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Drugs used in ocular treatment
B.C.P. Polak
49 Drugs used in ocular treatment Ophthalmic drugs topically applied have significant absorption, which may result in widespread adverse side effects. As previously in this series, ophthalmic drugs will for the sake of convenience, if somewhat arbitrarily, be classified into two main groups: diagnostic and therapeutic agents.
DIAGNOSTIC OPHTHALMIC DRUGS CYCLOPLEGICS AND MYDRIATICS
Antichofinergic agents Atropine (SED-9, 772; SEDA-5, 295; SEDA-6, 412; SEDA-7, 355) The effect of atropine on the central nervous system is due to its anticholinergic central action affecting stimulation of the medulla and higher cerebral centers. In toxic dosages this accounts for irritability, hallucinations, tachypnea and the probable thermoregulatory center dysfunction in homeostatic body temperature control. Children are especially sensitive. 31 children aged from 1 to 14 years w h o had been given atropine eye drops to measure refraction presented with the following side effects: increased temperature (9/31), dry red skin (8/31), reddened eye (3/31) and periorbital dermatitis (2/31) after single (22/31) or repeated (9/31) administration of atropine. In the epicutaneous test with atropine 1% (readings after 24, 48 and 72 hours) not a single child showed an allergic or toxic reaction. The rarity of allergy after administration of atropine eye drops is emphasized by the fact that periorbital dermatitis was observed in only 2 cases (1R). Recently atropine toxicity has been reported in identical twins.
Side Effects of DrugsAnnual 8
M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1984 ISBN 0 444 90339 9 $0.80 per article per page (tranmetional system) $0.20 per article per page (licensing system)
Both infants were 5-month-old white males, born after a full-term, uncomplicated pregnancy. Because of developmental delay and parental eoneem about their vision they were referred to an ophthalmologist. Approximately 30 minutes after instillation of one drop of 0.5% atropine sulfate solution into each eye the day prior to exarnination, both children developed irritability and fever prompting the parents to bring them to the emergency room. Both infants showed a free maeulopapular rash, warm dry skin, distended abdomen with decreased bowel sounds and dilated unreactive pupils. There was a temperature of 390C and 41"C respectively, a pulse rate of 200 and 180, a respiratory rate of 80 and a blood pressure of 106/30 and 94/44 respectively. After treatment with 0.5 mg of physostigmine intravenously the children became more alert; flushing and abdominal distension decreased, as well as pulse rate and temperature. Funduscopic examination revealed moderate optic nerve hypoplasia in one eye and marked optic nerve hypoplasia in the other eye of both children, with bilateral pale optic discs
(2C).
Optic nerve hypoplasia or atrophy and atropine toxicity or hypersensitivity have not been reported as occurring together before, and the association here may be purely coincidental. Careful instruction to parents about dosage schedules should be routinely provided, so that improper usage is minimized. Parents should also be informed about the toxic effects and be alerted to the signs and symptoms to watch for when using atropine eye drops.
THERAPEUTIC OPHTHALMIC DRUGS
Chofinergie agents Acetyleholine (SED-9, 776) Hypotension and mild bradycardia have been reported as systemic reactions following ophthalmologic use of acetylcholine. Recently a 83-year-old man, scheduled for cataract extraction under local anesthesia, developed bradycardia, hypotension, flushing, sweating and breathing difficulty after instillation of acetyl-
438
B.C.P. Polak
choline chloride solution into the anterior chamber following the removal of the lens
treatment. Most side effects are usually experienced after administration of the 0.5% solution.
Antiglaucomatous drugs. Sympathomimetic agents
Bilateral glaucoma simplex was diagnosed in a 70-year-old male patient; who had been suffering from moderate asthma since adolescence. Topical treatment with timolol in ophthalmic solution of 0.25% twice a day was initiated. During the following year the patient noticed that his dyspnea became consistently worse for 1-2 hours following application of the eyedrops. He was advised to discontinue timolol therapy, and his asthma subsequently ameliorated. In a provocation test, carried out 2 months later with the patient's informed consent, forced expiratory volume in the first second was reduced by 56% and bradycardia was induced after application of 2 drops of timolol (7e).
(3c).
Dipivefrine (dipivalylepinephrine; DPE; Propine) (SED-9, 780; SEDA-5, 429) Potlzntial advantages of this epinephrine pro-drug include increased duration of action, increased bioavailability, increased potency, increased stability and a decreased incidence of side effects. The effect on pupil size is minor and insignificant, no objective sightthreatening effects are observed, and central visual acuity and visual fields are not affected after application of 0.1% solution of dipivalylepinephrine into the eye. However, minor sporadic and transient burning or stinging sensations may be observed (4c). In aphakic glaucomatous eyes undergoing topical epinephrine therapy, cystoid macular edema may occur, which is completely reversed by discontinuing therapy. A similar untoward reaction was seen in a glaucomatous phakic eye after treatment with dipivefrine hydrochloride (Propine) (5c).
Beta-blockers Beta-blockers have a brief local anesthetic effect when applied to the cornea in drop form. With the electronic optical esthesiometer accurate, reproducible sensibility measurements are now possible. In a randomized study the local anesthetic side effects of the beta-blockers metipranolol and timolol were found to be comparable and dosage-dependent (6r).
Timolol (Timoptol; Tirnoptic) (SED-9, 779; SEDA-5, 425; SEDA-7, 458,) Systemic adverse effects of timolol ophthalmic solution include bradycardia, palpitations, hypotension, syncope, cardiac failure, sudden death, bronchospasm (asthma attacks), gastrointestinal distress (nausea and diarrhea), impotence, disorientation, anxiety, loss of memory, sedation, depression and fatigue. Ocular adverse reactions may be observed as burning sensations and dryness of eyes. The incidence of side effects in two prospective studies was about 20%, and some 40% of these had to discontinue timolol
The timolol 0.25% solution has so far been considered less prone to result in systemic beta-blockage. Even this concentration may, however, cause severe bronchoconstriction and bradycardia in patients with chronic airflow obstruction, and it represents a potential risk to patients suffering from cardiac failure or chronic obstructive pulmonary disease. The results of a 12-month blind randomized trial comparing the intraocular pressure lowering effect of timolol 0.25% with timolol 0.5% revealed little difference in effectiveness (8c). Timolol 0.25% should be the initial treatment of choice, and if this proves ineffective (either early or late), then alternative or additional therapy should be considered in preference to the common clinical practice of changing the concentration of timolol to 0.5%. However, one has to be aware of the existence and importance of long-term drift (or loss of control w i t h continuous long-term topical timolol). An additional ocular side effect of timolol is a marked (e.g. 40%) reduction in the magnitude of the light-insensitive component of the standing potential of the eye. This corresponds to the "dark trough" of the electro-oculogram (EOG) and might be attributed to the effect of timolol on the ciliary epithelium which contributes, as does the retinal pigment epithelium, to the standing potential. The other component of the EOG, the light rise, remains unaffected. The result would be a significant increase in the value of the EOG ratio (or Arden index) (9R).
Drugs used in ocular treatment
Antibiotics (SEDA-5, 428) Chloramphenicol Marrow aplasia from ophthalmic chloramphenicol has been reported. A 73-year-old woman died of aplastic anemia less than 2 months after undergoing cataract extraction and beginning topical therapy with chloramphenicol. The first signs of pancytopenia began within 1 month, and the pattern of aplastic anemia was associated with an idiosyncratic response to chloramphenicol (10R). Chloramphenicol is the agent most frequently associated with drug-induced aplastic anemia, but physicians faced with blood dyscrasias may fail to ask patients if they have ever received this agent topically in an ocular medication, and especially because significant hematopoietic reactions may occur many months after the drug is discontinued, the patient may not even remember having undergone topical ophthalmic treatment. The hematologic risk associated with topically administered ocular ehloramphenicol may therefore in fact be higher than the 4 earlier reported cases seem to indicate (SEDA-5, 428). Recently 2 patients were seen in The Netherlands with marrow aplasia associated with ocular chloramphenicol therapy: one patient died because of thrombocytopenia, the other recovered from marrow aplasia (unpublished data). Antivirals Ara-A (adenine arabinoside, vidarabine) and
acycloguanosine (aciclovir, Zovirax) (SEDA7, 459) In a double-blind clinical trialof3% aciclovir and 3% adenine arabinoside in 93 patients with herpetic corneal ulceration, patients treated with aciclovir healed more rapidly than those treated with Ara-A. 1 patient on aciclovir experienced an allergic response, which could also have been caused
439 by the atropine drops being administered concurrently; 1 patient on Ara-A complained of gritty feeling of the eye after application of the ointment (1 le). A combination of 3% aciclovir and 0.01% betamethasone eye drops was found to be effective in the management of disciform keratitis in a double-blind at-random treatment of 40 patients. The combination therapy showed a faster rate of healing, while other clinical parameters also improved more favourably. 3 patients showed mild transient punctate keratopathy (12e).
Newly developed therapeutic ophthalmic agents Silicone oil The use of silicone oil injection in the treatment of retinal detachment with massive periretinal proliferation has been found to induce macular attachment in a high percentage of treated patients when followed up over more than 5 years. There is no difference in the success rate between phakic and aphakic eyes. The filling of the vitreous cavity with silicone oil may, however, cause changes in refraction (13R). Complications attributed to intraocular silicone oil include cataract, keratopathy and glaucoma. Of 103 pbakic eyes, 73% developed lens opacities after 1 to 3 years. 87% after 3 to 5 years, and 90% after 5 years or longer. Few of these cataracts were sufficiently dense to require surgery, and those that did were managed with intra- or extracapsular lens extraction without difficulty. Keratopathy developed in 9 eyes, and in 2 of these penetrating keratoplasty was undertaken successfully. In 16 eyes persistently raised intraocular pressure (greater than 25 mm Hg) occurred; although silicone oil was found to be present in the chamber angle on gonioscopy in 33% of the cases, in only 6 eyes raised lOP was associated with oil in the anterior chamber (14r).
REFERENCES 1. GallasehG, Schlitz R, G•tz ML, Kraus-Mackiw E (1982) Atropinebewirkungen: pharmakologische, allergische, pseudoaUergische oder toxisehe Reaktionen? Klin. MonatsbL Augenheilkd., 181, 96. 2. Sanitato J J, Burke MJ (1983) Atropine toxicity in identical twins Ann. Ophthalmol., 15, 380. 3. Gombos GM (1982) Systemic reactions following intraocular acetylcholine instillation. Ann.
Ophthalmol., 15, 529. 4. Fajardo RV, Noche RR (1982) Ocular reactions of Filippino eyes to topical dipivalyl epinephrine. Philipp. J. Ophthalmol., 14, 8. 5. Mehelas TJ, Kollarits CR, Martin WG (1982) Cystoid macular edema presumably induced by dipivefrin hydrochloride (Propine). Am. J. OphthalmoL, 94, 682. 6. Draeger J, Schneider B, Winter R (1983) Die
440 lokalaniisthetische Wirkung yon Metipranolol im Vergleich zu Timolol. Klin. Monatsbl. Augenheilkd., 182, 210. 7. Ostergaard Laursen S, Bjermm P (1982) Timolol eyedrop-induced severe bronehospasm. Acta Med. 8cand., 211,505. 8. Mills KB (1983) Blind randomised non-crossover long-term trial comparing topical timolol 0.25% with timolol 0.5% in the treatment of simple chronic glaucoma. Br. J. Ophthalmol., 67, 216. 9. Levine L (1982) Clinical implications of reported timolol-induced side effects. Am. J. Optom. Physiol. Opt., .$9, 523. 10. Fraunfelder FT and Bagby GC (1982) Fatal aplastic anemia following topical administration of ophthalmic chloramphenieol. Am. J. OphthaL,
B. C.P. Polak 93, 356. 11. Young BJ, Patterson A, Ravenscroft T (1982) A randomised double-blind clinical trial of acyclovir (Zovirax) and adenine-arabinoside in herpes simplex corneal ulceration. Br. J. OphthalmoL, 66, 361. 12. Collum LMT, Logan P, Ravenscroft T (1983) Acyelovir (Zovirax) in herpetic disciform keratitis. Br. J. Ophthalrnol., 67, 115. 13. Launay F, Laroehe G, Limon S (1982) Modifications de la r6fracfion apr6s injections intraoeulaire$ de silicone liquide. J. Ft. OphtalmoL, 5,417. 14. Leaver PK, Lean JS (1982) Results and complications of silicone oil injection in the treatment of massive periretinal proliferation. Int. Ophthalmol., 5, 86.
49 Drugs used in ocular treatment Ophthalmic drugs topically applied have significant absorption, which may result in widespread adverse side effects. As previously in this series, ophthalmic drugs will for the sake of convenience, if somewhat arbitrarily, be classified into two main groups: diagnostic and therapeutic agents.
DIAGNOSTIC OPHTHALMIC DRUGS CYCLOPLEGICS AND MYDRIATICS
Antichofinergic agents Atropine (SED-9, 772; SEDA-5, 295; SEDA-6, 412; SEDA-7, 355) The effect of atropine on the central nervous system is due to its anticholinergic central action affecting stimulation of the medulla and higher cerebral centers. In toxic dosages this accounts for irritability, hallucinations, tachypnea and the probable thermoregulatory center dysfunction in homeostatic body temperature control. Children are especially sensitive. 31 children aged from 1 to 14 years w h o had been given atropine eye drops to measure refraction presented with the following side effects: increased temperature (9/31), dry red skin (8/31), reddened eye (3/31) and periorbital dermatitis (2/31) after single (22/31) or repeated (9/31) administration of atropine. In the epicutaneous test with atropine 1% (readings after 24, 48 and 72 hours) not a single child showed an allergic or toxic reaction. The rarity of allergy after administration of atropine eye drops is emphasized by the fact that periorbital dermatitis was observed in only 2 cases (1R). Recently atropine toxicity has been reported in identical twins.
Side Effects of DrugsAnnual 8
M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1984 ISBN 0 444 90339 9 $0.80 per article per page (tranmetional system) $0.20 per article per page (licensing system)
Both infants were 5-month-old white males, born after a full-term, uncomplicated pregnancy. Because of developmental delay and parental eoneem about their vision they were referred to an ophthalmologist. Approximately 30 minutes after instillation of one drop of 0.5% atropine sulfate solution into each eye the day prior to exarnination, both children developed irritability and fever prompting the parents to bring them to the emergency room. Both infants showed a free maeulopapular rash, warm dry skin, distended abdomen with decreased bowel sounds and dilated unreactive pupils. There was a temperature of 390C and 41"C respectively, a pulse rate of 200 and 180, a respiratory rate of 80 and a blood pressure of 106/30 and 94/44 respectively. After treatment with 0.5 mg of physostigmine intravenously the children became more alert; flushing and abdominal distension decreased, as well as pulse rate and temperature. Funduscopic examination revealed moderate optic nerve hypoplasia in one eye and marked optic nerve hypoplasia in the other eye of both children, with bilateral pale optic discs
(2C).
Optic nerve hypoplasia or atrophy and atropine toxicity or hypersensitivity have not been reported as occurring together before, and the association here may be purely coincidental. Careful instruction to parents about dosage schedules should be routinely provided, so that improper usage is minimized. Parents should also be informed about the toxic effects and be alerted to the signs and symptoms to watch for when using atropine eye drops.
THERAPEUTIC OPHTHALMIC DRUGS
Chofinergie agents Acetyleholine (SED-9, 776) Hypotension and mild bradycardia have been reported as systemic reactions following ophthalmologic use of acetylcholine. Recently a 83-year-old man, scheduled for cataract extraction under local anesthesia, developed bradycardia, hypotension, flushing, sweating and breathing difficulty after instillation of acetyl-
438
B.C.P. Polak
choline chloride solution into the anterior chamber following the removal of the lens
treatment. Most side effects are usually experienced after administration of the 0.5% solution.
Antiglaucomatous drugs. Sympathomimetic agents
Bilateral glaucoma simplex was diagnosed in a 70-year-old male patient; who had been suffering from moderate asthma since adolescence. Topical treatment with timolol in ophthalmic solution of 0.25% twice a day was initiated. During the following year the patient noticed that his dyspnea became consistently worse for 1-2 hours following application of the eyedrops. He was advised to discontinue timolol therapy, and his asthma subsequently ameliorated. In a provocation test, carried out 2 months later with the patient's informed consent, forced expiratory volume in the first second was reduced by 56% and bradycardia was induced after application of 2 drops of timolol (7e).
(3c).
Dipivefrine (dipivalylepinephrine; DPE; Propine) (SED-9, 780; SEDA-5, 429) Potlzntial advantages of this epinephrine pro-drug include increased duration of action, increased bioavailability, increased potency, increased stability and a decreased incidence of side effects. The effect on pupil size is minor and insignificant, no objective sightthreatening effects are observed, and central visual acuity and visual fields are not affected after application of 0.1% solution of dipivalylepinephrine into the eye. However, minor sporadic and transient burning or stinging sensations may be observed (4c). In aphakic glaucomatous eyes undergoing topical epinephrine therapy, cystoid macular edema may occur, which is completely reversed by discontinuing therapy. A similar untoward reaction was seen in a glaucomatous phakic eye after treatment with dipivefrine hydrochloride (Propine) (5c).
Beta-blockers Beta-blockers have a brief local anesthetic effect when applied to the cornea in drop form. With the electronic optical esthesiometer accurate, reproducible sensibility measurements are now possible. In a randomized study the local anesthetic side effects of the beta-blockers metipranolol and timolol were found to be comparable and dosage-dependent (6r).
Timolol (Timoptol; Tirnoptic) (SED-9, 779; SEDA-5, 425; SEDA-7, 458,) Systemic adverse effects of timolol ophthalmic solution include bradycardia, palpitations, hypotension, syncope, cardiac failure, sudden death, bronchospasm (asthma attacks), gastrointestinal distress (nausea and diarrhea), impotence, disorientation, anxiety, loss of memory, sedation, depression and fatigue. Ocular adverse reactions may be observed as burning sensations and dryness of eyes. The incidence of side effects in two prospective studies was about 20%, and some 40% of these had to discontinue timolol
The timolol 0.25% solution has so far been considered less prone to result in systemic beta-blockage. Even this concentration may, however, cause severe bronchoconstriction and bradycardia in patients with chronic airflow obstruction, and it represents a potential risk to patients suffering from cardiac failure or chronic obstructive pulmonary disease. The results of a 12-month blind randomized trial comparing the intraocular pressure lowering effect of timolol 0.25% with timolol 0.5% revealed little difference in effectiveness (8c). Timolol 0.25% should be the initial treatment of choice, and if this proves ineffective (either early or late), then alternative or additional therapy should be considered in preference to the common clinical practice of changing the concentration of timolol to 0.5%. However, one has to be aware of the existence and importance of long-term drift (or loss of control w i t h continuous long-term topical timolol). An additional ocular side effect of timolol is a marked (e.g. 40%) reduction in the magnitude of the light-insensitive component of the standing potential of the eye. This corresponds to the "dark trough" of the electro-oculogram (EOG) and might be attributed to the effect of timolol on the ciliary epithelium which contributes, as does the retinal pigment epithelium, to the standing potential. The other component of the EOG, the light rise, remains unaffected. The result would be a significant increase in the value of the EOG ratio (or Arden index) (9R).
Drugs used in ocular treatment
Antibiotics (SEDA-5, 428) Chloramphenicol Marrow aplasia from ophthalmic chloramphenicol has been reported. A 73-year-old woman died of aplastic anemia less than 2 months after undergoing cataract extraction and beginning topical therapy with chloramphenicol. The first signs of pancytopenia began within 1 month, and the pattern of aplastic anemia was associated with an idiosyncratic response to chloramphenicol (10R). Chloramphenicol is the agent most frequently associated with drug-induced aplastic anemia, but physicians faced with blood dyscrasias may fail to ask patients if they have ever received this agent topically in an ocular medication, and especially because significant hematopoietic reactions may occur many months after the drug is discontinued, the patient may not even remember having undergone topical ophthalmic treatment. The hematologic risk associated with topically administered ocular ehloramphenicol may therefore in fact be higher than the 4 earlier reported cases seem to indicate (SEDA-5, 428). Recently 2 patients were seen in The Netherlands with marrow aplasia associated with ocular chloramphenicol therapy: one patient died because of thrombocytopenia, the other recovered from marrow aplasia (unpublished data). Antivirals Ara-A (adenine arabinoside, vidarabine) and
acycloguanosine (aciclovir, Zovirax) (SEDA7, 459) In a double-blind clinical trialof3% aciclovir and 3% adenine arabinoside in 93 patients with herpetic corneal ulceration, patients treated with aciclovir healed more rapidly than those treated with Ara-A. 1 patient on aciclovir experienced an allergic response, which could also have been caused
439 by the atropine drops being administered concurrently; 1 patient on Ara-A complained of gritty feeling of the eye after application of the ointment (1 le). A combination of 3% aciclovir and 0.01% betamethasone eye drops was found to be effective in the management of disciform keratitis in a double-blind at-random treatment of 40 patients. The combination therapy showed a faster rate of healing, while other clinical parameters also improved more favourably. 3 patients showed mild transient punctate keratopathy (12e).
Newly developed therapeutic ophthalmic agents Silicone oil The use of silicone oil injection in the treatment of retinal detachment with massive periretinal proliferation has been found to induce macular attachment in a high percentage of treated patients when followed up over more than 5 years. There is no difference in the success rate between phakic and aphakic eyes. The filling of the vitreous cavity with silicone oil may, however, cause changes in refraction (13R). Complications attributed to intraocular silicone oil include cataract, keratopathy and glaucoma. Of 103 pbakic eyes, 73% developed lens opacities after 1 to 3 years. 87% after 3 to 5 years, and 90% after 5 years or longer. Few of these cataracts were sufficiently dense to require surgery, and those that did were managed with intra- or extracapsular lens extraction without difficulty. Keratopathy developed in 9 eyes, and in 2 of these penetrating keratoplasty was undertaken successfully. In 16 eyes persistently raised intraocular pressure (greater than 25 mm Hg) occurred; although silicone oil was found to be present in the chamber angle on gonioscopy in 33% of the cases, in only 6 eyes raised lOP was associated with oil in the anterior chamber (14r).
REFERENCES 1. GallasehG, Schlitz R, G•tz ML, Kraus-Mackiw E (1982) Atropinebewirkungen: pharmakologische, allergische, pseudoaUergische oder toxisehe Reaktionen? Klin. MonatsbL Augenheilkd., 181, 96. 2. Sanitato J J, Burke MJ (1983) Atropine toxicity in identical twins Ann. Ophthalmol., 15, 380. 3. Gombos GM (1982) Systemic reactions following intraocular acetylcholine instillation. Ann.
Ophthalmol., 15, 529. 4. Fajardo RV, Noche RR (1982) Ocular reactions of Filippino eyes to topical dipivalyl epinephrine. Philipp. J. Ophthalmol., 14, 8. 5. Mehelas TJ, Kollarits CR, Martin WG (1982) Cystoid macular edema presumably induced by dipivefrin hydrochloride (Propine). Am. J. OphthalmoL, 94, 682. 6. Draeger J, Schneider B, Winter R (1983) Die
440 lokalaniisthetische Wirkung yon Metipranolol im Vergleich zu Timolol. Klin. Monatsbl. Augenheilkd., 182, 210. 7. Ostergaard Laursen S, Bjermm P (1982) Timolol eyedrop-induced severe bronehospasm. Acta Med. 8cand., 211,505. 8. Mills KB (1983) Blind randomised non-crossover long-term trial comparing topical timolol 0.25% with timolol 0.5% in the treatment of simple chronic glaucoma. Br. J. Ophthalmol., 67, 216. 9. Levine L (1982) Clinical implications of reported timolol-induced side effects. Am. J. Optom. Physiol. Opt., .$9, 523. 10. Fraunfelder FT and Bagby GC (1982) Fatal aplastic anemia following topical administration of ophthalmic chloramphenieol. Am. J. OphthaL,
B. C.P. Polak 93, 356. 11. Young BJ, Patterson A, Ravenscroft T (1982) A randomised double-blind clinical trial of acyclovir (Zovirax) and adenine-arabinoside in herpes simplex corneal ulceration. Br. J. OphthalmoL, 66, 361. 12. Collum LMT, Logan P, Ravenscroft T (1983) Acyelovir (Zovirax) in herpetic disciform keratitis. Br. J. Ophthalrnol., 67, 115. 13. Launay F, Laroehe G, Limon S (1982) Modifications de la r6fracfion apr6s injections intraoeulaire$ de silicone liquide. J. Ft. OphtalmoL, 5,417. 14. Leaver PK, Lean JS (1982) Results and complications of silicone oil injection in the treatment of massive periretinal proliferation. Int. Ophthalmol., 5, 86.