Systemic Absorption Of Topically Administered Drugs

Vol. 22, No. 7 July 2000

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FOCAL POINT ★Although topical drugs may be absorbed in sufficient quantities to exert systemic pharmacologic and toxic effects, following a few simple protocols will significantly reduce the incidence of adverse effects.

KEY FACTS ■ The stratum corneum is the layer of the epidermis that provides the most important barrier for transdermal drug absorption. ■ Unless the topical bioavailability of a drug is low, the dose administered topically should not exceed the systemic dose. ■ Only a fraction of drug delivered to the eye by a commercial ophthalmic dropper actually remains in contact with the cornea and conjunctiva long enough to provide therapeutic effects. ■ Although blinking of the eyes actually increases the risk of systemic drug absorption after application of an ophthalmic drop, keeping the eyes closed decreases systemic drug absorption and increases the duration of drug contact with the cornea and conjunctiva.

Systemic Absorption of Topically Administered Drugs Washington State University

Katrina Mealey, DVM, PhD ABSTRACT: A growing number of pharmaceutical agents are being designed for topical application to the skin and eyes. Drug absorption, defined as movement of a drug from the site of administration to the systemic circulation, is not desired. Instead, the intent of these agents is to maximize the concentration of the drug at the disease site while minimizing potential systemic adverse effects. Although this goal is achieved in most situations, systemic toxicity—in both humans and animals—has been reported after topical administration of a number of drugs. As the number and variety of topical pharmaceutical agents on the market increase, the risk of systemic adverse effects will also rise. This article describes potential systemic adverse effects resulting from topical application of drugs in animals and examines drugs that may cause systemic toxicity, the clinical signs of toxicity associated with these agents, and methods that may be used to reduce systemic absorption of topical drugs.

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harmacologic therapy of the eyes and skin offers several unique opportunities. The topical route of application is especially appropriate for many diseases affecting these organs. In this article, topical therapy refers to drugs applied to the skin (including the external ear canal) and eyes (cornea and conjunctiva) with the intent of treating disease localized to these areas. No other organ systems are as readily accessible for treatment and/or for monitoring therapeutic efficacy. Additionally, this route of application generally allows for maximizing drug concentration at the desired site of action while minimizing the concentration of drug at other sites that may result in adverse effects. Therefore, the concentration of active drug supplied in many of these topical preparations is quite high relative to systemic doses of the same drug. A poor understanding of factors affecting the systemic bioavailability of these agents and the perceived safety level of topical drug preparations may engender inappropriate prescribing practices and result in excessive dosing. Consequently, sufficient amounts of a drug may be absorbed into the systemic circulation to cause clinical signs of toxicity. Although the general pharmacokinetic principles governing the use of drugs applied to the skin and eyes are the same as for oral and injectable preparations, special properties of these organs present unique opportunities and challenges for drug delivery.

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TRANSDERMAL DRUG skin.6 Regional variations in ABSORPTION drug penetration occur simply The physiologic function of because the thickness of the the skin is to provide a twostratum corneum varies with way barrier between the body’s anatomic location. Greater internal and external environdrug absorption would occur ments. The skin prevents the with an equivalent topical dose loss of water, electrolytes, and of a drug applied to the scroproteins from the body and tum or axillary region than protects the body’s internal to the footpads or dorsal thomilieu from physical, chemiracic region.2 It is also imporcal, and infectious environtant to remember that smaller mental insults. Transdermal animals have a greater surface drug absorption, therefore, area:mass ratio than do larger necessarily involves transgres- Figure 1—Schematic drawing of the structure of the stra- animals; therefore, an equivatum corneum. Keratinocytes function as a barrier to lipid- lent amount of drug applied sion of this barrier. soluble agents at the same time as the intercellular lipid The major variables influtopically results in a greater matrix functions as a barrier to water-soluble agents. encing the degree of transdersystemic dose in smaller pamal drug absorption that may tients. occur include the chemical characteristics of the drug, The vehicle within which a drug is contained greatly variables affecting the skin itself, and the nature of the affects the rate and extent of transdermal drug absorpvehicle containing the drug.1 Lipid-soluble drugs with tion. Examples of pharmaceutical vehicles include walow molecular weight formulated at high concentrater, alcohol, dimethyl sulfoxide (DMSO), or more tions will be absorbed to a greater extent than will largcomplex formulations such as ointments, lotions, gels, er water-soluble drugs formulated at low concentrapastes, aerosols, or creams.2 Vehicles have traditionally tions. Many factors involving the skin itself affect been considered pharmacologically inert, but many transdermal drug absorption. Healthy, intact skin genmay provide therapeutic benefits in and of themselves erally serves as an effective barrier to drug absorption, (via moistening or drying effects). The nature of a vehiand diseased or denuded skin provides a minimal obcle may increase or decrease drug absorption by a numstacle. The stratum corneum, the outermost layer of ber of mechanisms (Table I). Many of these factors the epidermis, is the most important component of this have unpredictable effects on the pharmaceutical and barrier.2,3 In fact, the rate of drug absorption through pharmacokinetic properties of a particular drug, makisolated stratum corneum is approximately equal to the ing it extremely difficult to predict the efficacy and porate of absorption through whole skin.1 Interestingly, tential toxicity of individual agents contained within an this layer provides a functional barrier for both lipiduntested, compounded formulation. Practitioners and water-soluble agents. Cells of the stratum corneum should be aware that the responsibility of ensuring the (keratinocytes) do not contain nuclei or cytoplasmic orsafety and efficacy of compounded products not apganelles. Instead, they are filled with several hydrophilic proved by the FDA resides solely with the veterinarian proteins (such as keratin) that function as a barrier to prescribing the drug. A simple example of a comlipid-soluble agents. The intercellular spaces of the strapounded product includes the formulation resulting tum corneum contain an abundance of high-molecularfrom the addition of an injectable antimicrobial agent weight lipid molecules, which serve as a barrier to wasuch as gentamicin or enrofloxacin solution to a comter-soluble agents (Figure 1). Thus, the stratum cornemercial otic preparation. Unpredictable interactions of um consists of multiple layers of keratinocyte “bricks” the vehicle within the commercial preparation may en(capable of repelling lipid-soluble agents) that are cehance systemic absorption of the added drug, resulting mented together with a lipid matrix (capable of rein an increased risk of systemic toxicity. pelling water-soluble agents). Pharmaceutical companies have exploited the conTransdermal drug absorption also varies from one cept of systemic absorption of topically applied drugs species to another2,4 and from one area of the body to for decades. The application of nitroglycerin ointment another.5 One probable reason for species differences in to the skin results in rapid systemic venodilation, drug absorption is simply that the thickness of the strademonstrating both the rate and extent of systemic tum corneum differs among species. Another reason drug absorption that can be achieved after topical admay be differences in the metabolic capacity of the ministration. Fentanyl and several antiparasitic agents LIPID-SOLUBLE DRUGS ■ STRATUM CORNEUM ■ PHARMACEUTICAL VEHICLES

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TABLE I Effect of Vehicle Characteristics on Transdermal Drug Absorption Characteristic

Effect on Absorption

Mechanism

High solubility of drug in vehicle

Decreased

If a drug has a higher affinity for the vehicle than for the stratum corneum, diffusion will be decreased

Ability of vehicle to hydrate stratum corneum

Increased

Hydration of stratum corneum increases permeability (i.e., ointments)

Stability of active ingredient in vehicle

Increased

Self-explanatory; stability of many compounded veterinary drugs is unknown

High concentration of soluble drug in vehicle

Increased

A high concentration of drug dissolved in vehicle provides a “steep” concentration gradient down which the drug can diffuse

Physical and chemical interactions of vehicle with skin

Increased or decreased

The best example is the ability of dimethyl sulfoxide to increase transdermal absorption of many drugs by increasing permeability

are formulated to be applied to the skin, undergo absorption, and exert systemic effects. A number of other drugs have the potential to produce systemic effects in veterinary patients when applied topically. In these cases, however, this is not the desired effect.

Systemic Effects Gentamicin-induced nephrotoxicity was diagnosed in a cat that was treated topically with injectable gentamicin solution.7 This patient had an infected, open wound that was lavaged with 10 ml of gentamicin solution (50 mg/ml). Serum concentrations of gentamicin measured after renal failure was detected were six times the maximum recommended therapeutic concentrations. The cat was euthanized owing to progressive azotemia. A similar incident involving a 40-kg rottweiler occurred when a veterinarian lavaged a draining tract with gentamicin solution. Plasma concentrations of gentamicin in this dog greatly exceeded therapeutic concentrations. This patient also developed acute renal failure and required intensive medical management for many days but eventually recovered. Adverse effects resulting from topical administration of over-the-counter medications has also been documented.8 A 30-kg dog treated for fleas with pennyroyal oil, obtained by the owner at a health food store, developed severe neurologic and hepatic toxicity. The dog began vomiting within 2 hours after application of the drug and died within 48 hours.8 In a study involving dogs, ointments containing either triamcinolone, fluocinonide, or betamethasone were applied to the skin once daily for 5 consecutive days.9 Cortisol and corticotropin (ACTH) concentra-

tions were determined in each dog before, during, and after administration of the corticosteroid products. All three corticosteroids caused prompt and sustained pituitary–adrenocortical suppression within 2 days of treatment. One week after the last application of corticosteroids, pre- and post-ACTH cortisol concentrations remained suppressed in all corticosteroid-treated dogs. Two weeks after the last treatment, the pre-ACTH plasma cortisol concentrations of corticosteroid-treated dogs returned to normal ranges but the post-ACTH plasma cortisol concentrations remained suppressed. By 3 weeks after the last treatment, post-ACTH plasma cortisol concentrations of dogs treated with triamcinolone acetonide had returned to normal ranges but remained suppressed in dogs treated with fluocinonide and betamethasone. By 4 weeks after the last treatment, all indices of pituitary–adrenocortical function were within the control range for all groups. Many other drugs used in veterinary medicine have the potential to be absorbed through the skin and cause systemic effects. The anticancer agent 5-fluorouracil has been reported to cause systemic effects after topical application.10 Organophosphate and carbamate insecticides are formulated for topical use on dogs and cats to control fleas, ticks, and mites. Systemic toxicities have occurred as a result of accidental exposure (i.e., when products labeled for use on dogs are used on cats or when cattle products are used on small animals), misuse (inappropriate dilution of dips), or excessive sensitivity.11

Decreasing Systemic Absorption Factors that increase the risk of systemic adverse ef-

GENTAMICIN ■ AZOTEMIA ■ CORTICOSTEROIDS ■ SYSTEMIC TOXICITIES

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fects as a result of topical um is the desired route for lodrug administration include calized ocular drug effects. the dose and dosing interval, For this to occur, a drug must the transdermal bioavailabiliremain in the cul-de-sac and ty of the drug (frequently not precorneal tear film.13,14 The eyes are relatively seknown), the size of the pacluded from access by drugs tient, and the condition of within the systemic circulathe skin. When administering tion, but the opposite is not a topical drug to an animal, I true. Drugs can reach the sysrecommend calculating the temic circulation after topical largest systemic dose that can ocular delivery by several routes safely be administered. For (Figure 2), including through example, if gentamicin soluthe aqueous humor, ciliary tion is to be used to lavage an open wound in a 4.5-kg cat, Figure 2—Potential course of an ophthalmic drug after body, iris, and, most importhe systemic dose of genta- topical administration. The most important route for sys- tantly, the nasal mucosa. Systemic absorption of a drug micin should be calculated. temic absorption is through the nasolacrimal system. through the nasal mucosa ocThe maximum systemic dose curs when fluid volume exceeds that which can be reof gentamicin (intravenous) for such an animal is aptained on the surface of the cornea and drains through proximately 18 mg every 12 hours. The quantity of the nasolacrimal ducts. Increased tear production and gentamicin used to lavage the wound should therefore blinking enhance nasolacrimal drainage. When the lids not exceed 18 mg in a 12-hour period. Furthermore, are closed during the blink reflex, muscular contracwhen considering concomitant drug therapies, the fact tions dilate the upper part of the lacrimal sac and comthat the patient is receiving gentamicin, or other drugs press the lower portion. Thus tears are aspirated into that might interact with gentamicin, should be taken the sac, and fluid that has collected in the lower part of into account. Aminoglycoside antibiotics should not be the lacrimal sac is forced down the nasolacrimal duct. administered to this patient by any other route, nor As the lids open, muscular relaxation causes the colshould other potentially nephrotoxic drugs such as lapse of the upper part of the lacrimal sac, squeezing furosemide or NSAIDs be administered because they fluid into the lower portion. In this way, the act of are additive risk factors for gentamicin-induced blinking exerts a suction-force-pump action in removnephrotoxicosis. A similar protocol should be followed ing excess fluid from the surface of the cornea and confor other topically administered drugs to minimize the junctiva and promotes drainage into the nasolacrimal likelihood of adverse effects. system.13 Because of its lipophilic nature, the stratum corneum 2,12 Normal tear volume in humans is approximately 7 may act as a reservoir for many drugs. Consequently, the local half-life may be sufficiently long to allow µl14 (tear volume in dogs and cats has not been reported). The human eye can hold a maximum volume of 30 once-daily application. In humans, for example, onceµl if the subject is not allowed to blink; however, with daily application of corticosteroid preparations is as efblinking only about 10 µl can be retained.14 Commerfective as are multiple applications in most circum2 cial eyedrops deliver a volume of 25 to 50 µl per drop.15 stances. Direct access to the skin may predispose the Thus when a drop is applied to the eye, a significant patient to frequent topical applications, increasing the portion is lost through overflow onto the eyelids, risk of systemic adverse effects. Because broken or through the nasolacrimal system, and into the nasal muabraded skin is an ineffective barrier, drugs applied to cosa. The nasal mucosa is supplied with a rich capillary such areas should be expected to achieve higher connetwork that is easily penetrated by most drugs. Venous centrations within the systemic circulation. drainage of the nasal mucosa occurs through the maxilOPHTHALMIC DRUG ABSORPTION lary vein, which empties into the external jugular vein. Although there are several routes of ocular drug adDrug absorption by this route avoids first-pass hepatic ministration (e.g., subconjunctival, intraocular), this metabolism; consequently, drugs that undergo hepatic discussion focuses only on topical ocular drug delivery. metabolism can attain high systemic concentrations. When a drug is applied topically to the eye, several posSystemic Effects sible pathways may be followed (Figure 2). Absorption Several ophthalmic drugs used in veterinary medicine of a drug through the corneal and conjunctival epitheliNEPHROTOXIC DRUGS ■ LIPOPHILIC NATURE ■ NASAL MUCOSA ■ HEPATIC METABOLISM

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have been reported to cause systemic toxicity. Phenylephrine is an α−adrenergic sympathomimetic amine. It is used ophthalmologically for its ability to vasoconstrict conjunctival vasculature and for inducing maximal pupillary dilation prior to ocular surgeries. Systemically, phenylephrine causes peripheral vasoconstriction with a resultant increase in diastolic and systolic blood pressures. In one report, three dogs scheduled for cataract surgery were treated topically with phenylephrine, flurbiprofen, atropine, and prednisolone.16 Each dog developed arterial hypertension, with systolic, diastolic, and mean arterial pressures ranging from 170 to 205, 90 to 112, and 123 to 148 mm Hg, respectively (normal values do not exceed 160 systolic, 100 diastolic, and 120 mm Hg mean). Systemic doses of phenylephrine as a pressor agent range from 0.01 to 0.1 mg/kg. The doses these dogs received for ocular effects were estimated to be 50 to 367 times greater than the intravenous dose required to increase arterial pressure by 50% in anesthetized dogs. The use of ocular adrenergic agents is contraindicated in humans receiving monoamine oxidase inhibitors or tricyclic antidepressants because of the potential for severe drug interactions. The risk of such an interaction in animals may increase as these classes of drugs are used more frequently for their behavior-modifying properties. Glucocorticoids are one of the most frequently used topical ophthalmic medications in veterinary medicine. These drugs are used to treat conditions such as blepharitis, conjunctivitis, episcleritis, keratitis, iritis, and uveitis. Systemic effects associated with ophthalmic glucocorticoid use have been reported in dogs.17,18 In one case, polymyopathy was reported to result from chronic ophthalmic administration of a 0.1% dexamethasone preparation.17 Topical ophthalmic use of both dexamethasone and prednisolone (1% prednisolone acetate) in dogs was reported to cause elevations in liver enzymes (alkaline phosphatase and alanine aminotransferase), altered hepatic glycogen metabolism resulting in marked glycogen accumulation in hepatocytes, and suppression of the hypothalamic-hypophysis-adrenocortical axis.17,18 Systemic absorption has been documented to occur following topical ophthalmic administration of atropine,19 cyclosporine (in rabbits),20 and timolol21 in animals. In one study, atropine sulfate 1% solution was administered topically to the left eyes of 19 dogs for 14 days and tear production in both eyes was monitored before, during, and after treatment. Although atropine was applied to the left eye only, tear production significantly decreased in both eyes. Three weeks after the last treatment, tear production remained significantly decreased compared with baseline values in both treated and untreated eyes.19 In another study,16 cyclosporine GLUCOCORTICOIDS ■ TEAR PRODUCTION

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2% eyedrops were administered to rabbits at a dosage of one drop every 12 hours for 5 days or one drop every 6 hours for 10 days. Low cyclosporine concentrations were detected in plasma. Although there are no reports of systemic absorption or systemic side effects of cyclosporine in dogs, routine use of topical cyclosporine for treatment of keratoconjunctivitis sicca in dogs had been somewhat limited. A commercially formulated veterinary product containing cyclosporine was recently introduced; therefore, ophthalmic administration of cyclosporine is likely to increase. Timolol (β1 and β2 antagonist) is used topically to treat glaucoma. This drug reduces intraocular pressure by inhibiting aqueous humor formation by the ciliary body.15 The recommended dose of ophthalmic timolol in dogs and cats is one drop of 0.5% solution two to three times daily.22 The actual quantity of timolol delivered in one drop (50 µl) is 0.25 mg. The oral dose of timolol for dogs is 0.5 to 5 mg three times daily.23 Because the oral bioavailability of timolol is only 50%, owing to first-pass hepatic metabolism, a single ophthalmic dose of timolol approaches the systemic dose. Systemic effects resulting from ophthalmic timolol in dogs reportedly include decreased heart rate and blood pressure.21 These effects may lead to decompensation of congestive heart failure in susceptible patients. Several deaths in human asthmatic patients have occurred after topical administration of timolol as a result of severe bronchoconstriction.24

Decreasing Systemic Absorption Systemic absorption of ophthalmic medications can be reduced by following a few simple procedures. Overflow of drug into the nasolacrimal system can be minimized by instilling only one drop of medication. If more than one drop is deemed necessary, the second drop should be administered a minimum of 10 minutes after the first one in order to avoid overflow into the nasolacrimal system. Prevention of drug entry into the nasolacrimal system can be accomplished by occluding the lacrimal ducts with gentle fingertip pressure over the medial aspect of the lower eyelid. Keeping the lids closed allows for greater retention of instilled ocular medication. Larger volumes are retained and no fluid enters the lacrimal sac when the lids are closed, resulting in greater delivery of drug to the eye with consequent reductions in system drug concentrations. Adherence to these techniques will not only help prevent systemic absorption of ophthalmic drugs but will also increase therapeutic efficacy. PREVENTING UNINTENTIONAL HUMAN EXPOSURE Systemic absorption of topically administered drugs

may also pose a threat to individuals who work with veterinary patients. Because of its venodilating effects, topical nitroglycerin paste is used to treat cardiogenic pulmonary edema.25 Because nitroglycerin paste is readily absorbed transdermally, individuals working with this drug should wear nonpermeable gloves. Altrenogest is an orally administered synthetic progestational agent indicated for estrus synchronization in mares. The solution can be absorbed transdermally, and the manufacturer recommends that pregnant women and individuals with hormone-responsive tumors or other diseases adversely affected by progesterone-type hormones do not handle the product. Rarely, topical exposure to chloramphenicol has resulted in aplastic anemias in humans.26 Dimethyl sulfoxide is a chemical that, during the course of its use as an agricultural solvent, was discovered to alleviate arthritic pain.27,28 It soon became widely and promiscuously used for the topical treatment of a variety of inflammatory conditions. The discovery of DMSO-induced lens opacities in animals resulted in termination of these uses.29–31 DMSO is rapidly absorbed through intact skin and has a remarkable capacity to enhance transdermal absorption of many other chemicals and drugs.32–35 Topical use of DMSO in humans has been reported to cause photophobia, disturbances in color vision, headache, nausea, diarrhea, and local inflammatory reaction (believed to result from the drug’s ability to degranulate mast cells).27,36 Rubber gloves should be worn when handling this drug. Organophosphates are routinely used in small animal veterinary hospitals for the topical treatment of fleas, ticks, and mites. Frequently, the same few individuals in one veterinary clinic are repeatedly exposed to these agents (i.e., the same person bathes and dips all animals). Chronic exposure to organophosphates can result in headaches, gastrointestinal disturbances, and central nervous system signs.37 Personnel working with these chemicals should wear protective clothing (e.g., water-impermeable aprons, long gloves).

CONCLUSION Topically administered medications are generally well tolerated in veterinary patients. However, they have been documented to cause adverse effects in dogs and cats. Because of the perceived high margin of safety of these drugs, neither the clinician nor the owner may associate drug administration with an adverse systemic effect. Veterinarians should be aware of the potential for systemic adverse effects associated with any topically applied drug, particularly when the drug is used chronically or when the patient has concurrent medical conditions (e.g., cardiac, endocrine, or respiratory disease)

TIMOLOL ■ DIMETHYL SULFOXIDE ■ ORGANOPHOSPHATES

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that may be exacerbated by topical drug administration. Drug interactions involving topically applied medications should be considered for patients receiving other medications, and the patients should be monitored accordingly. This article discussed adverse effects associated with topical administration of several drug classes, but certainly other drugs and routes of exposure also have the potential to cause toxicity in veterinary patients. Increased awareness of the potential complications resulting from topical drug administration should allow for improved client education and better monitoring of patients, minimizing the risk of iatrogenic disease.

REFERENCES 1. Wepierre J, Marty JP: Percutaneous absorption of drugs. Trends Pharmacol Sci 1:23–26, 1979. 2. Guzzo CA, Lazarus GS, Werth VP: Dermatological pharmacology, in Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, McGraw-Hill, 1996, pp 1593–1616. 3. Banks WJ: Integumentary system, in Banks WJ (ed): Applied Veterinary Histology. Baltimore, Williams & Wilkins, 1986, pp 348–379. 4. Aungst BJ, Blake JA, Rogers NJ, Hussain MA: Transdermal oxymorphone formulation development and methods for evaluating flux and lag times for two skin permeation-enhancing vehicles. J Pharm Sci 79(12):1072–1076, 1990. 5. Lin S, Xing QF, Chien YW: Transdermal testosterone delivery: Comparison between scrotal and nonscrotal delivery systems. Pharm Dev Technol 4(3):405–414, 1999. 6. Steinstrasser I, Merkle HP: Dermal metabolism of topically applied drugs: Pathways and models reconsidered. Pharm Acta Helv 70(1):3–24, 1995. 7. Mealey KL, Boothe DM: Nephrotoxicity associated with topical administration of gentamicin in a cat. JAVMA 204(12): 1919–1921, 1994. 8. Sudekum M, Poppenga RH, Raju N, Braselton WE: Pennyroyal oil toxicosis in a dog. JAVMA 200(6):817–818, 1992. 9. Zenoble RD, Kemppainen RJ: Adrenocortical suppression by topically applied corticosteroids in healthy dogs. JAVMA 191(6):685–688, 1987. 10. Dorman DC: Neurotoxic drugs in dogs and cats, in Bonagura JD (ed): Kirk’s Current Veterinary Therapy of Small Animal Practice, XII. Philadelphia, WB Saunders Co, 1995, pp 1140–1145. 11. Hansen SR: Management of organophosphate and carbamate insecticide toxicoses, in Bonagura JD (ed): Kirk’s Current Veterinary Therapy of Small Animal Practice, XII. Philadelphia, WB Saunders Co, 1995, pp 245–248. 12. Yagi S, Nakayama K, Kurosaki Y, et al: Factors determining drug residence in skin during transdermal absorption: Studies on beta-blocking agents. Biol Pharm Bull 21(11):1195– 1201, 1998. 13. Regnier A: Ocular pharmacology and therapeutic modalities, in Gelatt KN (ed): Veterinary Ophthalmology. Philadelphia, Lea & Febiger, 1991, pp 162–194. 14. Van Ootegham MM: Formulations of ophthalmic solutions and suspensions: Problems and advantages, in Edman P (ed): Biopharmaceutics of Ocular Drug Delivery. Boca Raton, FL, CRC Press, 1993, pp 27–42.

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15. Fraunfelder FT, Meyer SM: Systemic side effects from ophthalmic timolol and their prevention. J Ocular Pharm 3:177–184, 1987. 16. Pascoe PJ, Ilkiw JE, Stiles J, Smith EM: Arterial hypertension associated with topical ocular use of phenylephrine in dogs. JAVMA 205(11):1562–1564, 1994. 17. Glaze MB, Crawford MA, Nachreiner RF, et al: Ophthalmic corticosteroid therapy: Systemic effects in the dog. JAVMA 192(1):73–75, 1988. 18. Roberts SM, Lavach JD, Macy DW, Severin GA: Effect of ophthalmic prednisolone acetate on the canine adrenal gland and hepatic function. Am J Vet Res 45(9):1711–1714, 1984. 19. Hollingsworth SR, Canton DD, Ruyukmihci NC, Farver TR: Effect of topically administered atropine on tear production in dogs. JAVMA 200(10):1481–1484, 1992. 20. Bellot JL, Ali JL, Ruiz-Moreno JM, Artola A: Corneal concentration and systemic absorption of cyclosporin A following its topical application in the rabbit eye. Ophthalmic Res 24(6):351–356, 1992. 21. Svec AL, Strosberg AM: Therapeutic and systemic side effects of ocular β-adrenergic antagonists in anesthetized dogs. Invest Ophthalmol Vis Sci 27:401–405, 1986. 22. Brooks DE: Glaucoma in the dog and cat. Vet Clin North Am Small Anim Pract 20:775–798, 1990. 23. Muir WW: Pharmacology and pharmacokinetics of antiarrhythmic drugs, in Fox PR (ed): Canine and Feline Cardiology. New York, Churchill Livingstone, 1988, pp 309–333. 24. Everitt DE, Avorn J: Systemic effects of medications used to treat glaucoma. Ann Intern Med 112:120–124, 1990. 25. Rush JE: Emergency therapy and monitoring of heart failure, in Bonagura JD (ed): Kirk’s Current Veterinary Therapy of Small Animal Practice, XII. Philadelphia, WB Saunders Co, 1995, pp 713–721. 26. Fernandez-de-Sevilla T, Alegre J, Vallespi T, et al: Adult pure red cell aplasia following topical ocular chloramphenicol. Br J Ophthalmol 74(10):640, 1990.

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27. Jacob SW, Wood DC: Dimethyl sulfoxide (DMSO): Toxicology, pharmacology, and clinical experience. Am J Surg 114(3):414–426, 1967. 28. Gorog P, Kovacs IB: Antiarthritic and antithrombotic effects of topically applied dimethyl sulfoxide. Ann NY Acad Sci 243:91–97, 1975. 29. Van Heyningen R, Harding JJ: Some changes in the lens of the dimethylsulphoxide-fed rabbit. Exp Eye Res 14(2):91–98, 1972. 30. Heywood R: Drug-induced lenticular lesions in the dog. Br Vet J 127(7):301–303, 1971. 31. Rubin LF: Toxicity of dimethyl sulfoxide, alone and in combination. Ann NY Acad Sci 27:243:98–103, 1975. 32. Idson B: Percutaneous absorption. J Pharm Sci 64(6): 901–924, 1975. 33. Chandrasekaran SK, Shaw JE: Factors influencing the percutaneous absorption of drugs. Curr Probl Dermatol 7:142– 155, 1978. 34. Ghosh TK, Bagherian A: Development of a transdermal patch of methadone: In vitro evaluation across hairless mouse and human cadaver skin. Pharm Dev Technol 1(3):285–291, 1996. 35. Tsai JC, Guy RH, Thornfeldt CR, et al: Metabolic approaches to enhance transdermal drug delivery. 1. Effect of lipid synthesis inhibitors. J Pharm Sci 85(6):643–648, 1996. 36. Yellowlees P, Greenfield C, McIntyre N: Dimethylsulphoxide-induced toxicity. Lancet 2(2802):1004–1006, 1980. 37. O’Malley M: Clinical evaluation of pesticide exposure and poisonings. Lancet 349(9059):1161–1166, 1997.

About the Author Dr. Mealey is affiliated with the Department of Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman. She is a Diplomate of the American College of Veterinary Internal Medicine and the American College of Veterinary Clinical Pharmacology.