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

quinidine, streptokinase, and sulfonamides, have a “possible” causal relationship to uveitis.The treatment of uveitis depends on the likelihood that the reaction is causal to the drug therapy. Drug-induced uveitis is almost always reversible within weeks of discontinuation of the drug and treatment of the inflammation. Some OADRs related to the episclera, sclera, and uvea are listed in Table 35-7.

administration, or even to the relative activity of the disease being treated.

Management

Anterior segment inflammation may be treated without cessation of the bisphosphonate, but deeper inflammation of the uvea and sclera may require discontinuation of the systemic therapy.

Bisphosphonates

This class of drugs is used to treat hypercalcemia in osteolytic bone cancer and metastasis in breast cancer, multiple myeloma, and Paget disease of the bone. It is used more frequently to inhibit bone resorption in postmenopausal women and therefore has the potential for widespread effects despite a relatively low risk of ADRs.

The main drugs in this category shown to cause OADRs have been pamidronate,alendronic acid,and risedronate, although etidronate and sodium clodronate have also been implicated to a lesser degree. As of 2003, 438 ocular adverse reactions had been reported to the National Registry. These OADRs were considered to be “certain” by the WHO classification and included inflammation of the conjunctiva, episclera, sclera, and uvea as well as reduced vision, eye pain, and photophobia. Scleritis is the most vision-threatening ADR of this class of drugs and occurred within 48 hours in 82% of the 17 patients. “Possible” ADRs associated with these drugs included cranial nerve palsy and retrobulbar neuritis (see Appendix 35-1).

Etiology

These drugs have been shown to stimulate the release of cytokines (interleukin-1 and -6) that may stimulate lymphocytic proliferation and enhance immune complex disease. It is not clear why these particular tissues of the eye are targeted because the degree of inflammation seems unrelated to the dose of the drug, the route of

Rifabutin

Rifabutin is a semisynthetic rifamycin used to treat patients infected with human immunodeficiency virus as prophylaxis against Mycobacterium avium complex infections. Rifampin antibodies have been found to circulate and adhere to cells, so that when introduced to rifampin, the antigen–antibody complexes induce an inflammatory reaction. Rifabutin-associated uveitis has been reported in patients who were also taking fluconazole, which may have increased the bioavailability of rifabutin. Discontinuation of rifabutin and initiation of topical steroid therapy result in clinical improvement. The high prevalence of uveitis with rifabutin (including a large number of bilateral cases), increasing inflammation with dose increases, and improvement on dechallenge and exclusion of other possible causes strongly implicate rifabutin as having a “certain” causality with uveitis.

Prophylactic administration of rifabutin to human immunodeficiency virus–infected children has resulted in non–sight-threatening corneal endothelial deposits. The deposits are bilateral, are initially peripheral, are stellate shaped, are not associated with uveitis, and appear to increase in number with continued administration of rifabutin.

Tamsulosin

Intraoperative floppy iris syndrome (IFIS) was first formally documented in early 2005. It is characterized by a

triad of signs noted during intraocular surgery:(1) a flaccid iris stroma that billows on ocular irrigation, (2) a tendency of the iris to prolapse toward the side-port incisions and the phacoemulsification tip, and (3) progressive intraoperative miosis despite conventional pharmacologic measures to maintain pupillary dilation (cyclopentolate, phenylephrine, and NSAIDs).Though a floppy iris is noted on occasion during cataract surgery, this full syndrome was first documented and associated with systemic administration of the α1a-adrenoceptor antagonist, tamsulosin (Flomax).

The α1a- (and α1d-) selective adrenoceptor antagonist, tamsulosin (Flomax), is used to relax bladder and prostatic smooth muscle to improve urinary flow, usually in the treatment of benign prostatic hypertrophy. Other α1-adrenoceptor antagonists include the following nonsubtype selective agents, which also block α1b receptors: alfuzosin (Uroxatral), doxazosin (Cardura), and terazosin (Hytrin). These agents show more cardiovascular adverse effects and have been used for the treatment of hypertension. Each of these agents is effective in competitive antagonism, causing sympathetically mediated iris dilator relaxation.The prevalence of IFIS has been documented to be 0.7% to 2% of the general population; however, there is a high incidence of benign prostatic hypertrophy and lower urinary tract symptoms in males over age 50 (50%) and even more so for males over age 85 (90%), which suggests that the prevalence reported may be underestimated. IFIS has been strongly associated with tamsulosin, but 45% of eyes of patients taking doxazosin (Cardura) also demonstrate the characteristics of IFIS.

Etiology

Pupillary miosis occurs because tamsulosin blocks the iris dilator muscle, and this constant blockade is postulated to cause a form of disuse atrophy of the dilator smooth muscle. This may explain why some patients no longer taking the drug can still exhibit IFIS. Pupil dilation during cataract surgery is essential not only to visualize the full lens to enable its efficient and total removal, but also to minimize the risk of other complications such as rupture of the posterior capsule and the prevention of tears when iris retraction or stretching becomes necessary. Though poor pupillary dilation is common in other conditions, the pupillary miosis associated with tamsulosin is different in that the pupillary margin remains elastic, such that normal mechanical stretching of the iris is ineffective.

Management

All patients should be screened before intraocular surgery for a history or current use of tamsulosin. Some sources have suggested that this and other α1-antagonists should be withdrawn before surgery, the term of which depends on monitoring of blood pressure and/or recurrence of urinary symptoms. Various interventions have been suggested for IFIS, such as alterations in surgical technique and intracameral injections of various agents (phenylephrine, atropine, and epinephrine).

Etanercept

Etanercept and infliximab are tumor necrosis factor-α antagonists used on their own or in combination with other medications to reduce the pain and swelling associated with rheumatoid, juvenile rheumatoid, and psoriatic arthritis and ankylosing spondylitis. Recent evidence suggests that infliximab may have efficacy in treating ocular inflammation associated with these conditions, as well as Crohn’s disease, and idiopathic scleritis, uveitis, bird-shot retinochoroiditis, and uveitic cystoid macular edema. These medications are administered as biweekly injections and are used to moderate the immune system by blocking the activity of tumor necrosis factor, a substance in the body that causes activation of immune response and plays a significant role in chronic inflammation. Risk of infection is an indication (usually temporary) for discontinuation of injections due to the reduced immune response to eliminate the infectious organism. Reactivation of tuberculosis infection is one adverse effect of its use, and one case of reactivation of tubercu- losis-related chronic unilateral granulomatous panuveitis has been reported in a woman with rheumatoid arthritis. Similarly, some patients on etanercept developed scleritis, new-onset uveitis, and optic neuritis.

There is considerable discussion about whether ocular inflammation is paradoxically a potential adverse event of etanercept in either previously inflamed or previously uninflamed eyes. It is as yet unclear whether etanercept may induce new-onset uveitis or may prevent uveitis, although flares of uveitis have recently been shown to occur less than half as often in tumor necrosis factor- α–treated patients as placebo-treated control subjects. However, it seems clear that, because of a different mechanism of action, infliximab is more effective at treating certain types of ocular inflammation.

Cidofovir

The use of cidofovir is a primary risk factor in the subsequent development of immune recovery uveitis, a relatively new clinical entity introduced with the widespread use of highly active antiretroviral therapy. Patients who have responded to highly active antiretroviral therapy have an increase in CD4+ counts, allowing withdrawal of cytomegalovirus maintenance therapy. Up to 40% of immune-recovered patients may have immune recovery uveitis, which may consist of signs of inflammation such as uveitis, vitritis, macular edema, or epiretinal membrane formation. Eyes with immune recovery uveitis have a high risk of additional morbidity over and above that seen with cytomegalovirus retinitis, with several-fold higher risk of cystoid macular edema and epiretinal membrane. On average, patients developed immune recovery uveitis 3 months after discontinuing anticytomegalovirus therapy. Large cytomegalovirus lesions and use of intravitreal cidofovir are risk factors for immune recovery uveitis.

Ongoing treatment of healed cytomegalovirus retinitis after immune recovery does not appear to protect against the development of immune recovery uveitis.The risk is so significant that some recommend that other antiviral treatments for cytomegalovirus retinitis be substituted for cidofovir.

Tetracyclines

Tetracycline and its derivative, minocycline, are used for control of acne vulgaris. Minocycline therapy can cause a blue-gray discoloration of the sclera. The discoloration usually presents in a 3- to 5-mm band in the paralimbal area or in the temporal sclera within the interpalpebral fissure. Scleral pigmentation is usually associated with various degrees of pigmentary changes elsewhere, such as skin, teeth, and fingernails. Because no scleral biopsy has been performed, the precise nature of the lesions is unknown.The sooner the pigmentary changes are recognized and the drug discontinued, the greater the likelihood of resolution.The pigmentation may slowly resolve over several years, or it may be permanent.

DRUGS AFFECTING THE PUPIL

Pupil size and function can be affected by peripheral autonomic action and by centrally initiated impulses.The iris is an excellent indicator of autonomic activity because of the delicate balance between adrenergic and cholinergic innervation to the iris dilator and iris sphincter muscles, respectively. By acting directly on these muscles, both sympathetic and parasympathetic agents can influence pupil size and activity.

Drugs Causing Mydriasis

Anticholinergics, central nervous system stimulants and depressants, antihistamines, and phenothiazines can all cause mydriasis (Box 35-1).

Anticholinergics

Drugs with anticholinergic effects, such as atropine or related compounds, can cause significant mydriasis.Acute angle-closure glaucoma has been caused by administration of systemic atropine to treat bradycardia during angioplasty for an acute myocardial infarction.The anticholinergic effects of paroxetine, a selective serotonin reuptake inhibitor used as an antidepressant, have also led to angleclosure glaucoma. Nebulized ipratropium bromide, an anticholinergic agent, is often used for the emergency treatment of acute bronchospasm in both adults and children.Mydriasis and angle-closure glaucoma are believed to result from direct inoculation into the eye after leakage of drug from the face mask used for drug delivery.

Scopolamine, a semisynthetic derivative of atropine, is marketed as a transdermal delivery system (Transderm

–

Scop) to prevent motion sickness. The device, which is

Box 35-1 Drugs That Can Cause Mydriasis

or Miosis

placed behind the ear, consists of a 2.5-cm disk containing 1.5 mg of scopolamine in a polymeric gel.Approximately 0.5 mg of drug is released into systemic circulation over a 3-day period. Both mydriasis and reduced pupillary light response can occur when this device is used for several days. Direct contamination by rubbing the eye with the fingers after application of the patch to the skin or during wear can cause the observed pupillary dilation. Mydriasis can also occur when scopolamine is mixed with heroin. In addition to heroin-related central nervous system effects,anticholinergic manifestations include tachycardia, mild hypertension, dilated pupils, dry skin and mucous membranes, and diminished or absent bowel sounds. Similar toxicity can follow use of intranasal cocaine laced with atropine.

Central Nervous System Stimulants

Central nervous system stimulants include agents such as the amphetamines (Dexedrine) and methylphenidate hydrochloride (Ritalin), used to elevate mood, suppress appetite, and control hyperkinetic disorders in children. Other examples include the illegal drugs methamphetamine and cocaine. The mechanism of action of these drugs is to augment actions of the adrenergic nervous system.

High-dose long-term use of amphetamines has been observed to cause mydriasis and decreased pupillary light response. In patients with narrow anterior chamber angles, the mydriasis can precipitate an attack of acute or subacute angle-closure glaucoma.Angle-closure glaucoma can also be associated with intranasal cocaine abuse.The negative pressure generated by sniffing cocaine may allow retrograde ocular delivery via the nasolacrimal duct. Alternatively, cocaine could be absorbed across the nasal mucosa, and the systemically absorbed drug could cause mydriasis and potential angle closure due to the adrenergic agonist properties of the drug.

Central Nervous System Depressants

Central nervous system depressants include the barbiturates, such as phenobarbital, and the antianxiety drugs, including diazepam (Valium), chlordiazepoxide (Librium), oxazepam (Serax), flurazepam hydrochloride (Dalmane), and lorazepam (Ativan). The benzodiazepines, including diazepam, occasionally cause mydriasis, presumably because of their anticholinergic side effects.

Barbiturates have little effect on the pupils. However, in acute or chronic poisoning a sluggish pupillary light reaction is common.

Miscellaneous Drugs Causing Mydriasis

Other drugs with potential to cause mydriasis include the antihistamines and antipsychotic agents. Both classes of drugs have anticholinergic properties. Pupillary dilation has also been observed on exposure to certain plants.The dried pods of the jimson weed (Datura stramonium) are often used for floral arrangements during the winter. Children have been known to consume the “berries,” which contain significant concentrations of belladonna alkaloids. Systemic side effects are those typical of anticholinergic poisoning and include bilaterally dilated pupils.

Drugs Causing Miosis

Opiates such as heroin, morphine, and codeine and anticholinesterase agents can cause miosis (see Box 35-1).

Opiates

Heroin, morphine, and codeine can constrict the pupil. Moreover, the pupillary light response is enhanced. This response appears to be due to action on the central nervous system, possibly on the visceral nucleus of the oculomotor nuclear complex. Note, however, that either heroin or cocaine abuse can be associated with mydriasis if the drug is mixed with scopolamine or atropine.

Anticholinesterase Agents

Systemic absorption of agents that inhibit the cholinesterase enzymes can result in miosis. Such substances are present in most insecticides and many toxic nerve gases.Toxic episodes involving the pupil have occurred in workers in fields being dusted with insecticides from an airplane. The miotic pupils of affected patients may not return to normal until 30 to 45 days after exposure to the toxic agent.

DRUGS AFFECTING EXTRAOCULAR MUSCLES AND EYE MOVEMENTS

Drugs affecting the autonomic nervous system or central vestibular system or causing extrapyramidal effects have been associated with ocular manifestations such as nystagmus, diplopia, extraocular muscle palsy, and oculogyric crisis. Table 35-8 lists drugs that can affect extraocular muscles.

Table 35-8

Drugs That Can Affect Extraocular Muscle Movements

Various classes of drugs have been implicated in causing nystagmus, including salicylates, phenytoin (Dilantin), antihistamines, gold, alcohol, and barbiturates. The anticonvulsant agent carbamazepine has been associated with downbeat nystagmus in a dose-related manner. Many drugs that affect central nervous system activity can result in diplopia. Included are the phenothiazines, antianxiety agents, and antidepressants.

Lithium

The use of lithium in bipolar affective disorder has been associated with various neurologic symptoms, including nystagmus.

Clinical Signs and Symptoms

The patient usually presents with complaints of blurred vision, particularly in lateral gaze. Electrooculogram (EOG) recordings show a jerk nystagmus, present in both primary position and in down-gaze. The nystagmus is usually unaffected by head position, head velocity, or convergence. Saccadic eye movements are clinically normal, serum chemistry analysis is usually normal, and serum lithium levels are within the recommended therapeutic ranges.The nystagmus may not resolve with reduction of drug dosage or cessation of drug use. Prolonged drug withdrawal, up to 6 months or even years, may be necessary to produce improvement.

Management

Because downbeat nystagmus has neurologic significance and may be related to a variety of metabolic or drug-related causes, a careful medical history and communication with the prescribing physician are essential. Patients on long-term lithium therapy should have at least yearly ocular examinations.

Cetirizine

Cetirizine is a potent second-generation H1 receptor antagonist that is effective in the treatment of allergic

rhinitis, chronic urticaria, and pollen-induced asthma. Unlike many traditional antihistamines, it does not cause drowsiness or anticholinergic side effects.Tonic eye and lid elevation with neck hyperextension characterizes oculogyric crisis.Although oculogyric crisis is seen most commonly in association with phenothiazine toxicity, 72 drugs have been reported as possibly causing oculogyric crisis. Nine cases of oculogyric crisis due to cetirizine therapy were reported to the National Registry, with eight occurring in the pediatric age group. Two patients in this series were using other antihistamines that could have caused an additive effect. Dosage ranged from 5 to 10 mg orally, and time to onset of symptoms ranged from 3 to 184 days. Because six cases of oculogyric crisis had positive rechallenge data, the WHO category of the relationship of cetirizine as a cause of oculogyric crisis is “certain.”

Etiology

The etiology is thought to be similar to that seen with phenothiazine toxicity such that an imbalance of dopamine and cholinergic blockade causes the dystonia.

Management

Cessation of the drug causes rapid resolution of the crisis.

Alcohol

Alcohol clearly affects eye movement. Both smooth pursuit movements and saccades are impaired when blood ethanol concentrations reach the range of 60 to 100 mg/dl. There is a direct linear relationship between blood alcohol concentration and a reduction in smoothpursuit movement velocity.At a blood ethanol concentration of 80 mg/dl, the capacity of the eyes to track objects moving across the visual fields is impaired by 25%.

The fact that alcohol can affect eye movement ability has been used to devise a test known as the alcohol gaze nystagmus test. This procedure was developed to augment the traditional field evaluation of suspected drunk drivers by law enforcement officials. The test involves the observation of ocular version movements, end-point nystagmus, and angle of lateral deviation at which the nystagmoid movements begin. When administered and evaluated properly, the test can help to correctly identify approximately 80% of drivers with blood alcohol levels of 0.10% or higher.

DRUGS CAUSING MYOPIA AND ACCOMMODATIVE CHANGES

Numerous reports have described patients with acuteonset of myopia after use of various oral medications or drugs applied as vaginal suppositories or creams. In most cases the amount of drug-induced myopia has been slight, but in some cases myopia exceeding 5.00D has occurred. Commonly prescribed drugs that are

Box 35-2 Drugs That Can Cause Myopia

or Cycloplegia

widely recognized to cause myopia include sulfonamides, diuretics, and carbonic anhydrase inhibitors (Box 35.2). Isotretinoin use has also been associated with acute myopia.The reduction in acuity was reversed on discontinuation of the drug and recurred on subsequent rechallenge. In most instances the myopia is immediate in onset after administration of the drug and subsides within days or weeks after withdrawal of the medication.

Sulfonamides and Diuretics

Clinical Signs and Symptoms

Among the drugs most commonly implicated are the sulfonamides. Two cases of transient myopia associated with oral sulfonamides were described in which there was reduced accommodation, shallow anterior chamber angles, and moderate mydriasis. Chemosis occurred in one case. A 23-year-old woman was described who had 4.00D of increased myopia in one eye and 3.00D of increase in the fellow eye after the use of oral sulfonamides. Vaginal absorption of sulfonamides can also lead to myopia. A patient was reported with 1.00 to 1.50D of myopia after use of a vaginal sulfonamide suppository and another patient with 7.00D of induced myopia after use of a sulfonamide vaginal cream.

Diuretic agents can cause myopia. Transient myopia was associated with perimacular edema apparently caused from the use of 100 mg of hydrochlorothiazide. The drug induced approximately 3.00D of myopia, which resolved within 3 days. Carbonic anhydrase inhibitors are also known to cause myopia.A case of transient myopia associated with acetazolamide was reported, in which there was also narrowing of the anterior chamber angle.

Etiology

In general, transient myopia results from edema of the ciliary body, lenticular edema, or accommodative spasm. Topically administered cholinergic agonists are well

known to cause myopia by stimulating accommodation, but systemically administered cholinergic agents are implicated infrequently as a cause of myopia. Most drugs that cause myopia are thought to do so by causing a forward displacement of the lens as a result of allergic ciliary body edema and rotation. Lens thickening and anterior movement with a reduction of the anterior chamber depth is the mechanism of drug-induced transient myopia, with or without choroidal detachment (Figure 35-7). The ciliary body edema, occasionally associated with retinal edema, has led to the speculation that sulfonamideinduced myopia may be related to a hypersensitivity reaction. Choroidal detachment, if present, causes forward displacement of the lens–iris diaphragm, resulting in increased myopia and anterior chamber shallowing, with potential angle-closure glaucoma.

Because carbonic anhydrase inhibitors are sulfonamide derivatives, the mechanism for carbonic anhydrase inhibitor–induced myopia is expected to be similar to that associated with sulfonamides. Indeed, it has been speculated that myopia resulting from acetazolamide use is due to a hypersensitivity reaction that leads to ciliary body edema. The instillation of cycloplegics has little influence on the refractive error, which suggests that the mechanism is unrelated to ciliary spasm.

Management

Patients with well-documented acute myopia should be evaluated carefully to eliminate other causes of the refractive change. Intumescence of the lens associated with nuclear sclerosis is a common cause of increasing myopia and is often associated with somewhat reduced bestcorrected visual acuity. After eliminating these other factors, investigate the patient’s drug therapy as a cause of the myopia by reducing or discontinuing the drug under suspicion.This should be done only in consultation with the patient’s primary physician. When the offending

agent is reduced or discontinued, the refractive error change should subside within several days or several weeks.

Topiramate

Topiramate is an antiepileptic medication also used in an offlabel capacity to treat migraine headaches and bipolar disor- ders.Acute-onset myopia with topiramate use occurs due to a different mechanism than other causes of drug-induced myopia. The lens–iris diaphragm moves forward and the anterior chamber shallows due to choroidal effusion, resulting in acute myopia (up to 8.75D) and angle-closure glaucoma. Management consists of discontinuing the drug, with aggressive use of steroids and IOP-lowering agents.

Drugs With Anticholinergic Effects

Some drugs administered systemically are well known to have mild anticholinergic properties or side effects. These drugs include antianxiety agents, antihistamines, and tricyclic antidepressants.Agents with strong anticholinergic effects include atropine and scopolamine. Although these drugs can dilate the pupil and can cause dry eye symptoms due to the peripheral effects on the parasympathetic nervous system, the cycloplegic effects are encountered less frequently in clinical practice. Sulfadiazine and disopyramide can cause paralysis of accommodation, but the drugs whose association with clinical cycloplegia is most well documented are the phenothiazines.

Transient disturbances of accommodation often occur in patients taking chlorpromazine and other phenothiazines. These effects are most likely due to the anticholinergic properties of the medication and are most pronounced when benztropine mesylate (Cogentin) is administered along with the phenothiazine. The visual symptoms may also be ascribed to reduced tearing and drying of the cornea, which causes blurred vision. In patients with

narrow anterior chamber angles, acute or subacute angleclosure glaucoma secondary to pupil dilation could also contribute to symptoms of blurred vision.

Management

Because the cycloplegic effects are usually transient and related to drug dosage, symptoms of accommodative insufficiency can be managed by prescribing appropriate reading lenses during long-term drug therapy, or in consultation with the patient’s physician, drug dosages may be reduced or the drug discontinued. The cycloplegic effects often abate when the dosage is reduced, and accommodation completely returns to pretreatment levels after drug therapy is discontinued.

DRUGS AFFECTING INTRAOCULAR PRESSURE

Several classes of drugs may alter IOP by influencing either aqueous humor production or outflow (Box 35-3). Others have the potential to affect IOP by narrowing or occluding the angle. Pupillary block occurs only in susceptible individuals (usually small eyes, with hyperopia, steep corneal and lens curvatures, narrow angles, and in certain races) so that increasing IOP associated with the anticholinergic effects of medications affects only these select individuals.

Anticholinergics

Some systemic agents may possess sufficient anticholinergic activity to produce mydriasis and a weak cycloplegic effect.These medications include antimuscarinic drugs,antihistamines, phenothiazines, and tricyclic antidepressants (Table 35-9).

Clinical Signs and Symptoms

Systemic antimuscarinic agents, including atropine and scopolamine, can be administered in doses that could produce mild dilation of the pupil and accommodative paresis.The degree of mydriasis and decreased pupillary reactivity to light provide a clinical measure of antimuscarinic activity. Other commonly used systemic medications with antimuscarinic activity are the H1 receptor antagonists.

Box 35-3 Drugs That Alter Intraocular Pressure

Of the systemic antihistamines, the ethanolamines, including diphenhydramine, have significant antimuscarinic activity. In addition, the antipsychotic agents, particularly the phenothiazines such as thioridazine (Mellaril), have well-documented anticholinergic properties.Therapeutic doses of tricyclic antidepressants, like amitriptyline hydrochloride (Elavil) and imipramine (Tofranil), produce significant anticholinergic actions and thus have the potential for ocular side effects.

Etiology

Systemic agents with anticholinergic effects may result in sufficient mydriasis to produce pupillary block and precipitate acute or subacute angle-closure glaucoma in patients with narrow anterior chamber angles. In addition, the weak cycloplegic effect may be sufficient to increase IOP in some open-angle glaucoma patients. Relaxation of the ciliary muscle may decrease traction on the trabecular meshwork (TM) and increase resistance to aqueous outflow, especially when relatively high doses of medication are used.The risk, however, of elevating IOP is small with systemically administered anticholinergic agents in normal doses, even in patients with narrow anterior chamber angles.

Management

If symptoms or signs suggestive of acute or subacute angleclosure glaucoma develop, patients with narrow anterior chamber angles should have a prophylactic laser iridotomy to prevent pupillary block and subsequent angle-closure glaucoma. If acute angle-closure glaucoma occurs, the patient should be managed according to the guidelines described in Chapter 34. The offending drug should be withdrawn if medically possible. Accommodative paresis (cycloplegia) can be managed with reading lenses, as necessary, depending on the expected duration of treatment with the anticholinergic medication.

Beta-Blockers

Clinical Signs and Symptoms

Systemic beta-blockers are used extensively for the treatment of hypertension and other cardiovascular disorders. Of the available oral beta-blockers, atenolol, metoprolol, nadolol, pindolol, propranolol, and timolol have been documented to produce a dose-dependent reduction in IOP. The ocular hypotensive effect associated with systemically administered beta-blockers can be compared with that achieved with topically applied beta-blockers such as timolol. Although specific studies have not been conducted with most of the remaining systemic betablockers, these agents might also be expected to reduce IOP at clinically useful doses.

Etiology

Like topical beta-blockers (see Chapter 10), systemic beta-blockers may decrease aqueous formation via an

action linked to receptors (predominantly β2 receptors) on the nonpigmented ciliary epithelium.The reduction of IOP produced by systemic beta-blockers is linked with both the β-receptor selectivity and the dosage of the drug. Nonselective oral beta-blockers have been particularly effective ocular hypotensive agents.The degree of β-receptor blockade in the ciliary body from oral nonselective betablocker therapy appears to be nearly complete, because topical beta-blockers often produce little additional IOP reduction with concomitant administration.

Management

The reduction in IOP associated with systemic betablocker therapy may confuse the diagnosis of open-angle glaucoma. Thus, patients exhibiting glaucomatous optic neuropathy may be diagnosed incorrectly as having normal tension glaucoma. If beta-blocker therapy is subsequently discontinued, these patients may develop substantially higher IOP. In addition, glaucoma patients taking systemic nonselective beta-blockers may not show any additional ocular hypotensive effect after administration of a topical nonselective beta-blocker. Patients receiving a β1-selective oral agent, however, may show a further decrease in IOP with the concurrent use of a topical nonselective beta-blocker. To minimize ineffective topical therapy in these patients, a uniocular trial with a topical beta-blocker may be useful to determine its ocular hypotensive effect. Although many patients currently use oral beta-blockers for a variety of conditions, these agents are not approved for use as ocular hypotensive agents. Nevertheless, the ocular hypotensive activity of these agents may have a beneficial effect on IOP.

Cardiac Glycosides

Clinical Signs and Symptoms

When administered systemically, cardiac glycosides reduce IOP in humans. Systemic digoxin therapy has been shown to reduce IOP by 14% in the glaucomatous human eye, and aqueous humor formation can be reduced by as much as 45% after several days of digoxin therapy.

Etiology

The effect on IOP of the cardiac glycosides, primarily digitalis derivatives and ouabain, has been of interest for many years.The physiologic effects of these agents are produced by their ability to inhibit Na+K+ adenosine triphosphatase, and a ouabain-sensitive Na+K+ adenosine triphosphatase has been demonstrated in the ciliary epithelium. In the ciliary nonpigmented epithelium, as in other types of secretory epithelium, Na+K+ adenosine triphosphatase is thought to be responsible for the active transport of sodium, a process necessary for aqueous secretion to occur.

Management

Systemic administration of cardiac glycosides may reduce IOP to some degree in glaucomatous and nonglaucomatous eyes, but it is unlikely to produce adequate control of IOP when maximal medical therapy has failed to achieve this goal. In addition, cardiac glycosides have a low margin of safety and are frequently associated with toxicity. Gastrointestinal disturbances, fatigue, and visual complaints are among the most common side effects encountered with cardiac glycosides. Although all types of arrhythmias have been associated with cardiac glycoside toxicity, ventricular arrhythmias are of particular concern, because they may be life threatening due to decreased cardiac output. For this reason, systemic cardiac glycosides currently have no place in the treatment of glaucoma.

Corticosteroids

Corticosteroid administration by systemic (oral or intravenous), topical (ophthalmic and cutaneous), injected (periocular and subcutaneous), and inhalation and possibly nasal routes can elevate IOP. In patients who are steroid responders, oral steroids produce approximately 60% the increase in IOP as compared with topical agents, most likely because of differences in achieved anterior chamber concentrations of the drug. Those with primary open-angle glaucoma respond to steroids at a rate of 46% to 92% compared with 18% to 36% of

the normal population. Patients noted to be at greater risk include those with increasing age, diabetes, high myopia, connective tissue diseases such as rheumatoid arthritis, and with a first-degree relative with open-angle glaucoma.

Clinical Signs and Symptoms

Induction of ocular hypertension after corticosteroid administration depends on the specific drug,the dose,the route and frequency of administration, and the corticosteroid responsiveness of the patient. Generally, patients with elevated IOP are asymptomatic, so examination with applanation tonometry is the key to diagnosis. If the patient shows a steroid responsiveness, the onset of IOP elevations is not immediate but occurs after approximately 2 weeks of use. However, it can occur many weeks later, and this time to onset is generally longer for systemic steroids. In responsive patients the level of IOP rise with systemic steroids averages approximately 60% of that produced by topically applied steroids.

Etiology

The varied and complex steroid-induced morphologic and biochemical changes in the TM have been studied extensively.The result of the various known processes is an increased resistance to aqueous humor outflow resulting in ocular hypertension and, if untreated, secondary openangle glaucoma.

Steroid responsiveness is a complex pathophysiologic process involving a large number of factors. When activated by steroids, the steroid-specific receptors in the TM (glucocorticoid receptor-a) activateTM cells and cause an accumulation of amorphous material in the extracellular matrix, thickening of the trabecular beams and juxtacanalicular tissue and therefore decreasing outflow spaces in the TM. The glycosaminoglycans in the TM, a major portion of the extracellular matrix, have been shown to alter composition in the presence of steroids by increasing chondroitin, decreasing hyaluronate, and progressively increasing deposition of fibronectin. Further, steroids have been shown to cause a reduction in the essential function of the TM cells to phagocytose debris and to replace the extracellular matrix in the meshwork, which can also lead to an increase in resistance to outflow and therefore an increase in IOP.Activated TM cells lead to the induction of the GLC1A gene and increased expression of the myocilin protein in the TM, whereas other proteins are downregulated. Some mutations in the GLC1A gene have been shown to lead to the development of dominant juvenile and a small subset of adult-onset open-angle glaucoma. Other changes to the TM have been observed in the presence of steroids,including changes to the TM cytoskeleton and cellular adhesion molecules.

Management

The risk of developing steroid-induced glaucoma can be moderated with the judicious use of steroids and careful

monitoring and patient education to promptly identify IOP elevations when they occur. The IOP normally returns to pretreatment levels within 2 to 4 weeks of steroid taper or discontinuation. If continuation of systemic steroid therapy is necessary for the patient’s systemic condition, elevated IOP can often be controlled with topical antiglaucoma medications. In terms of topical steroids, modifications of the treatment in favor of alternative steroid preparations as well as NSAIDs may be of value. Ocular hypertension or steroid-induced glaucoma should be managed according to guidelines given in Chapter 34. The use of lowto medium-dosage inhaled steroids and nasal steroids appears to have little associated risk. Because one would expect patients with established open-angle glaucoma to be particularly sensitive to the pressure-elevating effects of systemic steroids, careful monitoring is required.

Topiramate

Topiramate is an antiepileptic medication also used in an off-label capacity to treat migraine headaches and bipolar disorders.

Clinical Signs and Symptoms

Eighty-five percent of the 86 cases of mostly bilateral acute angle-closure glaucoma reported to the National Registry of Drug-Induced Ocular Side Effects by 2003 were noted to have occurred within the first 2 weeks of treatment initiation. Topiramate is considered to have “certain” OADRs in the form of abnormal vision, acute secondary angle-closure glaucoma, acute myopia, and suprachoroidal effusions.

Etiology

The presence of protein in the cerebrospinal fluid in one patient with bilateral conjunctivitis, areflexic mydriasis, severe anterior chamber shallowing, myopic shift, and vitritis suggests that a common inflammatory mechanism may occur due to the topiramate use.

Management

Peripheral iridectomy is an ineffective treatment due to the secondary nature of choroidal effusions and inflammation. One case reported rapid resolution of the attack with methylprednisolone added to the intravenous mannitol.

Ethanol

Ethanol, taken orally, may reduce IOP by increasing serum osmolarity and functioning as a short-acting hyperosmotic agent. When consumed as alcohol-containing beverages, ethanol can reduce IOP in both normal and glaucomatous eyes. The maximal ocular hypotensive effect occurs 1 to 2 hours after consumption. Therefore the practitioner must consider the actions of ethanol if consumption by the patient has occurred before measuring IOP.

Cannabinoids

Derivatives of the marijuana plant, Cannabis sativa, make up a group of compounds known as cannabinoids. Various cannabinoids have been administered orally, topically, and by inhalation as a means of reducing IOP. Smoking and ingesting marijuana significantly reduces IOP. After smoking a single marijuana cigarette, patients with primary open-angle or secondary glaucomas can exhibit a significant reduction in IOP. The maximal ocular hypotensive response occurs 60 to 90 minutes after inhalation and lasts approximately 4 hours.These patients, however, have many systemic side effects, including postural hypotension, tachycardia, anxiety, drowsiness, euphoria, and hunger. Thus, systemic administration of presently available cannabinoids is an unacceptable route of administration for treatment of glaucoma, but the practitioner may encounter patients using marijuana and should be familiar with its ocular actions.

DRUGS AFFECTING THE RETINA

Numerous drugs have been associated with retinal toxicity (Table 35-10).These include medications obtained by prescription or over the counter. For example, phenylpropanolamine, an adrenergic agonist formerly available over the counter and used in cold preparations and as an anorectic, has been reported to cause central retinal vein occlusion associated with systemic hypertension. This emphasizes the importance of a careful drug history. Several mechanisms can result in drugs becoming retinotoxic. Depending on the specific drug, its dosage, and the duration of treatment, these retinotoxic effects are often reversible if recognized early. Data have been reviewed

Table 35-10

Drugs That Can Affect the Retina

suggesting that indomethacin, tamoxifen, thioridazine, and chloroquine all produce retinopathies via a common mechanism of ocular oxidative stress.

Chloroquine and Hydroxychloroquine

Chloroquine and hydroxychloroquine have been used to treat rheumatoid arthritis, discoid and systemic lupus erythematosus, and other collagen and dermatologic diseases since the early 1950s. Initially, retinal toxicity due to long-term use of chloroquine (Aralen) for malaria was reported, and this remains a concern in some parts of the world. Currently, hydroxychloroquine sulfate (Plaquenil) is the quinoline agent of choice for the treatment of autoimmune diseases with a far lower incidence of adverse reactions. Although chloroquine and hydroxychloroquine toxicity does occur and the results can be devastating to vision, the overall incidence is very low. Review of the published literature on these drugs suggests that well over 1,000,000 individuals have used them, whereas fewer than 20 cases of toxicity have been reported.

Clinical Signs and Symptoms

Even before visible ophthalmoscopic changes are detectable, a“premaculopathy”state can exist in which the drug interferes with metabolism of the macular tissues, causing subtle relative visual field defects in patients with ophthalmoscopically normal maculae. The first visible evidence of retinopathy is a fine pigmentary mottling within the macular area, with or without loss of the foveal reflex. As the macular pigmentary changes progress, a classic pattern develops consisting of a granular hyperpigmentation surrounded by a zone of depigmentation.