Ocular Pharmacodynamics

It is not the purpose of this text to present an in-depth review of the pharmacodynamics of ophthalmic drugs. For this purpose the reader is referred to one of the authoritative treatments of this subject (49-51). However, since this topic is not commonly covered in pharmacy school curricula, a brief treatment is presented here. For the most part, drugs used in the eye fall into one of several categories, including miotics, mydriatics (with or without cycloplegic activity), cycloplegics, anti-inflammatories, anti-infectives (including antibiotics, antivirals, and antibacterials), antiglaucoma drugs, surgical adjuncts, diagnostics, and a category of drugs for miscellaneous uses. The intended ophthalmic use will define more precisely what drug or combination of drugs are to be used, the appropriate dosage form, and route of administration. For example, the practitioner will, with knowledge of certain contraindications, use mydriatic drugs specifically for their pupillary and accommodative effects, both in the process of refraction and in the management of iridocyclitis, iritis, accommodative exotropia, and so on. Atropine, homatropine, scopolamine, tropicamide, and cyclopentolate are examples of parasympathomimetic drugs possessing mydriatic and cycloplegic activity, whereas phenylephrine and epinephrine are examples of sympathomimetic drugs possessing only mydriatic activity.

Drugs that may be chosen for use in the management of glaucoma may be topically applied miotics, such as pilocarpine hydrochloride or nitrate, carbachol, echothiophate iodide, or demecarium bromide; epinephrine prodrugs like dipivefrin hydrochloride, nonselective P-adrenergic blocking agents such as timolol maleate and bunolol hydrochloride, and selective P-adrenergic blocking agents such as racemic- or the more potent L-betaxolol hydrochloride, compounds devoid of pupillary effect; topically administered carbonic anhydrase inhibitors, such as dorzolamide and brinzolamide; prostaglandin analogs of the class PGF2ot, such as latanoprost and travoprost, capable of lowering IOP significantly with little or no inflammatory or vasodilatory response; or, they may be orally administered drugs to present an osmotic effect that will lower IOP, such as 50% glycerin or 45% isosorbide. Other drugs administered orally to lower IOP are the carbonic anhydrous inhibitors acetazolamide and methazolamide. Furthermore, the miotic drugs may be chosen to reverse the effect of mydriatics after refraction or during surgical procedures such as cataract removal. There is now available an antimydriatic drug devoid of pupillary activity, dapiprazole hydrochloride, which is gaining importance in the reversal of the effect of mydriatics.

Depending on the location of ocular inflammation, a specific corticosteroid in a specific dosage form may be chosen. For instance, a corticosteroid of high potency, such as prednisolone acetate, fluorometholone, or dexamethasone, may be chosen for deep-seated inflammation of the uveal tract. Further treatment of such inflammation may take the form of subtenon injections or oral (systemic) administration of selected corticosteroids, depending on the indication and the dosage forms available. For inflammation of a more superficial nature, the lower strengths of prednisolone acetate or the lower-potency corticosterioids, such as hydrocortisone or medrysone, will usually be chosen.

Drugs used for the treatment of ocular infection will generally be chosen on the basis of the presumptive diagnosis of the causative agent by the ophthalmologist. Laboratory confirmation by microbial culture and identification is routinely conducted concurrently with the initiation of therapy. This is generally necessary because of the severity and sight-threatening nature of some type of infections. For example, if a patient has a foreign body lodged in the cornea originating from a potentially contaminated environment, the physician may choose to begin treatment of the eye, after foreign body removal, with a single or combination antibiotic, such as gentamicin, tobramycin, chloramphenicol, and a neomycin-polymyxin combination. This is considered appropriate, since an infection with Pseudomonas aeruginosa can destroy a cornea in 24 to 48 hours, generally the time it takes to identify an infectious agent. Less fulminating, but no less dangerous, are infections caused by various staphylococcal and streptococcal organisms. For superficial bacterial infections of the conjunctiva and eyelids, sulfonamides, such as sodium sulfacetamide, are usually prescribed, as are yellow mercuric oxide and mild silver protein. Prophylactic therapy for ophthalmia neonatorum is nearly universally required in the United States, with silver nitrate, penicillin G, or erythromycin as the primary anti-infectives used. Pre- and postsurgical prophylaxis is becoming more commonplace with the popularity of surgically corrected vision, and combinations of anti-infectives with anti-inflammatory agents are frequently used to reduce surgical trauma to the eye.

For fungal and viral infections, there are a very few agents that the ophthalmologist can prescribe. These organisms' resistance and similarity to mammalian tissue make it difficult to find effective and safe therapies. For instance, idoxuridine, a selective metabolic inhibitor, has been shown to be useful against herpes simplex virus infection of the cornea. For the trachoma virus and viruses that cause inclusion conjunctivitis [i.e., TRIC (the single largest cause of blindness worldwide)], no specific antiviral agent has demonstrated satisfactory activity, and the secondary bacterial ramifications of this disease are managed by conventional antibiotics, such as tetracycline, chloramphenicol, and erythromycin. The trachoma virus itself seems to be somewhat susceptible to these antibiotics; however, up to six weeks of treatment, antibiotics are required three times per day to achieve an 80% cure rate (52,53).

A similar situation exists for the treatment of fungal keratitis. The antifungal antibiotic drugs nystatin and natamycin have been effective to varying degrees in superficial fungal infection, as have copper sulfate and sodium sulfacetamide (54,55). For both of these drugs iontophoresis of the topically administered drug produces enhanced activities.

Drugs used as surgical adjuncts are primarily irrigating solutions, solutions of proteolytic enzymes, viscoelastics and miotics employed in cataract removal, intraocular lens placement, vitrectomy, and procedures to preserve retinal integrity. These drugs are considered true parenteral dosage forms, the design and evaluation of which are discussed in greater detail elsewhere in this chapter.

Diagnostic drugs, such as sodium fluorescein, are administered topically or intravenously to aid in the diagnosis of such conditions as corneal abrasions or ulceration and various retinopathies. This agent has become the most widely used diagnostic agent in the practice of ophthalmology and optometry. Rose bengal has also been used topically, although to a far lesser degree than sodium fluorescein, which is available as well-preserved alkaline solutions in concentrations ranging from 0.5% to 2.0% (56,57), as fluorescein-impregnated absorbent sterile paper strips (58), or as unpreserved, terminally sterilized intravenous injections in concentrations ranging from 5% to 25% (59).

Several topically applied local anesthetics are routinely used by the eye care specialist in certain routine diagnostic procedures and for various relatively simple surgical procedures such as insertion of punctal plugs and surgical vision correction. The first of these to be used was cocaine, in concentrations ranging from 1% to 4% (60). However, more modern local anesthetics, such as tetracaine hydrochloride and proparacaine hydrochloride, have replaced cocaine as drugs of choice in these procedures. For surgical procedures of a more complex nature, lidocaine hydrochloride and similar local anesthetics as retrobulbar injections have been used (61).

The foregoing overview has presented the major classes of ophthalmic drugs. One additional class of drugs that merits brief discussion includes drugs used for the treatment of various dry eye syndromes. The most severe of these, keratoconjunctivitis sicca, involves diminished secretion of mucins, consisting of glycoproteins and glycosamino-glycans and their complexes. These materials serve to coat the corneal epithelium with a hydrophilic layer that uniformly attracts water molecules, resulting in even hydration of the corneal surface. Diminished secretion of these substances causes dry spots to develop on the cornea, resulting in corneal dehydration, which can lead to ulceration, scarring, or corneal opacities (62). Modern pharmaceutical products are available (Hypotears, Tears Naturale Forte) that contain mucomimetic high molecular weight polymers that serve to resurface the cornea temporarily, thereby preventing the aforementioned dehydration and affording the dry eye sufferer with a degree of relief previously unavailable (63,64). These agents are not pharmacologically active although recent research leads to the promise of drugs that will stimulate tear production for longer-term relief.

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