TEAR SUBSTITUTES Polysaccharides and Vinyl Derivatives

TEAR SUBSTITUTES AND STIMULATORS
Alison Clode, DVM, DACVO
North Carolina State University
College of Veterinary Medicine
Raleigh, North Carolina 27607
TEAR SUBSTITUTES
Solutions and ointments meant to substitute for inadequate quantity or quality of the precorneal tear
film serve a variety of functions, with the (temporary) restoration of ocular comfort being one of the most
significant. Additionally, optical clarity is restored and the overall ability of the surface epithelium to serve as
an effective protective barrier for the eye is restored. Various molecular properties are considered in the
development of tear replacers, with the goal being to mimic the natural precorneal tear film as closely as
possible. Such properties include the surface tension, which enables a solution or ointment to efficiently cover
the ocular surface when the eyelids are open while not restricting effective eyelid movement; the effect of
surfactants (i.e., mucin) on this surface tension; pH (slightly alkaline solutions are frequently more comfortable
than isotonic or acidic solutions); buffering; osmolality (mOsm/kg; higher osmolality is more beneficial); and
osmolarity (mosm/L; lower osmolarity is frequently more comfortable). Additionally, the presence or absence
of preservatives in such solutions is important, as more frequent application results in more exposure to and
potential toxicity from added preservatives (benzalkonium chloride [BAK], chlorobutanol, sodium perborate,
ethylenediaminetetraacetic acid [EDTA], polyquaternium, methylparaben, and propylparaben).
Most artificial tear preparations are water-based. Overall tear film stability is enhanced by addition of
polymers to increase viscosity, lubrication, and retention time. The polymers frequently used include
methylcellulose, polyvinyl alchohol, povidone, dextran, and propylene glycol. Other agents, such as gelatin,
glycerin, polyethylene glycol, poloxamer 407, and polysorbate 80, may also increase viscosity. Tonicity and
pH stabilization are provided by ions such as sodium chloride, potassium chloride, and boric acid.
Polysaccharides and Vinyl Derivatives
These include dextran, cellulose ethers, viscoelastic agents, and vinyl derivatives.
Cellulose ethers
Methylcellulose (MC), hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), and
carboxymethylcellulose are the most commonly encountered cellulose ethers. As a group, they increase the
viscosity of tear replacement solutions without altering the refractive index of the cornea or causing ocular
toxicity. MC is utilized at concentrations of 0.25% to 1%, which provide good viscosity at physiologic pH.
HPMC and other cellulose ethers are less viscous than MC, but maintain cohesive and emollient properties
similar to or better than those of MC. As a class, these are inert chemicals that mix well with other drugs, and
appear to have tear film stabilizing ability, enhancing their overall action. Additionally, MC tolerates the high
temperatures of heat sterilization with no adverse affects.
Viscoelastic agents
Sodium hyaluronate and chondroitin sulfate are mucopolysaccharides frequently utilized in intraocular
surgery. Both are naturally occurring polymers and sodium hyaluronate is involved in wound healing,
providing therapeutic benefit beyond that related to viscosity alone. Sodium hyaluronate does not appear to
sufficiently stabilize the precorneal tear film relative to other polymers, and it is more expensive than other
polymers, however concentrations for topical administration are generally lower than those for intraocular use.
A study comparing use of 10% chondroitin sulfate/ 0.3% tobramycin with 20% chondroitin
sulfate/0.3% ciprofloxacin as treatment for dogs with ulcerative keratitis associated with either spontaneous
chronic corneal epithelial defect syndrome (SCCED) or bullous keratopathy (BK) found a greater percent
healing in dogs receiving either medication for treatment of SCCED than for BK (53.6% versus 17.6% at two
weeks, respectively). 1 There were differences in the duration of disease prior to referral and inclusion in the

study between the two groups, and there was no control group, which may have allowed better assessment of
the individual effects of the chondroitin sulfate alone.
Vinyl derivatives
Vinyl derivatives are water-soluble polymers, with polyvinyl alcohol (PVA) being the most commonly
used. The viscosity of PVA is less than that of previously mentioned substances, however it has good retention
time because of highly adsorptive properties, and likely also stabilizes the tear film in a manner similar to MC
and HPMC, as manifested by an increased tear film breakup time. It can withstand high temperatures, making
heat sterilization possible. Its primary drawback is the potential for PVA-containing solutions to coagulate
when combined with sodium bicarbonate, sodium borate, and sulfates of sodium, potassium, and zinc.
Polyvinylpyrrolidone (PVP) is a vinyl derivative that is used to increase viscosity of solutions, and
may also have adsorptive properties similar to those of naturally-occurring mucin.
Other Viscosity-Enhancing Agents
Hydroxypropyl guar (HP-Guar), found in Systane eye drops, is a high-molecular-weight branched
polymer of mannose and galactose. Its lubricant properties come from its ability to mimic mucin in tears, as
well as to prolong contact time and rentention of polyethylene glycol 400 and propylene glycol (two viscosityenhancing
agents). At ph 7.0, HP-Guar is a liquid, but it is a gel at normal tear film pH 7.5. When transitioned
to a gel, a matrix forms which promotes adhesion of viscosity-enhancing agents, and provides mechanical
protection of the ocular surface.
Other components of tear replacement solutions
Electrolytes
Electrolytes serve to maintain the osmolarity of artificial tear preparations, and also provide nutrients
for epithelial metabolism. Tear preparations are either isotonic or hypotonic to natural tears, as hypertonic
solutions would attract water from the epithelial cells, potentially increasing damage associated with tear film
deficiency in the first place. Hyperosmolarity may also be part of the underlying pathophysiology of ocular
surface disorders, therefore hypotonic solutions may serve to dilute out tears in such cases. Both isotonic and
hypotonic tear replacement solutions appear to provide similar therapeutic benefit.
Buffers
Normal tear film pH is approximately 7.5, however slightly alkaline tear replacement solutions (ph
8.5) are generally preferred when treating dry eye. Use of phosphate, phosphate-acetate, phosphate-citrate,
phosphate-citrate-bicarbonate, borate, and sodium hydroxide help to achieve slightly alkalinity.
Preservatives
Preservatives are necessary to kill or inhibit growth of microorganisms in multi-dose vials.
Benzalkonium hydrochloride (BAK), polyquaternium, thimerosal, chlorobutanol, methylparaben,
propylparaben, and EDTA are examples. While these are necessary to prevent transmitting infection to the
ocular surface, they are known to induce epithelial toxicity, disrupt tear film stability, and cause hypersentivity
reactions. It is recommended that if administration of a tear replacment formulation is necessary four or more
times a day, a preservative-free preparation be used. Newer preservatives are being developed that preserve the
medication within the bottle, but then break down to nontoxic substances when exposed to light or the ocular
surface.
Nutrients
Nutrients supplied in tear replacement solutions include water, dextrose, sodium lactate, sodium
citrate, and vitamins A, B 12 , and C.
Mucolytic agents (Acetylcysteine)

Mucolytics function to make existing mucus more fluid, and also to improve the quality and
production of mucus from goblet cells.
TEAR STIMULANTS
Tear stimulants, also known as secretagogues or lacrimomimetics, are used to actually increase tear
production in patients with at least some degree of remaining functional lacrimal tissue.
Pilocarpine
Pilocarpine is a cholinergic (muscarinic) agonist that mimics acetylcholine at the effector cell (lacrimal
cell) level, directly stimulating tear production. Topical pilocarpine produces no significant nor long-term
elevation in tear production in normal dogs, and produces signs of ocular discomfort following instillation,
making it an ineffective topical treatment for keratoconjunctivitis sicca (KCS). Administered orally,
pilocarpine may have beneficial effects on tear production, particularly in animals with neurogenic KCS. In
those patients, the lacrimal gland tissue is presumably normal, however stimulation is absent (and therefore can
be provided directly by pilocarpine). Controlled studies regarding use of pilocarpine in this manner have not
been performed. Clinical signs associated with toxicity include profuse salivation, lacrimation, urination,
defecation, and diarrhea (SLUDDs), typical of parasympathetic overstimulation. A starting dose is typically 1
drop of 2% ophthalmic pilocarpine per 20 pounds twice daily, administered in the food. The dose is increased
by 1 drop per day every 2-3 days until either clinical improvement is seen (increased STT values) or signs of
systemic toxicity develop. If toxicity develops, the dose should be decreased.
Cyclosporin
Cyclosporin is an immunosuppressive medication which has multiple mechanisms of action that
improve clinical signs and tear production in dogs affected with KCS. T-cell suppression decreases immunemediated
attack on the lacrimal gland and increases lymphocyte apoptosis, while decreasing apoptosis of
lacrimal glandular cells and conjunctival epithelium. Conjunctival mucin stores are increased, leading to a
qualitative improvement in the tear film as well. 2 A direct lacrimomimetic effect has also been postulated.
Cyclosporin may be administered as a 0.2% ointment (Optimmune ® ), or as solutions compounded in
various oils, generally in either 1% or 2% formulations, and is generally administered twice daily. STT results
may take weeks to months to return to normal, and patients with initial STT measurements of >2 mm
wetting/min more slightly to experience a favorable response than patients with STT measurements between 0
and 2 mm wetting/min. 3 In addition to or independently of improvement in STT results, corneal vascularization
and pigmentation may decrease as well. 4 Ocular side effects may include irritation, which is self-limiting and
often improves with therapy. Systemic side effects may include reduced circulating lymphocyte numbers and
suppression of lymphocyte proliferation, however these variables do not seem to correlate to clinical sequelae of
immunosuppression. 5,6
Tacrolimus
Tacrolimus (FK506) is a macrolide antibiotic with an immunosuppressive mechanism similar to that of
cyclosporin (discussed elsewhere). When used in dogs newly diagnosed with KCS with an initial STT ≤10
mm/min, 83% of patients experienced an increase ≥5 mm/min within a mean of 6 weeks, while 25% of dogs
newly diagnosed with KCS with an initial STT 11-15 mm/min experienced an increase ≥5 mm/min within a
mean of ~5 weeks. 7 In the same study, after receiving tacrolimus for approximately 2 months, 27% of dogs with
KCS who previously exhibited a positive response to cyclosporin and 51% of dogs with KCS previously
unresponsive to cyclosporin experienced an additional increase in STT of ≥5 mm/min.
Pimecrolimus
Pimecrolimus has a similar mechanism of action to that of tacrolimus, with greater sensitivity
(mechanism discussed elsewhere). An uncontrolled evaluation of pimecrolimus 1%, administered three times
daily to clinical patients with KCS or chronic superficial keratitis (CSK) documented a favorable clinical
response in 10 of 14 animals, marked by an increase in STT and reduction in signs of corneal inflammation and

scarring. 8 A study comparing the effects of 1% pimecrolimus with those of 0.2% cyclosporin in dogs with KCS
found pimecrolimus resulted in comparable improvement in STT and clinical signs over the 8-week study
period to those documented with cyclosporin. 9
References
1. Ledbetter E, Munger R, Ring R, et al. Efficacy of two chondroitin sulfate ophthalmic solutions in the
therapy of spontaneous chronic corneal epithelial defects and ulcerative keratitis associated with bullous
keratopathy in dogs. Veterinary Ophthalmology 2006;9:77-87.
2. Moore M, Cherrington A, Palmer B, et al. Effect of cyclosporine on conjunctival mucin in a canine
keratoconjunctivitis sicca model. Investigative Ophthalmology and Visual Science 2001;42:653-659.
3. Kaswan R, Salisbury M, Ward D. Spontaneous canine keratoconjunctivitis sicca. A useful model for
human keratoconjuncitivitis sicca: Treatment with cyclosporine eye drops. Archives of Ophthalmology
1989;107:1210-1216.
4. Kaswan R, Martin C, Chapman W. Keratoconjunctivitis sicca: Histopathologic study of nictitating
membrane and lacrimal gland from 28 dogs. American Journal of Veterinary Research 1984;45:112-118.
5. Gilger B, Andrews J, Wilkie D, et al. Lymphocyte proliferation and blood drug levels in dogs with
keratoconjunctivitis sicca receiving long-terms topical ocular cyclosporine. Veterinary Comparative
Ophthalmology 1996;6:125-130.
6. Gilger B, Andrews J, Wilkie D, et al. Cellular immunity in dogs with keratoconjunctivitis sicca before
and after treatment with topical 2% cyclosporine. Veterinary Immunology and Immunopathology 1995;49:199-
208.
7. Berdoulay A, English R, Nadelstein B. Effect of topical 0.02% tacrolimus aqueous suspension on tear
production in dogs with keratoconjunctivitis sicca. Veterinary Ophthalmology 2005;8:225-232.
8. Nell B, Walde I, Billich A, et al. The effect of topical pimecrolimus on keratoconjunctivitis sicca and
chronic superficial keratitis in dogs: results from an exploratory study. Veterinary Ophthalmology 2005;8:39-
46.
9. Ofri R, Lambrou G, Allgoewer I, et al. Clinical evaluation of pimecrolimus eye drops for treatment of
canine keratoconjunctivitis sicca: A comparison with cyclosporine A. The Veterinary Journal 2009;79:7-077.