ATC code S01

ATC code S01 designates the therapeutic subgroup for ophthalmologicals within the Anatomical Therapeutic Chemical (ATC) classification system, a World Health Organization (WHO)-recommended method for organizing drugs based on their anatomical site of action, therapeutic use, and chemical properties.^[1] This code encompasses the majority of topical eye preparations, such as antiinfectives, antiinflammatories, and antiglaucoma agents, as well as systemic drugs that have clear indications for treating eye conditions.^[2] Small quantities of antiseptics, like benzalkonium, in these formulations do not alter their classification under S01.^[2] The ATC system, maintained by the WHO Collaborating Centre for Drug Statistics Methodology at the Norwegian Institute of Public Health, structures drugs hierarchically across five levels, with S01 falling under the broader anatomical group S for sensory organs.^[3] Defined daily doses (DDDs) are assigned specifically for antiglaucoma preparations in S01, based on 0.1 ml (two eye drops) for once-daily use or 0.2 ml for twice-daily use, where 0.1 ml is equivalent to two drops (approximately 0.05 ml each, one per eye).^[2] Preparations intended for both eye and ear use are classified in S03, while eye-only formulations remain in S01.^[2] Key subgroups under S01 include:

• S01A: Antiinfectives – Plain and combined antiinfective eye preparations, with combinations involving corticosteroids classified in S01CA.^[2]
• S01B: Antiinflammatory agents – Non-steroidal antiinflammatory drugs and corticosteroids, either plain or in combinations excluding antiinfectives.^[2]
• S01C: Antiinflammatory agents and antiinfectives in combination – Eye preparations combining corticosteroids or non-steroidal antiinflammatories with antiinfectives, potentially including other active substances.^[2]
• S01E: Antiglaucoma preparations and miotics – Local and systemic treatments for glaucoma, including miotics irrespective of primary indication.^[2]
• S01F: Mydriatics and cycloplegics – Agents used to dilate the pupil or induce cycloplegia.^[2]
• S01G: Decongestants and antiallergics – Drugs addressing symptoms of ocular allergy.^[2]
• S01H: Local anesthetics – Topical anesthetics for ocular use.^[2]
• S01J: Diagnostic agents – Topical preparations aiding in the diagnosis of eye diseases.^[2]
• S01K: Surgical aids – Agents employed in ophthalmological surgery.^[2]
• S01L: Agents for treatment of ocular vascular disorders – Drugs targeting vascular issues in the eye.^[2]
• S01X: Other ophthalmologicals – Miscellaneous products, including artificial tears and contact lens solutions.^[2]

This classification supports drug utilization research, pharmacoepidemiology, and international comparisons of medication use in ophthalmology.^[4]

Overview

Definition and Scope

The Anatomical Therapeutic Chemical (ATC) classification system, maintained by the World Health Organization (WHO), organizes medicinal substances according to their anatomical site of action, therapeutic use, and chemical structure through a five-level hierarchical coding scheme. At the first level, 14 main anatomical or pharmacological groups are defined, with "S" representing the group for sensory organs. The second level, S01, is dedicated to ophthalmologicals, focusing on drugs intended for the treatment of eye conditions.^[1][3] The scope of ATC code S01 is limited to preparations licensed for eye use, predominantly topical formulations such as eye drops, ointments, and gels, while excluding products primarily for the ear (classified in S02); preparations intended for both eye and ear use (or eye, ear, and nose) are classified in S03. It encompasses therapeutic categories including antiinfectives, antiinflammatory agents, antiglaucoma drugs, mydriatics and cycloplegics, decongestants, local anesthetics, diagnostic agents, surgical aids, agents for ocular vascular disorders, and other adjunctive ophthalmological products like artificial tears. Although the primary emphasis is on topical applications, certain systemic drugs with a clear main indication for ophthalmological treatment are included; however, broadly systemic therapies for eye conditions, such as oral carbonic anhydrase inhibitors, are classified here only when their ophthalmological use predominates, reinforcing the topical focus overall.^[2] Established in the 1970s during the development of the ATC system by the Nordic Council on Medicines in collaboration with WHO, the S01 category has undergone minor revisions over the decades to accommodate new substances and therapeutic insights, with no significant structural alterations to its subgroups as of 2025. This evolution supports international drug utilization monitoring and research.^[5][6]

Classification Principles and Defined Daily Doses (DDD)

The Anatomical Therapeutic Chemical (ATC) classification for S01, which encompasses ophthalmological preparations, assigns codes based on the primary therapeutic use or pharmacological class of the active substance when applied to the eye.^[3] This hierarchical system uses five levels, with the first level (S) denoting sensory organs, the second (S01) specifying ophthalmologicals, and subsequent levels delineating therapeutic, pharmacological, and chemical subgroups.^[3] One ATC code is assigned per route of administration, prioritizing the main indication to ensure unique classification for each medicinal product.^[7] Fixed combinations within S01 follow specific rules to reflect their therapeutic rationale; for instance, products combining antiinflammatory agents with antiinfectives are classified in the dedicated subgroup S01C, while other combinations receive separate fifth-level codes, often in the 50-series, under the subgroup of the primary ingredient.^[8][7] New substances are typically placed in existing "other" (X) subgroups unless sufficient evidence from at least two products justifies creating a new third or fourth level.^[7] The WHO Collaborating Centre for Drug Statistics Methodology handles updates semi-annually based on requests from manufacturers, regulators, or experts, with the 2025 edition incorporating minor refinements to classification guidelines but no major structural changes to S01.^[7] Defined Daily Doses (DDDs) for antiglaucoma preparations and miotics in S01E are established to facilitate pharmacoepidemiological studies of drug utilization in this subgroup, providing a standardized measure of consumption despite the primarily local action and low systemic absorption of eye preparations.^[9] DDDs are volume- or mass-based, assuming an average maintenance dose for the main indication in adults, and are assigned per ATC code and administration route.^[8] For eye drop solutions, a single dose equates to 0.1 ml (two drops, one per eye), with the DDD scaled by frequency: 0.1 ml for once-daily administration, 0.2 ml for twice daily, and so forth; single-use packages use the full package volume as one dose.^[8] Eye ointments have a DDD of 0.04 g (40 mg), based on one daily application of approximately 10 mm (20 mg) per eye.^[8] DDDs for antiglaucoma preparations and miotics (S01E) remain volume-based regardless of concentration, reflecting standard dosing practices.^[10] Viscoelastic substances in S01K (surgical aids) generally lack assigned DDDs due to their non-daily, procedural use.^[8] As an illustrative example, timolol (S01ED01), a beta-blocking agent for glaucoma, has a DDD of 0.2 ml, corresponding to twice-daily administration of one drop per eye.^[11] These DDD values enable comparable consumption metrics across countries, supporting global monitoring of ophthalmological drug trends.^[9]

Antiinfectives (S01A)

Defined daily doses (DDDs) are not assigned for topical antiinfectives in S01A, as they are generally based on volume for antiglaucoma preparations only in S01E.^[2]

Antibiotics (S01AA)

Topical antibiotics classified under ATC code S01AA are primarily used in ophthalmology to treat bacterial infections of the ocular surface, such as bacterial conjunctivitis and keratitis, by delivering high local concentrations with minimal systemic exposure.^[12] These agents target superficial anterior segment infections, including those caused by gram-positive and gram-negative bacteria, and are administered as eye drops or ointments to rapidly eradicate pathogens while reducing inflammation and preventing complications like corneal scarring.^[13] Targeted application helps mitigate the development of antimicrobial resistance by limiting unnecessary broad-spectrum use and promoting shorter treatment durations, typically 5-7 days for uncomplicated cases.^[14] Antibiotic stewardship programs in ophthalmology emphasize microbiological confirmation where possible and avoidance of prophylaxis in low-risk scenarios to preserve efficacy against emerging resistant strains.^[15] Key substances in this group include chloramphenicol (S01AA01), a broad-spectrum antibiotic effective against both gram-positive and gram-negative organisms commonly implicated in conjunctivitis.^[16] Gentamicin (S01AA11), an aminoglycoside particularly useful for gram-negative infections in keratitis, works by binding to the 30S ribosomal subunit to cause mRNA misreading and inhibit protein synthesis.^[16] Erythromycin (S01AA07), a macrolide indicated for chlamydial conjunctivitis, inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking translocation during translation.^[16] Tobramycin (S01AA10), another aminoglycoside, shares a similar mechanism to gentamicin and is often preferred for Pseudomonas aeruginosa-related keratitis due to its potency against this pathogen.^[16] Oxytetracycline (S01AA04), a tetracycline, prevents protein synthesis by binding to the 30S ribosomal subunit and blocking aminoacyl-tRNA attachment, making it suitable for atypical bacterial infections.^[16] Chloramphenicol exemplifies a unique regulatory profile: while banned for use in food-producing animals in many countries due to risks of aplastic anemia from systemic exposure, topical ocular formulations are permitted because absorption through the conjunctiva and nasolacrimal duct results in plasma levels too low to pose significant hematologic risks, with studies detecting no systemic accumulation after standard dosing in children.^[17][18] Other mechanisms in S01AA focus on protein synthesis inhibition across classes, distinguishing these from sulfonamides (S01AB), which block folic acid synthesis, and fluoroquinolones (S01AE), which target DNA gyrase and topoisomerase IV.^[19] As of the 2025 ATC/DDD Index update, no new substances have been added to S01AA, reflecting stable classification amid ongoing emphasis on stewardship to combat resistance, with combinations of these antibiotics and corticosteroids addressed separately in S01CA for cases involving both infection and inflammation.^[7][20]

Sulfonamides (S01AB)

Sulfonamides classified under ATC code S01AB represent a group of bacteriostatic antibiotics primarily employed for topical treatment of superficial ocular bacterial infections, such as bacterial conjunctivitis and trachoma.^[21] These agents target gram-positive and gram-negative bacteria by competitively inhibiting dihydropteroate synthase, an enzyme essential for bacterial folic acid synthesis, thereby disrupting DNA and protein production required for microbial growth.^[22] Unlike broader-spectrum antibiotics in S01AA, sulfonamides specifically block the para-aminobenzoic acid (PABA) pathway unique to bacteria, as humans obtain folic acid through diet.^[23] Sulfacetamide (S01AB04) stands as the most commonly used topical sulfonamide in ophthalmology, available as eye drops or ointments at concentrations of 10% or 30%.^[24] Another notable substance is sulfadicramide (S01AB03), which shares a similar profile but is less frequently prescribed today.^[25] Introduced in the 1930s following the discovery of Prontosil—a precursor dye with antibacterial properties—these drugs marked an early milestone in antimicrobial therapy for ocular conditions, including trachoma, where systemic or topical application demonstrated efficacy in reducing follicular inflammation and preventing scarring.^[26] Their historical role in mass treatment campaigns for endemic trachoma in resource-limited regions underscored their accessibility and low cost.^[27] Contemporary use of plain sulfonamides has declined due to widespread bacterial resistance, primarily mediated by plasmid-encoded dihydropteroate synthase variants that evade inhibition, rendering many strains unresponsive.^[28] Resistance patterns vary by region but are prevalent among common ocular pathogens like Staphylococcus aureus and Haemophilus influenzae, limiting monotherapy to mild cases or prophylaxis post-injury.^[29] Nonetheless, in resource-limited settings, sulfonamides retain value for their affordability—often under $1 per treatment course—and broad availability, serving as a viable option where advanced antibiotics like fluoroquinolones are inaccessible.^[30] Clinical guidelines emphasize short-duration therapy (5-7 days) to minimize resistance emergence while achieving resolution in susceptible infections.^[31]

Antivirals (S01AD)

The ATC subgroup S01AD classifies antiviral agents formulated for topical ophthalmic use, primarily addressing viral infections affecting the eye, such as herpes simplex virus (HSV)-induced keratitis and cytomegalovirus (CMV) retinitis in immunocompromised patients. These medications inhibit viral replication by targeting DNA synthesis, offering localized treatment to minimize systemic exposure and side effects like nephrotoxicity associated with oral or intravenous alternatives. Unlike bacterial antiinfectives in S01AA and S01AB, which target prokaryotic replication, S01AD agents specifically disrupt eukaryotic viral enzymes, such as DNA polymerase.^[32][33] Prominent substances include aciclovir (S01AD03), a guanosine nucleoside analogue that is phosphorylated by viral thymidine kinase to form a triphosphate inhibiting HSV DNA polymerase, effectively treating acute herpetic epithelial and stromal keratitis. Trifluridine (S01AD02), a pyrimidine analogue, similarly competes with thymidine to halt viral DNA chain elongation and is indicated for HSV keratitis, particularly in cases resistant to other therapies, with application as a 1% solution up to nine times daily. Ganciclovir (S01AD09), another nucleoside analogue, is used topically as a 0.15% gel for acute herpetic keratitis and intravitreally for CMV retinitis, where it is converted to ganciclovir triphosphate to block CMV DNA polymerase, providing efficacy in AIDS-related ocular infections.^[34][33] Vidarabine (S01AD06), an adenosine nucleoside analogue that inhibits viral DNA polymerase after conversion to its triphosphate form, was historically used for HSV keratitis but has been discontinued in many countries, including the United States since 2001, due to the superior efficacy, lower toxicity, and better bioavailability of aciclovir; it remains in the ATC classification for legacy purposes despite limited availability by 2025. These agents are typically applied as ointments or gels to enhance corneal penetration, with treatment durations ranging from 7 to 21 days depending on the infection severity, and combinations with corticosteroids (classified in S01CA) are avoided initially to prevent viral reactivation. Resistance, particularly in immunocompromised patients, underscores the need for viral sensitivity testing in refractory cases.^[35][36][33]

Fluoroquinolones (S01AE)

Fluoroquinolones classified under ATC code S01AE are synthetic antibacterial agents specifically formulated for topical ophthalmic administration to treat bacterial infections of the eye, offering broad-spectrum activity against both gram-positive and gram-negative pathogens common in ocular conditions. These agents are particularly valued for their potency in penetrating ocular tissues, providing effective coverage against resistant strains that challenge other antibiotic classes. Unlike broader antibiotic groups in S01AA, fluoroquinolones in S01AE exhibit enhanced bactericidal effects tailored for ocular environments, where factors like tear turnover and corneal barriers demand high local concentrations. The primary uses of S01AE fluoroquinolones include the treatment of bacterial corneal ulcers (keratitis) and prophylaxis against endophthalmitis following ocular surgeries such as cataract extraction. For instance, in corneal ulcers caused by Pseudomonas aeruginosa or Staphylococcus species, these drugs achieve rapid clinical resolution by inhibiting bacterial replication at the site of infection. Prophylactic application, often involving multiple drops pre- and post-operatively, has been shown to reduce endophthalmitis incidence to below 0.1% in large cohorts, underscoring their role in surgical outcomes. By 2025, their utilization has increased in response to rising multidrug-resistant ocular pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum beta-lactamase-producing gram-negatives, where empirical therapy relies on their reliable spectrum.^[37][38][39] These agents exert their mechanism of action by inhibiting bacterial topoisomerases, specifically DNA gyrase and topoisomerase IV, which are essential for DNA unwinding and replication during bacterial cell division. This dual-targeting stabilizes the enzyme-DNA cleavage complex, preventing religation and leading to double-strand DNA breaks and cell death. Key substances include ofloxacin (S01AE01), ciprofloxacin (S01AE03), levofloxacin (S01AE05), moxifloxacin (S01AE07), and besifloxacin (S01AE08). Notably, besifloxacin is uniquely designed for exclusive ophthalmic use, achieving negligible systemic exposure (less than 0.5 ng/ml in plasma after dosing), which minimizes the risk of contributing to broader resistance patterns seen with systemically absorbed fluoroquinolones. This eye-specific formulation enhances safety while maintaining high corneal and conjunctival concentrations for targeted therapy.^[40][41][42]

Other Antiinfectives (S01AX)

The S01AX subgroup within the ATC classification system includes miscellaneous antiinfective agents for ophthalmological use that are not categorized under antibiotics (S01AA), sulfonamides (S01AB), antivirals (S01AD), or fluoroquinolones (S01AE). These agents primarily consist of antiseptics, biguanides, and other compounds employed for targeted antimicrobial activity against non-bacterial pathogens or for prophylactic purposes in ocular procedures. Unlike the more specific pathogen-targeted classes, S01AX preparations address a range of infections, including protozoal conditions like Acanthamoeba keratitis, and serve as adjuncts in surgical settings to prevent postoperative infections.^[43] Indications for S01AX agents focus on prophylaxis during ocular surgery and treatment of rare but severe infections such as Acanthamoeba keratitis, a sight-threatening protozoal infection often associated with contact lens wear. For instance, povidone-iodine (S01AX18) is widely used as a 5% ophthalmic solution for peri-ocular and conjunctival antisepsis prior to intraocular surgery, reducing the risk of endophthalmitis by providing broad-spectrum activity against bacteria, fungi, and viruses. In neonatal care, 2.5% povidone-iodine has demonstrated superior efficacy over traditional silver nitrate in preventing ophthalmia neonatorum, with lower toxicity and faster bacterial clearance. For Acanthamoeba keratitis, biguanide agents like polihexanide (S01AX24, also known as polyhexamethylene biguanide or PHMB) and propamidine (S01AX15) are first-line therapies, often applied topically every 1-2 hours initially, achieving cure rates exceeding 90% when initiated early. These treatments target the cyst and trophozoite forms of Acanthamoeba, filling a gap left by conventional antibacterials.^[44][45][46] Key substances in this subgroup exemplify diverse chemical classes with unique antimicrobial profiles. Povidone-iodine functions as an iodophore, slowly releasing free iodine to penetrate microbial cells, where it denatures proteins, oxidizes cellular components, and disrupts nucleic acid synthesis, providing rapid bactericidal, fungicidal, and virucidal effects without significant resistance development. Polihexanide (S01AX24), a polymeric biguanide, exerts its action by binding to negatively charged bacterial and protozoal cell surfaces, disrupting phospholipid membranes and inhibiting DNA replication, making it particularly effective against Acanthamoeba cysts that resist other agents; clinical trials have confirmed its safety and efficacy in pediatric and adult patients with keratitis, with resolution in most cases within 6-12 months. Propamidine (S01AX15) and dibrompropamidine (S01AX07), diamidine derivatives, similarly target Acanthamoeba by interfering with DNA synthesis and membrane integrity. Chlorhexidine (S01AX09), another biguanide, offers broad antiseptic properties through electrostatic interactions that permeabilize cell walls, though its use in ophthalmology is more limited due to potential corneal toxicity at higher concentrations. No defined daily doses (DDDs) are assigned for most S01AX agents, as they are topical and used on an as-needed basis rather than for maintenance therapy.^{[47][48][46][49]} Historically, silver compounds (S01AX02) and mercury compounds (S01AX01) were included for their oligodynamic antimicrobial effects, where low concentrations disrupt microbial enzymes and respiratory chains via heavy metal ion binding. However, their use has significantly declined due to documented toxicity, including argyria (permanent blue-gray discoloration of ocular tissues and skin) from silver accumulation and potential neurotoxicity from mercury. By the mid-2020s, regulatory bodies and clinical guidelines have largely phased out these agents in favor of safer alternatives like iodophors and biguanides, citing risks of chronic exposure even at therapeutic levels. Other notable agents include nitrofural (S01AX04), which reduces bacterial enzymes via nitro group reduction, and bibrocathol (S01AX05), a mercury derivative with similar limitations. These older compounds underscore the evolution toward less toxic profiles in modern ophthalmological antiinfectives.^[50][51][43]

Antiinflammatory Agents (S01B)

Corticosteroids, Plain (S01BA)

Corticosteroids, plain, classified under ATC code S01BA, refer to topical ophthalmic preparations containing solely corticosteroids without additional active ingredients, primarily formulated as eye drops or ointments for direct application to the ocular surface. These agents are indicated for managing non-infectious inflammatory conditions of the eye, leveraging their potent anti-inflammatory properties to alleviate symptoms such as redness, swelling, and pain.^[52] The primary uses of S01BA corticosteroids include the treatment of anterior uveitis, where they help control intraocular inflammation and prevent complications like synechiae formation, and postoperative inflammation following procedures such as cataract surgery or corneal transplantation, reducing the risk of cystoid macular edema.^[53][54] Key substances in this subgroup encompass dexamethasone (S01BA01), a highly potent glucocorticoid commonly used for acute inflammatory episodes; prednisolone (S01BA04), valued for its intermediate potency and broad efficacy in corneal and conjunctival inflammation; and fluorometholone (S01BA05), a milder option preferred for superficial corneal conditions due to its lower penetration into the anterior chamber and reduced systemic absorption.^[55][56][57] These corticosteroids exert their therapeutic effects by binding to glucocorticoid receptors, which translocate to the nucleus and inhibit the enzyme phospholipase A2, thereby blocking the release of arachidonic acid and subsequent synthesis of prostaglandins and leukotrienes that drive ocular inflammation. A notable example is loteprednol (S01BA09), engineered through soft drug design where the molecule is rapidly metabolized into an inactive metabolite upon entering the aqueous humor, offering effective anti-inflammatory action with a minimized risk of elevating intraocular pressure compared to traditional steroids.^[58][59] However, prolonged use of S01BA agents, particularly potent ones like dexamethasone, carries a significant risk of inducing secondary glaucoma through trabecular meshwork dysfunction and elevated intraocular pressure, necessitating regular monitoring and tapered dosing regimens.^[60]

Corticosteroids and Mydriatics in Combination (S01BB)

The S01BB subcategory within the ATC classification system includes fixed-combination ophthalmic preparations that pair corticosteroids with mydriatics to address inflammatory ocular conditions requiring both anti-inflammatory action and pupillary dilation. These formulations are primarily indicated for the management of posterior uveitis, where inflammation affects the posterior segment of the eye, and dilation is essential to facilitate examination, reduce pain from ciliary muscle spasm, and prevent adhesions such as posterior synechiae. By combining these agents, the preparations offer synergistic benefits: the corticosteroid suppresses inflammatory responses, while the mydriatic promotes pupil enlargement for better posterior segment access and symptomatic relief.^[61][62] Representative substances in this category include hydrocortisone and mydriatics (ATC S01BB01), prednisolone and mydriatics such as phenylephrine (ATC S01BB02), and dexamethasone and mydriatics (ATC S01BB04), which exemplify the targeted approach for uveitis therapy. These combinations enhance efficacy by allowing concurrent delivery, minimizing the need for multiple instillations and improving patient adherence in acute settings. The mydriatic component, such as tropicamide (an anticholinergic) or phenylephrine (a sympathomimetic), induces rapid and controlled dilation, complementing the corticosteroid's role in stabilizing vascular permeability and reducing cellular infiltration in the uveal tract. Clinical use focuses on short-term application to avoid prolonged exposure risks, with dosing typically involving 1-2 drops several times daily, tapered based on response.^[61][63] The limited number of approved substances in S01BB reflects formulation challenges, including chemical stability issues arising from the differing pH sensitivities and solubility profiles of corticosteroids and mydriatics in aqueous eye drop vehicles, which can lead to degradation or precipitation over time. Unlike plain corticosteroids in S01BA, these combinations emphasize the integrated mydriatic effect for therapeutic dilation during inflammation management. As of the 2025 ATC index, no new additions have been incorporated into this subcategory, underscoring the established but constrained portfolio of options.^[6][64]

Non-Steroidal Antiinflammatory Agents (S01BC)

Non-steroidal anti-inflammatory agents classified under ATC code S01BC are topical ophthalmic formulations designed to alleviate ocular inflammation through inhibition of cyclooxygenase (COX) enzymes, which reduces prostaglandin synthesis responsible for pain, swelling, and redness in the eye. These agents offer a steroid-sparing alternative for managing postoperative inflammation, particularly after cataract surgery, without the associated risks of elevated intraocular pressure. Their mechanism primarily targets COX-1 and COX-2 isoforms to limit inflammatory cascades in ocular tissues, providing targeted relief while minimizing systemic absorption.^[65][66] Key therapeutic applications include the prevention and treatment of cystoid macular edema (CME), a common complication following ocular surgery characterized by retinal swelling due to disrupted blood-retinal barrier, and the symptomatic relief of allergic conjunctivitis, where they mitigate itching, redness, and chemosis by curbing histamine-mediated prostaglandin release. Representative examples encompass diclofenac (S01BC03), employed to control postoperative inflammation and pain after cataract extraction; ketorolac (S01BC05), indicated for seasonal allergic conjunctivitis and to reduce swelling post-refractive surgery; and nepafenac (S01BC10), a prodrug that achieves superior intraocular penetration by rapid hydrolysis to active amfenac in corneal and retinal tissues, enhancing efficacy against CME.^{[67][68][69][70]} Bromfenac (S01BC11) exemplifies advancements in this class, with U.S. FDA approval in October 2010 for a once-daily 0.09% formulation that sustains anti-inflammatory effects through prolonged COX-2 inhibition, improving patient adherence in postoperative settings. A primary advantage of S01BC agents is their lack of impact on intraocular pressure, allowing safer use in glaucoma-susceptible individuals compared to steroidal alternatives.^[71][72]

Antiinflammatory Agents and Antiinfectives in Combination (S01C)

Corticosteroids and Antiinfectives in Combination (S01CA)

The ATC code S01CA encompasses ophthalmic preparations that combine corticosteroids with antiinfective agents, primarily for topical use in treating inflammatory eye conditions accompanied by or at risk of bacterial infection. These formulations allow for simultaneous management of inflammation and microbial threats, with classification at the fourth level as S01CA for corticosteroids and antiinfectives in combination, with the fifth level specifying the corticosteroid component (e.g., S01CA01 for dexamethasone and various antiinfectives). Unlike plain corticosteroids classified under S01BA, which address non-infectious inflammation, S01CA products integrate antiinfectives to target scenarios where infection control is essential alongside anti-inflammatory action.^[73] The fifth-level codes under S01CA include:

• S01CA01: Dexamethasone and antiinfectives
• S01CA02: Prednisolone and antiinfectives
• S01CA03: Hydrocortisone and antiinfectives
• S01CA04: Fluocortolone and antiinfectives
• S01CA05: Betamethasone and antiinfectives
• S01CA06: Cortisone and antiinfectives
• S01CA07: Prednisolone and antiinfectives (different formulation)
• S01CA08: Rimexolone and antiinfectives
• S01CA09: Loteprednol and antiinfectives
• S01CA10: Fluorometholone and antiinfectives
• S01CA11: Clobetasone and antiinfectives
• S01CA12: Difluprednate and antiinfectives
• S01CA13: Triamcinolone and antiinfectives^[73]

Indications for S01CA preparations include steroid-responsive inflammatory conditions of the eyelids, conjunctiva, cornea, and anterior eye segment where bacterial involvement or risk is present, such as blepharitis, conjunctivitis, keratitis, and post-operative inflammation following ocular surgery. For instance, blepharitis treatment often involves these combinations to reduce eyelid inflammation and eradicate contributing bacteria, with clinical trials demonstrating significant improvement in signs like redness and discharge when antibiotics are paired with topical corticosteroids. Post-surgical use is common to prevent or treat infections while mitigating swelling after procedures like cataract extraction, where the dual action helps maintain visual recovery.^[74][75][76] Representative examples include dexamethasone combined with tobramycin (S01CA01), marketed as Tobradex, which is indicated for inflammatory ocular conditions with bacterial risk, including corneal ulcers and chronic anterior uveitis. Another is prednisolone acetate with gentamicin (S01CA02), as in Pred-G, used for similar inflammatory states like uveitis or allergic responses complicated by infection. These products balance anti-inflammatory effects that suppress swelling and redness with antiinfective properties that target pathogens, though defined daily doses (DDDs) are not assigned in the ATC system for S01CA due to variable formulations and lack of standardized consumption metrics beyond active components.^[74][77] A key risk associated with S01CA use is the potential for corticosteroids to mask signs of infection progression or exacerbate underlying issues if antiinfectives prove inadequate against resistant bacteria, leading to delayed diagnosis and complications like corneal perforation. This underscores the need for careful monitoring, as prolonged application without confirmed bacterial etiology can promote secondary infections or fungal overgrowth. Prescribers must weigh these benefits against risks, particularly in patients with thin corneal tissue or viral predispositions.^[78][79][80]

Corticosteroids/Antiinfectives/Mydriatics in Combination (S01CB)

The ATC subgroup S01CB includes ophthalmic formulations that integrate corticosteroids for anti-inflammatory action, antiinfectives to address bacterial pathogens, and mydriatics to induce pupil dilation, primarily for treating severe inflammatory conditions complicated by infection. These combinations are indicated for cases like severe anterior uveitis with bacterial involvement, where inflammation control, infection eradication, and prevention of iris adhesions (synechiae) are essential to avoid complications such as glaucoma or vision loss.^[81][82] The mydriatic component, often an alpha-adrenergic agonist, complements the dual corticosteroid-antiinfective therapies by facilitating examination and reducing ciliary spasm, extending utility beyond simpler combinations.^[62] The fifth-level codes under S01CB include:

• S01CB01: Dexamethasone, antiinfectives and mydriatics
• S01CB02: Prednisolone, antiinfectives and mydriatics
• S01CB03: Hydrocortisone, antiinfectives and mydriatics
• S01CB04: Betamethasone, antiinfectives and mydriatics
• S01CB05: Fluorometholone, antiinfectives and mydriatics^[83]

A key example in this subgroup is S01CB01, which includes combinations of dexamethasone with antiinfectives and mydriatics, targeting a broad spectrum of ocular bacteria while mitigating inflammation and promoting mydriasis. Other entries, such as S01CB02 (prednisolone-based) and S01CB03 (hydrocortisone-based), follow similar structures but are less commonly formulated with the full triad due to stability challenges in multi-component suspensions.^[83] These triple or quadruple combinations remain rare in clinical practice owing to formulation complexities, including chemical instability and manufacturing difficulties when incorporating multiple active agents into a single ophthalmic vehicle. Primarily consisting of older products approved decades ago, the subgroup has seen no new entries as of November 2025, reflecting a broader shift toward dual corticosteroid-antiinfective therapies that balance efficacy with simpler administration and reduced risk profiles.^[83] A notable challenge with S01CB preparations is the heightened potential for adverse effects from polypharmacy, including elevated intraocular pressure and cataract formation from prolonged corticosteroid use, ototoxicity or nephrotoxicity from aminoglycosides like neomycin in susceptible patients, and transient hypertension or allergic reactions from mydriatics like phenylephrine. Careful monitoring is required, with therapy typically limited to short courses under specialist supervision to minimize these risks while achieving therapeutic goals in acute, severe scenarios.^[84]

Non-Steroidal Antiinflammatory Agents and Antiinfectives in Combination (S01CC)

Non-steroidal antiinflammatory agents combined with antiinfectives represent a subclass of ophthalmic preparations designed to manage both inflammation and bacterial infection in the eye, particularly in scenarios where corticosteroid use is contraindicated due to risks such as elevated intraocular pressure (IOP).^[85] These combinations leverage the anti-inflammatory properties of NSAIDs, which inhibit cyclooxygenase (COX) enzymes to reduce prostaglandin synthesis and subsequent ocular inflammation, alongside antibiotics that target bacterial pathogens directly.^[86] Unlike plain NSAIDs (classified under S01BC), these formulations address infectious contexts by incorporating antimicrobial activity, offering a targeted approach for postoperative or traumatic ocular conditions.^[87] The fifth-level codes under S01CC include:

• S01CC01: Diclofenac and antiinfectives
• S01CC02: Indometacin and antiinfectives^[85]

The primary indications for S01CC preparations include the prevention and treatment of postoperative inflammation following cataract surgery, where they help control pain, swelling, and potential infection without the IOP elevation associated with steroids.^[88] They are also employed for managing traumatic corneal abrasions, reducing discomfort and preventing secondary bacterial infections in mild cases.^[89] This category avoids the dependency risks of corticosteroids, providing a safer profile for non-severe inflammatory infections in patients with glaucoma predisposition or those requiring short-term therapy.^[90] Key substances in this subclass include combinations under S01CC01 (diclofenac and antiinfectives) and S01CC02 (indometacin and antiinfectives). Diclofenac-gentamicin (0.1% diclofenac with 0.3% gentamicin) is a representative fixed-dose combination that demonstrates efficacy in suppressing early postoperative inflammation while preventing infection, showing superior or equivalent results to antibiotic monotherapy in clinical trials.^[88] Similarly, diclofenac-tobramycin (0.1% diclofenac with 0.3% tobramycin) has been evaluated for its tolerability and ability to reduce ocular inflammation post-surgery, with good ocular penetration and minimal adverse effects.^[91] For S01CC02, indomethacin-gentamicin (0.1% indomethacin with 0.3% gentamicin) effectively alleviates pain and inflammation in corneal abrasions, proving well-tolerated and superior to placebo in reducing discomfort.^[89] Another indomethacin-gentamicin formulation prevents cystoid macular edema and inflammation after cataract extraction, with studies confirming its safety profile.^[92] The mechanism of synergy in these combinations arises from the complementary actions: the NSAID component (e.g., diclofenac or indomethacin) inhibits COX-1 and COX-2 to decrease vascular permeability, leukocyte migration, and pain mediators, while the antibiotic (e.g., gentamicin or tobramycin) disrupts bacterial protein synthesis via aminoglycoside binding to the 30S ribosomal subunit, eradicating pathogens like Staphylococcus and Pseudomonas species common in ocular infections.^[86] This dual action enhances overall therapeutic outcomes in infectious-inflammatory states, such as post-cataract care, where inflammation can exacerbate infection risk.^[90] Clinical evidence supports their use in cataract surgery contexts, with formulations like diclofenac-gentamicin showing reduced anterior chamber cells and flare compared to controls.^[88]

Antiglaucoma Preparations and Miotics (S01E)

Sympathomimetics in Glaucoma Therapy (S01EA)

Sympathomimetics in glaucoma therapy, classified under ATC code S01EA, are adrenergic agonist medications primarily used to lower intraocular pressure (IOP) in patients with open-angle glaucoma, a condition characterized by impaired drainage of aqueous humor through the trabecular meshwork, leading to elevated IOP and potential optic nerve damage.^[93] These agents act on alpha-adrenergic receptors in the ciliary body to reduce the production of aqueous humor, thereby restoring the balance between fluid inflow and outflow essential for maintaining normal IOP levels around 10-21 mmHg.^[94] By targeting the inflow pathway, S01EA drugs provide an effective monotherapy or adjunctive option, particularly when first-line treatments like prostaglandin analogues are insufficient or contraindicated. The core mechanism of these sympathomimetics involves selective stimulation of alpha-2 adrenergic receptors, which inhibits adenylate cyclase activity in the ciliary epithelium, decreasing aqueous humor secretion; some also promote uveoscleral outflow through relaxation of the ciliary muscle.^[94] For instance, brimonidine (S01EA05), a highly selective alpha-2 agonist, reduces IOP by 20-25% within 1-2 hours of administration, with effects lasting up to 12 hours, making it suitable for twice-daily dosing at a defined daily dose (DDD) of 0.2 ml (0.1 ml per eye).^[95] Apraclonidine (S01EA03), another alpha-2 agonist, shares a similar mechanism but is primarily reserved for short-term use, such as preventing IOP spikes following argon laser trabeculoplasty, due to risks of tachyphylaxis and allergic reactions with prolonged application.^[96] In contrast, dipivefrine (S01EA02), a prodrug of epinephrine that enhances corneal penetration via its lipophilic nature, activates both alpha and beta receptors to reduce aqueous production and improve trabecular outflow while minimizing mydriasis compared to direct epinephrine; however, it has been discontinued in markets like the United States and Australia by 2025 due to limited demand and availability of superior alternatives.^[97][98][99] Clinical use of S01EA agents emphasizes their role in open-angle glaucoma management, often as second-line therapy after beta-blockers, with brimonidine demonstrating neuroprotective potential by improving ocular blood flow and reducing retinal ganglion cell apoptosis in preclinical models.^[100] Common adverse effects include conjunctival hyperemia, dry mouth, and eyelid dermatitis, particularly with apraclonidine, necessitating monitoring for systemic absorption in patients with cardiovascular comorbidities.^[101] While epinephrine (S01EA01) and clonidine (S01EA04) are also classified here, their topical use has declined due to higher side effect profiles and the advent of more selective alpha-2 agonists like brimonidine.^[102] Overall, these drugs underscore the importance of adrenergic modulation in aqueous dynamics, complementing outflow-enhancing strategies without directly altering trabecular resistance.^[93]

Parasympathomimetics (S01EB)

Parasympathomimetics classified under ATC code S01EB are miotic agents primarily employed in the management of angle-closure glaucoma, where they facilitate the outflow of aqueous humor by contracting the ciliary muscle and opening the trabecular meshwork.^[103] These drugs mimic the action of acetylcholine at muscarinic receptors, promoting parasympathetic stimulation that pulls the scleral spur and enhances conventional outflow pathways, thereby reducing intraocular pressure.^[104] Unlike sympathomimetics in S01EA, which mainly decrease aqueous production to lower pressure, S01EB agents target outflow augmentation through cholinergic mechanisms.^[105] Key substances in this group include pilocarpine (S01EB01), a direct muscarinic agonist commonly administered as eye drops, with a defined daily dose (DDD) of 0.4 ml for topical ocular use.^[106] Carbachol (S01EB02), another direct-acting agent resistant to hydrolysis by cholinesterase, shares a similar DDD of 0.4 ml and is used for its potent miotic effects in acute scenarios.^[107] These agents are typically dosed multiple times daily to maintain therapeutic miosis, though exact regimens vary based on severity and patient response.^[108] A notable example is echothiophate (S01EB03), an irreversible cholinesterase inhibitor that prolongs endogenous acetylcholine activity, leading to sustained ciliary muscle contraction and miosis lasting up to a week after discontinuation.^[109] It is particularly indicated preoperatively to induce miosis during cataract surgery or in refractory glaucoma cases unresponsive to other therapies.^[110] However, its systemic absorption can inhibit plasma and erythrocyte cholinesterase, potentially causing cholinergic side effects such as salivation, lacrimation, and gastrointestinal discomfort, necessitating careful monitoring and nasolacrimal occlusion during administration.^[111] The utilization of S01EB parasympathomimetics has significantly declined since the introduction of prostaglandin analogues in the late 1990s, as the latter provide superior intraocular pressure reduction with once-daily dosing and minimal visual side effects.^[104] Persistent miosis from these agents often induces accommodative spasm, blurred near vision, and reduced night vision, contributing to poor patient compliance and limiting their role to adjunctive or acute settings.^[112]

Carbonic Anhydrase Inhibitors (S01EC)

Carbonic anhydrase inhibitors (CAIs) in the ATC group S01EC are topical ophthalmic medications primarily used to lower intraocular pressure (IOP) in patients with open-angle glaucoma and ocular hypertension. These agents work by reducing the production of aqueous humor in the ciliary body, offering a targeted approach for glaucoma management when monotherapy or combination therapy is required. Unlike systemic CAIs, topical formulations minimize widespread side effects while providing localized efficacy, with typical dosing regimens involving one drop administered two to three times daily.^[113] The primary indications for S01EC drugs include elevated IOP associated with open-angle glaucoma, where they serve as adjunctive therapy to other antiglaucoma agents or as initial treatment in cases unresponsive to single agents. For instance, dorzolamide (S01EC03), a 2% ophthalmic solution, is indicated for reducing IOP in these conditions, with a defined daily dose (DDD) of 0.3 ml. Similarly, brinzolamide (S01EC04), available as a 1% suspension, shares the same indications and has a DDD of 0.2 ml, often preferred for its reduced blurring due to the suspension form. Acetazolamide (S01EC01) is classified here but is predominantly used systemically for glaucoma, with topical applications being rare and less common in clinical practice.^{[114][115][116]} These inhibitors target carbonic anhydrase II, an enzyme abundant in the ciliary processes of the eye, where it facilitates the formation of bicarbonate ions essential for aqueous humor secretion. By non-competitively binding to the enzyme, CAIs decrease bicarbonate production, leading to reduced sodium and fluid transport into the aqueous humor, thereby lowering IOP by approximately 15-20%. In 2025, fixed-dose combinations remain prevalent, such as dorzolamide-timolol, which enhance adherence by combining CAI action with beta-blockade in a single drop for better IOP control in open-angle glaucoma.^{[113][117][118]} Common side effects of topical CAIs include ocular irritation, such as burning, stinging, and redness upon instillation, affecting up to 30% of users for dorzolamide. A distinctive bitter or unusual taste arises from nasolacrimal drainage, reported in about 20-30% of patients. Brinzolamide may cause transient blurred vision due to its suspension formulation and less frequent corneal endothelium issues, though rare decompensation can occur in susceptible individuals with pre-existing corneal disease. Systemic absorption is minimal but can lead to paresthesia or fatigue in sensitive patients.^{[119][120][121]}

Beta Blocking Agents (S01ED)

Beta blocking agents classified under ATC code S01ED are topical ophthalmic beta-adrenergic antagonists primarily used to lower intraocular pressure (IOP) in patients with glaucoma by reducing the production of aqueous humor in the ciliary body.^[105] These agents are applied as eye drops and work through blockade of beta receptors, with non-selective agents like timolol inhibiting both beta-1 and beta-2 receptors, while selective agents like betaxolol primarily target beta-1 receptors to minimize systemic effects on the lungs and heart.^[122] In glaucoma therapy, they are often employed as first-line monotherapy for open-angle glaucoma, particularly in cases where prostaglandin analogues are contraindicated or in unilateral disease, achieving IOP reductions of approximately 20-25% with typical dosing.^[123][124] Key substances in this group include timolol (S01ED01), a non-selective beta blocker available as eye drops or gel-forming solution, with a defined daily dose (DDD) of 0.1 ml for once-daily gel administration or 0.2 ml for twice-daily solution; betaxolol (S01ED02), a cardioselective beta-1 blocker with a DDD of 0.2 ml twice daily, offering a safer profile for patients with mild respiratory issues; and levobunolol (S01ED03), another non-selective agent with a potentially longer duration of action than timolol, allowing once-daily dosing in some patients while maintaining a DDD of 0.2 ml twice daily.^{[11][125][126]} By 2025, generic versions of these drugs dominate the market, significantly reducing treatment costs compared to branded formulations, with generic prices having decreased by over 20% in recent years due to widespread availability and competition.^[127][128] These agents differ from carbonic anhydrase inhibitors (S01EC) by acting via adrenergic receptor blockade rather than enzymatic inhibition of aqueous production, making them complementary in combination therapies to enhance IOP control through multiple pathways.^[101] In contrast to prostaglandin analogues (S01EE), which primarily increase aqueous outflow, beta blockers focus on production reduction, providing an alternative mechanism for patients unresponsive to outflow enhancers.^[122] However, non-selective beta blockers like timolol and levobunolol carry contraindications in patients with pulmonary conditions such as asthma or chronic obstructive pulmonary disease, where they may exacerbate bronchospasm or reduce lung function due to beta-2 receptor blockade, even with topical administration.^[129][130] Cardioselective options like betaxolol are preferred in such cases to mitigate respiratory risks.^[131] Common practice includes combining these agents with carbonic anhydrase inhibitors for additive IOP-lowering effects in refractory glaucoma.^[132]

Prostaglandin Analogues (S01EE)

Prostaglandin analogues, classified under ATC code S01EE, represent a cornerstone in the pharmacological management of glaucoma by primarily enhancing uveoscleral outflow of aqueous humor. These agents are recommended as first-line monotherapy for patients with open-angle glaucoma or ocular hypertension due to their potent intraocular pressure (IOP)-lowering efficacy, once-daily dosing convenience, and favorable tolerability profile compared to other antiglaucoma classes. Unlike production-reducing agents such as beta blockers or carbonic anhydrase inhibitors, prostaglandin analogues remodel the trabecular and uveoscleral pathways to facilitate drainage, achieving approximately 25-35% IOP reduction in most patients.^{[133][134][135]} The mechanism of action involves selective agonism of the FP prostanoid receptor on ciliary muscle cells, which upregulates matrix metalloproteinases to remodel and relax the extracellular matrix, thereby enlarging uveoscleral outflow pathways without significantly affecting trabecular meshwork resistance. This receptor-mediated process distinguishes prostaglandin analogues from other outflow enhancers and contributes to their sustained IOP-lowering effects over 24 hours. Key examples include latanoprost (S01EE01), a prodrug of prostaglandin F2α with a defined daily dose (DDD) of 0.1 ml administered once daily, which was the first in its class approved for clinical use in 1996. Bimatoprost (S01EE03, DDD 0.1 ml once daily), a prostamide analogue, similarly activates FP receptors but is notably associated with eyelash hypertrichosis as a common side effect, leading to its separate approval for hypotrichosis treatment.^{[136][137][138][139]} Travoprost (S01EE04, DDD 0.1 ml once daily) and tafluprost (S01EE05, DDD 0.1 ml once daily) further exemplify the class, with tafluprost uniquely formulated as the first preservative-free option to minimize ocular surface irritation and allergic reactions in sensitive patients. Sustained-release implants, such as iDose TR (travoprost intracameral implant, approved by FDA in 2023), provide long-term delivery of travoprost for up to three years, offering an alternative for patients requiring consistent IOP control without daily dosing.^[140] More recently, latanoprostene bunod (S01EE06, DDD 0.1 ml once daily), approved in 2017 and with ongoing real-world validation through 2025, introduces a dual mechanism by metabolizing into latanoprost acid for uveoscleral enhancement and a nitrate moiety that releases nitric oxide to improve trabecular outflow, potentially offering superior IOP control in refractory cases. These innovations underscore the evolution of prostaglandin analogues toward optimized delivery and reduced side effects while maintaining their role as preferred initial therapy.^{[141][142][143][144]}

Other Antiglaucoma Preparations (S01EX)

The S01EX category encompasses miscellaneous antiglaucoma preparations that do not fit into the primary pharmacological classes such as sympathomimetics, parasympathomimetics, carbonic anhydrase inhibitors, beta blockers, or prostaglandin analogues, and are primarily employed for managing elevated intraocular pressure (IOP) in refractory glaucoma cases where standard therapies prove insufficient.^[145] These agents target novel pathways to enhance aqueous humor outflow, offering options for patients with open-angle glaucoma or ocular hypertension unresponsive to conventional treatments.^[146] Representative examples include rho-associated kinase (ROCK) inhibitors and selective prostaglandin receptor agonists, which promote trabecular meshwork relaxation and uveoscleral outflow through cytoskeletal modulation without relying on traditional receptor agonism.^[147] Ripasudil (S01EX07), the first approved ROCK inhibitor, is indicated for reducing IOP in open-angle glaucoma and ocular hypertension, particularly in refractory scenarios across various glaucoma subtypes.^[148] Its mechanism involves inhibition of ROCK enzymes, which disrupts actomyosin contraction in the trabecular meshwork and Schlemm's canal, leading to cytoskeletal reorganization that facilitates conventional aqueous outflow independent of uveoscleral pathways. Clinical evidence demonstrates its efficacy as an adjunct therapy, lowering IOP by approximately 20-25% when added to existing regimens, with sustained effects observed in Japanese approval studies since 2014.^[149] Common administration is as a 0.4% ophthalmic solution twice daily, with a favorable profile for use in treatment-resistant cases.^[150] Netarsudil (S01EX05), another ROCK inhibitor with dual action via norepinephrine transporter inhibition, is approved for once-daily topical use to lower IOP in open-angle glaucoma and ocular hypertension, often as monotherapy or add-on in refractory patients.^[146] By targeting ROCK, it induces similar cytoskeletal changes to enhance trabecular outflow, while norepinephrine transporter blockade increases uveoscleral outflow through adrenergic modulation, providing additive IOP reduction of 15-20% over baseline. FDA approval occurred in 2017, with ongoing real-world pharmacovigilance confirming its safety through 2025, including in combination formulations like netarsudil/latanoprost for broader refractory applications.^[151] As of 2025, expanded labeling supports its role in diverse patient populations, emphasizing minimal systemic absorption.^[152] Other agents in this category include dapiprazole (S01EX02), an alpha-adrenergic blocker used adjunctively in pigmentary glaucoma to prevent pigment dispersion and exercise-induced IOP spikes by stabilizing iris configuration without inducing miosis.^[153] Omidenepag isopropyl (S01EX06), a prodrug converted to the active EP2 receptor agonist, reduces IOP via dual enhancement of trabecular and uveoscleral outflow, offering an alternative for refractory cases with once-daily dosing and IOP lowering comparable to prostaglandins but with potentially fewer side effects like hyperemia. Emerging topical gene therapies targeting IOP-regulating genes, such as AAV-based therapies modulating trabecular meshwork function (e.g., AAV2-REP1 in Phase 3 trials as of 2025), are under investigation and may eventually be classified within S01EX upon approval.^[154]

Mydriatics and Cycloplegics (S01F)

Anticholinergics (S01FA)

Anticholinergics in the ATC subgroup S01FA are topical ophthalmic agents that induce mydriasis (pupil dilation) and cycloplegia (paralysis of the ciliary muscle for accommodation) through blockade of muscarinic acetylcholine receptors in the iris sphincter and ciliary body. These effects facilitate diagnostic procedures and symptomatic relief in inflammatory conditions by relaxing ocular smooth muscles and reducing spasm. Combinations with sympathomimetics remain classified here, while those with corticosteroids fall under S01BB.^[155] The primary indications for S01FA agents include cycloplegic refraction during eye examinations to obtain accurate measurements in children and adults, where active accommodation could otherwise distort results, and therapeutic use in anterior uveitis to alleviate pain from ciliary body spasm, prevent iris adhesions (posterior synechiae), and promote uvea rest. In uveitis management, these drugs are often co-administered with topical corticosteroids to enhance anti-inflammatory outcomes without exacerbating inflammation. Unlike sympathomimetics in S01FB, which achieve dilation mainly via alpha-adrenergic stimulation without pronounced cycloplegia, S01FA agents provide comprehensive paralysis of parasympathetic-mediated functions.^{[156][62][157]} Prominent substances in this group include atropine (S01FA01), a naturally derived alkaloid with long-acting properties suitable for sustained cycloplegia in uveitis; its effects on mydriasis can persist 7-14 days, though recovery from cycloplegia averages 10 days. Cyclopentolate (S01FA04), a synthetic analog, offers intermediate duration (6-24 hours), making it preferable for pediatric refraction due to faster offset and lower systemic risk. Tropicamide (S01FA06), another synthetic option, features the shortest action profile with mydriasis lasting 4-6 hours and cycloplegia up to 6 hours, ideal for brief diagnostic needs. Other agents like homatropine (S01FA05) and scopolamine (S01FA02) provide varying durations for similar applications.^{[158][159][160]} These drugs exert their effects via non-selective competitive inhibition of muscarinic receptors (primarily M3 subtype), preventing parasympathetic stimulation that normally constricts the pupil and enables focusing; this results in unopposed sympathetic dilation and temporary loss of near vision. Onset varies by agent—atropine takes 30-40 minutes for peak effect—while duration correlates with lipid solubility and receptor affinity, with tropicamide's brevity attributed to rapid hydrolysis. In pediatric populations, dosing such as 0.5% cyclopentolate for infants under 1 year or single-drop protocols helps minimize absorption and risks like behavioral changes.^{[161][162][163]} Adverse effects commonly encompass blurred near vision, photophobia requiring sunglasses, and transient stinging upon instillation, stemming directly from cycloplegia and mydriasis; these resolve with effect offset but can impair activities like driving. Systemic absorption, more pronounced in neonates or via nasolacrimal occlusion lapse, may cause anticholinergic toxicity including tachycardia, dry mouth, flushing, or confusion, necessitating cautious use in vulnerable groups. Monitoring for idiosyncratic reactions, such as angle-closure glaucoma precipitation in predisposed eyes, is essential.^[164][165]

Sympathomimetics Excluding Antiglaucoma Preparations (S01FB)

Sympathomimetics excluding antiglaucoma preparations, classified under ATC code S01FB, are primarily employed in ophthalmology to induce mydriasis for diagnostic procedures such as fundus examination and retinal imaging, without causing cycloplegia that affects accommodation.^[166] These agents act by stimulating alpha-adrenergic receptors in the iris dilator muscle, leading to pupil dilation that facilitates visualization of the posterior eye segment.^[167] Unlike anticholinergics in S01FA, which provide both mydriasis and cycloplegia for comprehensive refraction, S01FB drugs offer reversible, selective mydriasis suitable for short-term diagnostic needs.^[168] The principal agent in this group is phenylephrine (S01FB01), an alpha-1 adrenergic agonist available as ophthalmic solutions in concentrations of 2.5% to 10%, for eye drops.^[169] Administered topically, phenylephrine contracts the radial dilator muscle of the iris to produce mydriasis lasting 3-6 hours, aiding in ophthalmoscopy and preoperative pupil dilation without impacting the ciliary muscle.^[170] Other substances include ephedrine (S01FB02), a mixed alpha- and beta-agonist historically used at low concentrations (e.g., 0.1%) for mild mydriasis or conjunctival decongestion, though its ophthalmic application is now infrequent.^[171] Ibopamine (S01FB03), a prodrug of N-methyldopamine, similarly induces short-term mydriasis through adrenergic and dopaminergic stimulation, often in diagnostic contexts.^[172] A unique application within this category involves hydroxyamphetamine, an indirect sympathomimetic that releases norepinephrine from postganglionic sympathetic neurons to test for sympathetic denervation, such as in Horner's syndrome.^[173] Instilled as 1% eye drops, it dilates pupils with intact postganglionic fibers but fails to do so in third-order neuron lesions, helping localize the site of oculosympathetic dysfunction.^[174] As of 2025, hydroxyamphetamine's use for this purpose continues, though availability may be limited in some regions (e.g., requiring compounding in the US), with apraclonidine preferred for initial confirmation of Horner's syndrome via denervation supersensitivity.^[174]

Decongestants and Antiallergics (S01G)

Sympathomimetics Used as Decongestants (S01GA)

Sympathomimetics used as decongestants in the S01GA subgroup are alpha-adrenergic agonists formulated for topical ocular application to provide rapid relief from conjunctival hyperemia, a condition characterized by redness due to dilation and increased permeability of conjunctival blood vessels often triggered by irritants, allergens, or environmental factors. These agents work by selectively stimulating alpha-1 adrenergic receptors on vascular smooth muscle cells in the conjunctiva, leading to vasoconstriction that reduces blood flow, vessel leakage, and associated redness without significantly affecting pupil dilation at therapeutic concentrations.^{[175][176][177]} Prominent examples include naphazoline (S01GA01), an imidazoline derivative, and tetrahydrozoline (also known as tetryzoline; S01GA02), both of which are commonly available as over-the-counter (OTC) preparations in concentrations of 0.01% to 0.05%. Naphazoline and tetrahydrozoline offer onset of action within minutes and duration of 4-6 hours, making them suitable for symptomatic management of minor ocular irritations such as those from pollen, dust, or contact lens wear. Their OTC status, established under FDA monographs for ophthalmic vasoconstrictors, allows widespread accessibility for short-term self-treatment, though labeling requires consultation with a healthcare provider for use beyond 72 hours or in individuals with conditions like glaucoma or hypertension.^[178][179] Oxymetazoline (S01GA04), another key sympathomimetic in this group, exhibits prolonged vasoconstrictive effects lasting up to 8-10 hours due to its high affinity for both alpha-1 and alpha-2 receptors, providing extended relief in cases of persistent hyperemia. However, its extended action is associated with a higher risk of rebound hyperemia upon discontinuation, where chronic exposure leads to receptor downregulation and paradoxical vasodilation, exacerbating redness. FDA and EMA guidelines advise against application for more than 3-4 consecutive days to mitigate risks of tachyphylaxis, dependency, and potential allergic or toxic conjunctivitis, with emphasis on professional evaluation for recurrent symptoms.^{[180][181][182]}

Other Antiallergics (S01GX)

The S01GX subgroup encompasses topical ophthalmological preparations classified as other antiallergics, primarily consisting of mast cell stabilizers and antihistamines designed to mitigate symptoms of allergic ocular conditions such as vernal keratoconjunctivitis (VKC) and hay fever-induced allergic conjunctivitis.^[183] These agents target the underlying allergic cascade in the conjunctiva, where exposure to allergens like pollen triggers mast cell degranulation and histamine release, leading to itching, redness, and tearing.^[184] Unlike decongestants in S01GA, which provide symptomatic vascular relief but risk rebound hyperemia, S01GX drugs address the allergic response prophylactically or acutely without such complications.^[185] Mast cell stabilizers, such as cromoglicic acid (S01GX01), inhibit the release of inflammatory mediators like histamine, leukotrienes, and cytokines from sensitized mast cells upon allergen challenge, thereby preventing the early-phase allergic reaction and reducing subsequent inflammation.^[186] This mechanism is particularly beneficial for prophylactic use in chronic conditions like VKC, a severe, recurrent allergic disorder often affecting children in warm climates, where it helps control symptoms including giant papillae and shield ulcers.^[187] Cromoglicic acid eye drops are typically administered as 0.2 ml (one or two drops) four times daily, with onset of action requiring several days of consistent use for optimal efficacy in hay fever or VKC.^[188] Dual-action agents like olopatadine (S01GX09) combine H1 histamine receptor antagonism to block immediate itch and vasodilation with mast cell stabilization to inhibit mediator release, providing rapid relief (within minutes) and prolonged protection (up to 12 hours per dose) for seasonal allergic conjunctivitis associated with hay fever.^[189] This multifaceted approach enhances symptom control in VKC by addressing both acute histamine-driven effects and chronic inflammatory recruitment of eosinophils and T-cells, outperforming single-action stabilizers in clinical trials for reducing ocular pruritus scores.^[190] Similarly, ketotifen (S01GX08), another dual-action compound, functions as an H1 antagonist and mast cell stabilizer, dosed twice daily (one drop every 8-12 hours) to manage mild to moderate VKC or hay fever symptoms, with studies confirming its role in stabilizing conjunctival mast cells to curb histamine-induced hyperemia and chemosis.^[191] Bepotastine (S01GX11) is a dual-action H1 antagonist with additional inhibition of inflammatory cytokine release, used for allergic conjunctivitis and showing efficacy in studies for VKC, with once- or twice-daily dosing options suitable for pediatric patients.^[192] These S01GX preparations are generally well-tolerated, with transient stinging as the most common adverse effect, and their topical application minimizes systemic exposure while complementing non-pharmacologic measures like allergen avoidance in hay fever management.^[193]

Local Anesthetics, Diagnostic Agents, and Surgical Aids

Local Anesthetics (S01HA)

Local anesthetics classified under ATC code S01HA are topical agents designed to provide temporary numbing of the ocular surface for diagnostic and minor therapeutic procedures in ophthalmology. These medications are primarily used to facilitate painless interventions such as tonometry, gonioscopy, and removal of corneal foreign bodies or sutures, allowing clinicians to perform examinations without patient discomfort.^{[194][195][196]} Among the key substances in this category, tetracaine (S01HA03) is an ester-type local anesthetic known for its rapid onset and short duration of action, typically lasting 10-20 minutes, making it suitable for brief procedures. Proparacaine (S01HA04), also an ester anesthetic, offers a faster onset than tetracaine and is less irritating to the conjunctiva, providing effective anesthesia for up to 15-20 minutes with reduced stinging upon instillation. Oxybuprocaine (S01HA02), another ester-type agent, is particularly common in Europe for similar applications, including preparation for intravitreal injections and surface examinations, with a duration comparable to tetracaine.^{[197][198][199]} These agents exert their effect through blockade of voltage-gated sodium channels in neuronal membranes, inhibiting sodium ion influx and thereby preventing the generation and propagation of action potentials in sensory nerves of the cornea and conjunctiva. This mechanism ensures localized anesthesia without systemic absorption when used topically. In surgical contexts, they may be employed briefly to aid initial numbing during minor ocular interventions.^{[200][201][202]} Overuse of S01HA anesthetics poses significant risks, including corneal epithelial toxicity, delayed wound healing, and severe keratopathy, which can lead to persistent defects, stromal infiltration, and vision impairment. Prolonged or self-administered use, particularly for symptomatic relief in dry eye disease, has prompted warnings in guidelines as of 2025, emphasizing that such abuse can exacerbate ocular surface damage despite short-term pain relief; safe intermittent use under supervision is recommended for conditions like corneal abrasions.^{[203][204][205]}

Colouring Agents (S01JA)

Colouring agents classified under ATC code S01JA are topical diagnostic dyes employed in ophthalmology to enhance visualization of ocular surface defects, epithelial damage, and vascular structures. These agents function by selectively staining compromised tissues or binding to proteins, allowing clinicians to identify conditions such as corneal abrasions, ulcers, and dry eye syndrome through fluorescence or vital staining under specific illumination. Unlike systemic diagnostics, S01JA agents are formulated for direct ocular application, with no defined daily doses (DDDs) assigned due to their non-therapeutic, procedural use.^[206] Fluorescein (S01JA01) is the cornerstone substance in this category, a xanthene dye that exhibits intense green-yellow fluorescence when excited by blue cobalt light after binding to albumin and other proteins in areas of epithelial breakdown. Topically applied as impregnated strips or 1-2% solutions, it reveals corneal and conjunctival defects by pooling in damaged sites, facilitating diagnosis of foreign body injuries, herpetic keratitis, and contact lens overwear complications. Intravenously administered at doses of 5-7 mg/kg, fluorescein enables fundus angiography to assess retinal and choroidal circulation, highlighting leaks, non-perfusion, and neovascularization in conditions like diabetic retinopathy and age-related macular degeneration. Its safety profile includes transient nausea or urticaria in up to 5% of intravenous cases, but it remains a gold standard due to its high sensitivity and low toxicity.^{[207][208][209][210]} Rose bengal sodium (S01JA02), a tetraiodo-tetrachloro-fluorescein derivative, serves as a vital stain that preferentially accumulates in devitalized or keratinized epithelial cells, appearing as pinpoint red spots under white light without requiring fluorescence. It is particularly valuable for evaluating ocular surface health in dry eye disease, where it detects mucin layer deficiencies and squamous metaplasia, and in assessing conjunctival damage from chronic inflammation or allergy. Administered topically as 1% solution or strips (typically 1.0 mg per strip), it provides broader staining of the bulbar conjunctiva compared to fluorescein, aiding in the grading of ocular surface disease severity. Its use has declined in favor of less irritating alternatives like lissamine green for routine staining, with some formulations discontinued, though it remains employed in specialized applications as of 2025.^{[211][212][213][214][215]} Combinations of fluorescein with other agents (S01JA51) extend diagnostic utility by incorporating buffering or preservative enhancements for stability, though they retain the core properties of standalone fluorescein for routine slit-lamp examinations. Topical administration predominates for surface diagnostics, involving patient blinking to distribute the dye evenly, while intravenous routes are reserved for angiographic procedures requiring fundus cameras with barrier filters to capture emitted light. These techniques underscore the role of S01JA agents in precise, minimally invasive ocular assessment, distinct from other diagnostic modalities focused on refraction or deeper imaging.^{[216][211][217]}

Other Ophthalmological Diagnostic Agents (S01JX)

Other ophthalmological diagnostic agents, classified under ATC code S01JX, encompass topical preparations employed specifically for eye examinations, excluding colouring agents covered in S01JA and mydriatics/cycloplegics classified in S01F. This subgroup is intended for other diagnostic agents aiding in the diagnosis of eye diseases, such as those used in specific testing procedures beyond standard staining or dilation. According to the World Health Organization's Anatomical Therapeutic Chemical (ATC) classification system, this subgroup targets diagnostic applications in ophthalmology, distinguishing it from therapeutic uses.^[218][219] As of 2025, no specific substances are assigned to the 5th level under S01JX, reflecting the focused classification of common diagnostic tools elsewhere in S01J and S01F. Advancements in non-pharmacological diagnostics, such as digital autorefractors and machine learning models predicting refractive errors, continue to evolve, potentially reducing reliance on certain agents in routine screenings.^[220]

Viscoelastic Substances (S01KA)

Viscoelastic substances, classified under ATC code S01KA, are gel-like ophthalmic viscosurgical devices (OVDs) used primarily to maintain anterior chamber depth and protect intraocular structures during surgical procedures. These agents exhibit both viscous and elastic properties, allowing them to create and stabilize space within the eye while minimizing trauma to delicate tissues such as the corneal endothelium.^[221] In cataract extraction, viscoelastic substances facilitate capsulorhexis, nucleus manipulation, and intraocular lens implantation by providing a stable surgical field and cushioning against mechanical stress. They are also essential in corneal transplant surgeries, where they help preserve graft positioning and prevent collapse of the anterior chamber during suturing.^[222][221] The primary substance in this category is sodium hyaluronate (S01KA01), a high-molecular-weight glycosaminoglycan that imparts cohesive properties, enabling it to hold space effectively under low shear conditions and allowing for easier removal at the procedure's end. Combinations of hyaluronic acid with chondroitin sulfate (S01KA51) are dispersive agents, which spread more readily to coat and protect tissues during high-flow phases like phacoemulsification, offering better retention in turbulent environments.^{[223][221][222]} Cohesive viscoelastics, such as high-viscosity sodium hyaluronate, excel in space maintenance and pressure equalization but may fragment under high aspiration, while dispersive types, like chondroitin sulfate-based formulations, provide superior endothelial protection yet require more thorough irrigation for complete evacuation. By 2025, sodium hyaluronate production has shifted predominantly to bacterial fermentation methods, enhancing purity and scalability over animal-derived sources.^{[221][224][225]} Postoperatively, complete removal of these substances is critical, as residual material can obstruct trabecular meshwork outflow, leading to transient intraocular pressure elevation in up to 30% of cases if not addressed. Techniques such as hyperbaric irrigation or targeted aspiration are employed to minimize this risk, ensuring optimal recovery.^[226][227]

Other Surgical Aids (S01KX)

The ATC group S01KX encompasses other surgical aids utilized in ophthalmological procedures, primarily consisting of enzymatic agents and vital dyes that facilitate precise tissue manipulation without being classified as viscoelastics.^[228] These preparations support interventions such as cataract extraction and vitreoretinal surgery by enabling targeted enzymatic dissolution or enhanced visualization of ocular structures. Chymotrypsin (S01KX01), an alpha-chymotrypsin enzyme derived from bovine pancreas, is employed for enzymatic zonulolysis during intracapsular cataract extraction. Introduced in clinical practice in the late 1950s, it selectively hydrolyzes zonular fibers connecting the lens to the ciliary body, allowing gentler lens mobilization and reducing mechanical trauma to surrounding tissues.^[229] This technique, pioneered by Joaquin Barraquer, involves intracameral injection of a dilute solution (typically 0.1% to 0.5%), achieving zonular lysis within 2 to 4 minutes while minimizing endothelial damage when properly irrigated post-application.^[230] Its use has declined with the shift to extracapsular methods but remains relevant in select high-risk cases, such as mature cataracts or pseudoexfoliation syndrome, where zonular weakness complicates surgery.^[231] Trypan blue (S01KX02), a diazo dye, serves as a vital stain to improve visibility during anterior and posterior segment surgeries, particularly for lens capsule management in complicated cataracts. Approved for ophthalmic use, it selectively stains acellular structures like the anterior lens capsule and epiretinal membranes, aiding in precise capsulorhexis creation or internal limiting membrane peeling during vitrectomy.^[232] Applied at concentrations of 0.06% to 0.15% via air or viscoelastic injection, it provides transient blue coloration that resolves within minutes, with no significant toxicity to viable cells due to its exclusion from living tissues.^[233] In pediatric or white cataract cases with poor red reflex, trypan blue enhances surgical safety by delineating the capsule edge, reducing the risk of posterior capsular rupture.^[234] Irrigation solutions, such as balanced salt solutions (BSS), complement these aids by maintaining intraocular osmolarity and pH during surgery, though they are not explicitly coded in S01KX. These isotonic formulations (containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, and sodium citrate) mimic aqueous humor to protect corneal endothelium and facilitate tissue perfusion in procedures involving chymotrypsin or trypan blue.^[235]

Ocular Vascular Disorder Agents and Other Ophthalmologicals

Antineovascularisation Agents (S01LA)

Antineovascularisation agents in the S01LA subgroup target pathological blood vessel growth in the eye, primarily through inhibition of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis and vascular permeability. These agents are indicated for treating neovascular (wet) age-related macular degeneration (AMD), diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), and myopic choroidal neovascularization, where abnormal vessel proliferation leads to vision loss. Unlike topical ophthalmological preparations, they are administered exclusively via intravitreal injection to achieve therapeutic concentrations in the vitreous humor and retina.^[236] The primary mechanism of action for most S01LA agents involves binding to VEGF or its receptors, preventing downstream signaling that promotes endothelial cell proliferation, migration, and leakage. This reduces neovascularization and stabilizes or improves visual acuity in affected patients. For instance, pegaptanib (S01LA03), the first approved aptamer in this class, selectively binds the VEGF165 isoform with high affinity, inhibiting its pathological effects without broadly affecting other VEGF variants, as demonstrated in phase III trials for wet AMD. Ranibizumab (S01LA04), a recombinant humanized monoclonal antibody fragment, neutralizes all isoforms of VEGF-A, leading to regression of choroidal neovascularization; clinical studies show it preserves vision in approximately 90% of wet AMD patients over two years with monthly dosing. Aflibercept (S01LA05), a soluble decoy receptor fusion protein, binds VEGF-A, VEGF-B, and placental growth factor (PlGF), offering broader inhibition; its defined daily dose (DDD) is 0.05 ml (2 mg) administered intravitreally every four weeks for maintenance therapy in wet AMD and DME.^{[237][238][239]} Bevacizumab (S01LA08), a full-length monoclonal antibody targeting all VEGF-A isoforms, is widely used off-label for intravitreal treatment despite lacking specific ophthalmic approval, due to its comparable efficacy to ranibizumab in reducing macular thickness and improving vision in DME and wet AMD, as evidenced by large comparative trials. Its cost-effectiveness stems from repurposing the intravenous oncology formulation, which is approximately 40 times less expensive per dose than proprietary ophthalmic agents like ranibizumab (around $50 versus $2,000 per injection), enabling broader access in resource-limited settings while maintaining similar safety profiles. Other agents, such as brolucizumab (S01LA06) and faricimab (S01LA09), extend this class with single-chain antibodies or bispecific designs targeting VEGF and angiopoietin-2, respectively, for potentially longer durability between injections. Earlier agents like verteporfin (S01LA01), a photosensitizer used in photodynamic therapy, and anecortave (S01LA02), an angiostatic steroid, represent non-biologic approaches but are less commonly used today due to the dominance of anti-VEGF biologics.^[240][241] As of 2025, the introduction of biosimilars has significantly lowered barriers to treatment; ranibizumab biosimilars like ranibizumab-nuna (Byooviz) and aflibercept biosimilars, some of which have been recently approved, demonstrate equivalent efficacy and safety to originators in phase III equivalence trials, potentially reducing annual treatment costs by up to 30% and saving healthcare systems millions, as projected in economic models for wet AMD management. These biosimilars maintain the same intravitreal administration route and dosing regimens, fostering greater adoption without compromising outcomes.^[242][243]

Other Ophthalmologicals (S01XA)

The ATC code S01XA encompasses a diverse group of ophthalmological agents that do not fit into more specific therapeutic categories within the Anatomical Therapeutic Chemical classification system, serving primarily as supportive treatments for conditions such as dry eye syndrome and as adjuncts in cataract prevention or management.^[244] These include lubricants, protectants, and miscellaneous preparations that provide symptomatic relief, maintain ocular surface integrity, or address niche indications like corneal protection and experimental anticataract effects.^[245] Unlike targeted therapies in other S01 subgroups, S01XA agents focus on non-specific adjunctive roles, often with inert or indifferent formulations to minimize pharmacological activity while maximizing tolerability.^[1] A primary use of S01XA substances is in managing dry eye disease, where artificial tears and similar indifferent preparations lubricate the ocular surface, alleviate irritation, and prevent corneal damage from evaporative or aqueous-deficient tears. Hypromellose (S01XA20), a common semisynthetic polymer, exemplifies this category as an ophthalmic lubricant that forms a protective film over the eye, improving tear film stability without active pharmacological effects; it is widely used in preservative-free formulations for frequent application in chronic dry eye.^[246] Therapeutic contact lens solutions with lubricating properties are also classified here when they provide medicinal benefits beyond cleaning, such as enhancing comfort in extended-wear scenarios.^[244] In the realm of cataract prevention and treatment, S01XA includes antioxidants and experimental agents aimed at reducing oxidative stress or dissolving protein aggregates in the lens. Retinol (vitamin A, S01XA02), an essential nutrient for epithelial maintenance, is applied topically to support corneal health and prevent vitamin A deficiency-related keratopathy, which can contribute to cataract formation in at-risk populations.^[247] Emerging research as of 2025 explores lanosterol-based therapies, a sterol compound that has shown potential in preclinical models to reverse cataractous lens opacities by solubilizing crystallin aggregates, though human clinical trials remain ongoing without formal ATC assignment.^[248] This catch-all subgroup also accommodates autologous limbal stem cells (S01XA19), used in regenerative approaches for limbal stem cell deficiency, highlighting the evolving inclusion of cellular adjuncts for ocular surface reconstruction.^[245] Other notable S01XA agents address specific supportive needs, such as acetylcysteine (S01XA08) for mucolytic effects in filamentary keratitis or mercaptamine (S01XA21) for cystinosis-related corneal cystine crystal deposition, underscoring the category's role in miscellaneous ophthalmological care.^[249] Overall, these preparations prioritize safety and symptomatic control, with minimal systemic absorption and broad applicability in outpatient settings.^[1]