Table 3-3: Possible adverse ocular effects secondary to systemic drugs.

Table 3-4: Possible adverse systemic effects of topical ocular medications.

Table 3-5: Possible adverse ocular effects of topical ocular medications.

SYSTEMIC SIDE EFFECTS OF TIMOLOL

One example of a topical ocular drug with serious systemic side effects is timolol. Timolol by topical ocular administration is the most commonly used antiglaucoma medication in the world and has been associated with severe-even fatal-reactions. Plasma drug concentrations sufficient to cause systemic adrenoceptor blocking effects can occasionally result from topical ocular administration. When topical ocular timolol is administered in infants, blood levels are often more than six times what minimum therapeutic levels would be if the drug were given orally. If the lacrimal outflow system is functioning, an estimated 80% of a timolol eye drop is absorbed from the nasal mucosa and passes almost directly into the vascular system. This is called the first-order pass effect and is true for all drugs that can be easily absorbed through mucosal tissue in the head. The venous drainage is to the right atrium (first pass), and this blood containing the drug is pumped back to various target organs before returning to the left atrium (second pass). This blood containing the drug then reaches the liver or kidney, where it is detoxified. Therefore, a small amount applied to the nasal mucosa can result in therapeutic blood levels, whereas if given orally its first pass includes absorption via the gastrointestinal tract and then the liver, where 80-90% is detoxified before reaching the right atrium. In the United States, approximately 8% of the white population, 24% of blacks, and 1% of those of Japanese and Chinese genetic origin lack the cytochrome P450 enzyme (CYP2D6) that metabolizes timolol. Therefore, some groups are at higher risk of developing systemic side effects.

Cardiopulmonary histories should be taken for candidates of beta-blocker glaucoma therapy. Pulmonary function studies should be considered in patients with bronchoconstrictive disease, and electrocardiograms should be ordered on selected patients with cardiac disease. Specifically, the precautions set forth in the package insert should be heeded carefully. Patients with known bronchial asthma, chronic respiratory or cardiovascular disease, or sinus bradycardia may need screening before using timolol. The drug should be used with caution in patients receiving other systemic beta-blocking agents.

WAYS TO DIMINISH SYSTEMIC SIDE EFFECTS

One important principle in avoiding systemic side effects from topical ophthalmic medications is to prevent overdosing. The physician should prescribe the lowest concentration of medication that will be therapeutically effective. Only 1 drop of medication is needed at each dosage, since the volume the conjunctival sac can hold is much less than 1 drop.

The proper method of topical administration of ophthalmic medication is as follows:

1. Position the patient with head tilted back.

2. Grasp the lower eyelid below the lashes and gently pull the lid away from the eye (Figure 3-1).

3. Instill 1 drop of medication into the inferior cul-de-sac nearest the involved area, taking care that the tip of the medication bottle does not touch the lashes or eyelids, thus avoiding contamination (Figure 3-2).

4. To deepen the inferior cul-de-sac, the lower eyelid should then be gently lifted upward to make contact with the upper lid as the eye looks down (Figure 3-3).

5. The eyelids should be kept closed for 3 minutes to prevent blinking, which pumps the drug into the nose and increases systemic absorption. The patient may be shown how to obstruct the lacrimal drainage system with firm pressure over the inner corner of the closed eyelids, and this may even be more important than lid closure (Figure 3-4).

6. Excess medication in the medial canthus should be blotted away before pressure is released or the eyelids opened. The patient receiving multiple topical medications should wait 10 minutes between doses so that the first drug will not be washed out of the eye by the second.

NATIONAL REGISTRY OF DRUG-INDUCED OCULAR SIDE EFFECTS

The National Registry of Drug-Induced Ocular Side Effects is a clearinghouse of drug information on ocular toxicology. The principle underlying its establishment is the assumption that the suspicions of practicing clinicians regarding possible ocular toxicity of drugs can be pooled to increase the database and decrease the lag time before recognition of adverse responses. Physicians who wish to report suspected adverse drug reactions or would like to receive references pertaining to the data in Tables 3-3, 3-4 and 3-5 should call or write the Casey Eye Institute, Oregon Health Sciences University, 3375 S.W. Terwilliger Blvd., Portland, OR 97201; phone: 503-494-5686.

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