Miotics are a class of medication used primarily in ophthalmology to cause pupillary constriction (miosis). This effect is achieved by stimulating the parasympathetic nervous system within the eye, specifically targeting cholinergic receptors. By constricting the pupil and contracting the ciliary muscle, miotic drugs increase the outflow of aqueous humor, the fluid inside the eye, which lowers intraocular pressure (IOP). Historically, miotics were a primary treatment for glaucoma, but with the advent of newer, better-tolerated agents, their use is now more specialized. However, their importance remains for specific types of glaucoma, surgical procedures, and managing certain refractive conditions.
Classification of miotic drugs
Miotic drugs are broadly categorized based on their mechanism of action, primarily as direct-acting or indirect-acting cholinergic agents.
Direct-acting cholinergic agents
These drugs bind directly to muscarinic receptors on the iris sphincter muscle and ciliary body, mimicking the effect of the body's natural neurotransmitter, acetylcholine.
- Pilocarpine: This is one of the most well-known miotics and has been used for over a century, including for open-angle glaucoma. A newer formulation (Vuity) is also approved for treating presbyopia (age-related farsightedness) by creating a small pinhole effect that increases the eye's depth of focus. Pilocarpine is administered topically as eye drops or gel.
- Carbachol: Similar to pilocarpine, carbachol is a direct-acting miotic. It is often used during ophthalmic surgery, such as cataract extraction, to induce rapid and complete miosis after lens implantation. It is also used to lower IOP in glaucoma, particularly for patients who are intolerant or unresponsive to pilocarpine.
- Acetylcholine chloride (Miochol-E): This agent has an extremely short duration of action, which makes it ideal for inducing miosis during ophthalmic surgery, such as cataract surgery. It is administered intracamerally (injected directly into the anterior chamber of the eye).
Indirect-acting cholinergic agents
Also known as anticholinesterases, these drugs inhibit the enzyme acetylcholinesterase, which is responsible for breaking down acetylcholine. By blocking this enzyme, they cause acetylcholine to accumulate at the receptor sites, leading to a prolonged and exaggerated miotic effect.
- Echothiophate: This is a long-acting, irreversible anticholinesterase. While it is no longer commercially available in the U.S. for ophthalmic use due to its potential side effects and the availability of newer agents, it was historically used for glaucoma. It is a very strong miotic with effects lasting for weeks.
- Physostigmine: A reversible anticholinesterase, physostigmine is not as well-tolerated as other miotics and is rarely used for long-term glaucoma therapy. It has a longer duration of action than direct-acting miotics but shorter than irreversible agents.
Mechanism of action: Direct vs. indirect
Both types of miotic drugs cause pupil constriction, but they achieve this through different molecular pathways, leading to variations in onset, duration, and side effect profile. Direct-acting agents, like pilocarpine and carbachol, bind directly to and activate the muscarinic acetylcholine receptors. This causes the iris sphincter muscle and the ciliary muscle to contract. The contraction of the iris sphincter reduces the pupil's size, while the contraction of the ciliary muscle pulls on the trabecular meshwork, opening up the drainage pathways for aqueous humor.
Indirect-acting agents, like echothiophate, block the acetylcholinesterase enzyme. This prevents the rapid breakdown of acetylcholine, leading to a buildup of the neurotransmitter in the synaptic cleft. The elevated levels of acetylcholine then repeatedly stimulate the cholinergic receptors, resulting in prolonged and more potent miosis and ciliary muscle contraction. This effect is particularly strong and long-lasting with irreversible inhibitors, which is why they are not favored for routine use.
Comparison of common miotic drugs
| Feature | Pilocarpine | Carbachol | Echothiophate | Acetylcholine |
|---|---|---|---|---|
| Class | Direct-acting cholinergic agonist | Direct-acting cholinergic agonist (and weak anticholinesterase) | Indirect-acting anticholinesterase | Direct-acting cholinergic agonist |
| Onset of Action | Typically 10-30 minutes for topical solution | 2-5 minutes (topical); immediate (intraocular) | Within minutes | Immediate (intracameral) |
| Duration of Action | Several hours (variable based on formulation) | 4-8 hours (topical); 24 hours (intraocular) | Days to weeks (older, high-risk drug) | Very brief (minutes) |
| Primary Use | Glaucoma, presbyopia, reversing dilation | Inducing miosis during surgery, glaucoma | Historically for glaucoma (now rarely used) | Inducing rapid miosis during surgery |
| Route of Administration | Eye drops, gel, ocular insert | Eye drops, intraocular injection | Eye drops (reconstituted) | Intraocular injection |
| Side Effects | Blurred vision, accommodative spasm, headache, eye discomfort, retinal detachment (rare) | Blurred vision, eye irritation, headache, abdominal cramps, diarrhea | Greater risk of systemic and ocular side effects, cataracts, retinal detachment | Transient, typically during surgery |
Modern applications and side effects
While miotic drugs' use for long-term glaucoma treatment has decreased due to more effective and safer alternatives, they still play important roles. In acute angle-closure glaucoma, miotics like pilocarpine can rapidly constrict the pupil to open the blocked drainage angle and relieve pressure. In surgical settings, agents like carbachol and acetylcholine are invaluable for inducing miosis to prevent iris prolapse and protect the lens. Most recently, low-concentration pilocarpine formulations have emerged for treating presbyopia, providing clear near vision by reducing pupil size.
Side effects of miotics are related to their cholinergic mechanism and can range from mild and ocular to more severe and systemic. Common ocular side effects include blurred vision, difficulty seeing in dim light, accommodative spasm (a painful focusing spasm), and brow ache. Systemic side effects are less common with topical use but can include headache, nausea, sweating, and bronchial spasm. Healthcare providers minimize side effects by starting with lower concentrations, administering drops at bedtime, and advising patients about potential vision issues, especially when driving at night.
Conclusion
Common miotic drugs, including pilocarpine, carbachol, and acetylcholine, are a vital part of ophthalmology's pharmacological toolkit. Operating as either direct- or indirect-acting cholinergic agonists, their primary function is to cause pupillary constriction and improve aqueous humor outflow. While newer medications have supplanted them for routine glaucoma management, miotics remain crucial for specific conditions like acute angle-closure glaucoma, inducing miosis during surgery, and treating presbyopia. Proper patient selection and dosage management are essential to minimize side effects, ensuring these historically significant and still-relevant drugs are used safely and effectively.
More information on the pharmacology of acetylcholine can be found on the NCBI bookshelf.
