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Hazards of Medical Glaucoma Therapy in the Cataract Patient
Hazards of Medical Glaucoma Therapy in the Cataract Patient E. MICHAEL VAN BUSKIRK, MD
Abstract: Particular glaucoma drug hazards for cataract patients include miosis, exacerbation of lens opacity, pupillary block, and the development of systemic adrenergic or cholinergic adverse drug effects or interaction. Each available antiglaucoma drug needs to be selected in individual cases with the knowledge of side effects that are likely to develop. For the glaucoma-cataract patient, a glaucoma regimen need be designed to minimize visual impairment, to minimize exacerbation of cataract, and to prevent introduction of new ocular disorders. At the time of cataract surgery, the regimen should be reassessed to maximize a smooth operative course and minimize systemic operative and anesthetic complications. [Key words: cataract, drug side effects, glaucoma, medical therapy.] Ophthalmology 89:238-241, 1982
Glaucoma and cataract often co-exist as major ocular afflictions of the elderly. The past decade has seen dramatic changes in the philosophic approach toward the management of both conditions, with trends in glaucoma towards flow reducing rather than outflow enhancing agents and recently toward laser therapy as an alternative to surgery in some patients. By the same token, both the patient and surgeon are now faced with an ever changing array of mechanical devices for removing and replacing the cataractous lens. For the patient with combined cataract and glaucoma, however, this new spectrum of therapeutic options places an increasingly complex task before us to design the optimal therapeutic compromise for each individuaL
MIOTICS (TABLE 1) For years, the mainstay of glaucoma therapy was the miotics, pilocarpine, and, to a lesser degree, From the Department of Ophthalmology, Oregon Health Sciences University, Portland, Oregon. Presented at the Eighty-sixth Annual Meeting of the American Academy of Ophthalmology, Atlanta, Georgia, November 1-6, 1981. Reprint requests to E. Michael Van Buskirk, MD, Department of Ophthalmology, The Oregon Health Sciences University, 3181 S.w. Sam Jackson Park Road, Portland, OR 97201.
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physostigmine. In recent decades, the long-acting synthetic cholinesterase inhibitors, such as echothiophate and demarcarium, have enjoyed intermittent pockets of popularity. For the glaucoma patient who also has cataract, however, miotics need be chosen with care and foreboding. Not only will they further impair vision, but the stronger miotics have been shown to incite or exacerbate the cataract itself, in as many as 50% of glaucoma patients on echothiophate and in laboratory animals.1,2 In early nuclear sclerotic cataract, the patient may actually see better with his small pupil, but those with focal opacities in the visual axis will be impaired seriously by the pupillary constriction. Night vision will prove a problem for all. Irreversible miosis is an especially irksome consequence of prolonged therapy with these drugs because it hampers the ophthalmologist's continued diagnostic evaluation oflens, retina, and optic nerve. Such patients, with new visual loss, may require more expensive diagnostic maneuvers, such as laser interferometry or ultrasonography to detect occult, possibly druginduced, macular disorders or retinal detachment. Both pilocarpine and the cholinesterase inhibitors subject the patient to an increased risk of retinal detachment. 3 Regularly discontinuing miotic agents for approximately a day or two each year and pharmacologically dilating the pupil not only will permit continued documentation of cataract progression and 0161-6420/82/0300/238/$00.70
© American Academy of Ophthalmology
VAN BUSKIRK • HAZARDS OF GLAUCOMA THERAPY
Table 1. Hazards of Medical Glaucoma Therapy in the Cataract Patient Miotics Decreased vision Cataract Irreversible miosis Retinal detachment Angle closure Systemic cholinergic effects Cholinesterase inhibition
of optic disc changes, but also will facilitate examination of the peripheral fundus for retinal detachment. In spite of the special appeal of the miotics as outflow enhancing agents in this disease of impaired aqueous outflow, a particularly onerous and occult side effect is the introduction of new forms of glaucoma associated with closure of the anterior chamber angle, almost always occurring in the presence of advancing cataract (Figs 1, 2). With miotic therapy and cataract progression, the lens-iris diaphragm has shifted forward, progressively shallowing the anterior chamber and driving the enlarged lens more firmly against the posterior iris surface, increasing pupillary block. In addition, posterior synechia and hypertrophy of the pupillary iris epithelium may exacerbate block of flow from the posterior chamber. 4 Thus, angle closure is superimposed progressively upon the underlying component of open-angle glaucoma, but often in a subacute or chronic manner
without symptoms of acute rises of intraocular pressure. As discussed by Swan, this silent angle closure may initially appear, gonioscopically, as obliteration of the iris recess, especially in the inferior angle. 5 These patients, with previously well-controlled glaucoma, will seem to require stronger or additional medications, but they must have gonioscopy before stronger miotics are added (Fig 2). It is more preferable to proceed with laser or surgical iridotomy, with or without lens extraction, than to permit conversion of a well-controlled open-angle glaucoma to irreversible chronic synechial angle closure, among the most difficult of glaucomas to manage. An additional and, fortunately, rare variant of angle closure in the patient on strong miotics is that resulting from entrapment of aqueous, posterior to the lens-iris diaphragm, so called "malignant" or "ciliary block" glaucoma. This seems to occur after glaucoma or other anterior segment surgery in anatomically prone eyes and may be exacerbated by preoperative miotic therapy. It has been described in rare miotic-treated eyes without previous surgery. 6 .7 Chronic miotic therapy also increases the risks of complications during cataract surgery, but primarily if they are not recognized or anticipated. The strong miotics disrupt the blood-aqueous barrier and cause low-grade intra- and extra-ocular inflammation and iris edema, giving the iris a wooden, friable texture. s The rigidly miotic pupil may also compromise lens removal. The cholinesterase inhibitors should be discontinued four to six weeks prior to intraocular surgery. This will minimize their inflammatory effect and diminish con-
Fig 1. Slit-lamp view of right and left eyes of patient after 20 years on miot· ic therapy for open-angle glaucoma, showing pro· gressive shallowing of the anterior chamber. (pilo = 4% pilocarpine; echo 114% echothiophate)
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OPHTHALMOLOGY. MARCH 1982 • VOLUME 89 • NUMBER 3
and hypertension from epinephrine eye drops have been reported to the National Registry for Drug Induced Ocular Side Effects and in the ophthalmic literature, but considering the relatively high doses of epinephrine applied to the eye, they appear to occur less frequently than would be expected. IS ,16 Anderson has recently demonstrated that both epinephrine and dipivefrin eye drops are approximately 50% absorbed systemically in laboratory animals. 17 Thus, it is propitious to withhold epinephrine when administering agents, such as general anesthetics, that sensitize the heart to catacholamines .
Fig 2. Gonioscopic view of right eye shown in Figure 1. Partial angle closure has developed after 20 years on miotics.
junctival and episcleral bleeding during conjunctival dissection. By the same token, these agents are known to inhibit true and pseudo cholinesterase, ie, to prolong the action of the muscle relaxant, succinycholine, an important factor for patients in whom general anesthesia is contemplated. 9
ADRENERGIC AGONISTS (TABLE 2) The adrenergic agonist, epinephrine, has been used in the therapy of glaucoma for many years, and the epinephrine pro-drug, dipivefrin, has recently been introduced. 1O - 12 These agents are well tolerated locally, except for the propensity of epinephrine to incite allergic blepharoconjunctivitis. 10 Epinephrine, as an alpha agonist, will produce mydriasis in susceptible patients. Flack and Kramer have shown mydriasis to be more likely with long-term epinephrine useage, which eventually may simulate de nervation supersensitivity of the iris dilator fibers.13 Thus, epinephrine and dipivefrin should be avoided in the patient with narrow angles, particularly when used in combination with timolol, which tends to potentiate the epinephrine mydriatic effect. 14 Systemic catacholamine effects, including palpitations, tachycardia, premature ventricular contractions Table 2. Hazards of Medical Glaucoma Therapy in the Cataract Patient Epinephrine and Dipivefrin Local allergy Mydriasis-angie closure (timolol potentiated) Systemic effects Tachycardia Arrhythmias Hypertension Adverse drug interactions
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BETA ADRENERGIC BLOCKING AGENTS (TABLE 3) The past three years have seen us turning more frequently to the beta adrenergic blocking agent, timolol, in the therapy of glaucoma, particularly in patients with cataract or narrow angles, for whom the other agents seem less suitable. Timolol is generally well tolerated locally except for the mydriatic effect in combination with epinephrine, and the rare patient who develops keratopathy.I4,18 Of the one thousand cases of timolol side effects reported to the National Registry over the past three years, 12 have included cataract, but in none of these can timolol be implicated as the direct cause at this time . A worrisome aspect of topical ophthalmic beta blocker therapy has been the development of systemic adverse reactions, some of which could be attributed to systemic beta blockade and other effects. 19,20 Over one half of the timolol side effects reported to the Registry are systemic. 20 These effects may be particularly dangerous for the elderly cataract surgical patient with borderline cardiac or pulmonary compensation. The work of Manners and Walther, however, did not show an increase in the risk of general anesthesia from systemic beta blockade, even in patients with proven coronary artery disease; therefore timolol well tolerated before operation need not be discontinued prior to anesthesia as long as the attending physician is aware of its potential systemic effects.21 Haimann and Phelps advocated timolol to prevent alpha-chymotrypsin-induced glaucoma after lens extraction and found no adverse effects from its use in that setting. 22 Table 3. Hazards of Medical Glaucoma Therapy in the Cataract Patient Beta Blockers Mydriasis with epinephrine Systemic effects Cardiovascular Respi ratory CNS
VAN BUSKIRK • HAZARDS OF GLAUCOMA THERAPY
CARBONIC ANHYDRASE INHIBITORS Systemic glaucoma therapy with carbonic anhydrase inhibitors is becoming increasingly common and may be the only acceptable medical agent for the patient visually blurred by miotics and for whom epinephrine and timolol are systemically contraindicated. Although the carbonic anhydrase inhibitors cause a myriad of systemic side effects reported elsewhere, none of these are particularly specific for the cataract patient. 23 In preparation for cataract surgery, these patients should have evaluation of serum electrolytes, with particular attention to the presence of metabolic acidosis or hypokalemia. Although carbonic anhydrase inhibitor-induced acidosis is rarely serious, when it is superimposed upon the acid-base imbalance from other, concomitantly administered agents such as salicylates, marked acidosis and even coma may result. 24 By the same token, many elderly patients are taking thiazide diuretics in addition to their carbonic anhydrase inhibitors , making them prone to develop hypokalemia and possibly leading to serious cardiovascular complications during local and general anesthesia. 23
REFERENCES 1. Axelsson U, Holmberg A. The frequency of cataract after miotic therapy. Acta Ophthalmol 1966; 44:421-9. 2. Kaufman PL, Axelsson U. Induction of subcapsular cataracts in aniridic vervet monkeys by echothiophate. Invest Ophthalmol 1975; 14:863-6. . 3. Beasley H, Fraunfelder FT. Retinal detachments and topical ocular miotics. Ophthalmology 1979; 86:95-8. 4. Swan KC. Iris pigment nodules complicating miotic therapy. Am J Ophthalmol 1954; 37:886 - 9 5. Swan KC, Flaxel JT. Clinical pathologic correlations of long term miotic therapy versus surgical treatment of primary glaucoma. In : Bellows JG , ed . Contemporary Ophthalmology ; honoring Sir Stewart Duke-Elder. Baltimore: Williams & Wilkins, 1972; 168-75. 6. Simmons RJ . Malignant glaucoma . Br J Ophthalmol 1972; 56:263 - 72.
7. Shaffer RN, Hoskins HD Jr. Ciliary block (malignant) glaucoma. Ophthalmology 1978; 85:215-21 . 8. Kadin M. Studies on total protein and radio-iodinated serum albumin (RISA) content of primary aqueous humor. Am J Ophthalmol 1963; 55:93-9. 9. Leopold IH, Krishna N, Lehman RA. The effects ofanticholinesterase agents on the blood cholinesterases levels of normal and glaucoma subjects. Trans Am Ophthalmol Soc 1959; 57:63-85. 10. Podos SM. Epinephrine. Ophthalmology 1980; 87:721-3. 11 . Kaback MB, Podos SM, Harbin TS Jr, et aL The effects of dipivalyl epinephrine on the eye. Am J Ophthalmol 1976; 81 :768-72. 12. Mandell AI , Podos SM . Dipivalyl epinephrine (OPE): a new prodrug in the treatment of glaucoma. In: Leopold IH, Burns RP, eds. Symposium on Ocular Therapy. New York: Johh Wiley & Sons, 1977; 109- 17. 13. Flach AJ, Kramer SG. Supersensitivity to topical epinephrine after long-term epinephrine therapy. Arch Ophthalmol 1980; 98:482-3. 14. Goldberg I, Ashburn FS Jr, Palmberg PF, et aL Timolol and ep inephrine : a clinical study of ocular interactions. Arch Ophthalmol 1980; 98:484 - 6. 15. Ballin N, Becker B, Goldman ML. Systemic effects of epinephrine applied topically to the eye. Invest Ophthalmol 1966; 5:125 - 9. 16. Grant WM . Toxicology of the Eye . 2d ed. Springfield , IL: Charles C Thomas, 1974; 448 - 54. 17. Anderson JA. SystemiC absorption of topical ocularly applied epinephrine and dipivefrin . Arch Ophthalmol 1980; 98:350-3. 18. Van Buskirk EM. Corneal anesthesia after timolol maleate therapy.Am J Ophthalmol 1979; 88:739-43. 19. McMahon CD, Shaffer RN, Hoskins HD Jr, Hetherington J Jr. Adverse effects experienced of patients taki'rig timoloL Am J Ophthalmol 1979; 88:736 - 8. 20. Van Buskirk EM. Adverse reactions from Timolol adminisiration. Beta-adrenoceptor antagonism during anesthesia for coronary artery surgery. Ophthalmology 1980; 87:447-50. 21 . Manners JM, Walters FJ. Beta-adrenoreceptor blockade and anaesthesia. Anaesthesia 1979; 34:3 - 9. 22. Haimann MH, Phelps CD. Prophylactic timolol for the prevention of high intraocular pressure after cataract extraction. A randomized prospective double-blind trial. Ophthalmology 1981; 88:233-8. 23. Epstein DL, Grant WM . Carbonic anhydrase inhibitor side effects. Serum chemical analysis. Arch Ophthalmol 1977; 95: 1378 -82. 24. Anderson CJ, Kaufman PL, Sturm RJ. Toxicity of combined therapy with carbonic anhydrase inhibitors and aspirin. Am J Ophthalmol 1978; 86:516- 9.
241
Abstract: Particular glaucoma drug hazards for cataract patients include miosis, exacerbation of lens opacity, pupillary block, and the development of systemic adrenergic or cholinergic adverse drug effects or interaction. Each available antiglaucoma drug needs to be selected in individual cases with the knowledge of side effects that are likely to develop. For the glaucoma-cataract patient, a glaucoma regimen need be designed to minimize visual impairment, to minimize exacerbation of cataract, and to prevent introduction of new ocular disorders. At the time of cataract surgery, the regimen should be reassessed to maximize a smooth operative course and minimize systemic operative and anesthetic complications. [Key words: cataract, drug side effects, glaucoma, medical therapy.] Ophthalmology 89:238-241, 1982
Glaucoma and cataract often co-exist as major ocular afflictions of the elderly. The past decade has seen dramatic changes in the philosophic approach toward the management of both conditions, with trends in glaucoma towards flow reducing rather than outflow enhancing agents and recently toward laser therapy as an alternative to surgery in some patients. By the same token, both the patient and surgeon are now faced with an ever changing array of mechanical devices for removing and replacing the cataractous lens. For the patient with combined cataract and glaucoma, however, this new spectrum of therapeutic options places an increasingly complex task before us to design the optimal therapeutic compromise for each individuaL
MIOTICS (TABLE 1) For years, the mainstay of glaucoma therapy was the miotics, pilocarpine, and, to a lesser degree, From the Department of Ophthalmology, Oregon Health Sciences University, Portland, Oregon. Presented at the Eighty-sixth Annual Meeting of the American Academy of Ophthalmology, Atlanta, Georgia, November 1-6, 1981. Reprint requests to E. Michael Van Buskirk, MD, Department of Ophthalmology, The Oregon Health Sciences University, 3181 S.w. Sam Jackson Park Road, Portland, OR 97201.
238
physostigmine. In recent decades, the long-acting synthetic cholinesterase inhibitors, such as echothiophate and demarcarium, have enjoyed intermittent pockets of popularity. For the glaucoma patient who also has cataract, however, miotics need be chosen with care and foreboding. Not only will they further impair vision, but the stronger miotics have been shown to incite or exacerbate the cataract itself, in as many as 50% of glaucoma patients on echothiophate and in laboratory animals.1,2 In early nuclear sclerotic cataract, the patient may actually see better with his small pupil, but those with focal opacities in the visual axis will be impaired seriously by the pupillary constriction. Night vision will prove a problem for all. Irreversible miosis is an especially irksome consequence of prolonged therapy with these drugs because it hampers the ophthalmologist's continued diagnostic evaluation oflens, retina, and optic nerve. Such patients, with new visual loss, may require more expensive diagnostic maneuvers, such as laser interferometry or ultrasonography to detect occult, possibly druginduced, macular disorders or retinal detachment. Both pilocarpine and the cholinesterase inhibitors subject the patient to an increased risk of retinal detachment. 3 Regularly discontinuing miotic agents for approximately a day or two each year and pharmacologically dilating the pupil not only will permit continued documentation of cataract progression and 0161-6420/82/0300/238/$00.70
© American Academy of Ophthalmology
VAN BUSKIRK • HAZARDS OF GLAUCOMA THERAPY
Table 1. Hazards of Medical Glaucoma Therapy in the Cataract Patient Miotics Decreased vision Cataract Irreversible miosis Retinal detachment Angle closure Systemic cholinergic effects Cholinesterase inhibition
of optic disc changes, but also will facilitate examination of the peripheral fundus for retinal detachment. In spite of the special appeal of the miotics as outflow enhancing agents in this disease of impaired aqueous outflow, a particularly onerous and occult side effect is the introduction of new forms of glaucoma associated with closure of the anterior chamber angle, almost always occurring in the presence of advancing cataract (Figs 1, 2). With miotic therapy and cataract progression, the lens-iris diaphragm has shifted forward, progressively shallowing the anterior chamber and driving the enlarged lens more firmly against the posterior iris surface, increasing pupillary block. In addition, posterior synechia and hypertrophy of the pupillary iris epithelium may exacerbate block of flow from the posterior chamber. 4 Thus, angle closure is superimposed progressively upon the underlying component of open-angle glaucoma, but often in a subacute or chronic manner
without symptoms of acute rises of intraocular pressure. As discussed by Swan, this silent angle closure may initially appear, gonioscopically, as obliteration of the iris recess, especially in the inferior angle. 5 These patients, with previously well-controlled glaucoma, will seem to require stronger or additional medications, but they must have gonioscopy before stronger miotics are added (Fig 2). It is more preferable to proceed with laser or surgical iridotomy, with or without lens extraction, than to permit conversion of a well-controlled open-angle glaucoma to irreversible chronic synechial angle closure, among the most difficult of glaucomas to manage. An additional and, fortunately, rare variant of angle closure in the patient on strong miotics is that resulting from entrapment of aqueous, posterior to the lens-iris diaphragm, so called "malignant" or "ciliary block" glaucoma. This seems to occur after glaucoma or other anterior segment surgery in anatomically prone eyes and may be exacerbated by preoperative miotic therapy. It has been described in rare miotic-treated eyes without previous surgery. 6 .7 Chronic miotic therapy also increases the risks of complications during cataract surgery, but primarily if they are not recognized or anticipated. The strong miotics disrupt the blood-aqueous barrier and cause low-grade intra- and extra-ocular inflammation and iris edema, giving the iris a wooden, friable texture. s The rigidly miotic pupil may also compromise lens removal. The cholinesterase inhibitors should be discontinued four to six weeks prior to intraocular surgery. This will minimize their inflammatory effect and diminish con-
Fig 1. Slit-lamp view of right and left eyes of patient after 20 years on miot· ic therapy for open-angle glaucoma, showing pro· gressive shallowing of the anterior chamber. (pilo = 4% pilocarpine; echo 114% echothiophate)
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OPHTHALMOLOGY. MARCH 1982 • VOLUME 89 • NUMBER 3
and hypertension from epinephrine eye drops have been reported to the National Registry for Drug Induced Ocular Side Effects and in the ophthalmic literature, but considering the relatively high doses of epinephrine applied to the eye, they appear to occur less frequently than would be expected. IS ,16 Anderson has recently demonstrated that both epinephrine and dipivefrin eye drops are approximately 50% absorbed systemically in laboratory animals. 17 Thus, it is propitious to withhold epinephrine when administering agents, such as general anesthetics, that sensitize the heart to catacholamines .
Fig 2. Gonioscopic view of right eye shown in Figure 1. Partial angle closure has developed after 20 years on miotics.
junctival and episcleral bleeding during conjunctival dissection. By the same token, these agents are known to inhibit true and pseudo cholinesterase, ie, to prolong the action of the muscle relaxant, succinycholine, an important factor for patients in whom general anesthesia is contemplated. 9
ADRENERGIC AGONISTS (TABLE 2) The adrenergic agonist, epinephrine, has been used in the therapy of glaucoma for many years, and the epinephrine pro-drug, dipivefrin, has recently been introduced. 1O - 12 These agents are well tolerated locally, except for the propensity of epinephrine to incite allergic blepharoconjunctivitis. 10 Epinephrine, as an alpha agonist, will produce mydriasis in susceptible patients. Flack and Kramer have shown mydriasis to be more likely with long-term epinephrine useage, which eventually may simulate de nervation supersensitivity of the iris dilator fibers.13 Thus, epinephrine and dipivefrin should be avoided in the patient with narrow angles, particularly when used in combination with timolol, which tends to potentiate the epinephrine mydriatic effect. 14 Systemic catacholamine effects, including palpitations, tachycardia, premature ventricular contractions Table 2. Hazards of Medical Glaucoma Therapy in the Cataract Patient Epinephrine and Dipivefrin Local allergy Mydriasis-angie closure (timolol potentiated) Systemic effects Tachycardia Arrhythmias Hypertension Adverse drug interactions
240
BETA ADRENERGIC BLOCKING AGENTS (TABLE 3) The past three years have seen us turning more frequently to the beta adrenergic blocking agent, timolol, in the therapy of glaucoma, particularly in patients with cataract or narrow angles, for whom the other agents seem less suitable. Timolol is generally well tolerated locally except for the mydriatic effect in combination with epinephrine, and the rare patient who develops keratopathy.I4,18 Of the one thousand cases of timolol side effects reported to the National Registry over the past three years, 12 have included cataract, but in none of these can timolol be implicated as the direct cause at this time . A worrisome aspect of topical ophthalmic beta blocker therapy has been the development of systemic adverse reactions, some of which could be attributed to systemic beta blockade and other effects. 19,20 Over one half of the timolol side effects reported to the Registry are systemic. 20 These effects may be particularly dangerous for the elderly cataract surgical patient with borderline cardiac or pulmonary compensation. The work of Manners and Walther, however, did not show an increase in the risk of general anesthesia from systemic beta blockade, even in patients with proven coronary artery disease; therefore timolol well tolerated before operation need not be discontinued prior to anesthesia as long as the attending physician is aware of its potential systemic effects.21 Haimann and Phelps advocated timolol to prevent alpha-chymotrypsin-induced glaucoma after lens extraction and found no adverse effects from its use in that setting. 22 Table 3. Hazards of Medical Glaucoma Therapy in the Cataract Patient Beta Blockers Mydriasis with epinephrine Systemic effects Cardiovascular Respi ratory CNS
VAN BUSKIRK • HAZARDS OF GLAUCOMA THERAPY
CARBONIC ANHYDRASE INHIBITORS Systemic glaucoma therapy with carbonic anhydrase inhibitors is becoming increasingly common and may be the only acceptable medical agent for the patient visually blurred by miotics and for whom epinephrine and timolol are systemically contraindicated. Although the carbonic anhydrase inhibitors cause a myriad of systemic side effects reported elsewhere, none of these are particularly specific for the cataract patient. 23 In preparation for cataract surgery, these patients should have evaluation of serum electrolytes, with particular attention to the presence of metabolic acidosis or hypokalemia. Although carbonic anhydrase inhibitor-induced acidosis is rarely serious, when it is superimposed upon the acid-base imbalance from other, concomitantly administered agents such as salicylates, marked acidosis and even coma may result. 24 By the same token, many elderly patients are taking thiazide diuretics in addition to their carbonic anhydrase inhibitors , making them prone to develop hypokalemia and possibly leading to serious cardiovascular complications during local and general anesthesia. 23
REFERENCES 1. Axelsson U, Holmberg A. The frequency of cataract after miotic therapy. Acta Ophthalmol 1966; 44:421-9. 2. Kaufman PL, Axelsson U. Induction of subcapsular cataracts in aniridic vervet monkeys by echothiophate. Invest Ophthalmol 1975; 14:863-6. . 3. Beasley H, Fraunfelder FT. Retinal detachments and topical ocular miotics. Ophthalmology 1979; 86:95-8. 4. Swan KC. Iris pigment nodules complicating miotic therapy. Am J Ophthalmol 1954; 37:886 - 9 5. Swan KC, Flaxel JT. Clinical pathologic correlations of long term miotic therapy versus surgical treatment of primary glaucoma. In : Bellows JG , ed . Contemporary Ophthalmology ; honoring Sir Stewart Duke-Elder. Baltimore: Williams & Wilkins, 1972; 168-75. 6. Simmons RJ . Malignant glaucoma . Br J Ophthalmol 1972; 56:263 - 72.
7. Shaffer RN, Hoskins HD Jr. Ciliary block (malignant) glaucoma. Ophthalmology 1978; 85:215-21 . 8. Kadin M. Studies on total protein and radio-iodinated serum albumin (RISA) content of primary aqueous humor. Am J Ophthalmol 1963; 55:93-9. 9. Leopold IH, Krishna N, Lehman RA. The effects ofanticholinesterase agents on the blood cholinesterases levels of normal and glaucoma subjects. Trans Am Ophthalmol Soc 1959; 57:63-85. 10. Podos SM. Epinephrine. Ophthalmology 1980; 87:721-3. 11 . Kaback MB, Podos SM, Harbin TS Jr, et aL The effects of dipivalyl epinephrine on the eye. Am J Ophthalmol 1976; 81 :768-72. 12. Mandell AI , Podos SM . Dipivalyl epinephrine (OPE): a new prodrug in the treatment of glaucoma. In: Leopold IH, Burns RP, eds. Symposium on Ocular Therapy. New York: Johh Wiley & Sons, 1977; 109- 17. 13. Flach AJ, Kramer SG. Supersensitivity to topical epinephrine after long-term epinephrine therapy. Arch Ophthalmol 1980; 98:482-3. 14. Goldberg I, Ashburn FS Jr, Palmberg PF, et aL Timolol and ep inephrine : a clinical study of ocular interactions. Arch Ophthalmol 1980; 98:484 - 6. 15. Ballin N, Becker B, Goldman ML. Systemic effects of epinephrine applied topically to the eye. Invest Ophthalmol 1966; 5:125 - 9. 16. Grant WM . Toxicology of the Eye . 2d ed. Springfield , IL: Charles C Thomas, 1974; 448 - 54. 17. Anderson JA. SystemiC absorption of topical ocularly applied epinephrine and dipivefrin . Arch Ophthalmol 1980; 98:350-3. 18. Van Buskirk EM. Corneal anesthesia after timolol maleate therapy.Am J Ophthalmol 1979; 88:739-43. 19. McMahon CD, Shaffer RN, Hoskins HD Jr, Hetherington J Jr. Adverse effects experienced of patients taki'rig timoloL Am J Ophthalmol 1979; 88:736 - 8. 20. Van Buskirk EM. Adverse reactions from Timolol adminisiration. Beta-adrenoceptor antagonism during anesthesia for coronary artery surgery. Ophthalmology 1980; 87:447-50. 21 . Manners JM, Walters FJ. Beta-adrenoreceptor blockade and anaesthesia. Anaesthesia 1979; 34:3 - 9. 22. Haimann MH, Phelps CD. Prophylactic timolol for the prevention of high intraocular pressure after cataract extraction. A randomized prospective double-blind trial. Ophthalmology 1981; 88:233-8. 23. Epstein DL, Grant WM . Carbonic anhydrase inhibitor side effects. Serum chemical analysis. Arch Ophthalmol 1977; 95: 1378 -82. 24. Anderson CJ, Kaufman PL, Sturm RJ. Toxicity of combined therapy with carbonic anhydrase inhibitors and aspirin. Am J Ophthalmol 1978; 86:516- 9.
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