Download Vasoconstrictors: Myths and Realities

Review
Therapeutic Topics
Vasoconstrictors:
Myths and Realities
The facts about how vasoconstrictors work and thoughts about
mechanisms behind their purported negative side effects.
Mark B. Abelson, MD, CM, FRCS, FARVO and Lisa M. Smith, Andover, Mass.
F
or 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 selfurine 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.
safety concerns, and this labeling
has remained unchanged.
Vasoconstrictors Arrive
Mechanism of Action
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 Overthe-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
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 a1-AR, a2-AR and b-AR,
each with multiple and mixed subtypes. Local sub-type concentrations,
distributions and ligand binding affinities all define a given tissue’s response
to adrenergic agonists. The ophthalmic
vasoconstrictors are a1- or mixed a1/
a2-adrenergic receptor agonists.4
ARs mediate stimulation of smooth
muscle contraction and, systemically,
play a role in control of blood pressure.
a1-ARs are excitatory post-synaptic
52 | Review of Ophthalmology | August 2012
This article has no commercial sponsorship.
receptors, constricting larger arterioles. a2-ARs often work in opposition
to a1 receptors, mediating nociception, blood pressure and spinal reflexes. a2-ARs mediate smooth muscle
contraction, and also inhibit release
of norepinephrine by sympathetic postganglionic 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 a-ARs,
resulting in vasoconstriction. The imidazoles can be a2-AR agonists (e.g.,
brimonidine), or mixed a1-AR/a2-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.
Vasoconstrictors and the Adrenergic Cascade
Ca2+ Ca2+
Ca2+ Ca2+
Ca2+
Ca2+
2+
Ca2+
Ca
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Tachyphylaxis
G-protein-coupled adrenergic receptors activate phospholipase C, resulting in release of
intracellular calcium, ultimately leading to smooth muscle vasoconstriction.
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 a1-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
August 2012 | Revophth.com | 53
Review
Therapeutic
Topics
Table 1. Ocular Vasoconstrictors Available Worldwide*
Commercial Name
Decongestant/Other Active
Commercial Name
Component(s)
naphazoline 0.12%/PEG as humectant Naphcon-A
Decongestant/Other Active
Component(s)
naphazoline 0.025%/pheniramine 0.3%
antihistamine
naphazoline 0.1%
Advanced Eye Relief
Redness Instant Relief
Advanced Eye Relief
Redness Maximum Relief
AK-Con
naphazoline 0.03%/hypromellose as
lubricant
naphazoline 0.1%
Neo-Synephrine Ophthalmic phenylephrine 0.12%
AK-Nefrin
phenylephrine 0.12%
Neofrin
phenylephrine 0.12%
Albalon
naphazoline 0.1%
Ocu-Phrin
phenylephrine 0.12%
All Clear
Ocu-Zoline
tetrahydrozoline 0.05%
Ocu-Clear
oxymetazoline 0.025%
All Clear AR
naphazoline 0.012%/PEG as
humectant
naphazoline 0.012%/zinc sulfate as
astringent
naphazoline 0.03%/lubricants
Opcon-A
Allerest
naphazoline 0.012%
Opti-Clear
naphazoline 0.2625%/pheniramine
0.315% antihistamine
tetrahydrozoline 0.05%
Allersol
naphazoline 0.12%
Optigene 3
tetrahydrozoline 0.05%
Altazine
tetrahydrozoline 0.05%
Prefrin
phenylephrine 0.12%
Prefrin Liquifilm
phenylephrine 0.12%/lubricants
Refresh Redness Relief
phenylephrine 0.12%/lubricants
Tetrasine
tetrahydrozoline 0.05%
Vasoclear
naphazoline 0.02%
Vasoclear-A
All Clear ACR
Clear Eyes ACR
Nazil Ofteno
naphazoline 0.012%/zinc sulfate as
astringent, glycerin as lubricant
Clear Eyes Complete
naphazoline 0.0625%/zinc sulfate as
7 Symptom Relief
astringent, lubricants
Clear Eyes Cooling Itchy Eye naphazoline 0.012%/glycerin as
Relief
lubricant, zinc sulfate as astringent
Clear Eyes Maximum
naphazoline 0.3%/glycerin as
Redness Relief
lubricant
Clear Eyes Redness Relief
naphazoline 0.012%/glycerin as
lubricant
Collyrium Fresh
tetrahydrozoline 0.05%/glycerol as
lubricant
Comfort Eyedrops
naphazoline 0.03%
Vasocon
naphazoline 0.02%/zinc sulfate as
astringent
naphazoline 0.05%/antazoline 0.5%
antihistamine
naphazoline 0.1%
Degest 2
naphazoline 0.012%
Visine Original
tetrahydrozoline 0.05%
Estivin 2
naphazoline 0.012%
tetrahydrozoline 0.05%/lubricants
Eyesine
tetrahydrozoline 0.05%
Geneye
tetrahydrozoline 0.05%
Visine Maximum
Redness Relief
Visine Advanced
Redness Relief
Visine-A.C.
Geneye Extra
tetrahydrozoline 0.05%/unknown
Visine Totality
Isopto Frin
phenylephrine 0.12%
Visine L.R.
Murine Tears Plus
Visine-A
Nafazair
tetrahydrozoline 0.05%/lubricant,
povidone
naphazoline 0.1%
Naphcon
naphazoline 0.012%
Naphcon Forte
naphazoline 0.1%
54 | Review of Ophthalmology | August 2012
Vasocon-A
tetrahydrozoline 0.05%/lubricants
tetrahydrozoline 0.05%/zinc sulfate
as astringent
tetrahydrozoline 0.05%/zinc sulfate as
astringent, lubricants
oxymetazoline 0.025%
naphazoline 0.025%/pheniramine 0.3%
antihistamine
Zincfrin
phenylephrine 0.12%/zinc sulfate
as astringent
Zincfrin-A
naphazoline 0.5%/zinc sulfate as
astringent, antazoline 0.5% antihist.
* Trademarks are property of their respective owners.
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 goldstandard 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.
Unmet Need
Nine out of 10 subjects report selfmedicating for ocular redness, a condi-
tion 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 a1-AR-related phenomenon, research efforts have
shifted to a2-AR agonists as potential
vasoconstrictors. Studies have shown
that nasal decongestion evoked by a2AR activation might have lower cardiovascular side effects than a1- or nonselective a-AR vasoconstrictors such as
phenylephrine and oxymetazoline.10,11
Brimonidine is a second generation
a2-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 a2-ARs
(a2-AR/a1-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 inci(Continued on page 69)
August 2012 | Revophth.com | 55
56 | Review of Ophthalmology | August 2012
Review
Therapeutic
Topics
(Continued from page 55)
dence 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 a2-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.
1. http://thebeautybrains.com/2008/02/18/can-collyre-bleu-eyedrops-make-your-eyes-blue/. Accessed July 23, 2012.
2. Van der Kroon, C. The Golden Fountain: The Complete Guide to
Urine Therapy. Banbury, U.K.: Amethyst Books, 1996.
3. Abelson MB, Chambers WC, Smith LM. Conjunctival allergen
challenge: A clinical approach to studying allergic conjunctivitis.
Arch Ophthalmol 1990;108:84-88.
4. Cantor LB, WuDunn D, Gerber S, et al. Medical management
of glaucoma. Adrenergic agents. In: Albert DM, Jakobiec FA, eds.
Principles and Practices of Ophthalmology. Philadelphia: WB
Saunders, 2008:2788-2789.
5. Cao J, Chen M, Wang Q. Mechanisms of vascular desensitization
to agonists. Acta Academiae Medicinae Sinicae 1996;18:4:273-8.
6. Lake CF. Rhinitis medicamentosa. Proceedings Staff Meet
Mayo Clin 1946;21:367.
7. Abelson MB, Butrus SI, Weston JH, Rosner B. Tolerance
and absence of rebound vasodilation following topical ocular
decongestant usage. Ophthalmology 1984;91:1364-1367.
8. Fratelli, M, DeBlasi A. Agonist-induced alpha 1-adrenergic
receptor changes. FEBS Lett 1987;212:1:149-153.
9. Vaidyanathan S, Williamson P, et al. Fluticasone reverses
oxymetazoline induced tachyphylaxis of response and rebound
congestion. Am J Respir Crit Care Med 2010;182:1:19-24.
10. Corboz MR, Rivelli MA, Mingo GG, et al. Mechanism of
decongestant activity of a-2-adrenoreceptor agonists. Pulm
Pharmacol Ther 2008;21:449-54.
11. Corboz MR, Mutter JC, Rivelli MA, et al. a2-adrenoreceptor
agonists as nasal decongestants. Pulm Pharmacol Ther
2007;20:149-156.
12. Soparkar CN, Wilhelmus KR, Koch DD, Wallace GW, Jones
DB. Acute and chronic conjunctivitis due to over-the-counter
ophthalmic decongestants. Arch ophthalmol 1997;115:1:34-38.
13. Spector SL, Raizman MB. Conjunctivitis medicamentosa. J
Allergy Clini Immunol 1994;94:1:134-136.
14. Tappeiner C, Sarra GM, Abegg M. Abuse of vasoconstricting
eyedrops mimicking an ocular pemphigoid. Eur J Ophthalmol
2009;19:1:129-32.
15. Menger HC. New ophthalmic decongestant, tetrahydrozoline
hydrochloride; clinical use in 1,156 patients with conjunctival
irritation. JAMA 1959;170:2:178-09.
16. FDA OTC Monograph. Federal Register Vol. 53, No. 43: 7092.
17. Abelson MB, Yamamoto GK, Allansmith MR. Effects of ocular
decongestants. Arch Ophthalmol 1980;98:856-858.
18. Rahman, M. Q., K. Ramaesh, et al. Brimonidine for glaucoma.
Expert Opin Drug Saf 2010;9:3:483-491.
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