REVIEW ARTICLE
Drug-Induced Ocular Hypertension and Angle-Closure Glaucoma Badri P. Badhu, MD,* Balkrishna Bhattarai, MD,Þ and Himal P. Sangraula, MDþ
Abstract: The objective of this study was to review the available literature on the drugs causing ocular hypertension and glaucoma. Electronic literature search was carried out using the Web sites www.pubmed.gov and www.google.com published through the year 2011. The search words were ‘‘drug induced ocular hypertension’’ and ‘‘drug induced glaucoma’’ used in combination. The articles published or translated into English were studied. Quite a significant number of drugs commonly prescribed by various physicians of different specialties can induce ocular hypertension or glaucoma. A brief account of various drugs that can induce ocular hypertension has been given in this article. Those drugs are parasympatholytics; steroids; anticholinergics, adrenergics, and antidepressants; cholinomimetics; antineoplastic agents; antipsychotic and antiparkinsonism agents; H1 and H2 receptor blockers; botulinum toxin, cardiac agents, and anticoagulants; silicone oil; sulfa drugs; and anesthetic agents. Rational use of these drugs and knowledge of their potential adverse effects can help prevent the devastating complications resulting in loss of vision and compromised quality of life. Key Words: drug-induced ocular hypertension, secondary glaucoma
In this article, we present a brief account of how the following groups of drugs induce OHT and glaucoma. They are (a) parasympatholytics; (b) steroids; (c) anticholinergics, adrenergics, and antidepressants; (d) cholinomimetics; (e) antineoplastic agents; ( f ) antipsychotic and antiparkinsonism agents; (g) H1 and H2 receptor blockers; (h) botulinum toxin, cardiac agents, and anticoagulants; (i) silicone oil; ( j ) sulfa drugs; and (k) anesthetic agents
Parasympatholytics and Ocular Hypertension Several authors have documented a rise of IOP following the use of cyclopentolate and other parasympatholytics even in subjects with open angles.6Y8 It is interesting to note that the sympathomimetics do not provoke IOP elevation in healthy eyes9,10 and in those suspected to have open-angle glaucoma.11,12 However, a marked IOP elevation can be observed in eyes with open-angle glaucoma following the topical use of parasympatholytics.8,10,13Y16 Leydhecker7 explained the IOP rise by the vascular action of the mydriatic or cycloplegic drug.
(Asia-Pac J Ophthalmol 2013;2: 173Y176)
Steroid-Induced Ocular Hypertension
T
he intraocular pressure (IOP) above the reference range of 10 to 21 mm Hg is generally accepted as ocular hypertension (OHT). Although not everybody with it develops glaucoma, it is considered as a major risk factor for open-angle glaucoma. Ocular hypertension increases relative risk of glaucomatous optic nerve damage 13-fold if the IOP is 22 to 29 mm Hg, and the risk increases further for higher IOP.1 Some controversy exists in the literature as to whether the subjects with OHT require medical treatment or just a periodic observation.2,3 The Ocular Hypertension Study has reported that the risk of developing glaucomatous optic disc and/or visual field loss significantly reduces if the OHT is treated.4,5 We opine that the secondary rise of IOP following the use of certain drugs should be termed as secondary OHT in the absence of specific disc changes and visual field defects.
METHODS OF LITERATURE SEARCH Electronic literature search was carried out using the Web sites www.pubmed.gov and www.google.com published through the year 2011. The search words were ‘‘drug induced ocular hypertension’’ and ‘‘drug induced glaucoma’’ used in combination. The articles published or translated into English were studied.
From the *Ophthalmology, †Anesthesiology and Critical Care, and ‡Clinical Pharmacology departments, B. P. Koirala Institute of Health Sciences, Dharan, Sunsari, Nepal. Received for publication July 29, 2012; accepted March 25, 2013. The authors have no funding or conflicts of interest to declare. Reprints: Badri P. Badhu, MD, Department of Ophthalmology, BPKIHS, Dharan-18, Ghopa, Sunsari, Nepal. E-mail: [email protected]. Copyright * 2013 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0b013e318293c772
Asia-Pacific Journal of Ophthalmology
&
Normal population may respond to steroid use differently in terms of IOP rise. Approximately 5% of the population is high responders, 30% moderate, and 65% are nonresponders to corticosteroid use for 2 to 6 weeks.17,18 Topical use of steroids is more likely to cause OHT in 3 to 6 weeks’ time. The heavy dose of systemic steroids may induce OHT early in the course of the drug or several months or years later among the steroid responders.19,20 Among the steroid responders, many of them are myopes; some have diabetes or rheumatoid arthritis. They are likely to develop glaucoma later in their lifetime.21,22 Although reversible on withdrawal of steroids in the initial stage,21,23 steroidinduced OHT may cause similar optic nerve head and visual field changes22 as primary open-angle glaucoma. The mechanism of elevated IOP is increased aqueous humor outflow resistance at the trabecular meshwork (TM) like in primary open-angle glaucoma. The changes that occur in the TM are deposition of fibronectin,23,24 glycosaminoglycans,25,26 and reorganization of the actin cytoskeleton.27,28 Presence of ‘‘finger-like deposit’’ in TM is quite unique for steroid-induced glaucoma.29
Anticholinergics, Adrenergics, and Antidepressants In subjects with narrow angles, use of anticholinergics and adrenergics23,30 may induce acute onset of angle-closure glaucoma (ACG) due to pupillary block mechanism.21,31 Antidepressants such as tricyclic agents (amitryptyline and imipramine) and nontricyclic ones (mianserin hydrochloride, paroxetine, fluoxetine, fluvoxamine, and escitalopram) have been reported to induce acute ACG due to pupillary block mechanism as a result of their anticholinergic action and mydriasis.32,33 Monoamine oxidase inhibitors have a weak anticholinergic effect. They may precipitate similar effect if used with perphenazine, trifluoperazine, and fluphenazine.34,35
Volume 2, Number 3, May/June 2013
www.apjo.org
Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
173
Badhu et al
Asia-Pacific Journal of Ophthalmology
&
Volume 2, Number 3, May/June 2013
Acute onset of ACG following mydriasis is due to peripheral crowding of iris and subsequent closure of the angle structures by it. The aqueous flow experiences maximum resistance when the dilated pupil reaches the midYdilated position while being constricted or returning to its normal size after full dilatation. The subjects with hyperopia and nanophthalmic eyes are vulnerable to this occurrence.36,37 Use of miotics or prophylactic YAG laser peripheral iridotomy may reverse the condition in early stage usually within 72 hours. Later on, peripheral anterior synechiae may form or fibrotic changes in the TM may develop requiring filtration surgery.
in its management. Pilocarpine is in fact contraindicated because it can cause the condition further worse because of ciliary spasm and thickening of the lens size. The IOP should be lowered with agents that minimize the aqueous secretion. Cycloplegics and steroids are effective drugs in its management. The sulfa-containing drugs should be stopped immediately and not prescribed any longer. These are topiramate, acetazolamide, hydrochlorothiazide, cotrimoxazole, spironolactone, sulfonamides, and so forth. The physicians prescribing these drugs should be aware that the most common presenting feature of this condition is pseudomyopia that results from anterior shift of the lens.46Y49
Cholinomimetics
Anesthetic Agents and Ocular Hypertension
Use of higher concentration of cholinomimetics such as pilocarpine and carbachol may induce ACG due to ciliary body spasm, relaxation of zonules, and subsequent enlargement of the lens thickness. This can happen even in people with previously open angles.
Antineoplastic Agents Docetaxel and paclitaxel, which are used as antineoplastic agents, can also induce OHT.38 Imatinib has been reported to cause a rise of IOP elevation. The mechanism of IOP rise in these cases is not clear.36,38
Antipsychotic and Antiparkinsonism Agents Antipsychotic agents are less likely to induce ACG because of their weaker anticholinergic action as compared with tricyclic antidepressants. Perphenazine, trifluoperazine, and fluphenazine are known to cause OHT37,39 and ACG. TrihexyphenidylVthe antiparkinsonism drugVcan precipitate ACG.40
H1 and H2 Receptor Blockers The other drugs that can induce ACG are the H1 and H2 receptor blockers. Promethazine, cimetidine, and ranitidine are known to cause a rise in IOP.37
Botulinum Toxin, Cardiac Agents, and Anticoagulants Periocular injection of botulinum toxin can cause a pupillary dilatation resulting in acute ACG.43 The cardiac agents such as disopyramide phosphate also have anticholinergic action with potential to induce acute ACG.41,42 Whether the calcium-channel blockers raise IOP is controversial.43 Anticoagulants can induce massive vitreous and choroidal hemorrhage and ACG due to anterior shift of the iridolenticular diaphragm.44
Silicone Oil Use of silicone oil intravitreally during retinal detachment surgery may cause postoperatively acute ACG due to iridolenticular block. This condition can be treated with pupil dilation, anterior chamber irrigation, or an Nd:YAG laser iridotomy.45
Sulfa Drugs Irrational use of sulfa drugs may result in disappointing results. The medical practitioners may be used for the adverse effects of the drugs if used without justification. One of the adverse effects of these drugs is bilateral acute ACG. Several reports on this issue are available in the literature.46Y49 Individuals with open angles or closed angles can be susceptible to this idiosyncratic reaction. The mechanism is choroidal and ciliary effusion resulting in anterior rotation of the ciliary body, lens swelling, and anterior shift of the iridolenticular diaphragm resulting in acute ACG with quite high IOP. Because this is nonpupillary block mechanism glaucoma, there is no role of YAG laser peripheral iridotomy and of miotics
174
www.apjo.org
Quite a few drugs used in anesthetic practice cause increase in IOP. Of particular importance include suxamethonium and ketamine. Succinylcholine (suxamethonium), the only depolarizing muscle relaxant used widely for rapid sequence intubation, causes significant increase in IOP. The increase in IOP occurs both during routine induction and when used in steady state.50,51 The increase in IOP is on an average of 8 mm Hg with the standard intubating dose of succinylcholine. The peak IOP is observed 1 to 4 minutes after an intravenous bolus dose. Several mechanisms are attributable to the ocular hypertensive response of succinylcholine. Those include tonic extraocular muscle contraction, distortion of the globe with axial shortening, ocular smooth muscle relaxation, and choroidal vascular dilatation.52Y54 Although contracture of extraocular muscles following administration of succinylcholine is believed to be the main mechanism in the causation of OHT by many, its cycloplegic action causing decreased tension on the scleral spur from the ciliary muscle and creating outflow resistance55 has been considered to be the primary mechanism in a study by demonstrating increase in IOP in eyes with detached extraocular muscles.56 Several prophylactic measures have been suggested for reducing the OHT associated with succinylcholine use. These include intravenous pretreatment with a small dose of nondepolarizing muscle relaxant, which prevents tonic muscle contraction. Another option could be a small ‘‘self-taming’’ dose of succinylcholine itself. Use of acetazolamide as a preventive agent has also been advocated. The other reported options for attenuating succinylcholine-induced OHT include use of lignocaine, benzodiazepines, and short-acting opioids. In addition, induction of anesthesia using propofol with an additional dose immediately before intubation of the trachea has been suggested.57 However, none of the previously mentioned techniques are consistently and completely effective in blocking the ocular hypertensive response of succinylcholine. Even though the opinions may vary among the clinicians, it is useful to remember that succinylcholine should not be used in patients with penetrating eye injury or with the open globe particularly without pretreatment with attenuating drugs. Ketamine is a commonly used intravenous anesthetic with unique properties. It is chemically related to phencyclidine. Although initially believed to cause significant increase in IOP, its effect on IOP has remained controversial. Significant increase in IOP has been reported when particularly measured using indentation technique.58,59 The increase in IOP was unrelated to changes in blood pressure or depth of anesthesia. However, IOP measurement under ketamine anesthesia becomes inaccurate owing to difficulty in positioning of the tonometer due to nystagmus. Failure to show significant effect on IOP with the use of standard anesthesia-inducing dose of ketamine in a study * 2013 Asia Pacific Academy of Ophthalmology
Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Asia-Pacific Journal of Ophthalmology
&
Volume 2, Number 3, May/June 2013
Drug-Induced Glaucoma
involving adult subjects created controversy and confusion about the drug.60 Similarly, use of standard intramuscular dose of ketamine in a pediatric study failed to show increase in IOP.61 Use of different premedicants as well as the techniques of IOP measurement is the likely factor in creating this confusion and controversy. Although future studies may find the exact effect of ketamine on IOP, it is still a useful agent during measurement of IOP in children with glaucoma, as the results are believed to reflect the IOP that is very close to the awake value.
16. Lazenby GW, Reed JW, Grant WM. Short term tests of anticholinergic medication in open angle glaucoma. Arch Ophthalmol. 1968;80: 443Y448.
CONCLUSIONS
21. Clark AF, Morrison JC. Corticosteroid glaucoma. In: Morrison JC, Pollack IP, eds. Glaucoma: Science and Practice. New York: Thieme Medical Publishers; 2002:197Y206.
Quite a significant number of drugs commonly prescribed by various physicians of different specialties can induce OHT or glaucoma. Rational use of these drugs and knowledge of their potential adverse effects can help prevent the devastating complications resulting in loss of vision and compromised quality of life. REFERENCES 1. Sommer A, Tielsch JM, Katz J, et al. Relationship between IOP and POAG among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991;109:1090Y1095. 2. Kitazawa Y, Horie T, Aokis S, et al. Untreated ocular hypertension. Arch Ophthalmol. 1977;95:1180Y1184. 3. Lundberg L, Wettrell K, Linner E. A prospective twenty year follow up study. Arch Ophthalmol. 1987;65:705Y708. 4. Kass MA, Heever DK, Higginbotham EJ, et al. The Ocular Hypertension Study: a randomized trial determines that topical ocular hypertensive medication delays or prevents the onset of primary open angle glaucoma. Arch Ophthalmol. 2002;120:701Y713.
17. Armaly MF, Becker B. Intraocular pressure response to topical corticosteroids. Fed Proc. 1965;24:1274Y1278. 18. Becker B. Intra-ocular pressure response to topical corticosteroids. Invest Ophthalmol. 1965;4:198Y205. 19. Francois J. Corticosteroid glaucoma. Ann Ophthalmol. 1977;9:1075Y1080. 20. Carnahan MC, Goldstein DA. Ocular complications of topical, periocular, and systemic corticosteroids. Curr Opin Ophthalmol. 2000;11:478Y483.
22. Becker B, Balin N. Glaucoma and corticosteroid provocative testing. Arch Ophthalmol. 1965;74:621Y624. 23. Steely HT, Browder SL, Julian MB, et al. The effects of dexamethasone on fibronectin expression in cultured human trabecular meshwork cells. Invest Ophthalmol Vis Sci. 1992;33:2242Y2250. 24. Clark AF, Miggans ST, Wilson K et al. Cytoskeletal changes in cultured human glaucoma trabecular meshwork cells. J Glaucoma. 1995;4:183Y188. 25. Clark AF, Wilson K, de Kater AW et al. Dexamethasone-induced ocular hypertension in perfusion-cultured human eyes. Invest Ophthalmol Vis Sci. 1995;36:478Y489. 26. Knepper PA, Breen M, Weinstein HG, et al. Intraocular pressure and glycosaminoglycan distribution in the rabbit eye: effect of age and dexamethasone. Exp Eye Res. 1978;27:567Y575. 27. Johnson DH, Bradley JM, Acott TS. The effect of dexamethasone on glycosaminoglycans of human trabecular meshwork in perfusion organ culture. Invest Ophthalmol Vis Sci. 1990;31:2568Y2571.
5. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of POAG. Arch Ophthalmol. 2002;102:714Y720.
28. Clark AF, Wilson K, McCartney MD, et al. Glucocorticoid-induced formation of cross-linked actin networks in cultured human trabecular meshwork cells. Invest Ophthalmol Vis Sci. 1994;35:281Y294.
6. Valle O. The cyclopentolate provocative test in suspected or untreated open angle glaucoma. Acta Ophthalmologia. 1976;54:456Y472.
29. Clark AF, Brotchie D, Read AT, et al. Dexamethasone alters F-actin architecture and promotes cross-linked actin network formation in human trabecular meshwork tissue. Cell Motil Cytoskeleton. 2005;60:83Y95.
7. Leydhecker W. Effect of homatropine on tension of normal and glaucomatous eye. Albrecht Von Graefes Arch Ophthalmol. 1954;155:386Y396. 8. Galin MA. The mydriasis provocative test. Arch Ophthalmol. 1961;66: 353Y355. 9. Becker B, Gay AJ. Applanation tonometry in the diagnosis and treatment of glaucoma: an evaluation of decreased scleral rigidity. AMA Arch Ophthalmol. 1959;62:211Y215. 10. Kristensen P. Mydriasis-induced pigment liberation in the anterior chamber associated with acute rise in intraocular pressure in open-angle glaucoma. Acta Ophthalmol (Copenh). 1965;43:714Y724. 11. Bloomfield S, Kellerman L. The relative value of several diagnostic tests for chronic simple glaucoma. Am J Ophthalmol. 1947;30: 869Y877. 12. Schimek RA, Lieberman WJ. The influence of Cyclogyl and Neosynephrine on tonographic studies of miotic control in open-angle glaucoma. Am J Ophthalmol. 1961;51:781Y784. 13. Salem MG, Ahearn RS. The effects of atropine and glycopyrrolate on intra-ocular pressure in anaesthetised elderly patients. Anaesthesia. 1984;39:809Y812. 14. Christensen RE, Pearce I. Homatropine hydrochloride. Effect of topical administration upon the intra-ocular pressure and aqueous facility value of normal and chronic simple glaucomatous eyes. Arch Ophthalmol. 1963;70:376Y380. 15. Smeral I, Rehak S, Juran J. Combination of tonography with loading tests in the early diagnosis of glaucoma. Cesk Oftalmol. 1964;20: 289Y293.
* 2013 Asia Pacific Academy of Ophthalmology
30. Johnson D, Gottanka J, Flugel C, et al. Ultra-structural changes in the trabecular meshwork of human eyes treated with corticosteroids. Arch Ophthalmol. 1997;115:375Y383. 31. Read AT, Chan DW, Ethier CR. Actin structure in the outflow tract of normal and glaucomatous eyes. Exp Eye Res. 2006;82:974Y985. 32. Richa S, Yazbek JC. Ocular adverse effects of common psychotropic agents: a review. CNS Drugs. 2010;24:501Y526. 33. Ritch R, Krupin T, Henry C, et al. Oral imipramine and acute angle closure glaucoma. Arch Ophthalmol. 1994;112:67Y68. 34. Lachkar Y, Bouassida W. Drug-induced acute angle-closure glaucoma. Curr Opin Ophthalmol. 2007;18:129Y133. 35. Davidson SI. Reports of ocular adverse reactions. Trans Ophthalmol Soc UK. 1973;93:495Y510. 36. Fraunfelder FW, Solomon J, Druker BJ, et al. Ocular side-effects associated with imatinib mesylate. J Ocul Pharmacol Ther. 2003;19:371Y375. 37. Fabre-Guillevin E, Tchen N, Anibali-Charpiat MF, et al. Taxane-induced glaucoma. Lancet. 1999;354:1181Y1182. 38. Friedman Z, Neumann E. Benzhexol-induced blindness in Parkinson’s disease. Br Med J. 1972;1:605. 39. Corridan P, Nightingale S, Mashoudi N, et al. Acute angle-closure glaucoma following botulinum toxin injection for blepharospasm. Br J Ophthalmol. 1990;74:309Y310. 40. Ahmad S. Disopyramide: pulmonary complications and glaucoma. Mayo Clin Proc. 1990;65:521Y529.
www.apjo.org
Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
175
Badhu et al
Asia-Pacific Journal of Ophthalmology
&
Volume 2, Number 3, May/June 2013
41. Trope GE, Hind VM. Closed-angle glaucoma in patients on disopyramide. Lancet. 1978;1:329.
51. Murphy DF. Anaesthesia and intraocular pressure. Anaesth Analg. 1985; 64:520Y530.
42. Beatty JF, Krupin T, Nichols PF, et al. Elevation of intraocular pressure by calcium channel blockers. Arch Ophthalmol. 1984;102:1072Y1076.
52. Cunningham AJ, Barry P. Intraocular pressure-physiology and implications for anaesthetic management. Can Anaesth Soc J. 1986;33:195Y208.
43. Lentschener C, Ghimouz A, Bonnichon P, et al. Acute post-operative glaucoma after non-ocular surgery remains a diagnostic challenge. Anesth Analog. 2002;94:1034Y1035.
53. Adams AK, Barnett KC. Anaesthesia and intraocular pressure. Anaesthesia. 1966;21:202Y210.
44. Pavlidis M, Scharioth G, de Ortueta D, et al. Iridolenticular block in heavy silicone oil tamponade. Retina. 2010;30:516Y520. 45. Lee GC, Tam CP, Danesh-Meyer HV, et al. Bilateral angle closure glaucoma induced by sulphonamide-derived medications. Clin Experiment Ophthalmol. 2007;35:55Y58. 46. Fraunfelder FW, Fraunfelder FT, Keates EU. Topiramate-associated acute bilateral, secondary angle-closure glaucoma. Ophthalmol. 2004;111: 109Y111. 47. Richa S, Yajbeck JC. Ocular adverse effects of common psychotropic agents: a review. CNS Drugs. 2010;24:501Y526. 48. Spadoni VS, Pizzol MM, Muniz CH, et al. Bilateral angle-closure glaucoma induced by trimetoprim and sulfamethoxazole combination: case report. Arq Bras Oftalmol. 2007;70:517Y520. 49. Cook JH. The effect of suxamethonium on intraocular pressure. Anaesthesia. 1981;36:359Y365. 50. Lavery GG, McGalliard JN, Mirakhur RK, et al. The effects of atracurium on intraocular pressure during steady state anaesthesia and rapid sequence induction. A comparison with scuccinylcholine. Can Anaesth Soc J. 1986;33:437Y442.
54. Abramson DH. Anterior chamber and lens thickness changes induced by succinylcholine. Arch Ophthalmol. 1971;86:643Y647. 55. Kelly RE, Dinner M, Turner LS, et al. Succinylcholine increases intraocular pressure in the human eye with the extra-ocular muscles detached. Anesthesiology. 1993;79:948Y952. 56. Mirakhur RK, Shepherd WFI, Darrah WC. Propofol and thiopentone: effects on intraocular pressure associated with induction of anaesthesia and tracheal intubation (facilitated with suxamethonium). Br J Anaesth. 1987;59:431Y436. 57. Yoshikawa K, Murai Y. Effect of ketamine on intraocular pressure in children. Anaesth Analg. 1971;50:199Y202. 58. Corssen G, Hoy JE. A new parenteral anesthetic- CI581: its effect on intraocular pressure. J Pediatr Ophthalmol. 1967;4:20Y23. 59. Peuler M, Glass DD, Arens JF. Ketamine and intraocular pressure. Anesthesiology. 1975;43:575Y578. 60. Ausinsch B, Rayburn RL, Munson ES, et al. Ketamine and intraocular pressure in children. Anaesth Analg. 1976;55:773Y775. 61. Adams AK. Ketamine in paediatric ophthalmic practice. Anesthesia. 1973;28:212Y213.
‘‘Let every eye negotiate for itself and trust no agent.’’ William Shakespeare
176
www.apjo.org
* 2013 Asia Pacific Academy of Ophthalmology
Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Drug-Induced Ocular Hypertension and Angle-Closure Glaucoma Badri P. Badhu, MD,* Balkrishna Bhattarai, MD,Þ and Himal P. Sangraula, MDþ
Abstract: The objective of this study was to review the available literature on the drugs causing ocular hypertension and glaucoma. Electronic literature search was carried out using the Web sites www.pubmed.gov and www.google.com published through the year 2011. The search words were ‘‘drug induced ocular hypertension’’ and ‘‘drug induced glaucoma’’ used in combination. The articles published or translated into English were studied. Quite a significant number of drugs commonly prescribed by various physicians of different specialties can induce ocular hypertension or glaucoma. A brief account of various drugs that can induce ocular hypertension has been given in this article. Those drugs are parasympatholytics; steroids; anticholinergics, adrenergics, and antidepressants; cholinomimetics; antineoplastic agents; antipsychotic and antiparkinsonism agents; H1 and H2 receptor blockers; botulinum toxin, cardiac agents, and anticoagulants; silicone oil; sulfa drugs; and anesthetic agents. Rational use of these drugs and knowledge of their potential adverse effects can help prevent the devastating complications resulting in loss of vision and compromised quality of life. Key Words: drug-induced ocular hypertension, secondary glaucoma
In this article, we present a brief account of how the following groups of drugs induce OHT and glaucoma. They are (a) parasympatholytics; (b) steroids; (c) anticholinergics, adrenergics, and antidepressants; (d) cholinomimetics; (e) antineoplastic agents; ( f ) antipsychotic and antiparkinsonism agents; (g) H1 and H2 receptor blockers; (h) botulinum toxin, cardiac agents, and anticoagulants; (i) silicone oil; ( j ) sulfa drugs; and (k) anesthetic agents
Parasympatholytics and Ocular Hypertension Several authors have documented a rise of IOP following the use of cyclopentolate and other parasympatholytics even in subjects with open angles.6Y8 It is interesting to note that the sympathomimetics do not provoke IOP elevation in healthy eyes9,10 and in those suspected to have open-angle glaucoma.11,12 However, a marked IOP elevation can be observed in eyes with open-angle glaucoma following the topical use of parasympatholytics.8,10,13Y16 Leydhecker7 explained the IOP rise by the vascular action of the mydriatic or cycloplegic drug.
(Asia-Pac J Ophthalmol 2013;2: 173Y176)
Steroid-Induced Ocular Hypertension
T
he intraocular pressure (IOP) above the reference range of 10 to 21 mm Hg is generally accepted as ocular hypertension (OHT). Although not everybody with it develops glaucoma, it is considered as a major risk factor for open-angle glaucoma. Ocular hypertension increases relative risk of glaucomatous optic nerve damage 13-fold if the IOP is 22 to 29 mm Hg, and the risk increases further for higher IOP.1 Some controversy exists in the literature as to whether the subjects with OHT require medical treatment or just a periodic observation.2,3 The Ocular Hypertension Study has reported that the risk of developing glaucomatous optic disc and/or visual field loss significantly reduces if the OHT is treated.4,5 We opine that the secondary rise of IOP following the use of certain drugs should be termed as secondary OHT in the absence of specific disc changes and visual field defects.
METHODS OF LITERATURE SEARCH Electronic literature search was carried out using the Web sites www.pubmed.gov and www.google.com published through the year 2011. The search words were ‘‘drug induced ocular hypertension’’ and ‘‘drug induced glaucoma’’ used in combination. The articles published or translated into English were studied.
From the *Ophthalmology, †Anesthesiology and Critical Care, and ‡Clinical Pharmacology departments, B. P. Koirala Institute of Health Sciences, Dharan, Sunsari, Nepal. Received for publication July 29, 2012; accepted March 25, 2013. The authors have no funding or conflicts of interest to declare. Reprints: Badri P. Badhu, MD, Department of Ophthalmology, BPKIHS, Dharan-18, Ghopa, Sunsari, Nepal. E-mail: [email protected]. Copyright * 2013 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0b013e318293c772
Asia-Pacific Journal of Ophthalmology
&
Normal population may respond to steroid use differently in terms of IOP rise. Approximately 5% of the population is high responders, 30% moderate, and 65% are nonresponders to corticosteroid use for 2 to 6 weeks.17,18 Topical use of steroids is more likely to cause OHT in 3 to 6 weeks’ time. The heavy dose of systemic steroids may induce OHT early in the course of the drug or several months or years later among the steroid responders.19,20 Among the steroid responders, many of them are myopes; some have diabetes or rheumatoid arthritis. They are likely to develop glaucoma later in their lifetime.21,22 Although reversible on withdrawal of steroids in the initial stage,21,23 steroidinduced OHT may cause similar optic nerve head and visual field changes22 as primary open-angle glaucoma. The mechanism of elevated IOP is increased aqueous humor outflow resistance at the trabecular meshwork (TM) like in primary open-angle glaucoma. The changes that occur in the TM are deposition of fibronectin,23,24 glycosaminoglycans,25,26 and reorganization of the actin cytoskeleton.27,28 Presence of ‘‘finger-like deposit’’ in TM is quite unique for steroid-induced glaucoma.29
Anticholinergics, Adrenergics, and Antidepressants In subjects with narrow angles, use of anticholinergics and adrenergics23,30 may induce acute onset of angle-closure glaucoma (ACG) due to pupillary block mechanism.21,31 Antidepressants such as tricyclic agents (amitryptyline and imipramine) and nontricyclic ones (mianserin hydrochloride, paroxetine, fluoxetine, fluvoxamine, and escitalopram) have been reported to induce acute ACG due to pupillary block mechanism as a result of their anticholinergic action and mydriasis.32,33 Monoamine oxidase inhibitors have a weak anticholinergic effect. They may precipitate similar effect if used with perphenazine, trifluoperazine, and fluphenazine.34,35
Volume 2, Number 3, May/June 2013
www.apjo.org
Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
173
Badhu et al
Asia-Pacific Journal of Ophthalmology
&
Volume 2, Number 3, May/June 2013
Acute onset of ACG following mydriasis is due to peripheral crowding of iris and subsequent closure of the angle structures by it. The aqueous flow experiences maximum resistance when the dilated pupil reaches the midYdilated position while being constricted or returning to its normal size after full dilatation. The subjects with hyperopia and nanophthalmic eyes are vulnerable to this occurrence.36,37 Use of miotics or prophylactic YAG laser peripheral iridotomy may reverse the condition in early stage usually within 72 hours. Later on, peripheral anterior synechiae may form or fibrotic changes in the TM may develop requiring filtration surgery.
in its management. Pilocarpine is in fact contraindicated because it can cause the condition further worse because of ciliary spasm and thickening of the lens size. The IOP should be lowered with agents that minimize the aqueous secretion. Cycloplegics and steroids are effective drugs in its management. The sulfa-containing drugs should be stopped immediately and not prescribed any longer. These are topiramate, acetazolamide, hydrochlorothiazide, cotrimoxazole, spironolactone, sulfonamides, and so forth. The physicians prescribing these drugs should be aware that the most common presenting feature of this condition is pseudomyopia that results from anterior shift of the lens.46Y49
Cholinomimetics
Anesthetic Agents and Ocular Hypertension
Use of higher concentration of cholinomimetics such as pilocarpine and carbachol may induce ACG due to ciliary body spasm, relaxation of zonules, and subsequent enlargement of the lens thickness. This can happen even in people with previously open angles.
Antineoplastic Agents Docetaxel and paclitaxel, which are used as antineoplastic agents, can also induce OHT.38 Imatinib has been reported to cause a rise of IOP elevation. The mechanism of IOP rise in these cases is not clear.36,38
Antipsychotic and Antiparkinsonism Agents Antipsychotic agents are less likely to induce ACG because of their weaker anticholinergic action as compared with tricyclic antidepressants. Perphenazine, trifluoperazine, and fluphenazine are known to cause OHT37,39 and ACG. TrihexyphenidylVthe antiparkinsonism drugVcan precipitate ACG.40
H1 and H2 Receptor Blockers The other drugs that can induce ACG are the H1 and H2 receptor blockers. Promethazine, cimetidine, and ranitidine are known to cause a rise in IOP.37
Botulinum Toxin, Cardiac Agents, and Anticoagulants Periocular injection of botulinum toxin can cause a pupillary dilatation resulting in acute ACG.43 The cardiac agents such as disopyramide phosphate also have anticholinergic action with potential to induce acute ACG.41,42 Whether the calcium-channel blockers raise IOP is controversial.43 Anticoagulants can induce massive vitreous and choroidal hemorrhage and ACG due to anterior shift of the iridolenticular diaphragm.44
Silicone Oil Use of silicone oil intravitreally during retinal detachment surgery may cause postoperatively acute ACG due to iridolenticular block. This condition can be treated with pupil dilation, anterior chamber irrigation, or an Nd:YAG laser iridotomy.45
Sulfa Drugs Irrational use of sulfa drugs may result in disappointing results. The medical practitioners may be used for the adverse effects of the drugs if used without justification. One of the adverse effects of these drugs is bilateral acute ACG. Several reports on this issue are available in the literature.46Y49 Individuals with open angles or closed angles can be susceptible to this idiosyncratic reaction. The mechanism is choroidal and ciliary effusion resulting in anterior rotation of the ciliary body, lens swelling, and anterior shift of the iridolenticular diaphragm resulting in acute ACG with quite high IOP. Because this is nonpupillary block mechanism glaucoma, there is no role of YAG laser peripheral iridotomy and of miotics
174
www.apjo.org
Quite a few drugs used in anesthetic practice cause increase in IOP. Of particular importance include suxamethonium and ketamine. Succinylcholine (suxamethonium), the only depolarizing muscle relaxant used widely for rapid sequence intubation, causes significant increase in IOP. The increase in IOP occurs both during routine induction and when used in steady state.50,51 The increase in IOP is on an average of 8 mm Hg with the standard intubating dose of succinylcholine. The peak IOP is observed 1 to 4 minutes after an intravenous bolus dose. Several mechanisms are attributable to the ocular hypertensive response of succinylcholine. Those include tonic extraocular muscle contraction, distortion of the globe with axial shortening, ocular smooth muscle relaxation, and choroidal vascular dilatation.52Y54 Although contracture of extraocular muscles following administration of succinylcholine is believed to be the main mechanism in the causation of OHT by many, its cycloplegic action causing decreased tension on the scleral spur from the ciliary muscle and creating outflow resistance55 has been considered to be the primary mechanism in a study by demonstrating increase in IOP in eyes with detached extraocular muscles.56 Several prophylactic measures have been suggested for reducing the OHT associated with succinylcholine use. These include intravenous pretreatment with a small dose of nondepolarizing muscle relaxant, which prevents tonic muscle contraction. Another option could be a small ‘‘self-taming’’ dose of succinylcholine itself. Use of acetazolamide as a preventive agent has also been advocated. The other reported options for attenuating succinylcholine-induced OHT include use of lignocaine, benzodiazepines, and short-acting opioids. In addition, induction of anesthesia using propofol with an additional dose immediately before intubation of the trachea has been suggested.57 However, none of the previously mentioned techniques are consistently and completely effective in blocking the ocular hypertensive response of succinylcholine. Even though the opinions may vary among the clinicians, it is useful to remember that succinylcholine should not be used in patients with penetrating eye injury or with the open globe particularly without pretreatment with attenuating drugs. Ketamine is a commonly used intravenous anesthetic with unique properties. It is chemically related to phencyclidine. Although initially believed to cause significant increase in IOP, its effect on IOP has remained controversial. Significant increase in IOP has been reported when particularly measured using indentation technique.58,59 The increase in IOP was unrelated to changes in blood pressure or depth of anesthesia. However, IOP measurement under ketamine anesthesia becomes inaccurate owing to difficulty in positioning of the tonometer due to nystagmus. Failure to show significant effect on IOP with the use of standard anesthesia-inducing dose of ketamine in a study * 2013 Asia Pacific Academy of Ophthalmology
Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Asia-Pacific Journal of Ophthalmology
&
Volume 2, Number 3, May/June 2013
Drug-Induced Glaucoma
involving adult subjects created controversy and confusion about the drug.60 Similarly, use of standard intramuscular dose of ketamine in a pediatric study failed to show increase in IOP.61 Use of different premedicants as well as the techniques of IOP measurement is the likely factor in creating this confusion and controversy. Although future studies may find the exact effect of ketamine on IOP, it is still a useful agent during measurement of IOP in children with glaucoma, as the results are believed to reflect the IOP that is very close to the awake value.
16. Lazenby GW, Reed JW, Grant WM. Short term tests of anticholinergic medication in open angle glaucoma. Arch Ophthalmol. 1968;80: 443Y448.
CONCLUSIONS
21. Clark AF, Morrison JC. Corticosteroid glaucoma. In: Morrison JC, Pollack IP, eds. Glaucoma: Science and Practice. New York: Thieme Medical Publishers; 2002:197Y206.
Quite a significant number of drugs commonly prescribed by various physicians of different specialties can induce OHT or glaucoma. Rational use of these drugs and knowledge of their potential adverse effects can help prevent the devastating complications resulting in loss of vision and compromised quality of life. REFERENCES 1. Sommer A, Tielsch JM, Katz J, et al. Relationship between IOP and POAG among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991;109:1090Y1095. 2. Kitazawa Y, Horie T, Aokis S, et al. Untreated ocular hypertension. Arch Ophthalmol. 1977;95:1180Y1184. 3. Lundberg L, Wettrell K, Linner E. A prospective twenty year follow up study. Arch Ophthalmol. 1987;65:705Y708. 4. Kass MA, Heever DK, Higginbotham EJ, et al. The Ocular Hypertension Study: a randomized trial determines that topical ocular hypertensive medication delays or prevents the onset of primary open angle glaucoma. Arch Ophthalmol. 2002;120:701Y713.
17. Armaly MF, Becker B. Intraocular pressure response to topical corticosteroids. Fed Proc. 1965;24:1274Y1278. 18. Becker B. Intra-ocular pressure response to topical corticosteroids. Invest Ophthalmol. 1965;4:198Y205. 19. Francois J. Corticosteroid glaucoma. Ann Ophthalmol. 1977;9:1075Y1080. 20. Carnahan MC, Goldstein DA. Ocular complications of topical, periocular, and systemic corticosteroids. Curr Opin Ophthalmol. 2000;11:478Y483.
22. Becker B, Balin N. Glaucoma and corticosteroid provocative testing. Arch Ophthalmol. 1965;74:621Y624. 23. Steely HT, Browder SL, Julian MB, et al. The effects of dexamethasone on fibronectin expression in cultured human trabecular meshwork cells. Invest Ophthalmol Vis Sci. 1992;33:2242Y2250. 24. Clark AF, Miggans ST, Wilson K et al. Cytoskeletal changes in cultured human glaucoma trabecular meshwork cells. J Glaucoma. 1995;4:183Y188. 25. Clark AF, Wilson K, de Kater AW et al. Dexamethasone-induced ocular hypertension in perfusion-cultured human eyes. Invest Ophthalmol Vis Sci. 1995;36:478Y489. 26. Knepper PA, Breen M, Weinstein HG, et al. Intraocular pressure and glycosaminoglycan distribution in the rabbit eye: effect of age and dexamethasone. Exp Eye Res. 1978;27:567Y575. 27. Johnson DH, Bradley JM, Acott TS. The effect of dexamethasone on glycosaminoglycans of human trabecular meshwork in perfusion organ culture. Invest Ophthalmol Vis Sci. 1990;31:2568Y2571.
5. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of POAG. Arch Ophthalmol. 2002;102:714Y720.
28. Clark AF, Wilson K, McCartney MD, et al. Glucocorticoid-induced formation of cross-linked actin networks in cultured human trabecular meshwork cells. Invest Ophthalmol Vis Sci. 1994;35:281Y294.
6. Valle O. The cyclopentolate provocative test in suspected or untreated open angle glaucoma. Acta Ophthalmologia. 1976;54:456Y472.
29. Clark AF, Brotchie D, Read AT, et al. Dexamethasone alters F-actin architecture and promotes cross-linked actin network formation in human trabecular meshwork tissue. Cell Motil Cytoskeleton. 2005;60:83Y95.
7. Leydhecker W. Effect of homatropine on tension of normal and glaucomatous eye. Albrecht Von Graefes Arch Ophthalmol. 1954;155:386Y396. 8. Galin MA. The mydriasis provocative test. Arch Ophthalmol. 1961;66: 353Y355. 9. Becker B, Gay AJ. Applanation tonometry in the diagnosis and treatment of glaucoma: an evaluation of decreased scleral rigidity. AMA Arch Ophthalmol. 1959;62:211Y215. 10. Kristensen P. Mydriasis-induced pigment liberation in the anterior chamber associated with acute rise in intraocular pressure in open-angle glaucoma. Acta Ophthalmol (Copenh). 1965;43:714Y724. 11. Bloomfield S, Kellerman L. The relative value of several diagnostic tests for chronic simple glaucoma. Am J Ophthalmol. 1947;30: 869Y877. 12. Schimek RA, Lieberman WJ. The influence of Cyclogyl and Neosynephrine on tonographic studies of miotic control in open-angle glaucoma. Am J Ophthalmol. 1961;51:781Y784. 13. Salem MG, Ahearn RS. The effects of atropine and glycopyrrolate on intra-ocular pressure in anaesthetised elderly patients. Anaesthesia. 1984;39:809Y812. 14. Christensen RE, Pearce I. Homatropine hydrochloride. Effect of topical administration upon the intra-ocular pressure and aqueous facility value of normal and chronic simple glaucomatous eyes. Arch Ophthalmol. 1963;70:376Y380. 15. Smeral I, Rehak S, Juran J. Combination of tonography with loading tests in the early diagnosis of glaucoma. Cesk Oftalmol. 1964;20: 289Y293.
* 2013 Asia Pacific Academy of Ophthalmology
30. Johnson D, Gottanka J, Flugel C, et al. Ultra-structural changes in the trabecular meshwork of human eyes treated with corticosteroids. Arch Ophthalmol. 1997;115:375Y383. 31. Read AT, Chan DW, Ethier CR. Actin structure in the outflow tract of normal and glaucomatous eyes. Exp Eye Res. 2006;82:974Y985. 32. Richa S, Yazbek JC. Ocular adverse effects of common psychotropic agents: a review. CNS Drugs. 2010;24:501Y526. 33. Ritch R, Krupin T, Henry C, et al. Oral imipramine and acute angle closure glaucoma. Arch Ophthalmol. 1994;112:67Y68. 34. Lachkar Y, Bouassida W. Drug-induced acute angle-closure glaucoma. Curr Opin Ophthalmol. 2007;18:129Y133. 35. Davidson SI. Reports of ocular adverse reactions. Trans Ophthalmol Soc UK. 1973;93:495Y510. 36. Fraunfelder FW, Solomon J, Druker BJ, et al. Ocular side-effects associated with imatinib mesylate. J Ocul Pharmacol Ther. 2003;19:371Y375. 37. Fabre-Guillevin E, Tchen N, Anibali-Charpiat MF, et al. Taxane-induced glaucoma. Lancet. 1999;354:1181Y1182. 38. Friedman Z, Neumann E. Benzhexol-induced blindness in Parkinson’s disease. Br Med J. 1972;1:605. 39. Corridan P, Nightingale S, Mashoudi N, et al. Acute angle-closure glaucoma following botulinum toxin injection for blepharospasm. Br J Ophthalmol. 1990;74:309Y310. 40. Ahmad S. Disopyramide: pulmonary complications and glaucoma. Mayo Clin Proc. 1990;65:521Y529.
www.apjo.org
Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
175
Badhu et al
Asia-Pacific Journal of Ophthalmology
&
Volume 2, Number 3, May/June 2013
41. Trope GE, Hind VM. Closed-angle glaucoma in patients on disopyramide. Lancet. 1978;1:329.
51. Murphy DF. Anaesthesia and intraocular pressure. Anaesth Analg. 1985; 64:520Y530.
42. Beatty JF, Krupin T, Nichols PF, et al. Elevation of intraocular pressure by calcium channel blockers. Arch Ophthalmol. 1984;102:1072Y1076.
52. Cunningham AJ, Barry P. Intraocular pressure-physiology and implications for anaesthetic management. Can Anaesth Soc J. 1986;33:195Y208.
43. Lentschener C, Ghimouz A, Bonnichon P, et al. Acute post-operative glaucoma after non-ocular surgery remains a diagnostic challenge. Anesth Analog. 2002;94:1034Y1035.
53. Adams AK, Barnett KC. Anaesthesia and intraocular pressure. Anaesthesia. 1966;21:202Y210.
44. Pavlidis M, Scharioth G, de Ortueta D, et al. Iridolenticular block in heavy silicone oil tamponade. Retina. 2010;30:516Y520. 45. Lee GC, Tam CP, Danesh-Meyer HV, et al. Bilateral angle closure glaucoma induced by sulphonamide-derived medications. Clin Experiment Ophthalmol. 2007;35:55Y58. 46. Fraunfelder FW, Fraunfelder FT, Keates EU. Topiramate-associated acute bilateral, secondary angle-closure glaucoma. Ophthalmol. 2004;111: 109Y111. 47. Richa S, Yajbeck JC. Ocular adverse effects of common psychotropic agents: a review. CNS Drugs. 2010;24:501Y526. 48. Spadoni VS, Pizzol MM, Muniz CH, et al. Bilateral angle-closure glaucoma induced by trimetoprim and sulfamethoxazole combination: case report. Arq Bras Oftalmol. 2007;70:517Y520. 49. Cook JH. The effect of suxamethonium on intraocular pressure. Anaesthesia. 1981;36:359Y365. 50. Lavery GG, McGalliard JN, Mirakhur RK, et al. The effects of atracurium on intraocular pressure during steady state anaesthesia and rapid sequence induction. A comparison with scuccinylcholine. Can Anaesth Soc J. 1986;33:437Y442.
54. Abramson DH. Anterior chamber and lens thickness changes induced by succinylcholine. Arch Ophthalmol. 1971;86:643Y647. 55. Kelly RE, Dinner M, Turner LS, et al. Succinylcholine increases intraocular pressure in the human eye with the extra-ocular muscles detached. Anesthesiology. 1993;79:948Y952. 56. Mirakhur RK, Shepherd WFI, Darrah WC. Propofol and thiopentone: effects on intraocular pressure associated with induction of anaesthesia and tracheal intubation (facilitated with suxamethonium). Br J Anaesth. 1987;59:431Y436. 57. Yoshikawa K, Murai Y. Effect of ketamine on intraocular pressure in children. Anaesth Analg. 1971;50:199Y202. 58. Corssen G, Hoy JE. A new parenteral anesthetic- CI581: its effect on intraocular pressure. J Pediatr Ophthalmol. 1967;4:20Y23. 59. Peuler M, Glass DD, Arens JF. Ketamine and intraocular pressure. Anesthesiology. 1975;43:575Y578. 60. Ausinsch B, Rayburn RL, Munson ES, et al. Ketamine and intraocular pressure in children. Anaesth Analg. 1976;55:773Y775. 61. Adams AK. Ketamine in paediatric ophthalmic practice. Anesthesia. 1973;28:212Y213.
‘‘Let every eye negotiate for itself and trust no agent.’’ William Shakespeare
176
www.apjo.org
* 2013 Asia Pacific Academy of Ophthalmology
Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
