Tachyphylaxis, or acute drug desensitization, is a common effect of OTC ocular allergy medications as well as medications for other ophthalmic conditions, such as glaucoma. In this month's column, we will look at which ophthalmic drug classes are subject to tachyphylaxis and the molecular mechanisms involved. We'll also try to provide some pharmacological and clinical approaches to dealing with this phenomenon.
Tachyphylaxis is defined as a rapidly decreasing response to a drug following its initial administration. This decreased drug sensitivity, like the placebo effect, can occur with any drug. Tachyphylaxis occurs when the treated cells make molecular adjustments in order to return the receptor signaling levels to the pre-treatment equilibrium, or homeostasis. The major homeostatic mechanisms responsible for tachyphylaxis in many cellular systems involve either a change in the number of receptors, or a change in the ability of a receptor to affect the downstream signaling molecules. Tachyphylaxis differs from drug tolerance in that it is an acute rather than a gradual consequence of prolonged drug administration.1
The term tachyphylaxis is sometimes used incorrectly as a general synonym for receptor desensitization. In actuality, the molecular changes that contribute to tachyphylaxis can go in either direction (i.e., a decrease or in- crease in receptor number, known as receptor desensitization or hyper-sensitization, respectively). Thus, tachyphylaxis correctly refers to a cell's or tissue's loss of sensitivity to a therapeutic drug or a desensitization of response, not necessarily a desensitization of receptors.
In ophthalmic practice, the drugs for treating glaucoma and allergic conjunctivitis are the main classes subject to tachyphylaxis. The use of beta-adrenergic antagonists (beta-blockers) in glaucoma treatment can lead to a compensatory increase in beta-adrenergic receptors, rapidly diluting the patient's response to therapy. In ocular allergy, desensitization to the vasoconstrictors found in over-the-counter treatments occurs because of down-regulating alpha-adrenergic receptors. Additionally, up-regulation of the histamine receptor may also be possible in response to histamine blockers.
This is how tachyphylaxis affects two major classes of drugs:
• Allergic conjunctivitis. In ocular allergy, histamine is the major pre-formed mediator responsible for all the symptoms of the allergic response.2 Histamine binds to H2 receptors to induce smooth muscle dilation and endothelial gaping, which leads to redness and swelling, respectively. Histamine also binds to the H1 receptors, which leads to the itching that is characteristic of allergy.3 Thus, blocking the histamine receptors has been a major strategy for combating the allergic response.
Histamine tachyphylaxis, which has been described for over 45 years,4 occurs because of a compensatory increase in the number of H2 receptors in response to histamine antagonists.5 Signaling by the H2 receptor bears many similarities to beta-adrenergic signaling, including coupling to G-proteins and an increase in levels of the cAMP messenger upon receptor activation. Interestingly, the H2 receptor may also share its regulatory system with the well-characterized beta-adrenergic system. With this binding action, histamine antagonists increase the receptor's stability and cause more histamine receptors to remain on the cell surface.6 Furthermore, like beta-adrenergic systems, histamine antagonists contribute to tachyphylaxis not just by binding and stabilizing the receptor, but also by exerting an inhibitory effect on a cell's ability to remove the receptor from its surface.5,6
Over-the-counter ophthalmic decongestant drops, such as Visine (Pfizer), are another category of drugs that induce tachyphylaxis.7 In particular, these medications contain alpha-adrenergic amines—such as tetrahydrozoline, naphazoline or phenylephrine—that act as vasoconstrictors. These amines promote the normal action of alpha-adrenergic receptors, which can briefly reduce swelling and redness by limiting blood supply to the site of the reaction.
Unlike tachyphylaxis in response to beta-adrenergic and H2-receptor blockades, with these alpha-adrenergic receptor agonists, tachyphylaxis involves decreasing receptor density and efficacy. The result of this down-regulation of vasoconstrictor receptors is that patients may experience rebound vasodilatation after stopping treatment, in which the failure of endogenous vasoconstrictors to find receptors leaves their eyes more red and swollen than before treatment. Some patients become chronic users of such drugs and subsequently develop acute and chronic forms of the conjunctivitis they sought to treat.7
• Glaucoma. Beta-blocking drugs, which are used to treat open-angle glaucoma, provide one of the most widely known historical examples of tachyphylaxis. Intraocular pressure is regulated by beta-adrenergic receptors. These receptors interact with catecholamines (adrenaline and noradrenaline) and activate cyclic AMP messengers with the help of tightly coupled G-protein signaling molecules. Beta-blockers bind to the beta-adrenergic receptors, competing with the body's natural agonists that aim to increase aqueous secretion in the ciliary tissues of the eye.
The beta-blocker timolol was first observed 25 years ago as inducing a short-term "escape" and long-term "drift" in responsiveness over days, months and years of treatment.8,9 It has subsequently been shown that, in certain patients, treatment with beta-blockers can lead to a rapid increase in the density of beta-adrenergic receptors on the cell surface.10,11 This effect can occur within a day of the initial dosage.12 It should be noted that other, more recent studies have failed to detect evidence of tachyphylaxis over 12 months with twice-daily use of timolol.13
Regulation of the beta-adrenergic receptors has been studied in detail and can be controlled in three ways: 1) the genes required to make the receptor, localize, recycle it, or propagate its signal are turned on or off; 2) the messenger RNA encoding for any of these genes is degraded; and/or 3) the receptor itself is modified (e.g., phosphorylated), uncoupled from the downstream signaling proteins or recycled from the cell surface at a different rate.
In the case of beta-adrenergic receptors treated with beta-blockers, the evidence shows that tachyphylaxis can result from mechanisms at both post-translational and pre-translational stages of protein synthesis. In an attempt to compensate for the loss of beta-adrenergic signaling, the cell rapidly externalizes beta-adrenergic receptors that exist in ready-made vesicle reserve pools below the surface.14 The binding of the beta-blocker also increases the stability of the receptors that are already on the surface, slowing the turnover of receptors and acting to increase receptor density.11 Additionally, the enzymes that are capable of modifying the beta-adrenergic receptor to tag it for degradation are down-regulated as part of the tachyphylaxis response.15
Understanding the mechanisms of tachyphylaxis may leave many of us wondering what can be done. Since cells naturally act to restore homeostasis, how can the clinician counteract this compensatory mechanism and treat ocular disorders?
In treating ocular allergy, the optimal therapies are dual-action molecules that act to remedy both the symptoms and their source. For example, drugs such as olopatadine (Patanol, Alcon), ketotifen (Zaditor, Novartis), and azelastine (Optivar, MedPointe) antagonize the histamine receptor but also inhibit histamine release by stabilizing the mast cells responsible for its release.16 Of these three, Patanol has been shown to be the most comfortable and to provide superior relief from itching and redness.17,18 In addition, because Patanol does not interact with alpha-adrenergic receptors,19 it may be less susceptible to tachyphylaxis, tolerance, or rebound, unlike older treatments.
If a patient can be prescribed a dual-action treatment, over-the-counter vasoconstrictors are often unnecessary. The effects of tachyphylaxis on users of OTC allergic eye drops are best managed by discontinuing their use. Patients should be told to expect a temporary worsening of symptoms because of the rebound effect. The transition from rebound to recovery has been shown to take an average of four weeks, but correlates with the length of time that the drugs were used prior to initiating discontinuation.7
In the case of glaucoma medications, it's important for patients to take only what is necessary to achieve the desired lowering of pressure, and arriving at the proper dosage may mean using trial and error. One approach that may be helpful is to direct the patient to take her glaucoma medication once a day, on every day but Sunday. The weekly day without treatment can effectively prevent tachyphylaxis.
One important question to ask glaucoma patients who seem to be worsening is: Has the disease progressed or has the drug lost efficacy? A possible way to answer this question is to have the patient take a beta-blocker "holiday." Discontinuing use and then resuming it after a couple of months may circumvent any tachyphylaxis effects without harming the patient and allow the physician to get a clear picture of the state of disease progression.
For glaucoma, alternative treatments to beta-blockers exist or are being developed that act on different pathways to regulate IOP. For example, SR121463, a selective non-peptide antagonist to the V2 vasopressin receptor, has been shown to reduce IOP in a rabbit model of ocular hypertension without tachyphylaxis.20 Additionally, nipradilol, which is in development as a possible glaucoma therapeutic, may act as both a beta-blocker and alpha-receptor blocker. By acting on more than one target, this drug's combination therapy approach has been shown to reduce IOP without tachyphylaxis for two months, though longer trials are needed to determine whether tachyphylaxis can be avoided long term.21
For glaucoma treatment, awareness of the possibility of tachyphylaxis with drugs such as timolol is vital for assessing appropriate dosage, and be sure to monitor responsiveness to the drug after the initial dose is administered over the first several days.
With the availability of multi-mechanism anti-allergy drugs, perhaps the obstacle in dealing with the phenomenon of tachyphylaxis lies in awareness and doctor-patient communication. One solution is proactive diagnosis. Although the patient may not be experiencing an allergic response at the time of the office visit, questioning him or her about symptoms can help identify an allergy sufferer and lead to prescribing better therapies. Such proactive communication and awareness can prevent your patients from joining the millions of Americans self-medicating in the eye-drop aisle.
Dr. Abelson, an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. Ms. Vashlishan is currently a doctoral candidate in the Department of Genetics at Harvard Medical School.
1. Katzung BG, ed. Basics of Clinical Pharmacology, 8th ed. London: McGraw/Hill. 2001.
2. Abelson MB, Allansmith MR. Histamine in the eye. In: Silverstein AM, O'Connor GR, eds. Immunology and Immunopathology of the Eye. New York: Masson Publishing, 1979:362-364.
3. Abelson MB, Udell IJ. H2-receptors in the human ocular surface. Arch Ophthalmol 1981;99:402-422.
4. Bulbring E, Burnstock G. Membrane potential changes associated with tachyphylaxis and potentiation of the response to stimulating drugs in smooth muscle. Br J Pharmacol 1960;15:611-624.
5. Takeuchi K, Kajimura M, Kodaira M, et al. Up-regulation of the H2 receptor and adenylate cyclase in rabbit parietal cells during prolonged treatment with H2-receptor antagonists. Digestive Diseases and Sciences 1999;44:1703-1709.
6. Smit MJ, Leurs R, Alewijnse AE, et al. Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors. Proc Natl Acad Sci USA 1996;93:6802–6807.
7. Soparkar CN, Wilhelmus KR, Koch DD, et al. Acute and chronic conjunctivitis due to over-the-counter ophthalmic decongestants. Arch Ophthal 1997;115:34-38.
8. Boger WP. Long-term experience with timolol ophthalmic solution in patients with open angle glaucoma. Ophthalmology 1979;85:259-267.
9. Boger WP. Short term "escape" and longterm "drift." The dissipation effects of the beta adrenergic blocking agents. Surv Ophthalmol 1983;28:(S)235-42.
10. Neufeld AH. Influences on the density of beta-adrenergic receptors in the cornea and iris-ciliary body of the rabbit. Invest Ophthal and Vis Sci 1979;17:1059-1075.
11. Samama P, Bond RA, Rockman HA, et al. Ligand-induced over-expression of a constitutively active beta2-adrenergic receptor: Pharmacological creation of a phenotype in transgenic mice. Proc Natl Acad Sci USA 1997;94:137.
12. Molinoff PB, Aarons RD. Effects of drugs on beta-adrenergic receptors on human lymphocytes. J Cardiovasc Pharmacol 1983;5:S63–S67.
13. Schuman JS, Horwitz B, Choplin NT, et al. A 1-year study of brimonidine twice daily in glaucoma and ocular hypertension. A controlled, randomized, multicenter clinical trial. Chronic Brimonidine Study Group. Arch Ophthalmol 1997;115:847-52.
14. Milano CA, Dolber PC, Rockman HA, et al. Myocardial expression of a constitutively active alpha 1b-adrenergic receptor in transgenic mice induces cardiac hypertrophy. Proc Natl Acad Sci USA 1994;91:10109–10113.
15. Ping P, Gelzer-Bell R, Roth DA, et al. Reduced beta-adrenergic receptor activation decreases G-protein expression and beta-adrenergic receptor kinase activity in porcine heart. J Clin Invest 1995 Mar;95:3:1271-80.
16. Abelson MB. Evaluation of olopatadine, a new ophthalmic antiallergic agent with dual activity using the conjunctival allergen challenge model. Ann Allergy Asthma Immunol 1998;81:211-218.
17. Artal MN, Luna JD, Discepola M. A forced choice comfort study of olopatadine hydrochloride 0.1% versus ketotifen fumarate 0.05%. Acta Ophthalmol Scand Suppl 2000;230:64-5.
18. Abelson MB. A review of olopatadine for the treatment of ocular allergy. Expert Opin Pharmacother 2004;5:9:1979-94.
19. Rosenwasser LJ, O"Brien T, Weyne J. Mast cell stabilization and anti-histamine effects of olopatadine ophthalmic solution: a review of pre-clinical and clinical research. Curr Med Res Opin 2005;21:9:1377-87.
20. Lacheretz F, Barbier A, Serradeil-Le Gal C, et al. Effect of SR121463, a selective non-peptide vasopressin V2 receptor antagonist, in a rabbit model of ocular hypertension. J Ocul Pharmacol Ther 2000;16:203-216.
21. Kanno M, Araie M, Tomita K, Sawanobori K. Effects of topical nipradilol, a beta-blocking agent with alpha-blocking and nitroglycerin-like activities, on intraocular pressure and aqueous dynamics in humans. Br J Ophthalmol 2000;84:293-299.