This refers to side effects that arise from systemic absorption of eye drops used to treat glaucoma. Although eye drops are applied locally to the eye, much of the solution reaches the nasal mucosa through the nasolacrimal duct after instillation and is absorbed into the systemic circulation.
About 80% of a single eye-drop dose (approximately 25–50 μL) drains into the nasolacrimal duct and can be absorbed through the nasal mucosa and gastrointestinal tract1). Because absorption from the nasal mucosa is not subject to first-pass hepatic metabolism, some drugs (especially β-blockers) can reach systemic blood levels equal to or higher than those seen with oral administration1).
In older patients with glaucoma, cardiovascular and respiratory comorbidities are common, so the risk of side effects is higher2). With combination drugs, it is also easy for patients not to realize that they are using eye drops that contain a β-blocker.
About 80% of eyedrops drain into the nasolacrimal duct and are absorbed into the systemic circulation from the nasal mucosa1). Because absorption from the nasal mucosa does not undergo first-pass hepatic metabolism, beta-blockers in particular can reach relatively high blood concentrations. In patients with heart or respiratory disease and in infants, they can cause serious side effects.
The systemic side effects of each drug class are shown below.
Beta-blockers
Cardiovascular system: bradycardia, arrhythmia, worsening heart failure. One drop of timolol 0.5% eye drops can reach blood concentrations equivalent to 5–10 mg taken orally3).
Respiratory system: bronchoconstriction can worsen asthma and COPD. Due to beta2-receptor blockade.
Central nervous system: depression, fatigue, insomnia, nightmares, sexual dysfunction3).
Metabolic: masking of hypoglycemia (in patients with diabetes) and effects on lipid metabolism.
Prostaglandin analogues
Systemic side effects: Few. The frequency of systemic side effects is lower than with other drug classes.
Rare systemic symptoms: Reports of headache and muscle pain4).
Mainly local side effects: Periocular pigmentation, iris pigmentation, deepening of the upper eyelid sulcus, and eyelash growth4).
Notable examples: latanoprost, travoprost, tafluprost, and others.
Carbonic anhydrase inhibitors
Eye drops (dorzolamide, brinzolamide): bitter taste (taste disturbance) and contact dermatitis.
Sulfonamide allergy: Cross-reactivity with sulfa drug allergy is rare5).
Oral medication (acetazolamide): numbness in the limbs, loss of appetite, metabolic acidosis, and urinary stones5).
Caution: Contraindicated in patients with a history of hypersensitivity to sulfonamides.
α2-agonists (brimonidine)
Systemic symptoms: Dry mouth, drowsiness, and fatigue. In older adults, somnolence and dizziness → be mindful of fall risk6).
Infants and newborns: Contraindicated: Because the blood-brain barrier is immature, there is a risk of central nervous system depression (respiratory depression, bradycardia, hypothermia, hypotension)6).
Local side effects: Blepharitis and allergic conjunctivitis (common).
ROCK inhibitor (ripasudil)
Conjunctival hyperemia: Frequently seen as a local side effect7).
Systemic side effects: Rare. Few reports are available at present.
Note: This is a ROCK inhibitor developed in Japan and it promotes outflow through the aqueous humor drainage pathway (the Schlemm canal).
Parasympathomimetic agent (pilocarpine)
Systemic symptoms: Headache (due to ciliary muscle contraction), sweating, salivation, and nausea.
Effects of pupil constriction: Reduced vision in the dark and difficulty with near vision. Headaches may be more noticeable in younger people.
Local side effects: Posterior subcapsular cataract and risk of retinal detachment (with long-term use).
Beta-blocker eye drops block β2 receptors in the bronchi and can cause bronchoconstriction3). They are contraindicated in patients with asthma or COPD, and if you feel shortness of breath, wheezing, or difficulty breathing while using them, stop the drops immediately and consult your doctor. In an emergency, use a bronchodilator (such as isoproterenol).
After instillation, the drug solution mixes with tears and flows into the nasal cavity through the puncta, canaliculi, and nasolacrimal duct1). The nasal mucosa is highly vascular and has a large absorption surface area, so the drug enters the systemic circulation directly without first-pass metabolism in the liver1). This route may be more efficient than oral administration, and some drugs can reach unexpectedly high blood concentrations.
Topical beta-blockers are contraindicated in the following conditions and diseases.
Side effects are identified mainly through clinical evaluation.
The tests and assessments to check by drug class are listed below.
| Drug class | Tests and assessments to check |
|---|---|
| Beta blockers | ECG (bradycardia, arrhythmia) · pulse palpation · pulmonary function test (decreased FEV1) |
| Alpha-2 agonists | Assessment of central nervous system symptoms (alertness, blood pressure, respiratory rate) |
| Carbonic anhydrase inhibitors (oral) | Blood gas (metabolic acidosis) · urinary tract ultrasound (stones) |
| Pilocarpine | Check blood pressure, pulse, sweating, and salivation |
In older adults, systemic side effects from eye drops can be missed as a cause of fatigue, sleepiness, and depression-like symptoms2)6). In many cases, the internal medicine doctor does not know that glaucoma eye drops are being used, so using a medication notebook is helpful.
Yes, it is possible. With β-blocker eye drops, fatigue and depression-like symptoms have been reported3). In older adults, these symptoms are especially easy to miss, and coordination with internal medicine and dementia specialists is important. Brimonidine (an α2 agonist) can also cause central nervous system side effects such as drowsiness and somnolence6).
If side effects occur, seek instructions from a specialist promptly. The following are emergency measures.
As for pharmacokinetics after eye drop instillation, of the administered dose, no more than 5% passes through the cornea and reaches the intraocular tissues (anterior chamber and aqueous humor)1). Most of the rest is absorbed through the conjunctiva or drained through the nasolacrimal duct into the body.
Absorption from the nasal mucosa can bypass first-pass hepatic metabolism, so bioavailability may be higher than with oral administration1). With one drop of timolol 0.5% eye drops (about 50 μL, 250 μg), the amount absorbed systemically has been reported to reach blood concentrations equivalent to an oral dose of 5 to 10 mg3).
Nonselective β1/β2 beta-blockers act throughout the body through the following mechanisms.
β1-selective agents (betaxolol) have weaker action on β2 receptors and may have less effect on respiratory function than timolol in patients with asthma. However, this cannot be completely avoided8).
Brimonidine is an α2 receptor agonist that crosses the blood-brain barrier and stimulates central α2 receptors, producing sedative and hypotensive effects. In infants, the blood-brain barrier is immature, so central nervous system depression (altered consciousness, respiratory depression, bradycardia, hypothermia, and hypotension) is more likely to become severe, and it is considered contraindicated6). In older adults, it can also cause drowsiness and dizziness, increasing the risk of falls.
Measures such as lowering the dose, closing the eyes and pressing on the lacrimal sac after instillation, and sustained-release formulations are being studied to reduce systemic exposure1). The systemic side effect profiles of combination eye drops (such as prostaglandin/beta-blocker combinations) are also continuing to be evaluated2).
Research is progressing toward making eye drops unnecessary themselves. With DDS technologies such as sustained-release intraocular implants and microneedles, long-lasting drug effects are expected while avoiding systemic absorption9). This may lead to a fundamental solution to the problem of systemic side effects from eye drops.
Prospective studies on the risk of falls associated with the use of multiple glaucoma eye drops in older adults are being conducted6). Drowsiness, dizziness, and low blood pressure caused by brimonidine and beta-blockers may contribute to falls and fractures, and evaluation from a geriatric medicine perspective is needed.
A system has been reported that uses AI to integrate information such as a patient’s systemic comorbidities, medications, and kidney function to suggest the optimal glaucoma eye drops. From the standpoint of personalized medicine, it is expected to be applied to drug selection that minimizes the risk of side effects.
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Tanihara H, Inoue T, Yamamoto T, Kuwayama Y, Abe H, Araie M, et al. Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. American journal of ophthalmology. 2013;156(4):731-6. doi:10.1016/j.ajo.2013.05.016. PMID:23831221.
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Kompella UB, Hartman RR, Patil MA. Extraocular, periocular, and intraocular routes for sustained drug delivery for glaucoma. Progress in retinal and eye research. 2021;82:100901. doi:10.1016/j.preteyeres.2020.100901. PMID:32891866; PMCID:PMC8317199.
