METIPRANOLOL-INDUCED ADVERSE REACTIONS: II. LOSS OF INTRAOCULAR PRESSURE CONTROL

TAYO AKINGBEHIN and JOSE R. VILLADA Southport

SUMMARY ment of the metipranolol-induced adverse drug reactions This paper reviews the behaviour of intraocular pressure (ADRs) which was not unexpected in those eyes with (lOP) in glaucomatous eyes treated with metipranolol intraocular inflammation but was inexplicable in eyes with and without drug-induced adverse reactions with external ocular inflammation and those without any (ADRs). Two hundred and forty seven patients with open clinical signs of inflammation. angle glaucoma who were receiving the three different In this paper we continue our investigation of metipra­ strengths of metipranolol (0.1 %, 0.3 %, and 0.6 % ) in our nolo I-induced ADRs. We studied the behaviour of lOP in Department and the 7 patients who participated in the glaucomatous eyes with metipranolol-induced ADRs and metipranolol rechallenge trial were included in this study. also in those metipranolol treated eyes without clinical Out of the 247 patients, there were 52 eyes of 29 patients signs of ADRs. who showed 78 episodes of ADRs associated with meti­ pranolol. Forty five of these 78 episodes (57.6%) were PATIENTS AND METHODS associated with loss of lOP control. Two of the 7 eyes We reviewed retrospectively the case-notes of all patients treated with metipranolol in the rechallenge trial showed treated with metipranolol in our department and examined loss of lOP control, 1 of them without any signs of ocular those patients who responded to an invitation to attend inflammation. We further studied all the glaucomatous special clinics as described in the previous paper. 5 The eyes controlled with metipranolol 0.6% only and 22 eyes behaviour of the lOP in the eyes of those patients entered were identified with loss of lOP control but without rec­ into the rechallenge study were also analysed.6 ognisable signs or symptoms of ADR. Five other eyes in In the light of the preliminary results of the above two this group later developed metipranolol-induced ADRs. studies we further reviewed the behaviour of lOP in all The possible pathophysiological mechanisms for the loss glaucomatous eyes who had been controlled with metipra­ of lOP control are discussed and it is suggested that the active drug, metipranolol, could be directly implicated. nolol 0.6% only. RESULTS Elevation of intraocular pressure (lOP) is a well recog­ nised complication of intraocular inflammation but its Two hundred and forty seven glaucoma patients in our prevalence in the various inflammatory conditions as department were treated with guttae metipranolol: 109 reported by several authors vary markedly. For example, with metipranolol 0.6%, 103 with metipranolol 0.3% and the incidence of secondary glaucoma in patients with 35 with metipranolol 0.1 % acute uveitis is quoted between 12%1 and 15%,2 but in Seven patients completed the metipranolol rechallenge Fuch's Heterochromic Cyclitis estimates vary from 9%3 to study. 59%.4 There is however, very little in the literature on the From case-notes and clinical reviews we found 29 prevalence of secondary elevation of lOP in glaucomatous patients (52 eyes) with metipranolol-induced ADRs: eyes with ocular inflammation. granulomatous anterior uveitis (15 patients, 25 eyes); ble­ We described in a previous paper5 the adverse reactions pharoconjunctivitis (11 patients, 21 eyes); combined associated with the use of topical metipranolol in glauco­ granulomatous anterior uveitis and blepharoconjunctivitis matous eyes i.e. granulomatous anterior uveitis, marginal (2 patients, 4 eyes); periorbital dermatitis (1 patient, 2 keratitis, blepharoconjunctivitis and periorbital dermat­ eyes); and marginal keratitis (1 patient, 2 eyes). itis. Some of these glaucomatous eyes with controlled lOP There was a total of 78 different recorded episodes of exhibited secondary elevation in lOP with the develop- ADRs sufferedby the 52 eyes of the 29 patients. In 45 epi­ sodes (57.6%) there was a significant elevation in lOP Correspondence to: Mr Tayo Akingbehin MD FRCS FCOphth, Department of Ophthalmology, District General Hospital, Southport, (;:, 5 mm Hg) associated with the ADR. The distribution PR8 6NJ. of the patients, eyes and episodes in which there was loss

Eye (1992) 6,280-283 SECONDARY ELEVATION IN INTRAOCULAR PRESSURE DUE TO METIPRANOLOL 281

Table I. Distribution of patients, eyes and episodes in which there was medications (timolol maleate 0.5%, 10 eyes; carteolol 2%, a loss of lOP control 8 eyes; levobunolol 0.5%,2 eyes; pilocarpine 1 % 2 eyes)

Reaction No. of patients Eyes involved No. of episodes which controlled the lOP and were therefore not seen to develop any metipranolol-induced ADRs. GAU 10 17 27 BC 8 11 11 DISCUSSION BC&GAU 2 3 5 MK 1 2 2 The incidence of secondary glaucoma in patients with PD 0 0 0 acute uveitis in non-glaucomatous eyes in other studies 20* 33 45 varies between 12% (IOP>21 mm Hg on at least two *One patient is counted twice because she had dif f erent reactions in occasions)l and 15% (IOP>25 mm Hg).2 Jones7 review of each eye. glaucoma in 103 patients with Fuch's Heterochromic G A U granulomatous anterior uveitis B C blepharoconjunctivitis Cyclitis showed an incidence of 26.2% but other investi­ MK marginalkeratitis gators have reported estimates which vary from 9%3 to PD periorbital dermatitis 59%4 This paper reviews the secondary elevation in lOP seen of IOP control is shown Table I. In 42 out of the 45 in eyes with primary glaucoma treated by metripranolol (93.3%) episodes of ADR with elevation of IOP the with or without the various forms of metipranolol-induced responsible drug was metipranolol 0.6% and in the ADRs. As faras could be determined from the case notes remaining 3 episodes (6.7%) metipranolol 0.3% was the 52 eyes of the 29 patients who developed metiprano implicated (Table 11). � lo -mduced. ADRs had controlled lOPs i e. <22 mm Hg The 27 episodes (out of a total of 46 episodes) of granu­ � pnor to the first documentation of an ADR. Where an eye lomatous anterior uveitis with loss of lOP control had a suffered more than one episode of ADR (as there were a range of f:, lOP from 8 to 32 mm Hg with a mean f:, lOP total of 78 episodes in this group) the lOP returned to of 16.7 mm Hg (SD 6.3). There were 11 episodes of ble­ within normal limits on the same anti-glaucoma treatment pharoconjunctivitis with loss of lOP control (11 out of before the development of subsequent ADRs. In this 20), range of f:, lOP 5-18 mm Hg and mean f:, lOP 10.3 group of glaucomatous eyes therefore, further elevation in mm Hg (SD 4.6) and 3 episodes of combined granuloma­ lOP was only seen with an active ADR. tous anterior uveitis and blepharoconjunctivitis with sig­ In this study,loss of IOP control or significantelevation nificant elevation in lOP (3 out of 8), had a range f:, lOP in lOP is taken as an increase in lOP greater than 5 mm 8-22 mm Hg and mean f:, lOP 11.6 mm Hg (Table III). Hg. Two metipranolol 0.3% treated eyes of the 7 patients in The incidence of loss of lOP control was similar in the the rechallenge study showed an elevation of lOP within three sub-groups of ADRs: granulomatous anterior uveitis two weeks of the start of the study, 1 of them without any 59%, blepharoconjunctivitis 60% and granulomatous signs of ocular inflammation and a f:, lOP of 17 mm Hg. anterior uveitis and blepharoconjunctivitis combined The other eye had granulomatous anterior uveitis, blepha­ 62.5%. In the sub-group with marginal keratitis the 2 eyes roconjunctivitis, ectropion secondary to the skin changes affected showed this phenomenon (100%) but the number and a f:, IOP 22 mm Hg. is too small for any meaningful conclusion. The 2 glauco­ The further review of patients and case-notes revealed matous eyes with metipranolol-induced periorbital der­ 2 eyes of 14 p tien s on metipranolol 0.6% only with sig­ 7 � � matitis did not show any loss of lOP control. mficant elevatIOn m lOP (;::5 mm Hg) prior to the Panek! listed several pathophysiological mechanisms development of any recognisable clinical features of for the elevation of lOP in eyes with uveitis: �DRs. Five of these eyes later developed metipranolol­ mduced granulomatous anterior uveitis within a few Table III. Elevation of lOP in the dif f erent metipranolol-associated weeks. The other 22 eyes of 11 patients in this group were adverse reactions changed from metipranolol 0.6% to other anti-glaucoma mean elevation Table II. Distribution of episodes of ADRs associated with loss of ADR of lOP range SD lOP control and different strengths of metipranolol GAU 16.7 mm Hg 8-32 mmHg 6.3 metipranolol metipranolol metipranolol n=27 ADR 0. 1% 0.3% 0.6% BC 10.3 mmHg 5-18 mm Hg 4.6 n=l1 GAU 0 0 27 BC&GA BC 0 1 10 U 11.6 mm Hg 8-22 mm Hg 6 BC&GAU 0 0 5 n=5 MK 0 2 o MK 11 mmHg 8. 14 mmHg 4. 2 PD 0 0 o n=2 PD o 3 42 n=2

GAU granulomatous anterior uveitis GAU granulomatous anterior uveitis BC blepharoconjunctivitis BC blepharoconjunctivitis MK marginal keratitis MK marginalkeratitis PD periorbital dermatitis PD periorbital dermatitis 282 T. AKINGBEHIN ET AL.

(1) mechanical blockage of the trabeculum by serum gression of the glaucoma and not related to the use of meti­ components that are liberated because of vascular pranolol. The trend of elevation in lOP was not gradual as incompetence; would be expected for worsening of glaucoma and also the (2) hypersecretion associated with prostaglandin fact that lOP control was achieved very quickly with a mediated vascular hyperpermeability; comparable or less efficacious anti-glaucoma therapy, (3) overtaxing of outflow mechanisms by protein that both support the view that the loss of IOP control might be interferes with active transport; related to metipranolol. The lOPs in these eyes have (4) inflammation of the trabeculum itself with swelling remained within normal limits without additional anti­ which causes impaired outflow; glaucoma therapy for two years. (5) damage to trabecular endothelial cells by the inflam­ The mean elevation in lOP was highest in the uveitic matory process; sub-group ie 16.7 mm Hg. These eyes were managed in (6) mechanical obstruction of outflow by precipitates on different ways but unfortunately the number of eyes in the meshwork; each treatment group is too small for any objective con­ (7) sclerosis of trabecular meshwork as a result of chronic clusions. All the eyes showed return of lOP to within inflammation; or normal range except in one eye which had pseudoexfoli­ (8) obstruction of the trabeculum by a hyaline membrane ative glaucoma and finally required filtration surgery. The exact mechanism of the secondary elevation ofIOP All of these mechanisms are probably enhanced in eyes is unknown but probably associated with some changes in with primary open-angle glaucoma where the function of the trabecular meshwork caused by the active drug, meti­ the trabecular meshwork is already compromised. pranolol, itself. There were no additional findings in the The five sub-groups of metipranolol-induced ADRs iridocorneal recess on gonioscopic examination. Also represent three different forms of ocular inflammation. there were no significant differences in age, sex, time The granulomatous anterior uveitis and the combined since glaucoma was first diagnosed, period on metiprano- granulomatous anterior uveitis and blepharoconjunctivitis 101, associated diseases or other medications which may sub-groups both show signs of intraocular inflammation indicate any predisposition for the decompensation of tra­ which can be associated with elevation in lOP in 12-15% becular function with further reduction in outflow facility of normal eyes,2,3 but in our study the prevalence was 59% and consequently the loss ofIOP control. The rather quick and 62.5% respectively in the two sub-groups of glauco­ recovery of lOP control in these eyes, both those with and matous eyes with ADRs which is significantly higher. those without metipranolol-induced ADRs, when meti­ Kinshuck8 reported an elevation in lOP in 13 out of his 16 pranolol was discontinued suggest that the secondary ele­ glaucomatous eyes (87%) with metipranolol-associated vation in lOP was not due to progression of the disease. granulomatous anterior uveitis. The behaviour of the lOP in these metipranolol treated The two sub-groups of external ocular inflammation, eyes is not similar to that experienced with long term use i.e. blepharoconjunctivitis and marginal keratitis, are not of timolol (the 'long-term drift') which has been described !O often associated with secondary elevation in lOP unless by other authors.Y, Also, this phenomenon of loss ofIOP the external inflammation is so severe as to be accom­ control has been observed after a very short period of meti­ panied by decompensation of the blood-aqueous barrier. pranolol treatment, for example, the 2 eyes in the rechal­ In this study the prevalence of secondary elevation in lOP lenge study with marked elevation in lOP within two was 60% and 100% respectively in the two sub-groups. weeks of treatment with metipranolol 0.3% This evidence We were unable to findany figures in the literature for the is against progression of the disease or loss of drug effi­ prevalence of secondary glaucoma in normal or glauco­ cacy as the cause of the secondary elevation in lOP in matous eyes with external ocular inflammation but the these metipranolol treated eyes. figures obtained in our study are considerably higher than In conclusion, this study reveals a high incidence of would have been expected. The case of periocular der­ secondary elevation in lOP in glaucomatous eyes treated matitis represents inflammation of the adnexal structures with metipranolol 0.3% and 0.6% The intraocular inflam­ and would not have been expected to demonstrate a matory ADRs associated with metipranolol could com­ change in lOP. promise further the reduced outflow facility of these It is difficult to postulate a single mechanism of action glaucomatous eyes but this is not a plausible explanation for the elevation in lOP seen in the different forms of meti­ for the loss of lOP control in all the different types of pranolol-induced inflammations without implicating the ADRs, and in particular, for those eyes without clinical signs or symptoms of ADRs. It is suggested that the active active drug, i.e. metipranolol. 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