For generations, we have used ophthalmic products to make our eyes more attractive: There’s the alluring gaze brought on by belladonna drops and the bright contrast created by the astonishing formulations containing methylene blue (now banned by the Food and Drug Administration), which are still popular in the French product Collyre Bleu.1 There’s even the recommended routine of self-urine eye drops promoted by Ayurvedic medicine, and you might be surprised to hear that the purported beneficial properties of urine have trickled down to ophthalmic medicine in the original urea-containing formulation of Murine, whose eardrop line still contains this urine derivative.2
It’s during this quest for improved appearance that vasoconstrictors appeared. The easy entry of ocular vasoconstrictors into medical practice, their utility and relative safety and the thousands of patient-years of experience we have with them are all clear. However, critics allege that these agents suffer from rebound effects, tolerance issues and ocular tachyphylaxis. This article takes a closer look at vasoconstrictors’ various attributes, pros and cons.
Vasoconstrictors have been available for treating hyperemia for decades. When the cardiovascular activity of imidazoles was explored in search of therapies, their introduction as nasal decongestants in the mid-1940s was followed by ophthalmic preparations. To provide greater efficacy, ocular vasoconstrictors were paired early on with topical antihistamines to combat the itching and redness associated with allergic conjunctivitis. Legislation in 1962 mandated proof of efficacy for each of these components, prompting inception of the conjunctival allergen challenge model for evaluation of antihistamine/decongestant combinations.3 While studies of these agents’ duration of action have never been done, the FDA Over-the-Counter Code of Federal Regulations Title 21 Parts 349 and 369 recommend “up to four times daily dosage” for these first-generation vasoconstrictors due to theoretical safety concerns, and this labeling has remained unchanged.
Mechanism of Action
Vasoconstriction provides temporary relief from tissue congestion. The mechanism by which vasoconstrictors act is adrenergic receptor activation. All ocular vasoconstrictors available today, including naphazoline, tetrahydrozoline, phenylephrine and oxymetazoline, act as adrenergic receptor agonists. ARs mediate the physiological response to catecholamines, norepinephrine and epinephrine, and are central to cardiovascular and central nervous system activity. They are members of the superfamily of G-protein coupled receptors, classified as α1-AR, α2-AR and β-AR, each with multiple and mixed sub-types. Local sub-type concentrations, distributions and ligand binding affinities all define a given tissue’s response to adrenergic agonists. The ophthalmic vasoconstrictors are α1- or mixed α1/α2-adrenergic receptor agonists.4
|Vasoconstrictors and the Adrenergic Cascade|
|G-protein-coupled adrenergic receptors activate phospholipase C, resulting in release of intracellular calcium, ultimately leading to smooth muscle vasoconstriction.|
ARs mediate stimulation of smooth muscle contraction and, systemically, play a role in control of blood pressure. α1
-ARs are excitatory post-synaptic receptors, constricting larger arterioles. α2
-ARs often work in opposition to α1
receptors, mediating nociception, blood pressure and spinal reflexes. α2
-ARs mediate smooth muscle contraction, and also inhibit release of norepinephrine by sympathetic post-ganglionic fibers.
There are two classes of vasoconstrictors: sympathomimetic amines and imidazoles. Sympathomimetic amines mimic the actions of the sympathetic nervous system through the pre-synaptic release of norepinephrine in sympathetic nerves. Norepinephrine then binds post-synaptically to α-ARs, resulting in vasoconstriction. The imidazoles can be α2-AR agonists (e.g., brimonidine), or mixed α1-AR/α2-AR agonists (e.g., naphazoline), and act post-synaptically on sympathetic nerves to cause vasoconstriction. They may also lower production of norepinephrine, thus decreasing blood flow and reducing congestion.
Adrenergic-mediated vasoconstriction is associated with unwanted pharmacological and clinical phenomena, such as tachyphylaxis, tolerance, rebound vasodilation, toxicity and the potential for abuse. In contrast to tolerance, which occurs with chronic use of a drug, tachyphylaxis is a rapidly decreasing response to a drug following its initial administration. Tachyphylaxis occurs in the presence of alpha-adrenergic agonists by reducing the availability of receptors in an effort to maintain homeostasis within the affected cells. Beta-blocker tachyphylaxis involves binding and stabilizing receptors, as well as inhibiting a cell’s ability to remove receptors from its surface.5
As early as 1946, there were reports of the adverse rebound effects of nasal vasoconstrictor use.6 In fact, most of the studies describing rebound relate to the use of nasal vasoconstrictors. The picture is not as well-defined in the eye. In 1984, we showed that use of tetrahydrozoline was clearly associated with tachyphylaxis, but not rebound.7
Several studies suggest that tachyphylaxis and rebound nasal congestion are due to changes in the α1-AR population.8-11 Receptor sequestration has been proposed to be a rapid mechanism of desensitization to acute hyperstimulation, while down-regulation and reduction in receptor number might be an adaptive response to chronic exposure to agonists. The complexities of adrenergic-mediated vasoconstrictor tachyphylaxis and rebound will be discussed in an upcoming column.
Tachyphylaxis leads to a rapid reduction in efficacy of nasal and ocular vasoconstrictors, prompting the patient to overuse the medication and laying the groundwork for a subsequent rebound effect in the nose, and a potential toxic reaction and medicamentosa in the eye.
Rebound vs. Tachyphylaxis
Rebound is common in central nervous system pharmacology. It’s defined as a return of symptoms, to a degree stronger than present initially, upon discontinuation of a drug. It is a known risk of anxiolytics and nasal vasoconstrictors, and it’s assumed to occur with ocular vasoconstrictor use. Our early work didn’t demonstrate rebound with ocular vasoconstrictors,7 but other reports of it can be found in the literature.12,13
It’s difficult to distinguish actual rebound, (i.e., greater redness and vasodilation resulting from abrupt drug discontinuation), from tachyphylaxis due to dampening of receptors, and the resulting toxicity due to chronic abuse. OTC labeling warns of a possible rebound effect with ocular vasoconstrictor use, though a distinction of rebound vs. toxicity due to abuse hasn’t been established. Many cases of exaggerated redness are a combination of all these events. One study identified 70 patients with vasoconstrictor-associated conjunctivitis, though signs were present during therapy and appeared to be related more to chronic vasoconstrictor abuse due to tachyphylaxis rather than rebound.12 Another study reported five cases of eyes becoming redder after the suspension of a vasoconstrictor than they were before treatment.13 Medicamentosa,12 even with one case resembling ocular pemphigoid,14 is documented, as are reactions due to vasoconstrictors in subjects with acute angle-closure glaucoma.
Duration of Relief
With the exception of oxymetazoline, which is approved for dosing up to every six hours, naphazoline, tetrahydrozoline and phenylephrine are approved for dosing up to every four. However, these recommendations are based on historical usage patterns15 rather than pharmacokinetics, and are now integrated by default into OTC labeling. Consumer expectation is for a duration of several hours, and a lack of effect might lead to overuse and toxicity. Manufacturers have confounded the duration issue by using modifiers such as “maximum” and “advanced,” which suggest a longer duration due to lubricants meant to prolong comfort, yet with unchanged active ingredients and/or dose. Table 1 on p. 54 provides a list of ocular vasoconstrictors.
Key to the issue of duration is the indication for vasoconstrictors mandated by the FDA OTC Monograph,16 which provides the regulatory basis for the wording of package inserts: “relief of redness of the eye due to minor eye irritations.” This certainly translates to real-world use patterns: No one has yet thought to preventively whiten their eyes before heading out for a late night of festivities. Consumers are undoubtedly self-medicating for treatment of a self-limiting condition, and vasoconstrictors are used for relief of redness. Remarkably, given this mandated indication and recognized use, there are no published reports on relief of redness. Thirty years ago, our original work on vasoconstrictors in the histamine challenge model involved prevention of redness, with duration of action demonstrated at one to two hours after dosing for naphazoline, tetrahydrozoline and phenylephrine, but oxymetazoline was not tested.17 Studies today are still designed to establish the efficacy of vasoconstrictors by their prevention of redness induced by various challenges. Ongoing efforts to establish a model for relief of ocular redness induced by irritation with a chlorine, salt-water, allergen or histamine challenge might substantiate efficacy and duration in a more appropriate setting. Redness is most often the short-lived result of one discrete irritating or allergic stimulus that the eye can suppress on its own, rather than the result of continuous, redness-inducing stimuli. This natural decay makes it difficult to prove the efficacy of vasoconstrictors, and multiple challenges might be necessary to maintain a baseline redness that can then be modified pharmacologically.
We recently experienced this difficulty firsthand in a placebo- and active-controlled CAC evaluation (n: 17/arm) of the 15-minute, four-, six- and eight-hour efficacy and duration of action of 0.025% oxymetazoline, the gold-standard vasoconstrictor approved for use every six hours. Surprisingly, for the only vasoconstrictor with claims of being long-acting, no significant effect on prevention of redness was shown at any time point. This lack of effect prompted us to search without success for published studies that showed the efficacy and duration of oxymetazoline.
Nine out of 10 subjects report self-medicating for ocular redness, a condition associated with reduced quality of life and negative social connotations such as drinking and drug abuse, in addition to general fatigue and cosmetic concerns. In the United States, the OTC eye-care market represents approximately $500 to $700 million annually on sales of 60 to 80 million units. Redness relief products comprise ~ 37 percent of unit sales, and redness plus allergy relief is close to 60 percent.
While all vasoconstrictor package labeling contains the caveat to “stop use and ask a doctor if condition worsens or lasts more than 72 hours,” most eye-care specialists are confident that vasoconstrictors are used for relief of a temporary, self-limiting irritation and will not mask a serious underlying condition. Thus, there is an unmet need to develop a drug that provides clinically relevant relief of redness resulting from episodic irritation, without the drawbacks of tachyphylaxis, abuse and toxicity.
With emerging evidence that tachyphylaxis appears to be an α1-AR-related phenomenon, research efforts have shifted to α2-AR agonists as potential vasoconstrictors. Studies have shown that nasal decongestion evoked by α2-AR activation might have lower cardiovascular side effects than α1- or non-selective α-AR vasoconstrictors such as phenylephrine and oxymetazoline.10,11
Brimonidine is a second generation α2-AR agonist that was first approved by the FDA in 1997 for treatment of ocular hypertension with t.i.d. dosing. It has greater selectivity for α2-ARs (α2-AR/α1-AR binding affinity ratio ~ 1000:1) and lower lipid solubility than clonidine and apraclonidine, providing a greater ocular hypotensive effect with lower systemic side effects. The most common side effects associated with chronic ocular use of brimonidine for elevated intraocular pressure are dry mouth and ocular redness/conjunctivitis, the latter with a reported incidence of 10 to 30 percent.18 However, a retrospective analysis of these data showed that many original cases were not of drug-induced allergy, but coexisting seasonal allergies and bacterial infections. (Abelson MB, et al. IOVS 1999;40:ARVO Abstract 2718)
Exacerbation of redness by α2-agonists is thought to be dose-dependent; the doses used for ocular hypertension are relatively high at 0.5% and 0.2%. Low-dose formulations (0.1% or 0.15%) have since been introduced with a different preservative, chlorine dioxide (Purite, 0.005%), instead of benzalkonium chloride, after studies indicated that the latter contributed to the incidence of side effects. We are currently assisting in the development of low doses of brimonidine (0.01 to 0.025%) in an improved formulation with regard to comfort and safety, and tailored for use as an ocular vasoconstrictor/whitener. The agent we’re working with, Luminesse (0.025% brimonidine, Eye Therapies) has provided greater microvessel constriction at mucosal surfaces and is thought to retain more optimal blood flow from larger feeder vessels. The problems of tachyphylaxis, rebound and toxicity due to abuse might be resolved, and the eight-hour duration of action demonstrated for IOP might be preserved, providing us with a significantly longer-lasting vasoconstrictor. Results from initial studies of this low-dose drug showed clinically significant efficacy vs. placebo and superiority to 0.025% oxymetazoline, promising indications that it may be breaking new ground in this often problematic class of drugs.
Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at the Schepens Eye Research Institute. Ms. Smith is a medical writer at Ora Inc. The authors would like to thank Wiley Chambers, MD, for his assistance with the article.
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16. FDA OTC Monograph. Federal Register Vol. 53, No. 43: 7092.
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