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Published on 1 July 2004

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Adverse drug reactions in ophthalmology

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Bettine CP Polak
MD PhD
Professor of Ophthalmology
Ophthalmology Department
VU Medical Centre
Amsterdam
The Netherlands
E:bcp.polak@vumc.nl

Eyedrops are a specialised pharmaceutical formulation intended to produce a concentration of the active drug in ocular structures; a lower dose can be used in eyedrops than would be necessary to obtain the same effect by systemic administration. Eighty to ninety percent of the drug present in an eyedrop diffuses into the general circulation and may thus exert systemic effects, even at low concentrations. The lacrimal pump is the essential route of diffusion from an eyedrop into the systemic circulation, through active cellular absorption in the lacrimal secretory pathways. The active ingredient avoids the first-pass effect and reaches its site of action directly, after absorption by the mucosa of the nose and the throat, resulting in increased bioavailability. Thus, detoxification by the liver is avoided, which can lead to life-threatening side-effects. However, this form of treatment is generally very well tolerated, considering the immense volume of eyedrops prescribed by ophthalmologists each day.

Simultaneous administration of other medicines can reinforce both activity and side-effects of ophthalmologic preparations and the additional agents. On the other hand, systemic medication may cause serious side-effects threatening visual acuity. Oculotoxic medicines do not cause visual symptoms initially, and additional examinations are necessary to diagnose ocular damage at an early stage.
 
Diagnostic and therapeutic ophthalmic drugs

Anti- infective, antiseptic and antiallergic drugs
Allergic reactions may occur, but the incidence is low compared with the volume of prescriptions. These reactions consist of conjunctivitis, keratitis, palpebral and periocular eczema. Aminoglycosides are considered to be highly sensitising. Modifications of the saprophytic flora by antibiotic treatment and selection of resistant strains may occur.

Antibiotics in eyedrops or ointment can also induce systemic adverse effects. Systemic chloramphenicol, for example, is haematotoxic, but this general toxicity can also occur after administration via the ocular route. Chloramphenicol causes two types of bone marrow toxicity, one that is a dose-related, reversible depression generally affecting erythroid cells, and another, generally fatal, consisting of an idiosyncratic reaction affecting all three cell lines. Ocular chloramphenicol likely causes this idiosyncratic reaction in genetically predisposed patients only.

The overall risk of developing aplastic anaemia after oral administration of chloramphenicol is 1:30,000–1:50,000, which is 13 times greater than the risk of idiopathic aplastic anaemia in the whole population. Since topical administration achieves systemic effects by absorption through the conjunctival membrane or through drainage down the lacrimal duct with eventual absorption from the gastrointestinal tract, the risk may be similar to that after oral administration of the antibiotic. Based upon two case-control studies, a cohort study and a systematic review estimated the incidence of blood dyscrasia due to chloramphenicol eyedrops to be 1:100,000 patients. However, it remains difficult to justify the use of this drug to patients, as other antibiotics for use in the eye are available. In the USA, the Physician’s Desk Reference emphasises, with repeated warnings, the importance of not using ocular chloramphenicol unless there is no alternative, and this warning should be respected on both sides of the Atlantic.

Beta-adrenergic blockers
Dry eyes may develop after the ocular and systemic use of timolol. A reduction in the Schirmer’s test and tear film breakup time may occur.

If topical beta-adrenergic receptor blockers are required for use in asthmatic patients or in patients with a history of bronchial asthma, careful monitoring is essential. With betaxolol, a selective beta-blocking agent, the relative absence of beta-2-adrenergic inhibition reduces the incidence of some systemic effects. Systemic adverse reactions due to beta-blockers may be idiosyncratic and nondose-related, and similar to that observed with any oral beta-adrenergic receptor blocking agent. Cardiovascular, pulmonary and neurological effects may occur. Central nervous system (CNS) complaints (light-headedness, mental depression, weakness, fatigue, acute anxiety, dissociative behaviour, disorientation and memory loss) are most common in patients experiencing the greatest reduction in intraocular pressure. Patients may be unaware of the symptoms until the medication is stopped.

Endocrine effects can occur: hypoglycaemia may develop in insulin-dependent diabetic individuals, with masking of tachycardia (which usually provides a warning). On the other hand, in diabetic patients treated with oral antidiabetics, hyperglycaemia may develop due to a greater decrease in insulin secretion.

Corticosteroids
Topical ocular administration, but also facial application, may give rise to high corticosteroid concentrations in the anterior compartment of the eye. Serious visual loss may occur due to the development of cataracts and/or glaucoma in patients using corticosteroid creams or ointments.

Systemic adverse effects are dose-dependent and do not generally occur after limited topical administration to the eye. Precautions should be taken in administering systemic corticosteroids to patients with diabetes mellitus, congestive heart failure, peptic ulcers, hypertension, glaucoma and tuberculosis.

Mydriatics and cycloplegics
All anticholinergic agents can induce acute closed-angle glaucoma in patients with an anatomical predisposition. They can also cause photophobia and disturbances in accommodation, leading to difficulties in reading and driving.

The unwanted peripheral effects of all atropine-like drugs include flushing of the skin, dryness of the mucous membranes with fever, tachycardia, decreased salivary secretion and dryness of the mouth, drying up of the gastrointestinal secretions and decreased gastric acidity, decreased muscle tone in the gut and constipation. Bladder tone and frequency of micturition are decreased, and acute urinary retention is a risk, especially in older men. Nasal, bronchial and lacrimal secretions are decreased. CNS effects include confusion, excitement, hallucinations, sedation and tachypnoea. These complications essentially occur in children and in the elderly; they are dose-dependent, although there is a certain degree of individual susceptibility.

Sympathomimetics
Sympathomimetics are used to produce mydriasis for ophthalmoscopic examination. Mydriasis is not maximal (as is the case with anticholinergic mydriatics), but, especially in younger patients, sympathomimetic mydriasis is effective and causes little or no disturbance of accommodation. Sympathomimetic agents are also used as vasoconstrictors in surgical procedures, for symptomatic relief of allergic reactions and hyperaemia of the conjunctiva, and to lower intraocular pressure in open-angle glaucoma.

Conjunctival irritation and a feeling of ocular burning can occur, as well as reactive conjunctival vasodilatation following the initial vasoconstriction. Cystoid macular oedema has been reported to occur, especially in aphakic or pseudophakic eyes. Headache, blood pressure elevation, extrasystoles, tachycardia, faintness and cerebrovascular accidents have been reported. The 10% solution has sometimes caused extremely severe cardiovascular complications, including myocardial infarction. In many countries, phenylephrine is available in a nonprescription concentration of 0.12% for use as an ocular decongestant. Phenylephrine should be used cautiously in newborn infants, especially premature neonates, the elderly and patients with hypertension, coronary heart disease, aneurysms and diabetic autonomic neuropathy. There is also a clear interaction problem: patients on medication with pressor effects, such as monoamine oxidase inhibitors, tricyclic antidepressant and anticholinergic agents, should be monitored closely if phenylephrine is to be used.

Parasympathomimetics
The expected and inevitable effects of parasympathomimetic eyedrops are more intense in myopic and young patients, causing miosis, aggravation of the myopia, blurred vision and periorbital pain. The commonest systemic effects are headache and periorbital pain. Symptoms of vagal stimulation may be observed, with nausea, vomiting, sweating, hypersalivation, lacrimation, hypotension, bradycardia, bronchial constriction, respiratory failure and nightmares. These reactions may occur during treatment for acute closed-angle glaucoma, requiring frequent instillation of pilocarpine.

Local anaesthetics
Topical anaesthetics may alter lacrimation and tear film stability and cause direct epithelial toxicity. Endothelial toxicity may also occur. Furthermore, both the agent and its vehicle may serve as a reservoir of microbial contamination, with potential for infection. Benoxinate in combination with sodium fluorescein, in particular, may be easily contaminated, especially with Pseudomonas aeruginosa. Anaesthetics also reduce the reflex secretion of tears, allowing topically applied agents to be in contact with the epithelial surface for a prolonged period of time. Both idiosyncratic and allergic reactions may occur. Stevens– Johnson syndrome may be caused or exacerbated by topical anaesthetics.

Ocular adverse effects due to systemic medication
Ocular adverse reactions due to systemic medication may be reversible or irreversible, and sometimes vision-threatening. Patients who are chronically treated with potentially oculotoxic agents, such as chloroquine, prednisone, ethambutol, amiodarone and vigabatrin, should be advised to consult an ophthalmologist at regular intervals, even when these medications are prescribed in “safe dosages”.  Potential oculotoxic medicines do not initially cause visual symptoms, and additional ocular examinations are necessary to diagnose ocular damage at an early, sometimes reversible phase.

Discussion

Many diagnostic ophthalmologic preparations are applied not only by medical doctors, but also by non-medically trained staff, such as optometrists, orthoptists, opticians, nurses, ophthalmic photographers and other people involved in eyecare.

The importance of enquiring into the use of drugs cannot be overemphasised. Often, patients do not regard eyedrops as medication and omit this information in their medical history, with complaints being sometimes attributed to the ocular medication when the adverse reactions disappear after withdrawal of the eyedrops!

The systemic effects exerted by eyedrops are most pronounced in the case of agonists and antagonists of the autonomic nervous system. Beta-blockers in eyedrops can cause bronchospasm, heart failure, syncope and psychiatric disorders, especially at high doses and with nonselective beta-blockers, although these adverse reactions are usually related to failure to comply with the prescribing precautions. Alpha-adrenergic agonists, which exert dose-dependent effects, can induce hypertensive crises or angina pectoris attacks. Except in patients at special risk (children under the age of 30 months and the elderly), parasympathomimetics cause few systemic adverse effects. In the very young and the very old, atropinic eyedrops carry a risk of cardiovascular collapse and neuropsychiatric disturbances. Problems may also develop with anti-infectives, antiseptics (allergic reactions, sensibilisation and bacterial resistance) and contact lens products (allergic reactions, contamination).

Risk factors
The elderly, especially those who are treated by more than one doctor and in cases of polypharmacy (patients with chronic obstructive pulmonary disease, diabetes mellitus or heart failure) are particularly likely to make errors in the administration of ophthalmic medications, resulting in overdoses and adverse toxic effects or underdosage with inadequately controlled glaucoma or inadequately treated dry eyes. This may be reflected in impaired memory, mental confusion, impaired vision, hearing and mobility or a combination of these factors. It would be wise practice to assess both compliance and the administration technique of elderly patients to ensure the safe and effective use of ophthalmic preparations.

Conclusion
A few simple rules can reduce the incidence of adverse effects and improve compliance:

  • Respect the contraindications and precautions applicable to the drug.
  • Start with the lowest possible doses, especially in children and the elderly.
  • Never administer more than 30ml of an eyedrop and never more than one eyedrop at any time, and administer it only into the lower temporal corner of the eye, with the patient looking up. A second eyedrop should always be applied a few minutes after administration of the first eyedrop to avoid spoilage of the first drop by the second one. Eye ointment should be applied after administration of eyedrops: this formulation will stay in contact with conjunctiva and cornea for a longer time and will generally diffuse in lower amounts through the nasal paths.
  • Close, or ask the patient to close, the medial canthus with the finger after instillation of the eyedrop: this precaution will inhibit diffusion into the lacrimal system and into the general circulation.


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