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.
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