Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

acute or chronic impairment of pulmonary function.The patient should be monitored carefully for the development of progressive ocular lesions, especially of the neovascular type. Some suggest that the static nature of this condition indicates that, in the absence of ongoing intravenous drug use, close follow-up may not be necessary. Proliferative retinopathy can be treated with the use of argon laser photocoagulation, and vitreal hemorrhage may require vitrectomy.

Patients with microtalc retinopathy should be managed with annual threshold visual field testing and fundus photography. If other risk factors for glaucoma exist, affected patients may require prophylactic topical ocular hypotensive therapy to prevent progressive visual field loss.

DRUGS AFFECTING THE OPTIC NERVE

Drug toxicity must always be considered in the differential diagnosis of optic neuropathy. A careful history should attempt to uncover any prescribed or self-admin- istered drugs that may have been taken in the past or present. There has been speculation that maternal drug use during pregnancy may lead to optic nerve hypoplasia. Drugs reported to cause this condition include phenytoin, quinine, alcohol, and cocaine. Other drugs known or reported to cause significant optic nerve disease are listed in Table 35-12.The most important of these drugs, ethambutol, chloramphenicol, and amiodarone, are addressed in the following sections; newer drugs such as the PDE-5 inhibitors and drugs implicated in intracranial hypertension and drug-induced systemic lupus are addressed as well.

Ethambutol

Introduced in 1961 for the treatment of tuberculosis, ethambutol supplanted para-aminosalicylic acid for the initial treatment and retreatment of tuberculosis.

Clinical Signs and Symptoms

Ethambutol is well recognized to cause ocular symptoms of reduced visual acuity, changes in color vision, and visual field loss. Ocular toxicity can appear as early as several weeks after initial therapy, but the onset of ocular complications usually occurs several months after therapy has begun. Although various forms of optic neuritis have been described, the primary ocular manifestation of ethambutol toxicity is retrobulbar neuritis.This can occur in several forms (Table 35-13). The most common form involves loss of visual acuity associated with a central or paracentral scotoma and color vision disturbances and is caused by compromise of the central optic nerve fibers. Less commonly, ethambutol can affect the peripheral optic nerve fibers, causing defects in the peripheral visual field. Finally, in rare cases ethambutol can cause visible retinal manifestations, including hyperemia and swelling of the

Table 35-12

Drugs That Can Affect the Optic Nerve

optic disc, flame-shaped hemorrhages on the optic disc and in the retina, and macular edema.After several weeks, these signs can be followed by primary optic atrophy.

Color vision deficiencies are probably the most sensitive indicator of early ethambutol optic neuropathy and can occur even before visual acuity and visual fields are affected. Sometimes, contrast sensitivity can be affected before either visual acuity or color vision becomes impaired.

Table 35-13

Characteristics of Optic Neuropathy Due to Ethambutol Use

Modified from Garrett CR. Optic neuritis in a patient on ethambutol and isoniazid evaluated by visual evoked potentials: case report. Mil Med 1985;150:43–46.

Once changes have occurred in visual acuity, visual field, or color vision, these functional changes may continue to deteriorate even after ethambutol has been discontinued. More often, however, there is recovery of pretreatment visual acuity and visual field several months or years after discontinuation of the drug.The degree of recovery depends largely on the extent to which ethambutol has compromised optic nerve function. If the ocular toxicity is not recognized early, the drug can cause permanent loss of vision, especially in older patients.

Considerable evidence indicates that ocular toxicity associated with ethambutol therapy is dose related. It is now recognized that ethambutol rarely induces ocular changes at a dosage of 15 to 20 mg/kg of body weight daily, and this has led to the current recommendation that ethambutol dosages should not generally exceed 15 mg/kg of body weight daily. Some practitioners give the drug in dosages of 25 mg/kg daily for a period not exceeding 2 months, followed by a maintenance dosage of 15 mg/kg daily, and this has been shown to cause virtually no ocular complications. It should be noted that another antituberculosis drug, isoniazid, has also been reported to cause optic neuritis; however, the reports on this drug are far fewer, and neuropathy does not appear to occur in a dose-dependent manner.

Etiology

Although the mechanism by which ethambutol causes retrobulbar neuritis is largely unknown, it has been suggested that ethambutol may affect the amacrine and bipolar cells of the retina, because color vision can be affected without altering visual acuity. The drug may affect mitochondrial metabolism in the optic nerve by chelating copper, or the drug-induced vision loss may be mediated through an excitotoxic pathway involving glutamate. Renal impairment can also play a role by permitting high plasma drug levels to accumulate, which may contribute to the development of optic neuropathy.

Management

It is important for patients beginning treatment with ethambutol to have a baseline examination and frequent monitoring of visual acuity, visual fields, color vision (Farnsworth Panel D-15), and fundus appearance. Because it is rare for ocular toxicity to occur with dosages as low as 15 mg/kg daily, patients taking such dosages can be monitored every 3 to 6 months, including daily home monitoring of vision. Patients with renal insufficiency, however, should be monitored monthly because they have an impaired ability to excrete the drug and therefore may be at increased risk for developing ocular changes. Because there is some evidence that patients with lower plasma zinc levels have a higher incidence of optic neuropathy, these patients should also be examined more frequently.

Color vision and visual fields are usually more sensitive indicators of early optic neuropathy than is visual acuity

testing. The desaturated Panel D-15 test or the Farnsworth-Munsell l00-hue test can detect subtle redgreen or blue-yellow color vision changes associated with early ethambutol toxicity. Visual field studies using static threshold techniques aid in detecting early visual field abnormalities. Several authors have recommended use of visual evoked potentials for the routine monitoring of patients taking ethambutol. This procedure has been effective in detecting subclinical optic nerve disease that can precede changes in visual acuity and color vision.

Ethambutol therapy must be discontinued in patients who develop reduced visual acuity, color vision deficiency, or visual field defects characteristic of optic neuropathy. Symptoms of peripheral neuropathy may indicate early ethambutol toxicity and should serve as a warning sign of impending optic neuropathy. Thus, the ethambutol dosage in patients encountering peripheral neuropathy should be reduced to prevent the development of ocular toxicity. If discontinuation of drug therapy alone does not result in improvement of visual function, consideration can be given to treatment with hydroxocobalamin, which may help with recovery of visual acuity. Although the mechanism of action of hydroxocobalamin in the treatment of ethambutol-induced optic neuropathy is elusive, this vitamin may act by neutralizing the chelating action of ethambutol on the optic nerve.

Chloramphenicol

Chloramphenicol is used for the treatment of typhoid fever, bacterial meningitis, and certain anaerobic infections such as in the treatment of cystic fibrosis in children.

Clinical Signs and Symptoms

Characteristics of most cases of chloramphenicol-associated optic neuritis are severe bilateral reduction of visual acuity ranging from 20/100 to 5/400 with dense central scotomata. Although there may be no fundus changes (retrobulbar neuritis), the optic discs are usually edematous and hyperemic, the retinal veins are engorged and tortuous, and hemorrhages are often seen in the peripapillary area. Optic atrophy is a late sign. Peripheral neuritis characterized by numbness and cramps of the feet often precedes the visual complaints by 1 to 2 weeks and may therefore serve as an early warning sign of impending ocular toxicity.

Visual impairment associated with chloramphenicol therapy usually recovers after the drug is discontinued, but pretreatment visual acuity is often not regained and visual field defects may persist. Some patients may tolerate further prolonged treatment with chloramphenicol without recurrent optic neuritis, and, occasionally, patients can demonstrate improvement of visual function despite continued therapy.

Most cases of optic neuritis associated with chloramphenicol therapy have occurred in children with cystic fibrosis who were treated with large daily dosages of the

drug, from 1 to 6 g daily. Although visual symptoms can occur as early as 10 days after beginning therapy, ocular toxicity commonly occurs after several months or years of treatment, with optic neuritis being considered a dose-dependent OADR.

Etiology

The precise mechanism by which chloramphenicol produces optic neuritis is unknown.Although the view is not substantiated, several authors have proposed that chloramphenicol may induce optic neuropathy by causing a vitamin deficiency. Genetic factors may be involved, and it has also been hypothesized that chloramphenicol may be biotransformed into degradation products that are potentially toxic to the optic nerve.

Histopathologic studies have found bilateral optic atrophy with primary involvement of the papillomacular bundle, loss of the retinal ganglion cells, and gliosis of the nerve fiber layer. The presence of peripheral visual field defects in some patients is evidence that there is also involvement of the peripheral portion of the visual pathway.

Management

Patients who are to receive long-term chloramphenicol therapy should be given a comprehensive baseline examination consisting of visual acuity testing, visual field testing, color vision testing, and fundus examination.The risk of optic neuropathy is minimized if the daily dosage of drug is limited to 25 mg/kg of body weight, or less, for a period not exceeding 3 months. Patients or their caregivers should be encouraged to be alert to the development of peripheral neuritis, which might indicate impending loss of vision. Once signs or symptoms of optic neuropathy are detected, promptly discontinue drug therapy in consultation with the prescribing physician. Because the outcome of vitamin therapy is uncertain, the case for administration of megadose vitamins is not compelling.

Amiodarone

Not only is amiodarone well-known to cause corneal toxicity (see Drugs Affecting the Cornea and Crystalline Lens, above), but it also can cause optic neuropathy.

Clinical Signs and Symptoms

Although the precise incidence of amiodarone-induced optic neuropathy is unknown, it has been estimated to occur in approximately 2% of patients. The optic nerve appearance is characterized by disc swelling with or without peripapillary disc hemorrhages. Patients who receive amiodarone may be at increased risk for developing nonarteritic anterior ischemic optic neuropathy (NAION), and the two conditions may have strikingly similar appearances and patients may have similar risk factors (> 50 years of age, high blood pressure and cholesterol, diabetes, smoking, small optic disc cupping).

Optic neuropathy associated with amiodarone is characterized by an insidious onset, slow progression, bilateral vision loss, and long-standing disc swelling that tends to stabilize within months after the medication has been discontinued. In contrast,NAION is characterized by acute unilateral vision loss, and the disc edema resolves over several weeks. In amiodarone-induced optic neuropathy, the disc swelling and hemorrhages tend to persist for several months, whereas in NAION these signs usually resolve more quickly. Once drug therapy is stopped, visual acuity and visual field defects tend to stabilize or improve.

Etiology

A primary lipidosis has been described in human optic nerves affected by amiodarone. One study has shown that intracytoplasmic inclusions may mechanically or biochemically block axoplasmic flow in large optic nerve axons, resulting in optic disc edema and hemorrhage.

Management

Patients should receive a baseline ophthalmic examination before starting therapy with amiodarone and every 6 months thereafter. Amiodarone should be promptly discontinued in the event of optic neuropathy, as long as reasonable medical alternatives exist. These issues must be considered in consultation with the patient’s cardiologist or internist. Other recommendations have suggested that if simultaneous bilateral disc edema presents and tests are negative for arteritic ischemic optic neuropathy and increased intracranial pressure, the drug should be discontinued. However,if unilateral typical NAION occurs in a crowded disc and no other sign of systemic toxicity to amiodarone is noted, then continuation of amiodarone may be considered.

Sildenafil

Although color vision alterations, blurred vision, and light sensitivity are well-known transient OADRs that occur in less than 10% of users of the PDE-5 inhibitors, recent reports of NAION have generated considerable attention. Although NAION did not emerge in clinical trials as a possible OADR, approximately 25 published and unpublished cases have been reported to the National Registry of Drug-Induced Ocular Side Effects, most relating to sildenafil. Patients with many vascular risk factors may be at greatest risk for NAION;however,the risk in the general population may be equivocal or lower. The following factors suggest that there may not be a link between the use of these drugs and NAION:

1.The plasma half-life of sildenafil is 4 hours, and many of the reported events appeared to have occurred after this time frame.

2.The appearance of NAION does not appear to be dose dependent.

3.Dechallenge of the drug shows similar recovery to that of unrelated NAION.

4.No mechanism has been proven to date.There has been one positive rechallenge case report in the literature.

Etiology

Currently, the etiology for NAION with PDE-5 use is controversial. The association has been made with PDE- 5–related blood pressure lowering, exacerbating nocturnal hypotension, considered to be the most important feature in the development and progression of NAION. This may be exacerbated by the over-treatment of hypertension and other factors, increasing the risk of NAION in a previously predisposed patient.

Management

The risk factors for NAION have been reported to be age > 50 years, cardiovascular disease, cigarette smoking, diabetes,hyperlipidemia,hypertension,intraocular surgery, small cup-to-disc ratio, sleep apnea, factor V Leiden mutation, and history of NAION in one eye. Other potential causes include hypotension (especially nocturnal), increased IOP, migraine, and other vasospastic disorders. Therefore it is generally accepted that men with history of a previous NAION or with a number of risk factors, including diabetes, or those on aggressive antihypertensive drugs should be advised about the risk of NAION.

Given the number of prescriptions written for these medications every year, compelling evidence does not yet exist to discourage use of erectile dysfunction agents because of harmful ocular side effects.NAION is considered “possible” by WHO causality classification.

Drug-Induced Intracranial Hypertension

Drug-induced intracranial hypertension (pseudotumor cerebri) is especially of concern because it may be asymptomatic, and therefore patients with this condition may not seek ophthalmic care. However, the general presenting signs and symptoms are the same as for the idiopathic form, including headaches, transient visual obscurations, and bilateral disc edema (papilledema). Opening pressure of cerebrospinal fluid is generally over 200 mm of water (average 320 mm of water). Computed tomography and/or magnetic resonance imaging are normal, as is the content of the cerebrospinal fluid. The only other neurologic defect is possibly diplopia associated with a fourth cranial nerve palsy.The range of measurable visual field defects is great, from no field loss to marked loss, and is likely dependent on the length of time that the optic discs have been swollen and to what degree. Treatment for the idiopathic form generally includes weight loss (where applicable), carbonic anhydrase inhibitors, and occasionally surgery to lower the intracranial pressure.

Intracranial hypertension has been linked to a number of medications (Table 35-14), including corticosteroids (withdrawal), nalidixic acid, nitrofurantoin, danazol, ciprofloxacin, and amiodarone. The main two categories

Table 35-14

Drugs That May Cause Intracranial Hypertension

(Pseudotumor Cerebri)

of drugs include the tetracyclines and their derivatives, minocycline and doxycycline, and the retinoids, from vitamin A to synthetic derivatives such as isotretinoin (Accutane), etretinate, and retinoin.

Tetracyclines

The onset of symptoms may be hours to days of beginning tetracycline treatment, though it is usually seen months from initiation. Minocycline, a semisynthetic tetracycline, has been associated as a cause or precipitating factor in numerous cases. Symptoms have been found to occur within 8 weeks of starting minocycline therapy in standard dosages, although others have not manifested the condition until over a year of therapy. Although most patients are symptomatic and are diagnosed promptly, others have no symptoms and may have optic disc edema long before a diagnosis is made. After drug withdrawal and resolution of the elevated intracranial pressure, some patients may be left with residual optic disc swelling or pallor and visual field abnormalities. The association between intracranial hypertension and doxycycline is the least well established, although it has been seen in patients taking this drug for malaria prophylaxis. This decreased frequency of this serious OADR may be due to a decreased propensity for doxycycline to produce increased intracranial pressure, or it may reflect less frequent prescription of this agent over minocycline.

Because patients can be asymptomatic, periodic ophthalmoscopic examination is warranted for patients on long-term therapy with tetracycline, minocycline, or doxycycline.

Etiology

The mechanism of minocycline-induced intracranial hypertension may be similar to that postulated for the tetracyclines, which has been shown to be related to reduced cerebrospinal fluid absorption due to an effect

on cyclic adenosine monophosphate in the arachnoid villi. Because minocycline is more lipid soluble than tetracycline, it is capable of crossing the blood–brain barrier more effectively and therefore may show more of a tendency to intracranial hypertension than tetracycline.

Management

Patients who are taking a retinoid, especially in combination with a tetracycline, should be carefully counseled to seek evaluation in the event of the development of blurred vision (static or transient), double vision, and/or headaches.These patients should have been counseled to avoid vitamin A. Discontinuation of treatment usually permits resolution of the raised intracranial pressure and disc edema, but other interventions may be undertaken if warranted.

Retinoids

The retinoids are used to treat dermatologic conditions such as severe nodular acne and psoriasis. Although isotretinoin (Accutane) has been documented in many more case studies than the tetracyclines to cause “certain” intracranial hypertension, other retinoids have not been included in this classification until recently.This designation has been changed from “possible”to “certain” recently as a close temporal relationship has been shown (mean, 2.3 months) to development of the condition (more than 80 cases of positive dechallenge and 6 cases of positive rechallenge have been documented) and because isotretinoin belongs to a class of agents known to cause intracranial hypertension. However, the number of reported cases has decreased in recent years likely due to awareness of this potentially serious adverse effect.

The use of systemic tetracyclines in combination with the retinoid may lead to a higher risk of intracranial hypertension. Factors including obesity have been noted

in a number of the few cases of this condition and may therefore further complicate the diagnosis.

Etiology

The mechanism of how retinoids cause intracranial hypertension is unclear; however, isotretinoin is thought to both increase the secretions from and impede the absorption by the arachnoid villi.

DRUG-INDUCED LUPUS

ERYTHEMATOSUS

Drug-induced lupus erythematosus has been recognized as a condition similar in presentation to idiopathic systemic lupus erythematosus, although the demographics of patients who develop this disease are somewhat different, including older age and equal gender distribution. Some clinical features differ, and the presentation in druginduced lupus erythematosus tends to be milder than in systemic lupus erythematosus. Systemic lupus erythematosus is a relapsing and remitting autoimmune disorder characterized by a wide spectrum of multisystem involvement. The diagnosis is often complicated and often takes years to establish. Box 35-6 lists many of the retinal vascular, neuroophthalmic, and anterior segment manifestations of systemic lupus erythematosus. In terms of drug-induced lupus, the onset is variable, reported to be as soon as 1 month but as late as 12 years after drug initiation. Clinical presentation may be somewhat different from systemic lupus erythematosus, with fever, arthralgias, pleuritis, pericarditis, mild leukopenia, thrombocytopenia, anemia, and elevated erythrocyte sedimentation rate but not malar rash, alopecia, discoid lesions, and photosensitivity.

More than 80 drugs have been associated with druginduced lupus erythematosus, including procainamide, hydralazine, isoniazid, and minocycline (Box 35-7).

HERBAL AGENTS AND NUTRITIONAL SUPPLEMENTS

Alternative therapies for human ailments and diseases are a rapidly growing segment of health care. Many are used specifically for ocular diseases (approximately 60 products), whereas others have potential ocular adverse drug effects.

Canthaxanthin, a carotenoid used as a food coloring and tanning agent, has been shown to cause a “certain” dose-related adverse effect consisting of deposition of crystals in the macular region that are slowly reversible on discontinuation.

Chamomile is considered to be a “probable” OADR, causing severe conjunctivitis when applied around the eyes. Interestingly, there are ocular “indications” for this herbal product, which include treatment of styes, inflammation, and epiphora. Echinacea purpurea is used to treat the common cold and other disorders but has been shown to cause“possible”conjunctivitis and eye irritation when applied topically.

Jimson weed is a form of Datura that can have relatively high concentrations of antimuscarinic agents and therefore is considered to be “certain” to cause pupillary dilation.

Ginkgo biloba is used widely for a number of disorders, including peripheral occlusive arterial disease, dementia, tinnitus, asthma, angina, and tonsillitis. Hemorrhage has been seen with this agent, both in the eye (spontaneous hyphema is considered “possible,” whereas retinal hemorrhages are considered “probable”) and in the brain (subarachnoid hemorrhage, subdural hematoma) and therefore should be used with caution in patients already using blood-thinning agents such as warfarin (Coumadin) and aspirin.

Licorice has been shown to have anti-inflammatory and antiplatelet effects. Large doses of this agent have

been linked to migrainous-like events considered to be a “possible” OADR. It also can cause seriously low potassium levels and digitalis toxicity if allowed to interact with diuretics and cardiac glycosides.

Niacin has been used for its triglyceride and cholesterollowering effects, but a “certain”association has been made to cystoid macular edema. Blurred vision is considered “probable” with this agent. Other associations include dry eyes, discoloration of the eyelids, eyelid edema, loss of brow and lash hair, and superficial punctate keratitis.

Excessive use of vitamin A can result in ocular dryness, loss of lashes, night blindness, and even intracranial hypertension, the latter of which is similar to that occurring with the other forms of vitamin A such as isotretinoin, approved for the treatment of cystic acne. With large doses, increased intracranial pressure is considered “certain.”

DETECTION AND PREVENTION

OF ADVERSE REACTIONS

Ophthalmic practitioners must protect the well-being of their patients by detecting signs and symptoms of drug toxicities so that appropriate action can be taken to prevent or minimize serious ocular consequences. The detection process begins with the initial patient interview, during which a detailed drug history may reveal use of medications, herbals, nutritional supplements, and recreational agents with potential ocular side effects. A careful history is especially important in elderly patients, who typically use more medications than do younger individuals. Although most patients over age 60 years regularly take several medications, many patients are unable to identify the drugs they take. This emphasizes the importance of patient education regarding prescribed and self-administered medications.