid drops in the manner described, as a constant routine, resulted in the decrease of circulating blood eosinophils from 300/mm. to zero on one occasion and from 128/mm. to zero on an other occasion. 2. Reduction of circulating eosinophils to zero or near zero was accomplished after allergic symptoms were present, and while the allergens were continued, by the use of topical corticosteroids instilled in the con junctival sac. 3. Without the use of the topical corti costeroids the allergic symptoms continued unabated as long as the allergens were sup plied. Use of the corticosteroid, however, re sulted in disappearance of the allergic symp toms and their continued absence as long as the drops were used, even though the con sumption of unlimited quantities of citrus fruits and juices continued. With the recognized use of potent topical corticosteroids in ophthalmology have come problems of their side-effects, the most re cent being glaucoma. A case is presented in which a systemic effect was apparent after the use of topical ophthalmic corticosteroids. It is suggested that controlled studies should be undertaken to demonstrate the amount of systemic absorption and effect of topically applied ophthalmic corticosteroids. 2163 Torrance Boulevard. 3
3
ACKNOWLEDGEMENT
I am indented to S. Rodman Irvine, M.D., for reading this paper and suggesting its publication.
29
AMYLOIDOSIS
13. Mathur, S. P., and Matliur, B. P . : Conjunctival amyloidosis. Brit. J . Ophth., 43:765, 1959. 14. Hameed, S., and Nath, K . : Bone formation in the tarsal plate. Am. J . Ophth., 49:814, 1960. 15. Guerry, O., and Weisinger, Η.: Amyloid disease of conjunctiva and tarsus. Am. 1. Ophth., 4 9 : 1413, 1960. 16. Mishra, R. K . : Amyloid degeneration of bulbar conjunctiva. J . All-Indian Ophth. Soc. 1 0 : 1 6 - 1 7 , 1962. 17. Scott, R. Α., and Berghorn, Β. Μ.: Results of therapy of localized amyloidosis using derminjected triamcinolone suspension. Arch. Dermat., 8 2 : 7 4 6 , 1960. 18. Kaufman, Η. E., and Thomas, L. B . : Vitreous opacities diagnostic of familial primary amyloido sis. New England J . Med., 2 6 1 -.1267, 1959.
SYSTEMIC
EFFECTS
OF
THE
TOPICAL
CORTICOSTEROID JOHN
F . NTJRSALL,
Torrance,
It is well recognized that solutions and suspensions for topical use in ophthalmology contain amounts of active principle far in excess of that used by oral or parenteral routes. The systemic reaction to atropine or homatropine from the application of a few drops in the conjunctival sac is but one ex ample of a potential danger. Other prepara tions are known to produce side-reactions of a more or less severe nature when used topically. For years ophthalmologists have used corticosteroid suspensions and solutions containing sufficient amounts of various drugs to give a systemic response if absorp tion takes place, either through the ocular membranes, the nasolacrimal passages or the gastrointestinal tract, when swallowed. Many patients do complain of the "taste" of their eyedrops draining into the nasolacrimal sys tem. A case is presented here illustrating at least one instance of an apparent systemic response to a corticosteroid solution applied to the eye topically. CASE REPORT On April 29, 1960, a 26-year-old Caucasiou woman was operated on for an exotropia.A recession of the right lateral rectus muscle and a resection of the right medial rectus muscle were done. Su tures of 5-0 mild chromic catgut were used to anchor the muscles. The conjunctival incision was closed with silk sutures, which were removed a week later. There was a good cosmetic and func tional result.
USE
OF
OPHTHALMIC
PREPARATIONS M.D.
California An inordinate amount of swelling and redness persisted in the region of the buried sutures. On May 27, 1960, 0.25-percent Neodeltacortcf ophthal mic suspension was begun, being used every three hours. Only a moderate local response was noted but the young woman reported that, although she had a known allergy to vitamin-C tablets, citrus fruits and juices, since using the drops in her eye she could again tolerate orange juice and citrus fruit without the usual skin rash, itching, nasal congestion and headache. When the eyedrops were not used skin rash, itching, nasal congestion and headache followed the consumption of citrus fruits and juices. An absolute eosinophil count was performed as a baseline. Citrus fruits were then eaten for three days until nasal congestion was marked, hives and headache appeared. Another eosinophil count was taken prior to the use of drops in the eye. After the drops were used three days, symptoms had sub sided and another eosinophil count was taken. The whole routine was repeated several times with the willing co-ooeration of the patient, who was a med ical technician and understood the theory we had in mind. No other medication was taken during the time of testing and observation. Normal values, by the method used, for an ab solute eosinophil count were 50 to 250 mm. To he considered as evidence of an effect on circulating eosinophils, a drug should produce a drop in the count of at least 50 percent. 3
COMMENT
The corticosteroid preparation used con tained 0.25-percent (2.5 mg.)/cc. predniso lone acetate. Rased on an average of 20 drops/cc, each drop would contain 0.125 mg. of the drug. Used four times daily, two drops would result in a total exposure of 1.0 mg. daily. The usual daily dose of the predniso-
30
JOHN
F.
NURSALL
TABLE
1
EXPOSURE POTENTIAL OF WELL-KNOWN DRUGS
Corticosteroid /cc. (20 drops/cc.)
Daily Total Exposure (2 d r o p s X 1 6 )
1. Prednisolone acetate 1 % (Prednefrin-forte)
10 mg./cc. (0.5 mg./drop)
16 mg.
2. Dexamethasone 0 . 1 % (Maxidex)
1.0 mg./cc. (0.05 mg./drop)
1.6 mg.
3. Prednisolone acetate 0.5% (Metimyd)
5.0 mg./cc. (0.25 mg./drop)
8.0 mg.
Drug & Trade Name
lone acetate for therapeutic regimens is given as 5.0 to 20 mg./day. In the case described, a syscemic effect was apparent with an exposure of one mg. daily. How much was absorbed cannot be said because facilities for accurate assays were not available. Consider the exposure potential with other topical corticosteroids for ophthalmic use. Many treatment regimens call for the use of two drops hourly, during a 16-hour day. Some are less frequent, others more frequent in dosage prescribed. As examples, using the two drops hourly for 16 hours, several wellknown preparations might result in the ex posure indicated in Table 1. Greater exposure would result from use in both eyes and less if less frequent dosage schedules were followed. Another important facet of the problem presents when pediatrics cases are considered, because of the weightfor-weight consideration. The problem of topical corticosteroid ab sorbed percutaneously is recognized in der matology.* No extensive study of the sys temic effect of topically applied ophthalmic corticosteroids had been reported to the date of this writing. CONCLUSIONS
While results of the tests do not lend themselves to graphs or tables because of the single individual involved and the ex* Scoggins, R. B.: Decrease of urinary corticos teroids following application of fluocinalone acetonide under an occlusive dressing. J. Invest. Dermat., 39:473-474, 1962.
pected variation in the count, observation did allow the following conclusions: 1. The use of the corticosteroid drops in the manner described, as a constant routine, resulted in the decrease of circulating blood eosinophils from 300/mm. to zero on one occasion and from 128/mm. to zero on an other occasion. 2. Reduction of circulating eosinophils to zero or near zero was accomplished after allergic symptoms were present, and while the allergens were continued, by the use of topical corticosteroids instilled in the con junctival sac. 3. Without the use of the topical corti costeroids the allergic symptoms continued unabated as long as the allergens were sup plied. Use of the corticosteroid, however, re sulted in disappearance of the allergic symp toms and their continued absence as long as the drops were used, even though the con sumption of unlimited quantities of citrus fruits and juices continued. With the recognized use of potent topical corticosteroids in ophthalmology have come problems of their side-effects, the most re cent being glaucoma. A case is presented in which a systemic effect was apparent after the use of topical ophthalmic corticosteroids. It is suggested that controlled studies should be undertaken to demonstrate the amount of systemic absorption and effect of topically applied ophthalmic corticosteroids. 2163 Torrance Boulevard. 3
3
ACKNOWLEDGEMENT
I am indented to S. Rodman Irvine, M.D., for reading this paper and suggesting its publication.