Continuing Education Activity

Tropicamide is a safe drug for pupillary dilation before a comprehensive eye exam or ocular procedure. Pupillary dilation is also necessary for specific intraocular procedures such as cataract surgery to reduce intraoperative complications and for better exposure to the cataract during surgery. Pupillary dilation is also essential for retinal surgery and investigations of the posterior segment. The use of mydriatic agents such as tropicamide has, therefore, become ubiquitous in optical settings. This activity will review drug indications, mechanisms of action, side effects, and how an interprofessional approach can improve patient management.

Objectives:

• Describe the indications for tropicamide
• Summarize the mechanism through which tropicamide acts in each indication
• Review the adverse effects of tropicamide, including at-risk patients for which prescribers require extra caution.
• Explain some interprofessional team strategies for improving care coordination and communication to advance tropicamide where it is indicated and improve patient outcomes.

Indications

FDA Approved Indications

• Intended for diagnostic purposes: to achieve mydriasis

The preferred practice pattern of the American Academy of Ophthalmology recommends periodic dilated eye exams in different age groups.[1]

Achieving a clinically effective pupil diameter of 6 mm is essential for viewing structures in the posterior segment. The most common indication for a comprehensive exam with pupillary dilation is screening for diabetic retinopathy. The nondilated exam gives the correct classification for the presence or stage of diabetic retinopathy in only  50% of cases.[2] Pupillary dilation is necessary for specific intraocular procedures such as cataract surgery to reduce intraoperative complications and for better exposure to the cataract during surgery.[3] Pupillary dilation is also necessary for retinal surgery and investigations of the posterior segment. The use of mydriatic agents such as tropicamide has, therefore, become ubiquitous in each optical setting. Tropicamide comes in two formulations, 0.5% and 1.0%.[4]

The lower concentration of 0.5% produced less ocular discomfort with the same efficacy in dilating the pupil as the 1% solution in a study on 30 adolescents (aged 12 to 18 years) with type 1 diabetes.[5] Conversely, the higher concentration is typically used in adults and in eyes that dilate poorly, such as those with pigmented iris, peripheral iridotomy, and posterior synechia. Tropicamide binds with pigment and may take longer to act on darker irises.[6] Interestingly, one pilot study that evaluated the use of multiple drops of tropicamide concluded that a single drop of 0.5% is not inferior to two drops of 0.5% in pigmented eyes.[7]

• Intended for diagnostic purposes: cycloplegia

Eyecare specialists are interested in accommodation paralysis, also known as cycloplegia, when determining a patient's refractive error. Cycloplegic agents inactivate the ciliary muscle, so the patient cannot influence the refractive measurement. For example, an accurate evaluation is necessary before LASIK (laser-assisted in situ keratomileuses) surgery. In a 2017 meta-analysis, the more popular cycloplegic drug of choice, cyclopentolate, was compared to tropicamide. The research concluded that tropicamide is a viable alternative.[8]

FDA Non-approved, Off-label Use

• Parkinson Disease

The properties of anticholinergics can counter the imbalanced dopaminergic to cholinergic activity in neurological disorders such as Parkinson's disease. One randomized pilot study observed the safety and efficacy of tropicamide reduce sialorrhea in neurodegenerative diseases. Tropicamide was given orally as a dissolving film. Although the small sample size limited the power, a significant decrease in perceived symptoms on the visual analog scale and saliva volume measured with cotton balls occurred.[9] Tropicamide may have a role in alleviating the characteristic tremor exhibited by patients with Parkinsonism.

Mechanism of Action

Mechanism for Dilation

• As a parasympathetic antagonist, tropicamide exerts its dilatory effects by acting on the pupillary sphincter muscle to cause its relaxation.[10]  Like other anticholinergic agents, tropicamide inhibits the parasympathetic drive, allowing sympathetic actions to dominate.[11]  As the radial muscles of the iris (dilator pupillae), which are innervated by the sympathetic nervous system, are unaffected, they contract and cause the pupil to dilate. Its optimal effect occurs 25 to 30 minutes post-administration.[12] Typically, mydriasis reverses within 4 to 8 hours. However, it may take 24 hours for the mydriatic effect to wear off in some individuals. Weaker strength may cause mydriasis with little cycloplegia.

Mechanism for Cycloplegia

• Accommodation becomes hindered when tropicamide blocks the muscarinic receptors of the ciliary body. Its cycloplegic effect can last anywhere from 4 to 10 hours, with the onset of action occurring within 20 to 30 minutes.[13] This leads to reduced near vision.

The mechanism for Reduction of Sialorrhea

• Inhibition of the muscarinic acetylcholine receptors on salivary glands is responsible for decreasing hypersalivation in patients with Parkinson's disease.[9][14] Its potential therapeutic utility is because it is relatively selective for M4 receptors.[15] Researchers have seen promising results in abolishing drug-induced tremulous jaw movement in rodent models.[15] Future studies will be necessary to determine if the tremorolytic effects can be clinically useful and extended to man.

Administration

Administration requires the removal of contact lenses. This topical ophthalmic solution is instilled into the eye in droplet form. The lacrimal sac should be compressed with the fingertip for 2 to 3 minutes after administration to reduce systemic absorption and systemic adverse effects. The tip of the dropper should not touch any surface as it might contaminate the drug. In a child, ensure the drug does not get to their mouth. Hands require washing before and after instilling the drop. The individual should avoid driving and not engage in potentially hazardous activities during pupillary dilation. After pupillary dilation, sensitivity to light may occur, and sunglasses may be necessary.

An infrequently used option is spray application. Several studies have shown that using tropicamide in its vaporized form is just as effective in achieving increased pupil diameter but with less patient-reported discomfort.[16][17][18] In a randomized clinical trial, researchers concluded that administration via an ophthalmic insert, Mydriasert (containing 5.4 mg of phenylephrine hydrochloride and 0.28 mg of tropicamide), was safe and effective for use in neonates.[19]

Along with the active ingredient (tropicamide), the drop has multiple inactive ingredients. These include benzalkonium chloride (preservative), purified water, edetate disodium dihydrate, and boric acid. Hydrochloric acid and/or sodium hydroxide are used to adjust pH to 4.0 to 5.8. For refraction, one drop of tropicamide 1% is put in each eye 5 minutes apart. For examination of the fundus, 0.5% strength is an option. Tropicamide may dilate pupils in acute anterior uveitis, and one drop every 5 to 10 minutes should optimally dilate the pupil.

Adverse Effects

Ocular adverse events include transient stinging, photophobia, superficial punctate keratitis, blurred vision, and a rise in intraocular pressure.

Potential anticholinergic effects include dry mouth, high temperature, constipation, increased heart rate, and headache. Young children and the elderly are most susceptible to these side effects. Fortunately, due to its low affinity for muscarinic receptors and very low receptor occupancy in plasma, tropicamide applied as an eye drop rarely causes the systemic effects listed above.[20] The use of anticholinergic drugs carries a small risk of central nervous system (CNS) disturbance, including psychotic reactions and behavioral problems.[21]

Serious adverse events, especially vasomotor and cardiorespiratory collapse, behavioral changes, and psychotic reactions, have been reported rarely in children with the use of anticholinergic drugs, especially cyclopentolate.[22] Phenylephrine present in some mydriatic drops can cause systemic arterial hypertension, arrhythmia, tachycardia, myocardial infarction, syncope, and subarachnoid hemorrhage, and caution should be exercised while using these eye drops in preterm low birthweight babies or elderly patients with cardiovascular risk factors.[23] The medicine should remain out of the reach of children. Other side effects include nausea, vomiting, pallor, allergic reactions, and muscular rigidity.[24] 

Precipitating angle closure in primary open-angle glaucoma patients, as well as the potential increase in intraocular pressure after mydriasis, is a frequent concern to many ophthalmologists.[25] However, multiple studies involving high-risk groups demonstrated that the incidence is relatively low, and the risk of underdiagnosing vision-threatening diseases should be prioritized.[26] The importance of getting a clear view of the fundus should not be undermined. Nonetheless, clinicians should carefully monitor and educate at-risk patients regarding what symptoms to look out for, such as headache and eye pain. Pupillary dilation should be avoided in fellow eyes of acute angle closure glaucoma until an open peripheral iridotomy is ensured. Tropicamide is a category C drug in pregnancy, and it is unknown whether it is excreted in human milk. 

Allergic contact dermatitis or allergic blepharoconjunctivitis due to mydriatics:

Allergic contact dermatitis has been reported with phenylephrine[27] and less commonly with tropicamide, though the preservative agent, benzalkonium chloride, may also be responsible.[28] Methods to detect the offending agent include a skin patch test and conjunctival challenge test.[29] The conjunctival challenge test was shown to be safe and useful.[29] The conjunctival challenge test may detect the allergy when the skin patch test is negative.[29] A study on 37 patients with acute conjunctivitis after using mydriatic eye drops found phenylephrine to be the offending agent in 93.5% of cases, and one patient had an allergy to preservatives.[29] The allergic reaction to phenylephrine starts at around 3 to 4 hours and gradually subsides in 72 hours.[30] Management includes avoidance or stoppage of the offending agent and topical and/or systemic steroids/antiallergics. Such patients should be informed about the allergy, and the medical records should highlight this boldly so that the offending agent is avoided in future visits.

Contraindications

Hypersensitivity to any active/inactive ingredient constitutes a contraindication for its use. There have been no studies on tropicamide use during breastfeeding, but nursing mothers can reduce the amount that reaches the nasolacrimal duct by applying pressure to the lacrimal sac for some time (at least 1 minute) and wiping away any excess solution.[31]

Monitoring

There are no recommended diagnostic exams for monitoring the use of tropicamide. Pupillary dilation and dimness of near vision denote that the drug's action has started. If the pupil reacts to light, that means that the pupil is not fully dilated, and more time or more administration of tropicamide eye drops is needed for the maximal action to come.

Toxicity

Although tropicamide is a short-acting drug, and the frequency of associated adverse events is rare, there are certain instances when reversal of mydriasis is necessary, including decreasing the risk of angle-closure glaucoma, improving blurry vision, and decreasing recovery time for patient comfort. Presumably, a cholinergic agent like pilocarpine should be able to undo the effects of an anticholinergic drug. However, several studies have reported conflicting pupillary responses.[32][33][26][34] At times, only a partial reversal was observed.[35]

A study of 23 healthy subjects demonstrated that pilocarpine had an insignificant impact on returning pupil diameter to baseline. Seventeen percent of subjects reportedly had a reduction in visual acuity, indicating that pilocarpine use is futile and possibly detrimental.[33] For these reasons, its use after tropicamide-induced dilation has not gained wide acceptance. Alternatively, an adrenergic blocking agent, such as dapiprazole (0.5% eye drop) or moxisylyte (thymoxamine), can be used. This class of drugs exerts its effect by causing relaxation of the dilator muscle.[35] 

The use of dapiprazole can cut recovery time in half compared to waiting for tropicamide to wear off on its own.[36] Unfortunately, FDA has removed dapiprazole from the market for reasons unrelated to safety and efficacy. Currently, there are no approved methods of reversing tropicamide-induced mydriasis, and patients should wear sunglasses to mitigate light sensitivity.

Enhancing Healthcare Team Outcomes

Intravenous injection of tropicamide and other eye drops is a non-clinical use that has been on the rise in polydrug misusers. A recently published review describes factors such as low cost, easy access, and enhancement of heroin's effects as reasons for its misuse.[37] Healthcare professionals should be informed to recognize better high-risk populations of drug users and patients with psychiatric disorders.

There is limited information on interprofessional communication and tropicamide, as the absence of associated adverse events is well established. Nonetheless, coordinated care between the interprofessional healthcare team, including the pharmacist, optician, nurse practitioner, and ophthalmologist, ensures better outcomes. Suggestions for improvement include proper medication documentation and routine patient education. The use of tropicamide in the clinical setting requires an interprofessional approach, including open communication and accurate record keeping, with each caregiver operating in a team structure that leads to optimal patient results and minimizes adverse events. [Level 5]