DRUG-INDUCED GLAUCOMA

 

Almost 50 topically and systemically administered drugs have been found to cause temporary or chronic intraocular pressure (IOP) elevation, sometimes causing glaucomatous changes.

The mechanisms of IOP elevation occur through both closed-angle and open-angle patho-physiologies.

Ultrasound biomicroscopy (UBM) is occasionally required to confirm the cause and rule out conditions such as accommodative spasm and primary angle closure.

OPEN-ANGLE GLAUCOMA

Corticosteroids:

Details about steroid-induced glaucoma are presented here: 

https://ourgsc.blogspot.com/search?q=steroid

Patients have been categorized by Armaly and Becker into three categories depending on their response to topical steroids. Five percent of the population are high responders, developing an IOP increase >15 mm Hg and IOP >31 mm Hg after daily corticosteroid use for 4 to 6 weeks. Moderate responders, approximately one-third of the population, exhibit increased IOP of 6 to 15 mm Hg and have IOP between 20-31 mm Hg. Approximately two-thirds of the population are non-responders, with pressure increases of <6 mm Hg and IOP of <20 mm Hg.

Most studies have reported an increase in IOP between 3-6 weeks after topical steroid use.

Risk factors for high responders are patients with primary open-angle glaucoma and their first-degree relatives; elderly or young (<6 years) patients; and patients with type 1 diabetes or connective tissue disease (especially rheumatoid arthritis), high myopia, and angle recession glaucoma are at greater risk of steroid-induced glaucoma.

The likelihood of IOP elevation with systemic steroids seems to be less than with the topical route.

Tripathi et al found a significant relationship between IOP and the dose of corticosteroid administered (1.4 mm Hg increase in mean IOP for each 10 mg increase in the average daily prednisolone dose).

Fluorometholone, medrysone, rimexolone, and loteprednol are less potent topical corticosteroids with a lower risk of a rise in IOP.

Steroids increase the resistance to aqueous outflow through the trabecular meshwork.

The exact mechanisms are unknown but probably involve changes in the microstructure of the trabecular meshwork (cross-linked actin network formation) and cell activities causing decreased proliferation, migration, and phagocytosis of trabecular meshwork cells. These all cause progressive accumulation of extracellular debris and increased aqueous outflow resistance.

There is also increased production and deposition of glycosaminoglycan, elastin, fibronectin, laminin, and collagen type IV, coupled with decreased destruction from steroid-induced inhibition of matrix metalloproteinase inhibitors leading to increased outflow resistance.

In short, it includes discontinuation of the steroid or replacement with a non-steroidal anti-inflammatory agent and medical or occasionally surgical control of IOP.

Anecortave acetate is an angiostatic steroid synthesized from cortisol acetate. In a case series, a total of 8 eyes with medically uncontrolled intraocular pressure after steroid therapy, a periocular depot injection of anecortave acetate reduced the mean baseline intraocular pressure by 34.5% at one month. The mechanism underlying the effect seen with this agent is unclear.

Antineoplastic Agents:

Docetaxel, paclitaxel, as well as Imatinib mesylate, have been reported to increase IOP in one patient each.

Spasmolytics:

Propantheline bromide and dicyclomine have been documented to elevate the IOP in patients with open-angle glaucoma.

 CLOSED-ANGLE GLAUCOMA

Drug-induced acute angle-closure glaucoma (AACG) is seen in individuals at risk for occludable angles.  The risk factors for AACG include race (Asians, Inuit Eskimos, and Hispanics), older age, female gender, hyperopia (farsightedness, wearing plus glasses that magnify objects), narrow-angle, family history positive for angle closure, and previous angle closure in the fellow eye.

A database analysis of the FDA Adverse Event Reporting System (FAERS) by Aftab et al found the 50 most common drugs associated with angle-closure glaucoma. [SEE FIGURE] The most frequently reported drugs included topiramate (520 reports), citalopram (69 reports), levothyroxine (68 reports), escitalopram (58 reports), duloxetine (45 reports), and salbutamol (44 reports). The most frequently reported drug category was sulfonamides (642 reports), specifically topiramate. Serotonergic agents were the second-most commonly reported class of drugs at 318 reports.

Tropicamide and acetazolamide were other drugs associated with angle-closure glaucoma.

Sulfa Agents:

Sulfa drugs like topiramate, a sulfamate-substituted monosaccharide antiepileptic agent, precipitate AACG by inducing ciliary body edema, idiosyncratic lens swelling, shallowing of the anterior chamber, choroidal effusion, and retinal edema. Typically, this AACG is a bilateral non-pupillary block angle-closure glaucoma that occurs within the first several doses of the medication.

Drug-induced changes in membrane potential have been hypothesized to cause ciliary body edema, leading to relaxation of zonules and resultant lens thickening. Anterolateral rotation of the ciliary body about its attachment to the scleral spur leads to anterior displacement of the lens and iris and concomitant shallowing of anterior chamber. Associated choroidal detachment and supraciliary effusion are known to occur.

The fact that effusion occurs only in a few patients taking topiramate and, more importantly, it typically occurs on doses well within the normal therapeutic range and in patients with normal anterior chamber depth suggests an idiosyncratic etiology.

No known risk factors exist for this syndrome.

Other sulfa-based drugs known to be associated with AACG include acetazolamide, hydrochlorothiazide, cotrimoxazole, quinine and tetracycline.

Patients usually develop blurred vision from the induced myopia from the anterior lens movement. Glaucoma is reported between days 1 and 49 (average 7) after drug initiation. In 85%, the glaucoma developed within the first 2 weeks of initiation of the drug.

The condition usually resolves after discontinuation of the agent. However, one case of permanent IOP elevation after withdrawal has been reported.

Antidepressants:

Tricyclic agents, amitriptyline, and imipramine, and the non-tricyclic drugs mianserin hydrochloride, paroxetine, fluoxetine, fluvoxamine, citalopram, and escitalopram have been associated with AACG. The glaucoma arises as the result of the anticholinergic action of these medications, which produces mydriasis and blockage of the angle. Supraciliary effusion seen on UBM has also been identified as a pathogenetic mechanism.

Monoamine Oxidase Inhibitors:

These antidepressant agents have weak anti-cholinergic effects. When these agents are prescribed along with other drugs having anti-cholinergic properties, the possibility of angle-closure glaucoma increases.

Phenelzine sulfate and tranyl-cypromine sulfate have been reported to induce AACG.

Antipsychotics:

Antipsychotics have a relatively weaker anticholinergic action on the ocular smooth muscles compared with tricyclic antidepressants, and the risk of these causing glaucoma is lower.

Perphenazine, trifluoperazine, and fluphenazine have been reported to induce glaucoma.

Antihistamines:

The H1 and H2 receptor blockers also have anticholinergic activity that may induce glaucoma through pupillary mydriasis.

Promethazine has been shown to produce an idiopathic swelling of the lens that could increase the risk of pupillary block AACG. Cimetidine and ranitidine have been reported to increase IOP in a patient being treated for duodenal ulcer.

Anti-Parkinson's:

Trihexyphenidyl has been shown to precipitate AACG in susceptible individuals. The drug can also have prolonged cumulative effects causing creeping angle-closure glaucoma.

Orphenadrine also has been documented to precipitate AACG.

Sympathomimetics:

Alpha-adrenergic agents, especially those with alpha-1 agonistic activity, cause mydriasis that can precipitate AACG.

Phenylphrine eye drops for pupillary dilation and systemically for flu, anesthesia or locally for epistaxis can precipitate AACG.

Apraclonidine, an alpha-2 agonist eyedrop and dipivefrin, an antiglaucoma eyedrop, can cause acute angle-closure.

Parasympatholytics:

Nebulized ipratropium bromide and tiotropium bromide for obstructive pulmonary disease can cause acute angle-closure attack. The drug can leak through face masks and get absorbed through cornea and conjunctiva.

Scopolamine, an anti-emetic, can cause AACG in susceptible individuals.

Parasympathomimetic Agents:

Pilocarpine is an antiglaucoma medication, while acetylcholine and carbachol are used to constrict the pupil during intraocular surgery. These agents can rarely induce AACG because of anterior movement of the iris-lens diaphragm especially in eyes with zonular weakness and exfoliation syndrome.

Botulinum Toxin:

Used for blepharospasm, it can cause pupillary dilation when injected peri-ocularly. The postulated mechanism is diffusion of the drug towards the ciliary ganglion and impedance of cholinergic innervation of the pupil.

Cardiac Agents:

Disopyramide phosphate seems to have anticholinergic activity and may induce AACG.

There are mixed reports about the effect of calcium channel blockers on IOP.

Anticoagulant Therapy:

Anticoagulant therapy, in the form of heparin as well as low molecular weight heparin (enoxaparin, warfarin), can cause AACG by inducing massive vitreous, choroidal or subretinal hemorrhage.

Risk factors for the same include anticoagulants, exudative age-related macular degeneration and nanophthalmos.

Anesthetic Agents:

Succinylcholine and ketamine can elevate IOP. Usually, the IOP elevation is temporary.

Anticholinergic (atropine, scopolamine, and muscle relaxants) or adrenergic (ephedrine, epinephrine) anesthetic agents can also cause AACG.

TAKE HOME MESSAGE:

• It is important for the physician to be aware of risk factors which can precipitate AACG. A patient wearing thick glasses that magnify objects suggests a hypermetropic error and crowding of the anterior segment.
• A quick torchlight examination by throwing light in the anterior chamber from the sides can show shallowness in predisposed eyes.
• Ophthalmological consultation is warranted in a predisposed patient before starting treatment with drugs capable of potentiating AACG.
• Any patient who has a red eye and a subjective vision loss postoperatively (after anesthesia) should be examined urgently as the patient may not be able to convey his symptoms such as blurred vision and pain due to elevated IOP.

REFERENCES:

1. Razeghinejad MR, Myers JS, Katz LJ. Iatrogenic glaucoma secondary to medications. Am J Med. 2011 Jan;124(1):20-5. doi: 10.1016/j.amjmed.2010.08.011. Epub 2010 Nov 17. PMID: 21092926.
2. Khurana AK, Khurana B, Khurana AK. Drug-induced Angle-Closure Glaucoma. J Curr Glaucoma Pract. 2012 Jan-Apr;6(1):6-8. doi: 10.5005/jp-journals-10008-1100. Epub 2012 Oct 16. PMID: 27990064; PMCID: PMC5159452.
3. Aftab OM, Khan H, Khouri AS. Blind Spots in Therapy: Unveiling Drug-Induced Angle-Closure Glaucoma Through a National Analysis. Ophthalmol Glaucoma. 2024 Sep-Oct;7(5):485-490. doi: 10.1016/j.ogla.2024.04.006. Epub 2024 Apr 27. PMID: 38679326.
4. Tripathi RC, Kirschner BS, Kipp M, et al. Corticosteroid treatment for inflammatory bowel disease in pediatric patients increases intraocular pressure. Gastroenterology. 1992;102:1957-1961.