Symposium on Drugs f f f

INTERIM REPORT: NATIONAL REGISTRY OF POSSIBLE DRUG-INDUCED OCULAR SIDE EFFECTS

FREDERICK T. FRAUNFELDER, MD PORTLAND, OREGON

Recent data concerning 1%, 2.5%, and 10% topical ocular phenylephrine, topi­cal ocular local anesthetics, carbonic anhydrase inhibitors, diazepam, liquid high-protein diets, sodium fluoride gel, naproxen, and thiabendazole are re­viewed. Clinicians are encouraged to report possible adverse drug reactions to the National Registry of Drug-In­duced Ocular Side Effects, which has been moved to the Department of Oph­thalmology, University of Oregon Health Sciences Center, Portland, OR 97201.

INTRODUCTION

THE intent of this paper is to re­view data that will be, or has re­cently been published, guided in part by trends within the National Registry for Drug-Induced Ocular Side Effects. A detailed analysis within the Registry will not be forthcoming until the Registry has been in existence for four to five years so that an adequate data base is available. Only if a par­ticular trend becomes evident, such as with 10% topical ocular phenyl­ephrine,! will data be released earlier. In this way, it is hoped that the Registry can protect the clini­cian and the pharmaceutical in­dustry as well as patients from

Submitted for publication Oct 6, 1978.

From the Department of Ophthalmology, Univer­sity of Oregon Health Sciences Center, Portland.

Reprint requests to University of Oregon Health Sciences Center, 3181 SW Sam J ackson Rd, Port­land, OR 97201 (Dr Fraunfelder).

prema ture conclusions or disclo­sures.

PHENYLEPHRINE

As recently reported,l there are 33 cases of possible adverse effects related to the use of topical ocular 10% phenylephrine. These cases in­cluded 15 myocardial infarctions, 11 of which were terminal. There were seven additional cases requir­ing cardiopulmonary resuscitation. These side effects were primarily in elderly patients with pre-existing cardiac disease. Recently a case, highly publicized in the lay press, occurred in Toronto, Canada. A 49-year-old woman died after re­ceiving topical ocular phenylephrine, and the cause of death was intra­cranial bleeding from the rupture of an aneurysm of the anterior com­municating artery. She was on pro­pranolol (Inderal), and it was pos­tulated that the systemic absorp­tion of the phenylephrine with a subsequent increase in blood pres­sure was more serious than usual, since reflex vasodilation was blocked or prevented by the propranolol. A number of additional cases of topi­cal ocular phenylephrine with re­lated serious cardiovascular prob­lems have been reported to the Registry.

Kenneth A. Batko, MD, from the Ophthalmology Department at the University of Wisconsin School of Medicine in Madison, reported to

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SYMPOSIUM ON DRUGS 127

the Registry two significant eleva­tions of systemic blood pressure precipitated by 1 ()to and 2.5% phenyl­ephrine eyedrops. The patients in both cases were on clonidine hydro­chloride for hypertension, which was abruptly stopped two days preoperatively. Dr Batko states that if this drug is not tapered off over two to four days, a rebound hyper­tension may result. Atropine sul­fate was also given intramuscularly preoperatively to an already sensi­tized patient, so that the blood pressure elevation that occurred may have been more severe than normal. Phenylephrine preparations should be used judiciously in pa­tients who have preexisting hyper­tension and are on drugs that may potentiate the pressure effects of phenylephrine. A recent report2

concludes that 10% topical ocular phenylephrine can be hazardous if given preoperatively to patients with long-standing insulin-depen­dent diabetes, or in hypertensive patients receIvmg reserpine or guanethidine. However, M.R. Coff­man, MD, et al of the Aerospace Medical Division, Brooks Air Force Base, Tex, report that topical oc­ular mydriacyl or 10% phenyl­ephrine, when used in healthy, normal, young or middle-aged per­sons, had little or no cardiovascular effect (unpublished data, 1977).

Based on data in the Registry and the package inserts, the follow­ing guidelines for the clinical use of 10% topical ocular phenylephrine are suggested.

(1) Ten percent topical ocular phenylephrine should be used with caution in patients with known cardiac disease, hypertension, an­eurysm, long-standing insulin-de­pendent diabetes, or advanced ar­teriosclerosis.

(2) Only 2.5% or weaker solutions should be used in infants, the de­bilitated, and the elderly.

(3) The practice of using 10% topical ocular phenylephrine to ir­rigate the lacrimal system, in con­junctival pledgets or by subcon­junctival injection, should be dis­couraged.

(4) Only one application of this solution should be allowed per hour to each eye.

(5) This drug is contraindicated in patients taking monamine oxi­dase inhibitors or tricyclic anti­depressants, or if the patient has been given large doses of systemic atropine. It should be used with caution in patients on antihyper­tensive medication, since the pres­sor effects of phenylephrine are potentiated when it is given in combination with, or with cessa­tion of, the medication.

TOPICAL OCULAR LOCAL ANESTHETICS

There have been 36 reports of possible adverse effects related to the application of topical ocular local anesthetics submitted to the Registry of Drug-Induced Ocular Side Effects by ophthalmologists in the last two years.3 While a few drops of topical ocular local anes­thesia rarely give rise to significant adverse reactions, acute adverse effects that require immediate med­ical management occasionally oc­cur. These include excessive ocular cardiac reflex, fainting, convul­sions, personality changes, and marked apprehension. While these factors are suggestive of sudden

128 FREDERICK T. FRAUNFELDER OPHTH AAO

cortical stimulation caused by a drug effect, at these low dosages they may also be an idiosyncratic or exaggerated emotional response. The possibility of emotional factors playing a significant role in many of these adverse responses needs to be considered. The clinician should use caution in applying topical ocular medication to the markedly apprehensive or the emotionally agitated patient. Irregardless, med­ical management of these reactions is often essential. There are, of course, no indications for long-term use of any topical ocular local anes­thetic, since secondary complica­tions are inevitable.4

CARBONIC ANHYDRASE INHIBITORS

Carbonic anhydrase inhibitors are under increasing scrutiny as to drug interactions and adverse ef­fects. Paul Kaufman, MD, from the University of Wisconsin School of Medicine at Madison, has found that patients receiving high dos­ages of aspirin, as for rheumatoid arthritis or osteoarthritis, show increased nonionized salicylate in the blood stream if placed on car­bonic anhydrase inhibitors. Non­ionized salicylate penetrates the CNS more easily than does the ionized form. Therefore, the car­bonic anhydrase inhibitors increase the risk of salicylate intoxication in patients who are already on high aspirin dosages. This has oc­curred with both acetazolamide and methazolamide. Acetazolamide also accelerates the development of osteomalacia in patients who are on anticonvulsant therapy such as Dilantin.5

Generalized malaise, weight loss, fatigue, and depression may be as-

sociated with this group of drugs. There is increasing evidence that these agents may also cause meta­bolic acidosis and decreased libido.6

The ophthalmologist should be aware of the potential for these agents to aggravate metabolic acidosis. Pa­tients who are on known CO2 re­tainers, if placed on carbonic an­hydrase inhibitors, can in rare in­stances increase their acidosis to critical levels. There have been re­ports to the Registry of patients recently placed on carbonic anhy­drase inhibitors by their ophthal­mologist going into acidotic coma. Metabolic acidosis can be caused by any process that decreases pul­monary ventilation, such as CNS disease, a neuromuscular disorder, or chest wall injury. Pneumonia, emphysema, and chronic bronchitis also cause acidosis. This type of patient should be watched carefully if carbonic anhydrase inhibitors are necessary for ocular care. David Epstein, MD, at the Massachusetts Eye and Ear Infirmary, would ap­preciate case reports of patients with this type of drug-related prob­lem.

A recent paper by Wallace et aF reports 40 cases of decreased libido caused by carbonic anhydrase in­hibitors. Many of these patients were taken off the drug and re­challenged with the return of this adverse effect. This adverse effect may be caused by the generalized fatigue and malaise associated with carbonic anhydrase use. During the past 12 months there have been two cases of anaphylactic reaction associated with the taking of ace­tazolamide reported to the Registry.

It is recognized that aplastic anemIa and various other blood

V{)LUMt~ Hfi .IANlIAHY m7!1 SYMPOSIUM ON DRUGS 129

dyscrasias can occur with the use of acetazolamide, but there have been no reports of these occurring with methazolamide. However, a report from the University of Cali­fornia at Davis and a number of cases from Johns Hopkins Univer­sity School of Medicine now sug­gest that various blood dyscrasias may occur with this agent as well. Recently, there has been a report of kidney stones associated with methazolamide.8 Data of Epstein and Dahlen from the Massachu­setts Eye and Ear Infirmary (Arch Ophthalmol, to be published) show a lower incidence of kidney stones with methazolamide as compared with acetazolamide because of in­creased urinary citrate excretion with methazolamide. This is pri­marily true only at higher dosage levels, since at lower dosage levels citrate excretion is similar with both agents.

DIAZEPAM

The most common prescription drug in the world is probably diaze­pam (Valium). There is increasing evidence that an allergic conjuncti­vitis can be associated with the initial use of this agent.9 The symp­toms usually occur approximately 30 minutes after taking the drug, often reaching a peak within four hours. This may last for some time, but in most cases it subsides within 24 to 48 hours. The symptoms in­clude ocular burning, itching, and a possible ocular foreign body sensa­tion. This appears to be completely reversible on cessation of the drug or, in many cases, even if the drug is continued. There is also the ques­tion of photosensitivity with this agent and of a decrease in the electro-oculogram (EOG).lo

LIQUID HIGH-PROTEIN DIETS

There has been a marked interest in liquid high-protein diets for weight reduction. Because of ECG abnormalities and cardiac compli­cations, the indiscriminate use of these diets has, however, been cur­tailed. ll ,12 During the height of this fad, reports of adverse ocular re­sponses came to the Registry. The first was from Ken Richardson, MD, of Anchorage, Ala, who re­ported a patient on a liquid high­protein diet who had a sudden onset of 2 diopters of induced hy­peropia. Physicians who specialize in weight reduction with liquid high-protein diets claim that this is not an unusual effect in some pa­tients. It usually occurs within the first two weeks of the diet, and returns to normal within one month after onset, even when the diet is continued. The hyperopia is most likely the result of an osmotic effect on the lens of the eye. Ophthal­mologists should be a ware of this complication, since they may un­necessarily prescribe glasses for pa­tients who are following this pro­gram of weight reduction. Liquid high-protein diets such as Pro­Digest are still commercially avail­able.

SODIUM FLUORIDE GEL

Recently two investigators, H.N. Bernstein, MD, from Rockville, Md, and M.R. Coffman, MD, from Brooks Air Force Base, Tex, have inde­pendently noted pigmentary macu­lopathy in children following dental treatments with sodium fluoride gel. Any cases suggestive of this relationship can be reported to the Registry or directly to either of these physicians.

130 FREDERICK T. FRAUNFELDER OPHTH AAO

NAPROXEN

An agent of increasing popularity is naproxen (Naproxyn). This non­steroidal, anti-inflammatory agent is primarily used in treating the signs and symptoms of rheumatoid arthritis. The Registry has received a number of reports of visual dis­turbances in patients on this drug. These include macular edema, lens changes, abnormal accommodation, lacrimal gland disorders, decrease in color vision, diplopia, and pos­sible optic neuritis. While it is well documented that this drug can cause jaundice and urticarial-type responses, few ocular findings are clearly defined.

THIABENDAZOLE

Austin Fink, MD, of New York described, at the American Oph­thalmological Society meeting, a severe, long-lasting sicca syndrome, caused by thiabendazole (Mintezol), an antihelmintic agent used in a mother and daughter.13 This syn­drome occurred after only one or two doses and lasted for many months. The clinical picture in­cluded keratoconjunctivitis sicca, xerostomia, cholangiostatic hepati­tis, and possible pancreatic dys­function. This is apparently an im­munologic response, and the drug possibly acted as a hapten. These, as with practolol,14 may be the first two instances of an oral medication affecting the periocular tissue by this type of mechanism.

REFERENCES

1. Fraunfelder FT, Scafidi AF: Possible adverse effects from topical ocular 10% phenylephrine. Am J Ophthalmol 85:447-453, 1978.

2. Kim JM, Stevenson CE, Mathewson HS: Hypertensive reactions to phenylephrine eyedrops in patients with sympathetic de­nervation. Am J Ophthalmol 85:862-868, 1978.

3. Fraunfelder FT, Sharp JD, Silver BE: Possible adverse effects from topical ocular anesthetics, in Prof John Harris, Jubilee edition or Documenta Ophthalmologic Pro­ceedings Series. The Netherlands, Junk Publishing Co, 1978, pp 341-345.

4. Epstein DL, Paton D: Keratitis from misuse of corneal anesthetics. N Engl J Med 279:396-399, 1968.

5. Mallette LE: Acetazolamide-accelerated anticonvulsant osteomalacia. Arch Intern Med 137:1013-1017, 1977.

6. Epstein DL, Grant WM: Carbonic an­hydrase inhibitor side effects. Arch Ophthal­mol 95:1378-1382, 1977.

7. Wallace TR, Fraunfelder FT, Epstein DL, et al: Decreased libido: A side effect of carbonic anhydrase inhibitors. Ann Oph­thalmol, to be published.

8. Shields MB, Simmons RJ: Urinary calculus during methazolamide therapy. Am J Ophthalmol 81:622-624, 1976.

9. Lutz EG: Allergic conjunctivitis due to diazepam. Am J Psychiatr 132:548, 1975.

10. Muller W, Haase E: Questions con­cerning the effect of diazepam in the EOG. Albrecht von Graefes Arch Klin Ophthalmol 197:159-164, 1975.

11. Singh BN, Gaarder TD, Kanegae T, et al: Liquid protein diets and torsade pointes. JAMA 240:115-119, 1978.

12. Brown JM, Yetter JF, Spicer MJ, et al: Cardiac complications of protein-sparing modified fasting. JAMA 240:120-145, 1978.

13. Fink AI, Cutler SS, MacKay CJ: Sicca syndrome with cholangiostatic hepatitis as a complication of thiabendazole administra­tion. Trans Am Ophthalmol Soc 76, 1978, to be published.

14. Wright PG, Fraunfelder FT: Practolol induced oculomucocutaneous syndrome, in Leopold IH, Burns RP (eds): Ocular Ther­apy, vol 9. New York, John Wiley & Sons, 1976, pp 97-118.