3. Analgesics, narcotic antagonists and agents used to treat arthritis

Systemic administration


Probable





Clinical significance


Fingolimod is the first FDA approved oral agent for the management of relapsing forms of multiple sclerosis (MS). In general this drug has few and quite-rare ocular side effects. The one of importance is macular edema. The incidence is variable, dependent on the dosage. It will be under 3%; and at current recommended dosage (0.5 mg/day), it is 0.2% (Tedesco-Silva et al 2006). The incidence increases in patients with uveitis and diabetes. The macular edema developed within the first 3–4 months. Presentation may be asymptomatic to metamorphopsia and decreased vision. Bilateral macular edema occurs in 25% of patients. Compared to some other drug-related macular edema, with this drug there appears to be intramacular leakage on fluorescein angiography. Jain et al (2012) confirms intraretinal cysts characteristic of cystoid macular edema in patients with fingolimod-associated macular edema. Minuk et al (2013) and Afshar et al (2013) have reported cystoid macular edema as well. The National Registry has over 200 cases of suspected macular edema in patients on this drug.





Class: Antipsychotic Agents


Generic Name:


Aripiprazole.



Proprietary Name:


Abilify.



Primary use


Aripiprazole is a partial dopamine agonist of a second generation of antipsychotics called atypical antipsychotics. This drug is proposed to cause less-adverse drug reactions than traditional antipsychotics, i.e. less weight gain, fewer extrapyramidal side effects and less somnolence. The drug has antidepressant properties and is used to treat schizophrenia, bipolar disorder and clinical depression.




Clinical significance


Two hundred and seventy-nine case reports of adverse ocular reactions were collected at the National Registry of Drug-Induced Ocular Side Effects. The average duration of therapy until development of ocular side effects is approximately 144 days. The most frequent ocular side effect reported is oculogyric crisis. Overall there are five main categories of eye related side effects: oculogyric crisis (196 case reports), blepharospasm (28 case reports), drug-induced myopia (14 case reports), mydriasis (36 case reports), and combinations of the above (five case reports). In this latter category, blepharospasm occurred with oculogyric crisis (three case reports) and myopia occurred with oculogyric crisis (two case reports). Removal of aripiprazole therapy leads to resolution of most ocular ADRs; however, there are rare instances where adverse effects are chronic. Early recognition of these drug-related ocular side effects could lead to improved care for patients as earlier withdrawal of aripiprazole therapy usually leads to resolution of oculogyric crisis, blepharospasm, drug-induced myopia, and ocular mydriasis. It appears as treatment approaches five months of therapy, these ocular ADRs can appear, although there is a standard deviation of five months or more from the available data. Oculogyric crisis has the strongest association with aripiprazole therapy and should be noted by clinicians in their care for patients requiring therapy with this drug. It is unknown how aripiprazole could cause oculogyric crisis or the other ocular ADRs. Oculogyric crisis is often associated with drug therapy. In the case of aripiprazole, it has been revealed recently that different manifestations of tardive dyskinesia are possible even though this drug is supposed to cause this type of side effect less often. Oculogyric crisis can be a type of tardive dyskinesia related to antipsychotic therapy, even atypical antipsychotics. Frequently, tardive dyskinesia can be chronic or even permanent. This may explain why there are rare instances of negative rechallenge from the spontaneous reports, as the oculogyric crisis may continue to occur even if the drug is removed. Fortunately, this is rare and most instances of drug dechallenge led to resolution of the oculogyric crisis and the other ocular ADRs. Mydriasis and myopia occurring in patients taking aripiprazole may indicate there is a change in the pupil in conjunction with the lens/iris diaphragm. If there is dilation of the pupil, the lens/iris diaphragm can move forward and lead to induced myopia. Past studies have revealed a significant drug-induced myopia through this mechanism. Sometimes this is caused by suprachoroidal effusions which can be documented by ultrasonography. To date, there have not been B-scan ultrasounds in patients experiencing these ADRs. It is hoped that clinicians around the world consider this diagnostic study in their patients should they encounter an aripiprazole induced myopia and mydriasis.



Generic Names:


1. Chlorpromazine; 2. fluphenazine; 3. perphenazine; 4. prochlorperazine; 5. promethazine; 6. thiethylperazine; 7. thioridazine.



Proprietary Names:


1. Thorazine, Sonazine; 2. Prolixin; 3. Generic only; 4. Comprazine, Compro; 5. Phenadoz, Phenergan, Prometh, Promethegan; 6. Torecan; 7. Generic only.



Primary use


These phenothiazines are used in the treatment of depressive, involutional, senile or organic psychoses and various forms of schizophrenia. Some of the phenothiazines are also used as adjuncts to anesthesia, antiemetics and in the treatment of tetanus.



Ocular side effects


Systemic administration


Not all of the ocular side effects listed have been reported for each phenothiazine.







Clinical significance


As a class, phenothiazines are some of the most widely used drugs in the practice of medicine. The most commonly prescribed drug in this group is chlorpromazine. This medication has been so thoroughly investigated that over 10,000 publications have been written on this agent alone. Even so, these drugs are remarkably safe. Their overall rate of side effects is estimated at only 3%. However, if patients are on phenothiazine therapy for a number of years, a 30% rate of ocular side effects has been reported. If therapy continues over 10 years, the rate of ocular side effects increases to nearly 100%. Side effects are dose and drug dependent, with the most significant side effects reported with chlorpromazine because this agent is the most often prescribed. These drugs in very high dosages can cause significant ocular adverse effects within a few days, while the same reactions usually would take many years to develop in the normal-dosage range. Each phenothiazine has the potential to cause ocular side effects, although it is not likely to cause all of those mentioned. Pinpointing the toxic effects to a specific phenothiazine is difficult because most of these patients are taking more than one drug. The most common adverse ocular effect with this group of drugs is decreased vision, probably due to anticholinergic interference. Chlorpromazine, in chronic therapy, can cause pigmentary deposits in or on the eye, with multiple reports claiming that other phenothiazines can cause this as well. These deposits are first seen on the lens surface in the pupillary aperture, later near Descemet’s membrane or corneal endothelium, and only in rare cases in the corneal epithelium. Pigmentary changes in the cornea seem to be reversible, but lens deposits may be permanent. Lens deposits are described as not interfering with vision (pseudocataracts). A report by Isaac et al (1991) clearly showed an increased incidence of cataract surgery in patients taking these agents; and an anterior capsular opacity seems characteristic in long-term therapy (Webber et al 2001; Leung et al 1999; Siddal 1966; Rasmussen et al 1976).


Retinopathy, optic-nerve disease and blindness are exceedingly rare at the recommended dosage levels, and then they are almost exclusively found in patients on long-term therapy. A phototoxic process has been postulated to be involved in both the increased ocular pigmentary deposits and the retinal degeneration. These groups of drugs with piperidine side chains (thioridazine has been removed from the market) have a greater incidence of causing retinal problems than the phenothiazine derivatives with aliphatic side chains (chlorpromazine), which has had relatively little retinal toxicity reported. Power et al (1991) reported a patient taking fluphenazine for 10 years and developing bilateral maculopathy after 2 minutes of unprotected welding arc exposure. Lee and Fern (2004) described bilateral maculopathy after 10 years of exposure to fluphenazine without increased light exposure. The phenothiazines combine with ocular and dermal pigment and are only slowly released. This slow release has, in part, been given as the reason for the progression of adverse ocular reactions even after use of the drug is discontinued.


Retrobulbar injections of chlorpromazine with or without alcohol have been used to control ocular pain. Most reports are various degrees of inflammation and edema, some requiring temporary tarsorrhaphy to a case involving forehead, cheek and ipsilateral eyelids (McCulley et al 2006). Cotliar et al (2008) reported a case of secondary diffuse orbital fibrosis probably due to retrobulbar chlorpromazine. Hauck et al (2012) reported a case of neurotrophic corneal ulcer felt to be due to chlorpromazine causing neurosensory denervation of the cornea. Kuruvilla et al (2012) described systemic chlorpromazine side effects with retrobulbar injection.




Generic Name:


1. Clozapine; 2. loxapine.



Proprietary Name:


1. Clozaril; 2. Loxitane.



Primary use


These dibenzoxazepine derivative represents a subclass of antipsychotic agents used in the treatment of schizophrenia.




Clinical significance


Neuromuscular reactions, including oculogyric crises, are fairly frequently reported, usually during the first few days of treatment. These reactions occasionally require reduction or temporary withdrawal of the drug. The anticholinergic effects – blurred vision, mydriasis and decreased accommodation – are more likely to occur with concomitant use of anti-Parkinsonian agents. The possibility of pigmentary retinopathy and lenticular pigmentation from these drugs cannot be excluded but seems quite rare or unlikely.



Generic Names:


1. Droperidol; 2. haloperidol.



Proprietary Names:


1. Inapsine; 2. Haldol.



Primary use


These butyrophenone derivatives are used in the management of acute and chronic schizophrenia, and manic depressive, involutional, senile, organic and toxic psychoses. Droperidol is also used as an adjunct to anesthesia and as an antiemetic.




Clinical significance


Most ocular side effects due to these agents are transient, reversible, and quite rare. While, on occasion, significant bilateral pupillary dilation occurs due to haloperidol, seldom does this precipitate narrow-angle glaucoma. Myopia is associated with the use of haloperidol, possibly secondary to drug-induced hyponatremia (Mendelis 1981). There is a report by Nishida et al (1992) that in rare individuals, who are often on multiple tranquilizing agents including haloperidol, the endothelium may be damaged and give a clinical picture of bilateral bullous keratopathy. Stopping the drugs allows for the corneas to return to normal. The decreased intraocular pressure due to these drugs is not a sufficient amount to be of clinical value. Uchida et al (2003) reported a case with positive rechallenge of haloperidol causing the outlines of small objects or patterns to appear increasingly vivid, with the effects lasting for 1 hour after taking the drug. Honda (1974), along with similar case reports received by the National Registry, supports these agents as having been associated with the onset of subcapsular cataracts after long-term therapy. These appear as subepithelial changes near the equator. Histologically, they appear as large, round, balloon cells without proliferation of lens epithelium. An epidemiologic study by Isaac et al (1991) supports these agents as causing cataracts.



Generic Name:


Lithium carbonate.



Proprietary Names:


Eskalith, Eskalith CR.



Primary use


This lithium salt is used in the management of the manic phase of manic depressive psychosis.




Clinical significance


Lithium salts have been widely used for decades and lithium intoxication is common because therapeutic blood levels have a narrow range before toxicity occurs. Lithium therapy is mainly prophylactic, with therapy lasting years to decades. The review article by Fraunfelder et al (1992) is probably the definitive work on the effects of lithium on the visual system.


Lithium affects many areas of the visual system, including direct effects on the central nervous system and on endocrine glands, leading to ocular effects. In general, the ocular side effects of lithium are reversible on withdrawal of the drug or lowering of the dosage. However, other side effects, such as downbeat nystagmus, can be permanent. Blurred vision is probably the most common side effect experienced by patients taking lithium, but is seldom significant enough to require the cessation of therapy. Usually with time, even while keeping the same dosage, blurred vision will disappear. Blurred vision, however, can be a signal of pending problems, such as intracranial hypertension. In most cases, patients who develop intracranial hypertension have been taking lithium for many years.


Lithium can cause various forms of nystagmus, the most characteristic being downbeat. This can occur at therapeutic dosage ranges of lithium and may be the only adverse drug effect. While some patients have a full recovery after stopping or reducing the dosage of lithium, it may develop into irreversible downbeat nystagmus. If downbeat nystagmus occurs, one needs to reevaluate the risk–benefit ratio of lithium therapy. Lithium can also cause extraocular muscle abnormalities, especially vertical or lateral far-gaze diplopia. In therapeutic dosages, Gooding et al (1993) have shown no effect of lithium on smooth pursuit eye tracking performance. Diplopia in any patient taking lithium may require a workup for myasthenia gravis, especially if associated with ptosis. Ptosis can occur alone. Oculogyric crises have been reported primarily in patients also taking haloperidol.


Thyroid-related eye disease in various forms secondary to hypo- or hyperthyroidism has been seen in patients receiving lithium therapy. While this is uncommon, exophthalmos has occurred. Lithium is secreted in the tears and may cause an irritative forum of conjunctivitis, causing epiphoria. However, with time many patients complain of a dry mouth and at about the same time as ocular dryness. Lithium has been reported to cause cornea and the conjunctiva deposits, but the documentation for this is limited. Lithium can cause a decrease in accommodation, which may occur in up to 10% of patients. However, this primarily occurs in young patients and is rare in older patients. In general, this side effect is minimal and usually resolves after a few months, even while taking the drug. Etminan et al (2004), in a case control study, showed that lithium use in the elderly increased the risk of injurious motor vehicle accidents.



Generic Name:


Pimozide.



Proprietary Name:


Orap.



Primary use


This diphenylbutylpiperidine derivative is used for suppression of motor and vocal tics of Tourette syndrome.




Clinical significance


Up to 20% of patients on this drug have some form of visual disturbance (Physicians’ Desk Reference 2006). This is mainly blurred vision, which is reversible. Decreased accommodation is not uncommon. All ocular side effects are reversible and of little clinical significance. This drug can cause a dry mouth and therefore can probably aggravate ocular sicca.



Generic Name:


Quetiapine fumarate.



Proprietary Name:


Seroquel.



Primary use


This drug belongs to a new chemical class, dibenzothiazephine derivatives, used in the management of bipolar mania or in schizophrenia.




Clinical significance


Ocular side effects attributed to quetiapine are rare, transitory and infrequent. Ocular sicca is probable, because dry mouth is one of the most frequent systemic side effects of this agent. Because this drug has caused lens changes in dogs and is an inhibitor of cholesterol biosynthesis, there has been interest as to the cataractogenic potential of this agent. Valibhai et al (2001) have reported a clinically suspect case. Large postmarketing surveillance studies have not found a higher incidence of cataracts. The lack of a characteristic pattern led to the conclusion, at worse, that the drug has a very weak cataractogenic potential. There are however 278 spontaneous reports in the National Registry of lens changes associated with quetiapine use.


Ghosh et al (2008) reported a case of oculogyric crisis. There are an additional 28 cases in the National Registry. Yong et al (2011) reported a case of retinal vein occlusion and Plana et al (2006) a case of fear of the dark.



Recommendations


The manufacturer recommends that any patient receiving chronic treatment be examined at the initiation of treatment and then twice yearly for lens changes. Fraunfelder (2004) recommended only having patients examined as per the guidelines established by the American Academy of Ophthalmology, regardless of whether or not the patient is on quetiapine. In a letter to the editor, Gaynes (2005) preferred more frequent examinations; but, in reply, Fraunfelder (2005) did not concur.



Generic Names:


Tiotixene.



Proprietary Name:


Navane.



Primary use


This thioxanthene derivative is used in the management of schizophrenia.




Clinical significance


In short-term therapy, ocular side effects due to this drug are reversible and usually insignificant. This drug has antimuscarinic properties, which may account for the occasional patient who gets blurred vision and mydriasis. Dry mouth is not uncommon, so ocular sicca may be aggravated or occur. In long-term therapy, however, cases of corneal or lens deposits or lens pigmentation have been reported. Retinal pigmentary changes are exceedingly rare and only occur with long-term therapy. These are strong photosensitizing agents.



Class: Depressants


Generic Name:


Alcohol (ethanol, ethyl alcohol).



Proprietary Name:


Generic only.



Primary use


This colorless liquid is used as a solvent, an antiseptic, a beverage and as a nerve block in the management of certain types of intractable pain.



Ocular side effects


Systemic administration – acute intoxication


Certain







Clinical significance


Consumption of alcoholic beverages leads to a host of well-known ocular side effects. Acute intoxication may result in nystagmus, a finding used by law enforcement personnel to screen for inebriated motor-vehicle operators. Pupil abnormalities, ptosis and strabismus are also well-known effects of inebriation. Also reported are temporary corneal clouding and a methanol-like loss of vision associated with alcohol-induced metabolic acidosis. When chronic, alcoholism leads to malnutrition in severe cases, with resultant xerophthalmia or toxic amblyopia. Wang et al (2008), in their literature review, point out that there is no consistent evidence supporting a major role of moderate alcohol consumption in the development or progression of any common eye diseases. Various types of cataracts have been reported to be more common in heavy users of ethanol, but data from various studies suggests that moderate alcohol ingestion may reduce the need for cataract surgery (Kanthan et al 2010). Knudtson et al (2007) showed no effect – increase or decrease – of alcohol use on the risk of age-related macular degeneration. It is suspected that alcoholics are also more prone to infectious keratitis. Children born with fetal alcohol syndrome have multiple orbital and ocular structural abnormalities.


Kim et al (2012) has shown that oral alcohol is secreted in human tears. This causes hyperosmolarity, shortened tear film break-up time and ocular surface disease. This process is probably aggravated in those who abuse alcohol. Inadvertent splashes of alcoholic beverage onto the eye surface are a frequent occurrence and result in irritation of the conjunctiva and cornea, but there are no reports of permanent damage. Most distilled alcoholic beverages are 40% alcohol by volume, but concentrations up to 75% are available commercially in the United States. In the photorefractive keratectomy procedure, ophthalmic surgeons use concentrations of less than 40% alcohol to remove corneal epithelium. It has been shown that the duration of application of 20% alcohol is important to corneal epithelial cell survival. A 30-second or less application allows cell survival, while a 60-second application may lead to cell death. There is a report of an adverse event in which alcohol was placed in the anterior chamber during cataract surgery, resulting in permanent endothelial damage.




Generic Name:


Methanol.



Synonyms:


Methyl alcohol, wood alcohol, wood spirits.



Proprietary Names/Products Containing:


Found in automobile engine cleaners, antifreeze, de-icers and paint/stain removers.



Primary use


Known as wood alcohol, methanol was once produced by the distillation of wood. It is now produced synthetically. Methanol is the simplest alkyl alcohol. It is used primarily as a solvent and as an antifreeze. It is also found in several cleaners and is used to denature ethanol. Methanol occurs in small amounts naturally in the environment.





Recommendations


People who are suspected to have ingested methanol need immediate care, preferably in an intensive care unit setting. Treatment of systemic methanol poisoning consists of trying to prevent the metabolism of methanol to formaldehyde, which then is converted to formic acid. Formic acid inhibits cytochrome oxidase, a key protein in the production of ATP within mitochondria, and its formation is thought to precipitate the neurological side effects of methanol consumption. Peak concentrations of methanol occur within an hour of ingestion. A latent period occurs while the methanol is converted to formic acid, and a metabolic acidosis ensues. Visual loss often precedes the potentially fatal side effects of the formic acidosis. To block the metabolism towards formic acid, competitive inhibition of alcohol dehydrogenase may be achieved by giving the patient ethanol or fomepizole (which does not cause inebriation).


Hemodialysis may enhance the elimination of methanol and its metabolic by-products, allowing improved chances of recovery.


Desai et al (2013) have shown that the degree of acidosis at presentation appears to determine the final vision. They found early presentation did not significantly change the visual outcome, especially in severe poisoning.



Class: Psychedelic Agents


Generic Names:


1. Dronabinol (tetrahydrocannabinol, THC); 2. hashish; 3. marihuana (marijuana).



Proprietary Name:


1. Marinol (Canad.); 2. Generic only; 3. Generic only.



Street Names:


1. The one; 2. bhang, charas, gram, hash, keif, black Russian; 3. ace, Acapulco gold, baby, Belyando sprue, boo, brown weed, bush, cannabis, charas, dank, dope, gage, ganja, grass, green, gungeon, hay, hemp, herb, home grown, jay, joint, kick sticks, kryptonite, lid, locoweed, Mary Jane, Mexican green, MJ, muggles, OJ (opium joint), Panama red, pot, rainy-day woman, reefer, roach, rope, sinsemilla, stick, tea, twist, weed, wheat.



Primary use


These psychedelic agents are occasionally used as cerebral sedatives and are narcotics commonly available on the illicit drug market. Dronabinol is also medically indicated for the treatment of the nausea and vomiting associated with chemotherapy.




Clinical significance


Marijuana is the most widely used illicit drug in the United States and one of the oldest recorded medicines in the world. It is almost always smoked. The oral form, dronabinol, is largely unappealing to the addict and therefore has a very low abuse potential. Levi et al (1990) as well as Laffi et al (1993) found vision disturbances lasting 24 hours after marijuana use. Each report involved only a few patients but included alterations of depth perception, sensorial disconnection when talking with people, intermittent light phenomena, strobe-like effects, bright spots flickering randomly in high frequency and alteration of the sensory perception of one’s external environment. Ocular side effects due to these agents are transient and seldom of clinical importance. However, Steimetz et al and Kowal et al (2011) have shown that probable irreversible disruption of classic eye blink may occur in heavy users,.


Semple et al (2003), using binocular depth inversion testing, discovered persistent sensory visual abnormalities in chronic marijuana users. There is some evidence that marijuana decreases basal lacrimal secretion, decreases photosensitivity, increases dark adaptation, increases color-match limits and increases Snellen visual acuity. Huestegge et al (2010) have shown defects in visual spatial working memory in cannabis users. Possibly in some, within the first 5–15 minutes on these agents, some pupillary constriction may occur. However, most do not show pupillary constriction; and, to date, there is no long-term pupillary effect noted. Conjunctival hyperemia is not uncommon and is more pronounced at 15 minutes after exposure.


The cannabinols found in marijuana can lower intraocular pressure by an average of 25%, but the effect only lasts 3–4 hours. There is significant variation in the individual response to these agents, as well as diminished response with time. Most patients on this agent for glaucoma control cannot use it for prolonged periods due to lack of glaucoma control. Isolated cannabinols, which lower intraocular pressure, have the complicating factor that one cannot separate the central nervous system high from its ocular pressure lowering effect, so their value clinically is quite limited. Few patients are able to use marijuana for long-term control of their glaucoma and remain functional in the workplace. These drugs are occasionally used medically, but have no long-term value in clinical ophthalmology.

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Nov 21, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on 3. Analgesics, narcotic antagonists and agents used to treat arthritis

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