In 2020, glaucoma was found to be the second leading global cause of blindness in those aged 50 years and older.1 It was expected that 76 million people worldwide would suffer from glaucoma by 2020, of which an estimated 57.5 million would suffer from primary open angle glaucoma (POAG). It is estimated that by 2040, the number of those suffering with glaucoma will increase to 111.8 million worldwide.2,3
Elevated IOP is the only modifiable glaucoma risk factor,4 but eyecare practitioners still encounter patients with progressive visual field loss despite controlled IOPs, suggesting there are other factors involved that cause disease progression.5
Systemic medications influence (or are suspected to influence) glaucoma risk through mechanisms that directly affect IOP or otherwise.5 As longevity increases, the risk of developing multiple chronic conditions increases, resulting in the need for treatment with multiple prescription medications at a time.6 This is referred to as polypharmacy, whereby a patient is prescribed five or more medications simultaneously.7 Polypharmacy, along with the ever increasing glaucoma burden, stresses the importance of understanding how systemic medications affect glaucoma risk.
This article will highlight common systemic medications and their effects on glaucoma risk, particularly OAG. As a bonus, it includes a downloadable cheat sheet summarizing common systemic medications, their associated glaucoma risk, and management recommendations for future patients.
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Download the Cheat Sheet!
This comprehensive cheat sheet outlines medications, associated glaucoma risks, and management recommendations.
Steroid-induced glaucoma risk factors
Prolonged use of corticosteroids are known to induce intraocular hypertension and can lead to steroid-induced glaucoma
Corticosteroids are commonly prescribed to patients with autoimmune disorders and inflammatory conditions but have been shown to induce ocular hypertension.8 Prolonged steroid use with sustained elevated IOP can result in glaucomatous optic neuropathy, termed steroid-induced glaucoma.
Steroids have been found to increase resistance of aqueous humor (AH) outflow through trabecular meshwork (TM) dysfunction9, 10 and do this by:
- Increasing expression of several proteins, including glycosaminoglycans (GAGs), fibronectin, elastin, and laminin, within TM cells, which increases outflow resistance. Also, accumulated GAGs within the TM become hydrated, producing biological edema, which also increases outflow resistance.
- Inhibiting phagocytosis within endothelial cells in the TM, resulting in accumulation of debris.
- Altering TM cell morphology by causing an increase in nuclear size and DNA content.
- Decreasing prostaglandin production, which regulates IOP outflow.
Patients at risk of developing steroid-induced glaucoma include:
- Patients with POAG.
- Patients with high myopia or history of refractive surgeries.
- Young patients (<10 years) and older adults.
- Eyes with pigment dispersion syndrome or traumatic angle recession.
- Individuals with endogenous hypercortisolism.
Any patient who experiences an increase in IOP after steroid use is termed a “steroid responder.” In general, it has been found that the pressure-inducing effect is directly proportional to its anti-inflammatory potency but pressure-inducing potency is related to drug dosage.9
The first line of managing a rise in IOP after steroid use is to discontinue using the drug. An acute IOP increase usually resolves within days, while chronic IOP increase resolves within one to four weeks. If it is necessary to maintain steroid usage, reduce the dosage or prescribe a weaker steroid. Steroids can also be substituted with non-steroidal, anti-inflammatory drugs (NSAIDs) or steroid-sparing agents.11
If the above fails to decrease IOP, it may be necessary to include an anti-glaucoma regimen, such as use of beta-blockers, alpha-2 agonists, prostaglandin analogues, and topical carbonic anhydrase inhibitors. Laser trabeculoplasty and surgical management may be required if IOP fails to respond to medical management.10
Corticosteroid use amongst the general population has been estimated to be as high as 7%.12 Therefore, it is important that medical practitioners communicate and consult with eye care practitioners to monitor IOP response to prolonged use or high dosage of corticosteroids.
Beta-blockers reduce glaucoma risk
Beta-blockers are known to decrease the risk of glaucoma by reducing aqueous humor production but it can increase glaucoma risk with unmonitored blood pressure.
𝛽-blockers are usually prescribed to patients as antiarrhythmic and antihypertensive drugs13, and can be categorized as selective 𝛽-blockers, which inhibit 𝛽-1 receptors, and nonselective 𝛽-blockers which inhibit both 𝛽-1 and 𝛽-2 receptors within the body. 𝛽-blockers reduce IOP by binding to 𝛽-1 and 𝛽-2 receptors and blocking these receptors within the ciliary epithelium, effectively decreasing AH production.14
One study found that patients using oral 𝛽-blockers had 1 mmHg lower IOP than those not using oral 𝛽-blockers, and this difference would translate into a 14% reduced risk of incident glaucoma at the population level.15 Another found that oral 𝛽-blockers decreased IOP by 18.5-26% in patients with POAG and atrial hypertension over a one-year period.16
Care should be taken when managing hypertensive patients, as there are complex interactions between blood pressure (BP), ocular perfusion pressure (OPP), and IOP.17 High BP can increase IOP production through increased blood flow to the ciliary body and decrease AH outflow through increased episcleral venous pressure, thus increasing IOP.
On the other hand, low BP, occurring spontaneously or with antihypertensive medications, decreases OPP and increases the risk of optic nerve damage due to ischaemia.
For this reason, topical 𝛽-blockers should not be coupled with systemic 𝛽-blockers, as they have additive systemic effects, which further lowers BP and heart rate.18 Furthermore, studies have shown that the IOP lowering effect of topical 𝛽-blockers is reduced when coupled with systemic 𝛽-blockers.14 In this instance, alternatives such as alpha-2 agonists should be considered in patients taking systemic 𝛽-blockers, as it does not pose cardiovascular risk.6
Contradictory findings with CCBs
Glaucoma risk associated with calcium channel blockers is contradictory and is yet to be determined.
Calcium channel blockers (CCBs) are used widely for cardiovascular indications6, as CCBs block the inward movement of calcium by binding to calcium channels within the heart, vascular smooth muscle, and pancreas. This results in decreased heart rate and decreased systemic BP.19
The mechanism by which CCBs reduce IOP is unclear, but it may alter AH inflow by interfering with the gap junctions between the pigmented and nonpigmented ciliary epithelium to increase conventional outflow facility via the TM.20
There are contradictory findings about CCB use, effect on IOP and glaucoma risk. Some studies have suggested that CCBs increase optic nerve head and choroidal blood flow, which can potentially slow visual field deterioration in OAG patients,6 while another study has observed that CCBs have potential neuroprotective properties, as it inhibits an influx of calcium ions into retinal ganglion cells undergoing apoptotic and necrotic processes. Both processes are triggered by a calcium ion influx.20
However, other studies found that CCB use is associated with an increased risk of OAG and this effect was brought about primarily by amlodipine, the most commonly prescribed CCB in the study (21). Another study determined that patients using CCBs had a 1.8-fold higher risk of developing incident OAG.22
CCBs are not usually prescribed as first or second line treatments for hypertension but are prescribed in patients with refractory hypertension,6 which is an OAG glaucoma risk factor. Whether or not CCBs adversely affect glaucoma risk remains to be determined.
Promising research regarding Metformin
Metformin shows promise of decreasing glaucoma risk, but more research needs to be done to definitively determine this.
Metformin is a frequently prescribed drug of choice for patients with type 2 diabetes as it has clear benefits in relation to glucose metabolism. Metformin is a caloric restriction mimetic drug that has been found to have protective properties that delay or reduce the risk of various age-related systemic diseases.23
One study found that metformin use is associated with a reduced risk of developing OAG by 25% but other diabetic medications did not confer a similar risk reduction. Additionally, it was determined that patients taking a standard dose of 2 g of metformin per day for two years were predicted to have a 21% reduction in the risk of developing OAG.24 This suggests that metformin may affect OAG risk on multiple levels, of which involve glycemic control and other mechanisms outside of glycemic control such as neurogenesis, inflammatory systems, or longevity pathways targeted by this class of drug.
Another retrospective study concluded that patients with preexisting OAG failed to demonstrate that metformin could reduce risk of progression.6 However, this study used receipt of filtration surgery as a proxy for OAG progression even though there are many patients who experience progression with other treatment options.
While there is some support in metformin being beneficial in reducing OAG risk, more studies need to be done to arrive at a definitive conclusion before metformin can be prescribed as prevention or treatment for OAG.25 Furthermore, metformin’s effect of IOP is not yet clear but there may be a link between glucose levels and IOP that needs further research. 26
The controversial neuroprotective qualities of statins
The neuroprotective properties of statins is controversial: Some studies show decreased glaucoma risk while others show increased glaucoma risk, so more research is necessary.
Statins are a class of lipid-altering drugs used in the treatment of hyperlipidemia and aid in primary and secondary cardiovascular disease prevention. They reduce cholesterol synthesis and modulate lipid metabolism by inhibiting the enzyme that produces cholesterol precursors.27
Evidence showed that statins provide neuroprotection against cerebrovascular disease which triggered studies into their neuroprotective roles. Statins have been associated with decreased risk of developing OAG, unlike other cholesterol-lowering agents, which suggests that statins have unique properties in lowering glaucoma risk.6
The mechanism by which statins exert neuroprotection is not yet definitive but there are several theories.6 One proposed mechanism involves upregulation of endothelial nitric oxide synthase, causing vasodilation and increased retinal blood flow, thus potentially improving preservation of the optic nerve and retinal nerve fibre layer.
In addition to this, there is some increased outflow facility through the TM that results in decreased IOP through inhibition of rho-kinase activity. Finally, statins may decrease cytotoxicity and protect against apoptosis within the central nervous system, thereby reducing glaucoma progression.27, 28
The findings of several studies and reviews have been controversial. One study found that the risk of developing POAG increased by 7% for every 20 mg/dL increase in total serum cholesterol and that statin therapy was associated with a 15% lower risk of developing POAG. If patients used statins for more than five years, then they were 21% less at risk of developing POAG.29
A systematic review analysis found that short-term statin use of less than two years was associated with a reduced incidence of glaucoma.30 In contrast, another study found that high dosage of statin use resulted in a 1.24-fold increased risk of OAG and that the risk increased with an increased statin dosage.31
Since recent evidence on the neuroprotective properties of statins is controversial, a large prospective multicentre randomized controlled trial is needed to determine the true relationship between statin use and its associated glaucoma risk.6
Mixed findings with SSRIs
Studies on the use of selective serotonin reuptake inhibitors have elicited mixed findings on its associated glaucoma risk & so requires further research
Selective serotonin reuptake inhibitors (SSRIs) are prescribed as first line treatment for depression and other psychiatric conditions.6 They are commonly prescribed due to their high efficacy but an increased use of these medications increase the occurrence of adverse effects, prompting studies to determine if there is a relationship between SSRIs and IOP.32
It has been hypothesized that SSRIs may affect IOP through serotonergic effects on ciliary body muscle activation.33 SSRIs have been known to cause mydriasis, which is problematic in hyperopic and/or narrow angle patients as constant mydriasis can induce angle closure glaucoma32, but the effect of SSRIs on IOP and its associated glaucoma risk in open angle patients have been controversial.
One study evaluated the short-term and long-term effects of SSRIs on IOP in open angle eyes and concluded that the use of SSRIs lead to a decrease in IOP, regardless of length of use.32 Another found that there may be a delayed progression of glaucoma in patients using SSRIs.34 A different study found that long-term SSRI use did not influence the risk of POAG,31 while yet another concluded that treatment with SSRIs was associated with a greater risk of a glaucoma diagnosis, particularly in patients with longer duration and/or higher dosage of SSRI.35
The mixed findings of these studies indicate that further research needs to be done to determine the true relationship between SSRIs and glaucoma risk.
Positive effects of bupropion
Bupropion may decrease glaucoma risk with prolonged use and may also possess neuroprotective properties that prevent loss of retinal ganglion cells.
Bupropion is an antidepressant that is also prescribed for aiding with smoking cessation. It is a norepinephrine-dopamine reuptake inhibitor that suppresses production of tumor necrosis factor (TNF), that mediates retinal ganglion cell death in glaucoma.36
A few studies have found that bupropion use is connected to a decreased risk for OAG. Each additional month of bupropion use was associated with a 0.6% reduction in risk of developing OAG compared with patients who were not using bupropion, and the association did not differ among patients taking the medication for depression or for other purposes like smoking cessation.36
Another study concluded that patients who reported using bupropion for more than one year had 90% decreased odds of a glaucoma diagnosis, as compared to those not using bupropion or those using bupropion for less than one year.37
Anti-TNF drugs confer neuroprotective properties towards retinal ganglion cells38 and an animal model study found that etanercept is a TNF antagonist has been found to inhibit the inflammatory response mediated by microglial cells, preventing axonal degeneration and subsequent loss of retinal ganglion cells in rat models.6 This shows that further research needs to be done to substantiate whether bupropion and other medications that inhibit TNF play a role in glaucoma risk reduction or disease progression.
PMHs may modulate glaucoma risk
Postmenopausal hormones may decrease glaucoma risk with long-term use through neuroprotection and decreased IOP - suggesting there may be sex-specific factors that affect glaucoma risk.
Postmenopausal hormones (PMHs) usually consist of oral preparations containing estrogen, estrogen-progesterone, or estrogen-androgen combinations.6
There is evidence that PMHs may play a role in modulating the risk of glaucoma, more specifically, PMHs may exhibit neuroprotective properties. The exact mechanism of its protective effect is unknown, but it has been theorized that estrogen activates the synthesis of collagen fiber at the lamina cribrosa, thus improving compliance of the structure. This could relieve compression of the retinal ganglion cells and aid in their survival.39
Estrogen has also been found to decrease IOP via multiple mechanisms, including reducing production of AH, improving outflow facility, and reducing venous pressure through estrogen receptors in the ciliary epithelium, TM,, and blood vessels.40
A study done to determine the potential association between PMH use and POAG concluded that PMH preparations may reduce the risk for POAG, especially with long-term use. They found that with each additional month of PMH use containing estrogen only, the associated POAG risk was 0.4%, while POAG risk did not differ with each additional month of estrogen-progesterone use or estrogen-androgen combination use.41
Another study examined the association between PMH use and IOP in the context of a large randomized trial. They found that estrogen therapy in postmenopausal women was associated with a small but significant IOP reduction of 0.5 mmHg. Whether this is clinically significant or not remains to be seen.40
Lifetime exposure to estrogen may alter the pathogenesis of glaucoma and this highlights that there are unique, sex-specific risk factors in women, such as PMH use, early menache and early menopause that affect the risk of glaucoma.39
And, most controversial of all—cannabinoids
Cannabinoids are the most controversial and should not be recommended for glaucoma treatment without long-term & conclusive studies that focus on ONH health.
Cannabis consists of many chemical constituents, a subset of which are known as cannabinoids. Amongst them, Δ9-tetrahydrocannabinol (Δ9-THC, THC) and cannabidiol (CBD) have been found to affect IOP.42
The exact mechanism of action of the cannabinoids and their influence on IOP is vague, but the effects come about through CB-1 and CB-2 receptors within the body. Notably, CB-1 receptors have been found in the corneal endothelium, ciliary epithelium, ciliary body vessels, ciliary muscle, TM, Schlemm’s canal and retina.42, 43
Most likely IOP is decreased due to the influence on AH production, TM outflow and uveoscleral outflow. THC was found to decrease the amount of AH produced by acting on the CB-1 receptors within the ciliary processes, thus resulting in a lower IOP.42
Both cannabinoids cause vasodilation of the blood vessels throughout the body, including the anterior uvea vessels, which may result in better drainage through uveoscleral outflow. The cannabinoids also cause a lower systemic BP, including the capillary vessels involved in uveoscleral outflow, thus giving rise to a pressure change that results in increased uveoscleral outflow.42, 44
The IOP-reducing effect of cannabinoids is transient and lasts up to three hours.45 Therefore, to maintain controlled IOP with cannabinoids, patients would need substantial and frequent doses which puts them at risk of adverse systemic effects, including vasodilation and decreased BP, and psychotropic effects including euphoria, impairment of coordination and cognitive function.42
There have been controversial findings on cannabinoids and their effect on IOP. While THC was found to decrease IOP, CBD had an opposite effect. One study found that sublingual administration of 5 mg THC decreased IOP, 20 mg CBD had no effect on IOP and 40 mg CBD increased IOP.46 This is especially significant as cannabis strains are unregulated and vary widely, but it is expected that those with higher THC content will lower IOP while higher CBD content will raise IOP.45
Furthermore, some research suggests that cannabinoids possess neuroprotective properties as it may prevent cell death by ischaemia.42 Additionally, cannabinoids have vasorelaxant properties and may be able to increase ocular blood flow. However, cannabinoids also decrease systemic BP which may result in decreased ocular perfusion pressure and progressive optic nerve damage.44
Due to these mixed findings on cannabinoid use, cannabinoids should not be recommended as treatment for glaucoma without the presence of long-term and conclusive studies that focus on optic nerve health.47
Conclusion
Overall, it has been demonstrated through much research that these common medications can affect perfusion of the optic nerve, retinal ganglion cell survival, AH production, and its outflow facility, suggesting that these medications can influence the risk of OAG development and progression.
To summarize:
- Corticosteroids increase glaucoma risk by induction of ocular hypertension.
- Beta-blockers decrease glaucoma risk by reducing AH production but may increase risk through unmonitored BP.
- Metformin, bupropion and postmenopausal hormones may decrease glaucoma risk through their neuroprotective properties to prevent retinal ganglion cell death.
- Calcium channel blockers, statins, selective serotonin reuptake inhibitors and cannabinoids all have mixed findings in literature.
Eyecare practitioners and medical practitioners routinely prescribing these medications should be familiar with their side effects and are encouraged to undertake and develop a shared-care system so that IOP, BP, and OPP are constantly monitored to ensure that any adverse effects are detected early to prevent disease progression.
