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Metipranolol-associated Granulomatous Iritis
Metipranolol-associated Granulomatous Iritis Ronald B. Melles, M.D., and Ira G. Wong, M.D. PURPOSE: Topical metipranolol therapy for pri mary open-angle glaucoma has been associat ed with anterior granulomatous uveitis in the United Kingdom. We studied granulomatous uveitis reactions to topical metipranolol 0.3% therapy for primary open-angle glaucoma in two patients in the United States. METHODS: Two patients, aged 71 and 81 years, were given topical metipranolol 0.3% therapy for primary open-angle glaucoma. RESULTS: Both developed granulomatous uvei tis. The iritis was associated with an increase in intraocular pressure in both patients and resolved on discontinuation of the drug. One patient was inadvertently rechallenged with metipranolol, and the iritis recurred. CONCLUSIONS: Topical metipranolol 0.3% ther apy may be associated with the development of granulomatous uveitis and a paradoxical increase in intraocular pressure. M.ETIPRANOLOL is a nonselective (beta-1 and beta-2) beta-adrenergic blocking agent similar in efficacy to other nonselective beta blockers in reducing intraocular pressure. 1,2 In the United Kingdom, a well-known complication of topical metipranolol therapy for primary open-angle glaucoma is acute anterior granulomatous uvei tis. Since the introduction of metipranolol (Glauline, Smith and Nephew, Essex, England) in 1986 to its withdrawal from the market in 1991, at least 60 cases of uveitis associated with the medication have been reported. 3 See also pp. 716 and 805.
Metipranolol (Optipranolol, Bausch & Lomb, Tampa, Florida ) was introduced in the United States in 1990 in a slightly different formula tion. To our knowledge, one case of anterior uveitis associated with this formulation of met-
Accepted for publication July 29, 1994. From the Department of Ophthalmology, Kaiser Per manente Medical Center, Redwood City, California. Reprint requests to Ronald B. Melles, M.D., Depart ment of Ophthalmology, Kaiser Permanente Medical Center, 1150 Veterans Blvd., Redwood City, CA 94063. 712
ipranolol has been reported in this country. 4 We treated two additional patients with anterior granulomatous uveitis associated with topical metipranolol 0.3% therapy, both of whom had marked increases in intraocular pressure. One patient was inadvertently rechallenged with metipranolol, and the uveitis recurred.
Case Reports Case 1
Primary open-angle glaucoma was diagnosed in a 71-year-old white woman in March 1993. Her visual acuity was R.E.: 20/25 and L.E.: 20/60. Intraocular pressure was 26 mm Hg in each eye. The anterior chambers were normal, with open angles and mild trabecular meshwork pigmentation. The cup/disk ratios were 0.6 and 0.8 in the right eye and left eye, respec tively. The visual field in the right eye had moderately dense superior and inferior arcuate defects; the left eye had severe superior and inferior arcuate defects with near split fixation. After initial therapy with metipranolol 0.3% twice a day in each eye and subsequent laser trabeculoplasty in both eyes, her intraocular pressure was 23 mm Hg in each eye. Pilocarpine hydrochloride ointment 4% in each eye at bedtime was added, and one month later the intraocular pressure was 22 mm Hg in the right eye and 20 mm Hg in the left eye. After seven months of metipranolol 0.3% and two months of pilocarpine hydrochloride oint ment 4%, the patient had pain, redness, and blurred vision in both eyes. Visual acuity was R.E.: 20/25 and L.E.: 20/50, and intraocular pressure was 39 mm Hg in the right eye and 37 mm Hg in the left eye. She had bilateral conjunctival injection, chemosis and ciliary flush, medium-sized mutton fat keratic precipitates in the right eye, and smaller mutton fat keratic precipitates in the left eye, with moderate cell and flare reaction in the anterior chamber of each eye. The iris in the right eye had two small Koeppe nodules. No inflammatory cells were in the vitreous. Because we suspected a possible drug reac-
©AMERICAN JOURNAL OF OPHTHALMOLOGY 118:712-715, DECEMBER, 1994
Vol. 118, No. 6
Metipranolol-associated Iritis
tion, the metipranolol and the pilocarpine hydrochloride were discontinued. Prednisolone acetate 1% every hour and levobunolol hydrochloride 0.5% and oral methazolamide, 100 mg, twice a day, were started. Within two weeks her keratic precipitates and the anterior cham ber cell and flare cleared, and the intraocular pressure decreased. The prednisolone acetate 1% was discontinued without recurrence of the inflammation, and the methazolamide was de creased to 50 mg twice a day. Results of systemic examination of her granulomatous uveitis, including a history and phys ical examination, chest x-ray, angiotensinconverting enzyme level, lysozyme, reactive plasma reagin, microhemagglutination assay for antibodies to Treponema pallidum, and tu berculin and anergy skin tests were normal. Two months later, a pharmacist inadvertently refilled her prescription with the original meti pranolol 0.3% instead of levobunolol hydrochloride 0.5%. Two weeks thereafter, she noted a decrease in her vision and returned to our office. Her visual acuity was R.E.: 20/40 and L.E.: 20/70, and the intraocular pressure was 54 mm Hg in the right eye and 50 mm Hg in the left eye. She again had signs of bilateral ante rior iritis. The anterior chamber had a moderate cell and flare reaction. Multiple small- and medium-sized keratic precipitates were seen in the right eye, and a few small keratic precipi tates were in the left eye. Gonioscopic analysis showed an open anterior chamber angle and no trabecular meshwork precipitates or synechiae. The iritis was treated with prednisolone acetate 1% every hour. The high intraocular pressure was treated with 500 mg of oral acetazolamide (Sequels), topical levobunolol hydrochloride 0.5%, and apraclonidine hydrochloride 0.5%, each twice a day. Within two days the intraocular pressure was 22 mm Hg in the right eye and 20 mm Hg in the left eye, and the inflammation decreased. After one week of treatment, the keratic precipitates nearly re solved and the anterior chamber reaction cleared. The prednisolone acetate 1% was dis continued without recurrence of the inflamma tion. Case 2 Primary open-angle glaucoma was diagnosed in an 81-year-old white man in January 1993. His visual acuity was 20/30 in each eye, and intraocular pressure was 30 mm Hg in the right eye and 32 mm Hg in the left eye. The anterior chamber angle was open, the lens had mild
713
nuclear sclerosis, and the cup/disk ratio was 0.5 in the right eye and 0.6 in the left eye. Visual field tests showed a superior arcuate defect in the right eye and dense inferior and superior arcuate defects in the left eye. He was started on a regimen of metipranolol 0.3% in each eye twice a day. The intraocular pressure decreased to 21 mm Hg in the right eye and 23 mm Hg in the left eye. However, six months later the pressure rose to 26 mm Hg in the right eye and 28 mm Hg in the left eye. The visual acuity had worsened to R.E.: 20/60 and L.E.: 20/50 because of progression of the cata racts. Argon laser trabeculoplasty was per formed in the left eye, and one week later the intraocular pressure was 20 mm Hg in the right eye and 21 mm Hg in the left eye, while meti pranolol 0.3% was still applied to both eyes twice a day. Two months after the laser trabeculoplasty and eight months after starting topical meti pranolol, the patient complained of blurred vision and redness of both eyes. Visual acuity was R.E.: 20/400 and L.E.: counting fingers at 5 feet, with intraocular pressure of 20 mm Hg in the right eye and 32 mm Hg in the left eye. The conjunctiva showed bilateral chemosis, injec tion, and follicular and papillary reaction, with the follicles most prominent in the nasal inferi or tarsal area. Many medium-sized stellate and mutton fat keratic precipitates occurred in both eyes, with severe cell and moderate flare in both eyes and several posterior synechiae in each eye. No cells were observed in the vitreous. A systemic examination to detect conditions associated with granulomatous uveitis included history and physical examination, chest x-ray, angiotensin-converting enzyme level, lyso zyme, reactive plasma reagin, microhemagglu tination assay for antibodies to T. pallidum, and tuberculin and anergy skin testing. Results of all tests were normal. The metipranolol 0.3% was discontinued, and the intraocular pressure decreased with oral acetazolamide (500 mg) and topical levo bunolol hydrochloride 0.5% twice a day. Three days later the visual acuity was 20/400 in each eye, and the intraocular pressure was 14 mm Hg in the right eye and 18 mm Hg in the left eye. Because there was persistent anterior chamber cellular reaction, prednisolone acetate 1% ev ery hour was started. During the following two weeks, the inflammation resolved, and the prednisolone acetate 1% was tapered and then discontinued. Three months later, the eyes re mained uninflamed, and visual acuity returned to 20/60 in both eyes. The intraocular pressure
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was 18 mm Hg in the right eye and 16 mm Hg in the left eye, while on a regimen of oral acetazolamide (500 mg) and levobunolol hydrochloride 0.5% twice a day.
Discussion Beta-blocker eyedrops have gained wide spread usage in the treatment of glaucoma because of their efficacy, prolonged therapeu tic action, and limited ocular side effects. Metipranolol is a nonselective beta blocker that is rapidly converted into its active form, desacetyl-metipranolol, when it passes through the cornea 5 and that reduces intraocular pres sure by suppressing aqueous humor produc tion. 6 Topical metipranolol is similar in efficacy to other nonselective beta blockers. 1,a Metipranolol was introduced into the United Kingdom in 1986 and was marketed as Glauline (Smith and Nephew, Essex, England) in three strengths: 0.1%, 0.3%, and 0.6%. In 1991, Akingbehin and Villada 3 described granuloma tous anterior uveitis in 26 eyes of 15 patients on topical metipranolol therapy for glaucoma. Only one of their 15 patients was using the 0.3% dosage of metipranolol; the others were using 0.6% metipranolol. An increase in intra ocular pressure greater than 5 mm Hg was measured in more than 50% of their patients. Akingbehin, Villada, and Walley7 rechallenged seven patients with metipranolol 0.3% in one eye and timolol 0.5% in the fellow eye for up to 14 days. All seven eyes that received the meti pranolol rechallenge developed either granu lomatous anterior uveitis, marked intraocular pressure increase, blepharoconjunctivitis, or periorbital dermatitis within two weeks. Within another two weeks after discontinuing the met ipranolol, all patients had complete resolution of symptoms. Kinshuck 8 later described three patients on 0.3% metipranolol and five patients on 0.6% metipranolol, who had similar findings of uve itis and increased intraocular pressure. Initial ly, only the 0.6% strength of Glauline was removed from the market, 9 but by 1991 more than 60 episodes of metipranolol-associated uveitis had been reported to the United King dom's Committee on Safety of Medicines and all strengths of Glauline were withdrawn by the manufacturer. 3 On the basis of sales figures for Glauline in the United Kingdom, Akingbe hin and Villada 3 estimated the incidence of
December, 1994
metipranolol-associated anterior uveitis to be approximately 0.38% for metipranolol 0.6% and 0.11% for metipranolol 0.3%, although they also noted that the incidence appeared to be increasing. 3 No descriptions of uveitis reac tions in patients taking the 0.1% strength of metipranolol were available. At our institution, 407 patients have been on topical metipranolol 0.3% therapy for more than six months; hence we have an approximate 0.49% incidence of this reaction. There has been some controversy regarding the possible cause of the uveitis in patients taking metipranolol. O'Connor 10 has proposed that differences in the preparation of meti pranolol in the United Kingdom might account for the higher incidence of this adverse reaction reported there. Metipranolol is marketed in the United States under the name Optipranolol in a 0.3% strength, which contains less benzalkonium chloride than Glauline (0.044% vs 0.1%, respectively). Optipranolol bottles are pre pared in a sterile fashion, whereas after January 1989 Glauline preparations in the United King dom were sterilized by gamma radiation. There is some evidence that bottles sterilized by gamma radiation can lead to free radical production, which in turn may be associat ed with oxidative tissue damage and intraocular inflammation. 11 However, Akingbehin, Villada, and Walley7 also identified metipranolol-as sociated adverse reactions in patients whose medication bottles were sterilized by ethylene oxide and noted that there had been reports of anterior uveitis associated with metipranolol use on the European continent, where meti pranolol bottles are not sterilized by gamma radiation. Akingbehin 12 believes that the more common usage of the higher-dose 0.6% meti pranolol in the United Kingdom accounts for the greater incidence of uveitis reactions in that country. Granulomatous anterior uveitis is inflamma tion of the anterior segment of the eye with mutton fat keratic precipitates or iris nodules (of Koeppe or Busacca). Iritis implies inflamma tion limited to the anterior chamber, while iridocyclitis refers to inflammation in both the anterior chamber and the anterior vitreous. Both of our patients and the patient described by Schultz, Hoenig, and Charles 4 had anterior chamber inflammation and typical mutton fat keratic precipitates without vitreous cells, that is, granulomatous iritis. Early iritis, however, even if destined to become granulomatous, will initially be nongranulomatous, as it may take
Metipranolol-associated Iritis
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days or even weeks for the g r a n u l o m a t o u s m a n ifestations to d e v e l o p . Both of our p a t i e n t s w e r e on topical m e t i p r a n o l o l t h e r a p y w h e n a r g o n laser t r a b e c u l o plasty was performed, a n d in each p a t i e n t the iritis occurred w i t h i n a few m o n t h s after the t r e a t m e n t . P e r h a p s the i n t r a o c u l a r i n f l a m m a tion n o r m a l l y associated w i t h laser t r a b e c u l o plasty played s o m e role in s e n s i t i z i n g t h e s e p a t i e n t s to the m e t i p r a n o l o l m e d i c a t i o n . The paradoxical rise in i n t r a o c u l a r p r e s s u r e in p a t i e n t s w i t h g l a u c o m a is the m o s t a l a r m ing aspect of m e t i p r a n o l o l - a s s o c i a t e d a n t e r i o r g r a n u l o m a t o u s uveitis. Most of the p a t i e n t s from the U n i t e d K i n g d o m d e s c r i b e d as h a v i n g uveitis r e a c t i o n s h a d i n t r a o c u l a r p r e s s u r e in creases of over 5 m m Hg, s o m e w i t h i n c r e a s e s of over 20 m m Hg. 13 We can only s p e c u l a t e as to the m e c h a n i s m of this increase in i n t r a o c u l a r p r e s s u r e , a l t h o u g h a d e c r e a s e in outflow facili ty is likely. The t r a b e c u l a r m e s h w o r k may be blocked by inflammatory cells, s u c h as m a c r o p h a g e s , w h i c h are p r o m i n e n t in g r a n u l o m a t o u s uveitis, or there may be a direct toxic effect o n trabecular cells. Eye-care p r o v i d e r s s h o u l d be aware of this p o t e n t i a l a d v e r s e r e a c t i o n to m e t i p r a n o l o l , b e c a u s e the associated i n c r e a s e in intraocular p r e s s u r e may cause p r o g r e s s i o n of glaucomatous damage.
References 1. Krieglstein GK, Novack GD, Voepel E, Schwarz bach G, Lange U, Schunck KP, et al. Levobunolol and metipranolol: comparative ocular hypotensive
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efficacy, safety, and comfort. Br J Ophthalmol 1987;71:250-3. 2. Mills KB, Wright G. A blind randomised cross over trial comparing metipranolol 0.3% with timolol 0.25% in open-angle glaucoma: a pilot study. Br J Ophthalmol 1986;70:39-42. 3. Akingbehin T, Villada JR. Metipranolol-assoc iated granulomatous anterior uveitis. Br J Ophthal mol 1991;75:519-23. 4. Schultz JS, Hoenig JA, Charles H. Possible bilat eral anterior uveitis secondary to metipranolol (Optipranolol) therapy [letter]. Arch Ophthalmol 1993; 111:1606-7. 5. Kessler C, Bleckmann H, Kleintges G. Influence of the concentration of metipranolol eye drops on the drug concentration in human aqueous humour. Graefes Arch Clin Exp Ophthalmol 1991;229:48791. 6. Serie JB, Lustgarten JS, Podos SM. A clinical trial of metipranolol, a noncardioselective beta-adrenergic antagonist, in ocular hypertension. Am J Ophthalmol 1991;112:302-7. 7. Akingbehin T, Villada JR, Walley T. Metipranolol-induced adverse reactions, I: the rechallenge study. Eye 1992;6:277-9. 8. Kinshuck D. Glauline (metipranolol) induced üveitis and increase in ocular pressure [letter]. Br J Ophthalmol 1991,75:575. 9. Geraint M. Withdrawal of 0.6% Glauline (meti pranolol) [letter]. Br J Ophthalmol 1991;75:64. 10. O'Connor GR. Granulomatous uveitis and metipranolol. Br J Ophthalmol 1993,77:536. 11. Rao NA. Role of oxygen free radicals in retinal damage associated with experimental uveitis. Trans Am Ophthalmol Soc 1990;88:797-850. 12. Akingbehin AO. In discussion: O'Connor GR. Granulomatous uveitis and metipranolol. Br J Oph thalmol 1993;77:536-7. 13. Akingbehin T, Villada JR. Metipranololinduced adverse reactions, II: loss of intraocular pressure control. Eye 1992;6:280-3.
Metipranolol (Optipranolol, Bausch & Lomb, Tampa, Florida ) was introduced in the United States in 1990 in a slightly different formula tion. To our knowledge, one case of anterior uveitis associated with this formulation of met-
Accepted for publication July 29, 1994. From the Department of Ophthalmology, Kaiser Per manente Medical Center, Redwood City, California. Reprint requests to Ronald B. Melles, M.D., Depart ment of Ophthalmology, Kaiser Permanente Medical Center, 1150 Veterans Blvd., Redwood City, CA 94063. 712
ipranolol has been reported in this country. 4 We treated two additional patients with anterior granulomatous uveitis associated with topical metipranolol 0.3% therapy, both of whom had marked increases in intraocular pressure. One patient was inadvertently rechallenged with metipranolol, and the uveitis recurred.
Case Reports Case 1
Primary open-angle glaucoma was diagnosed in a 71-year-old white woman in March 1993. Her visual acuity was R.E.: 20/25 and L.E.: 20/60. Intraocular pressure was 26 mm Hg in each eye. The anterior chambers were normal, with open angles and mild trabecular meshwork pigmentation. The cup/disk ratios were 0.6 and 0.8 in the right eye and left eye, respec tively. The visual field in the right eye had moderately dense superior and inferior arcuate defects; the left eye had severe superior and inferior arcuate defects with near split fixation. After initial therapy with metipranolol 0.3% twice a day in each eye and subsequent laser trabeculoplasty in both eyes, her intraocular pressure was 23 mm Hg in each eye. Pilocarpine hydrochloride ointment 4% in each eye at bedtime was added, and one month later the intraocular pressure was 22 mm Hg in the right eye and 20 mm Hg in the left eye. After seven months of metipranolol 0.3% and two months of pilocarpine hydrochloride oint ment 4%, the patient had pain, redness, and blurred vision in both eyes. Visual acuity was R.E.: 20/25 and L.E.: 20/50, and intraocular pressure was 39 mm Hg in the right eye and 37 mm Hg in the left eye. She had bilateral conjunctival injection, chemosis and ciliary flush, medium-sized mutton fat keratic precipitates in the right eye, and smaller mutton fat keratic precipitates in the left eye, with moderate cell and flare reaction in the anterior chamber of each eye. The iris in the right eye had two small Koeppe nodules. No inflammatory cells were in the vitreous. Because we suspected a possible drug reac-
©AMERICAN JOURNAL OF OPHTHALMOLOGY 118:712-715, DECEMBER, 1994
Vol. 118, No. 6
Metipranolol-associated Iritis
tion, the metipranolol and the pilocarpine hydrochloride were discontinued. Prednisolone acetate 1% every hour and levobunolol hydrochloride 0.5% and oral methazolamide, 100 mg, twice a day, were started. Within two weeks her keratic precipitates and the anterior cham ber cell and flare cleared, and the intraocular pressure decreased. The prednisolone acetate 1% was discontinued without recurrence of the inflammation, and the methazolamide was de creased to 50 mg twice a day. Results of systemic examination of her granulomatous uveitis, including a history and phys ical examination, chest x-ray, angiotensinconverting enzyme level, lysozyme, reactive plasma reagin, microhemagglutination assay for antibodies to Treponema pallidum, and tu berculin and anergy skin tests were normal. Two months later, a pharmacist inadvertently refilled her prescription with the original meti pranolol 0.3% instead of levobunolol hydrochloride 0.5%. Two weeks thereafter, she noted a decrease in her vision and returned to our office. Her visual acuity was R.E.: 20/40 and L.E.: 20/70, and the intraocular pressure was 54 mm Hg in the right eye and 50 mm Hg in the left eye. She again had signs of bilateral ante rior iritis. The anterior chamber had a moderate cell and flare reaction. Multiple small- and medium-sized keratic precipitates were seen in the right eye, and a few small keratic precipi tates were in the left eye. Gonioscopic analysis showed an open anterior chamber angle and no trabecular meshwork precipitates or synechiae. The iritis was treated with prednisolone acetate 1% every hour. The high intraocular pressure was treated with 500 mg of oral acetazolamide (Sequels), topical levobunolol hydrochloride 0.5%, and apraclonidine hydrochloride 0.5%, each twice a day. Within two days the intraocular pressure was 22 mm Hg in the right eye and 20 mm Hg in the left eye, and the inflammation decreased. After one week of treatment, the keratic precipitates nearly re solved and the anterior chamber reaction cleared. The prednisolone acetate 1% was dis continued without recurrence of the inflamma tion. Case 2 Primary open-angle glaucoma was diagnosed in an 81-year-old white man in January 1993. His visual acuity was 20/30 in each eye, and intraocular pressure was 30 mm Hg in the right eye and 32 mm Hg in the left eye. The anterior chamber angle was open, the lens had mild
713
nuclear sclerosis, and the cup/disk ratio was 0.5 in the right eye and 0.6 in the left eye. Visual field tests showed a superior arcuate defect in the right eye and dense inferior and superior arcuate defects in the left eye. He was started on a regimen of metipranolol 0.3% in each eye twice a day. The intraocular pressure decreased to 21 mm Hg in the right eye and 23 mm Hg in the left eye. However, six months later the pressure rose to 26 mm Hg in the right eye and 28 mm Hg in the left eye. The visual acuity had worsened to R.E.: 20/60 and L.E.: 20/50 because of progression of the cata racts. Argon laser trabeculoplasty was per formed in the left eye, and one week later the intraocular pressure was 20 mm Hg in the right eye and 21 mm Hg in the left eye, while meti pranolol 0.3% was still applied to both eyes twice a day. Two months after the laser trabeculoplasty and eight months after starting topical meti pranolol, the patient complained of blurred vision and redness of both eyes. Visual acuity was R.E.: 20/400 and L.E.: counting fingers at 5 feet, with intraocular pressure of 20 mm Hg in the right eye and 32 mm Hg in the left eye. The conjunctiva showed bilateral chemosis, injec tion, and follicular and papillary reaction, with the follicles most prominent in the nasal inferi or tarsal area. Many medium-sized stellate and mutton fat keratic precipitates occurred in both eyes, with severe cell and moderate flare in both eyes and several posterior synechiae in each eye. No cells were observed in the vitreous. A systemic examination to detect conditions associated with granulomatous uveitis included history and physical examination, chest x-ray, angiotensin-converting enzyme level, lyso zyme, reactive plasma reagin, microhemagglu tination assay for antibodies to T. pallidum, and tuberculin and anergy skin testing. Results of all tests were normal. The metipranolol 0.3% was discontinued, and the intraocular pressure decreased with oral acetazolamide (500 mg) and topical levo bunolol hydrochloride 0.5% twice a day. Three days later the visual acuity was 20/400 in each eye, and the intraocular pressure was 14 mm Hg in the right eye and 18 mm Hg in the left eye. Because there was persistent anterior chamber cellular reaction, prednisolone acetate 1% ev ery hour was started. During the following two weeks, the inflammation resolved, and the prednisolone acetate 1% was tapered and then discontinued. Three months later, the eyes re mained uninflamed, and visual acuity returned to 20/60 in both eyes. The intraocular pressure
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AMERICAN JOURNAL OF OPHTHALMOLOGY
was 18 mm Hg in the right eye and 16 mm Hg in the left eye, while on a regimen of oral acetazolamide (500 mg) and levobunolol hydrochloride 0.5% twice a day.
Discussion Beta-blocker eyedrops have gained wide spread usage in the treatment of glaucoma because of their efficacy, prolonged therapeu tic action, and limited ocular side effects. Metipranolol is a nonselective beta blocker that is rapidly converted into its active form, desacetyl-metipranolol, when it passes through the cornea 5 and that reduces intraocular pres sure by suppressing aqueous humor produc tion. 6 Topical metipranolol is similar in efficacy to other nonselective beta blockers. 1,a Metipranolol was introduced into the United Kingdom in 1986 and was marketed as Glauline (Smith and Nephew, Essex, England) in three strengths: 0.1%, 0.3%, and 0.6%. In 1991, Akingbehin and Villada 3 described granuloma tous anterior uveitis in 26 eyes of 15 patients on topical metipranolol therapy for glaucoma. Only one of their 15 patients was using the 0.3% dosage of metipranolol; the others were using 0.6% metipranolol. An increase in intra ocular pressure greater than 5 mm Hg was measured in more than 50% of their patients. Akingbehin, Villada, and Walley7 rechallenged seven patients with metipranolol 0.3% in one eye and timolol 0.5% in the fellow eye for up to 14 days. All seven eyes that received the meti pranolol rechallenge developed either granu lomatous anterior uveitis, marked intraocular pressure increase, blepharoconjunctivitis, or periorbital dermatitis within two weeks. Within another two weeks after discontinuing the met ipranolol, all patients had complete resolution of symptoms. Kinshuck 8 later described three patients on 0.3% metipranolol and five patients on 0.6% metipranolol, who had similar findings of uve itis and increased intraocular pressure. Initial ly, only the 0.6% strength of Glauline was removed from the market, 9 but by 1991 more than 60 episodes of metipranolol-associated uveitis had been reported to the United King dom's Committee on Safety of Medicines and all strengths of Glauline were withdrawn by the manufacturer. 3 On the basis of sales figures for Glauline in the United Kingdom, Akingbe hin and Villada 3 estimated the incidence of
December, 1994
metipranolol-associated anterior uveitis to be approximately 0.38% for metipranolol 0.6% and 0.11% for metipranolol 0.3%, although they also noted that the incidence appeared to be increasing. 3 No descriptions of uveitis reac tions in patients taking the 0.1% strength of metipranolol were available. At our institution, 407 patients have been on topical metipranolol 0.3% therapy for more than six months; hence we have an approximate 0.49% incidence of this reaction. There has been some controversy regarding the possible cause of the uveitis in patients taking metipranolol. O'Connor 10 has proposed that differences in the preparation of meti pranolol in the United Kingdom might account for the higher incidence of this adverse reaction reported there. Metipranolol is marketed in the United States under the name Optipranolol in a 0.3% strength, which contains less benzalkonium chloride than Glauline (0.044% vs 0.1%, respectively). Optipranolol bottles are pre pared in a sterile fashion, whereas after January 1989 Glauline preparations in the United King dom were sterilized by gamma radiation. There is some evidence that bottles sterilized by gamma radiation can lead to free radical production, which in turn may be associat ed with oxidative tissue damage and intraocular inflammation. 11 However, Akingbehin, Villada, and Walley7 also identified metipranolol-as sociated adverse reactions in patients whose medication bottles were sterilized by ethylene oxide and noted that there had been reports of anterior uveitis associated with metipranolol use on the European continent, where meti pranolol bottles are not sterilized by gamma radiation. Akingbehin 12 believes that the more common usage of the higher-dose 0.6% meti pranolol in the United Kingdom accounts for the greater incidence of uveitis reactions in that country. Granulomatous anterior uveitis is inflamma tion of the anterior segment of the eye with mutton fat keratic precipitates or iris nodules (of Koeppe or Busacca). Iritis implies inflamma tion limited to the anterior chamber, while iridocyclitis refers to inflammation in both the anterior chamber and the anterior vitreous. Both of our patients and the patient described by Schultz, Hoenig, and Charles 4 had anterior chamber inflammation and typical mutton fat keratic precipitates without vitreous cells, that is, granulomatous iritis. Early iritis, however, even if destined to become granulomatous, will initially be nongranulomatous, as it may take
Metipranolol-associated Iritis
Vol. 118, No. 6
days or even weeks for the g r a n u l o m a t o u s m a n ifestations to d e v e l o p . Both of our p a t i e n t s w e r e on topical m e t i p r a n o l o l t h e r a p y w h e n a r g o n laser t r a b e c u l o plasty was performed, a n d in each p a t i e n t the iritis occurred w i t h i n a few m o n t h s after the t r e a t m e n t . P e r h a p s the i n t r a o c u l a r i n f l a m m a tion n o r m a l l y associated w i t h laser t r a b e c u l o plasty played s o m e role in s e n s i t i z i n g t h e s e p a t i e n t s to the m e t i p r a n o l o l m e d i c a t i o n . The paradoxical rise in i n t r a o c u l a r p r e s s u r e in p a t i e n t s w i t h g l a u c o m a is the m o s t a l a r m ing aspect of m e t i p r a n o l o l - a s s o c i a t e d a n t e r i o r g r a n u l o m a t o u s uveitis. Most of the p a t i e n t s from the U n i t e d K i n g d o m d e s c r i b e d as h a v i n g uveitis r e a c t i o n s h a d i n t r a o c u l a r p r e s s u r e in creases of over 5 m m Hg, s o m e w i t h i n c r e a s e s of over 20 m m Hg. 13 We can only s p e c u l a t e as to the m e c h a n i s m of this increase in i n t r a o c u l a r p r e s s u r e , a l t h o u g h a d e c r e a s e in outflow facili ty is likely. The t r a b e c u l a r m e s h w o r k may be blocked by inflammatory cells, s u c h as m a c r o p h a g e s , w h i c h are p r o m i n e n t in g r a n u l o m a t o u s uveitis, or there may be a direct toxic effect o n trabecular cells. Eye-care p r o v i d e r s s h o u l d be aware of this p o t e n t i a l a d v e r s e r e a c t i o n to m e t i p r a n o l o l , b e c a u s e the associated i n c r e a s e in intraocular p r e s s u r e may cause p r o g r e s s i o n of glaucomatous damage.
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