The history of glaucoma pharmacology began nearly 150 years ago but has followed an exponential curve when one considers that all the drugs used routinely to control intraocular pressure (IOP) have become available in just the last 35 years. Interestingly, the term glaucoma dates back millennia, but medical therapy for glaucoma was delayed by thousands of years by a near-complete misunderstanding of what glaucoma actually was.
The term glaucoma was first used by Hippocrates in Greece in 400 BC to describe a dimming of vision. This non-specific term applied to most blinding conditions of the eye. Even the origin of the word glaucoma is muddied. Most sources attribute it to the ancient Greek word glaukos meaning cataract. But even then, cataract did not actually mean cataract in its modern sense—it was not known that cataract was a disorder of the lens until the French ophthalmologist Brisseau definitively placed cataract there in 1707.1 More likely, the word glaucoma came from the Latin glauca, meaning bluish green or gray (for example, the blue shark is known in Latin parlance as Prionace glauca, and blue fescue grass is termed Festuca glauca). These etymologically related root words are likely physiologically related as well, for a dense enough cataract in ancient days may well have been perceived as a change in the eye's color to a milky blue-gray-green tone.
With all this confusion over what glaucoma really was, it is no small wonder that there was little innovative glaucoma pharmacology taking place in the olden days. In fact, after Brisseau realized that cataracts were lens-related lesions, he incorrectly concluded that glaucoma must therefore be an opacification of the vitreous. (Although, to be fair, the lens itself was thought to reside in the center of the vitreous cavity until 1601 and old habits die hard.)
The English ophthalmologist Richard Bannister was the first to link glaucoma and IOP in 1622, but not much came of this until Charles Babbage and Hermann von Hemholtz independently assembled the first direct ophthalmoscope in mid-century, affording clinicians their first in vivo view of the posterior segment. Soon thereafter, in 1855, the German Adolf Weber proposed the concept of glaucomatous optic neuropathy as a “pressure excavation.”1 Fascinated by this concept, fellow German Albrecht von Graefe began a series of clinical descriptions that solidified the modern phenotypes we think of as the glaucomas.
Once the concept of IOP reduction for glaucoma took hold, it was not long—just 1862—before Sir Thomas Fraser introduced the field of glaucoma pharmacology by giving us the first IOP-lowering medication: the calabar bean. Those tempted to roll their eyes at the notion of complementary and alternative medicinal approaches would do well to recall that many of our modern drugs are derived from plants: digitalis from the common garden foxglove, aspirin derived from a substance found in willow bark, and taxol from the bark of the Pacific yew tree. And indeed, the calabar bean is not quackery but rather the original source of physostigmine (aka eserine), a potent miotic.
Alas, as with so much of glaucoma's history, even the first IOP-lowering agent was misunderstood. The calabar extract was quickly added to von Graefe's iridectomy surgical regimen solely for its miotic effects; its ability to lower IOP—not to mention its ability to break attacks of angle-closure glaucoma—went unappreciated until both Laqueur and Weber independently reported such in 1876.1 Pilocarpine, the second miotic, came along just a year later, thanks to Weber's efforts and was much better tolerated. Over 130 years later, pilocarpine remains an occasional adjunctive therapy for many patients with glaucoma, particularly pseudophakes and aphakes.
The second class of IOP-lowering drugs, the adrenergic agonists, debuted with epinephrine in 1901. The Frenchman Jean Darier first found its IOP effect while studying adrenal extracts for other purposes and eventually described the first adjunctive medication use in glaucoma: pilocarpine and epinephrine.1 Interestingly, this would later become the first commercially available fixed combination of IOP drugs for glaucoma. Epinephrine did not become commercially available for glaucoma management until the 1950s, followed soon after by clonidine (which is available in topical form in some international markets but not the United States because of its frequent association with dramatic drops in blood pressure).
Apraclonidine is a derivative of clonidine, and its development as a glaucoma medication is an example of serendipity. The drug is more highly selective for the α2 adrenergic receptor than clonidine by virtue of the addition of an amide group, and so hypotension is less of a concern. Its IOP-lowering efficacy was discovered when it was being tested as a means of controlling intraocular hemorrhage after Nd:YAG laser iridotomies.2 Apraclonidine has little effect on bleeding but did have a significant impact on blunting postlaser IOP spikes. Packaged as a 1% solution, apraclonidine was quickly approved by the United States FDA for the prevention of IOP spikes after anterior segment laser procedures in 1987. A few years later, in 1993, the 0.5% solution was approved for short-term management of chronic glaucoma; long-term use was often limited by a gradual loss of effect with chronic dosing (tachyphylaxis). Three years later, in 1996, brimonidine 0.2% was approved for long-term IOP management and has endured as the preferred adrenergic agonist for chronic use in glaucoma.
Carbonic Anhydrase Inhibitors
Systemic carbonic anhydrase inhibitors emerged in the late 1930s and early 1940s, when the sulfonamides were first used for antibacterial and diuretic applications. Acetazolamide appeared in the early 1950s, and by 1954, Bernard Becker had demonstrated its potent IOP-lowering effect.3 Unfortunately, systemic carbonic anhydrase inhibitors had a number of unpleasant and often unsafe side effects. Even more unfortunately, topical formulations of acetazolamide had little or no effect on IOP. The years between 1954 and 1979 saw a number of research groups searching for a carbonic anhydrase inhibitor that would be effective in topical form but with no success. In retrospect, the problem was this: a high degree of inhibition of the carbonic anhydrase enzyme system is necessary to achieve any degree of IOP reduction. By the mid-1970s, most teams were convinced that a topical carbonic anhydrase inhibitor would never be developed and abandoned the search.4 Only Thomas Marin persisted.
Thank goodness he did. In what would become a model for industry-academia collaborations, Marin at the University of Florida formed a collaborative relationship with Merck Research Laboratories. With their resources, >1500 candidate molecules were synthesized and screened before a series of partial successes led to MK-507, which would later be known as dorzolamide and marketed by Merck as Trusopt after FDA approval in 1995.4 Dorzolamide met all the criteria for a successful topical carbonic anhydrase inhibitor: it was both water- and lipid-soluble, had good corneal penetrance, and was highly effective at inhibiting the carbonic anhydrase enzyme system. Best of all, its side effect profile was much more favorable than systemically dosed carbonic anhydrase inhibitors. Not long after Trusopt was released, Alcon Laboratories developed and won FDA approval for a second topical carbonic anhydrase inhibitor dubbed brinzolamide and marketed as Azopt. Both Trusopt and Azopt remain available in the U.S. marketplace today.
Propranolol was the first beta blocker, introduced in 1967, and was quickly noted to lower IOP after intravenous administration. The drug was not viable as a topical agent, however, because of both corneal anesthetic properties and a negative effect on tear production.2 Other candidate beta blockers had additional limitations, such as profound dry eyes syndrome, subconjunctival fibrosis, and tachyphylaxis. In 1976, Merck's timolol was shown to lower IOP in healthy volunteers, and over the next 2 years, Thom Zimmerman and Herb Kaufman spearheaded the development of topical timolol as a treatment for glaucoma5 after an initial report by Katz than the drug-lowered IOP in healthy volunteers.6 Merck's Timoptic was approved by the FDA in 1978 and heralded the beginning of the modern age of glaucoma pharmacology.
For the next 20 years, timolol and its inevitable me-toos (levobunalol, metipranolol, and carteolol) represented the optimal first-line therapy for most patients with glaucoma. Once or twice daily dosing, no pesky miosis, and no inky staining of the conjunctiva, all positioned timolol ahead of pilocarpine and epinephrine for most prescribers. Soon after timolol's debut, the relatively cardioselective beta blocker betaxolol was approved for use in the United States, in the early 1980s. Betaxolol has a somewhat more favorable safety profile in patients with pulmonary disease, but the drug is generally regarded as less effective in lowering IOP compared with the non-selective beta blockers. Although these drugs have largely been displaced as first-line therapy by the prostaglandin analogs, they remain in common use as adjunctive therapy.
Perhaps no class of IOP-lowering drugs has changed the therapeutic landscape as dramatically as the prostaglandin analogs. The drugs in this class represent an almost unheard-of combination in medicine: the safest and most effective glaucoma drugs to date. Because of these two key characteristics, the prostaglandin class of IOP-lowering agents quickly supplanted beta blockers as the preferred first-line agents for most patients with glaucoma. Interestingly, these drugs were identified as potential IOP-lowering agents incidentally to research probing the mediators of ocular inflammation.7
The Hungarian physiologist (and novelist) Lazlo Bito developed the prototype molecule—latanoprost—while at Columbia University in 1982, after he and Carl Camras demonstrated that PGF2α lowered IOP in both healthy and glaucomatous monkeys.8 A collaboration between Columbia and Swedish drug maker Pharmacia ensued, but it took until 1996 to achieve an approvable formulation (Xalatan, marketed by Pharmacia before being acquired by Pfizer). Latanoprost represented a major milestone in glaucoma therapeutics and in all of ophthalmic therapeutics: it was the first drug to achieve annual global sales exceeding U.S. $1 billion.9 Five years after the debut of latanoprost, the FDA approved a pair of additional prostaglandin analogs: Alcon's travoprost (Travatan) and Allergan's bimatoprost (Lumigan). A fourth drug in this class—Ciba Vision's unoprostone (Rescula)—was briefly available in the U.S. marketplace, but the drug never gained traction. Twice daily dosing and inferior IOP reductions compared with latanoprost10 limited its appeal. In addition, Merck's tafluprost is available in overseas markets but remains in phase III testing in the United States.
Summary and Unmet Needs
The past 150 years have produced a plethora of IOP-lowering drugs with a variety of mechanisms of action, most of which remain available and in common usage. Given the accelerated rate of discovery over the past 15 years, the future is likely to produce any number of new drugs to complement our current pharmamentarium. There remain several unmet needs in glaucoma pharmacology. Despite five drug classes, there is no clear choice for adjunctive therapy to prostaglandin analogs—most of the remaining drug classes are relatively inefficacious in combination with the prostaglandins. (In part for this reason, there remains no fixed combination product containing a prostaglandin available in the U.S. marketplace.) Improvements in drug delivery—specifically longer-acting topical drugs or sustained-release formulations—would also benefit patients with glaucoma. Adherence is notoriously low with glaucoma medications; absolving the patient of the responsibility of daily dosing would be greatly impactful in the management of this chronic disease. Moreover, developing drugs for glaucoma that work by mechanisms other than IOP reduction is an unmet need. Accomplishing this will require that we better understand the pathophysiology of glaucoma on the molecular level. In particular, drugs that protect the optic nerve from damage—so-called neuroprotection—would be tremendously useful in the management of glaucoma. Human trials of memantine for optic neuroprotection have been bitter failures, but other potential neuroprotective drugs are in varying stages of development and testing. These issues are currently being addressed by both industry and academia, and the next 150 years will undoubtedly bring new discoveries that will continue to improve the lives of patients with glaucoma.
This work was supported, in part, by an unrestricted grant from Research to Prevent Blindness, Inc.
Within the past 12 months, the author has worked as a paid consultant for Alcon Laboratories, Aqueous Biomedical, and Pfizer, Inc.
Department of Ophthalmology
West Virginia University Eye Institute
West Virginia University
Morgantown, West Virginia 26505
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