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Vol. 22, No.

7 July 2000 V

CE Refereed Peer Review

Systemic Absorption of
FOCAL POINT Topically Administered
★Although topical drugs may be
absorbed in sufficient quantities
to exert systemic pharmacologic
Drugs
and toxic effects, following a few
simple protocols will significantly Washington State University
reduce the incidence of adverse Katrina Mealey, DVM, PhD
effects.

ABSTRACT: A growing number of pharmaceutical agents are being designed for topical appli-
KEY FACTS cation 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 sys-
■ The stratum corneum is the layer
temic adverse effects. Although this goal is achieved in most situations, systemic toxicity—in
of the epidermis that provides
both humans and animals—has been reported after topical administration of a number of
the most important barrier for
drugs. As the number and variety of topical pharmaceutical agents on the market increase, the
transdermal drug absorption. 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
■ Unless the topical bioavailability cause systemic toxicity, the clinical signs of toxicity associated with these agents, and meth-
of a drug is low, the dose ods that may be used to reduce systemic absorption of topical drugs.
administered topically should
not exceed the systemic dose.

P
harmacologic therapy of the eyes and skin offers several unique oppor-
■ Only a fraction of drug delivered tunities. The topical route of application is especially appropriate for
to the eye by a commercial many diseases affecting these organs. In this article, topical therapy refers
ophthalmic dropper actually to drugs applied to the skin (including the external ear canal) and eyes
remains in contact with the (cornea and conjunctiva) with the intent of treating disease localized to these
cornea and conjunctiva long areas. No other organ systems are as readily accessible for treatment and/or
enough to provide therapeutic for monitoring therapeutic efficacy. Additionally, this route of application
effects. generally allows for maximizing drug concentration at the desired site of ac-
tion while minimizing the concentration of drug at other sites that may result
■ Although blinking of the eyes in adverse effects. Therefore, the concentration of active drug supplied in
actually increases the risk of many of these topical preparations is quite high relative to systemic doses of
systemic drug absorption after the same drug. A poor understanding of factors affecting the systemic
application of an ophthalmic bioavailability of these agents and the perceived safety level of topical drug
drop, keeping the eyes closed preparations may engender inappropriate prescribing practices and result in
decreases systemic drug excessive dosing. Consequently, sufficient amounts of a drug may be absorbed
absorption and increases the into the systemic circulation to cause clinical signs of toxicity. Although the
duration of drug contact with general pharmacokinetic principles governing the use of drugs applied to the
the cornea and conjunctiva. 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.
Small Animal/Exotics Compendium July 2000

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 two- stratum corneum varies with
way barrier between the body’s anatomic location. Greater
internal and external environ- drug absorption would occur
ments. The skin prevents the with an equivalent topical dose
loss of water, electrolytes, and of a drug applied to the scro-
proteins from the body and tum or axillary region than
protects the body’s internal to the footpads or dorsal tho-
milieu from physical, chemi- racic region.2 It is also impor-
cal, and infectious environ- tant 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 equiva-
sion of this barrier. tum corneum. Keratinocytes function as a barrier to lipid- lent amount of drug applied
soluble agents at the same time as the intercellular lipid
The major variables influ- topically results in a greater
matrix functions as a barrier to water-soluble agents.
encing the degree of transder- systemic dose in smaller pa-
mal 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 absorp-
vehicle containing the drug.1 Lipid-soluble drugs with tion. Examples of pharmaceutical vehicles include wa-
low molecular weight formulated at high concentra- ter, alcohol, dimethyl sulfoxide (DMSO), or more
tions will be absorbed to a greater extent than will larg- complex formulations such as ointments, lotions, gels,
er water-soluble drugs formulated at low concentra- pastes, 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 gen- may 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 vehi-
and diseased or denuded skin provides a minimal ob- cle may increase or decrease drug absorption by a num-
stacle. 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, mak-
isolated stratum corneum is approximately equal to the ing it extremely difficult to predict the efficacy and po-
rate of absorption through whole skin.1 Interestingly, tential toxicity of individual agents contained within an
this layer provides a functional barrier for both lipid- untested, 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 or- safety and efficacy of compounded products not ap-
ganelles. 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 com-
lipid-soluble agents. The intercellular spaces of the stra- pounded product includes the formulation resulting
tum corneum contain an abundance of high-molecular- from the addition of an injectable antimicrobial agent
weight lipid molecules, which serve as a barrier to wa- such as gentamicin or enrofloxacin solution to a com-
ter-soluble agents (Figure 1). Thus, the stratum corne- mercial 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 ce- hance systemic absorption of the added drug, resulting
mented together with a lipid matrix (capable of re- in an increased risk of systemic toxicity.
pelling water-soluble agents). Pharmaceutical companies have exploited the con-
Transdermal 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 stra- demonstrating both the rate and extent of systemic
tum corneum differs among species. Another reason drug absorption that can be achieved after topical ad-
may be differences in the metabolic capacity of the ministration. Fentanyl and several antiparasitic agents

LIPID-SOLUBLE DRUGS ■ STRATUM CORNEUM ■ PHARMACEUTICAL VEHICLES


Compendium July 2000 Small Animal/Exotics

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

Stability of active ingredient Increased Self-explanatory; stability of many compounded


in vehicle veterinary drugs is unknown

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

Physical and chemical interactions Increased or The best example is the ability of dimethyl sulfoxide to
of vehicle with skin decreased increase transdermal absorption of many drugs by
increasing permeability

are formulated to be applied to the skin, undergo ab- tions were determined in each dog before, during, and
sorption, and exert systemic effects. A number of other after administration of the corticosteroid products. All
drugs have the potential to produce systemic effects in three corticosteroids caused prompt and sustained pitu-
veterinary patients when applied topically. In these cas- itary–adrenocortical suppression within 2 days of treat-
es, however, this is not the desired effect. ment. One week after the last application of cortico-
steroids, pre- and post-ACTH cortisol concentrations
Systemic Effects remained suppressed in all corticosteroid-treated dogs.
Gentamicin-induced nephrotoxicity was diagnosed Two weeks after the last treatment, the pre-ACTH plas-
in a cat that was treated topically with injectable gen- ma cortisol concentrations of corticosteroid-treated
tamicin solution.7 This patient had an infected, open dogs returned to normal ranges but the post-ACTH
wound that was lavaged with 10 ml of gentamicin solu- plasma cortisol concentrations remained suppressed. By
tion (50 mg/ml). Serum concentrations of gentamicin 3 weeks after the last treatment, post-ACTH plasma
measured after renal failure was detected were six times cortisol concentrations of dogs treated with triamcin-
the maximum recommended therapeutic concentra- olone acetonide had returned to normal ranges but re-
tions. The cat was euthanized owing to progressive mained suppressed in dogs treated with fluocinonide
azotemia. A similar incident involving a 40-kg rottweil- and betamethasone. By 4 weeks after the last treatment,
er occurred when a veterinarian lavaged a draining tract all indices of pituitary–adrenocortical function were
with gentamicin solution. Plasma concentrations of within the control range for all groups.
gentamicin in this dog greatly exceeded therapeutic Many other drugs used in veterinary medicine have
concentrations. This patient also developed acute renal the potential to be absorbed through the skin and cause
failure and required intensive medical management for systemic effects. The anticancer agent 5-fluorouracil
many days but eventually recovered. Adverse effects re- has been reported to cause systemic effects after topical
sulting from topical administration of over-the-counter application.10 Organophosphate and carbamate insecti-
medications has also been documented.8 A 30-kg dog cides are formulated for topical use on dogs and cats to
treated for fleas with pennyroyal oil, obtained by the control fleas, ticks, and mites. Systemic toxicities have
owner at a health food store, developed severe neuro- occurred as a result of accidental exposure (i.e., when
logic and hepatic toxicity. The dog began vomiting products labeled for use on dogs are used on cats or
within 2 hours after application of the drug and died when cattle products are used on small animals), mis-
within 48 hours.8 use (inappropriate dilution of dips), or excessive sensi-
In a study involving dogs, ointments containing ei- tivity.11
ther triamcinolone, fluocinonide, or betamethasone
were applied to the skin once daily for 5 consecutive Decreasing Systemic Absorption
days.9 Cortisol and corticotropin (ACTH) concentra- Factors that increase the risk of systemic adverse ef-

GENTAMICIN ■ AZOTEMIA ■ CORTICOSTEROIDS ■ SYSTEMIC TOXICITIES


Small Animal/Exotics Compendium July 2000

fects as a result of topical um is the desired route for lo-


drug administration include calized ocular drug effects.
the dose and dosing interval, For this to occur, a drug must
the transdermal bioavailabili- remain in the cul-de-sac and
ty of the drug (frequently not precorneal tear film.13,14
known), the size of the pa- The eyes are relatively se-
tient, and the condition of cluded from access by drugs
the skin. When administering within the systemic circula-
a topical drug to an animal, I tion, but the opposite is not
recommend calculating the true. Drugs can reach the sys-
largest systemic dose that can temic circulation after topical
safely be administered. For ocular delivery by several routes
example, if gentamicin solu- (Figure 2), including through
tion is to be used to lavage an the aqueous humor, ciliary
open wound in a 4.5-kg cat, Figure 2—Potential course of an ophthalmic drug after body, iris, and, most impor-
the systemic dose of genta- topical administration. The most important route for sys- tantly, the nasal mucosa. Sys-
micin should be calculated. temic absorption is through the nasolacrimal system. temic absorption of a drug
The maximum systemic dose through the nasal mucosa oc-
of gentamicin (intravenous) for such an animal is ap- curs when fluid volume exceeds that which can be re-
proximately 18 mg every 12 hours. The quantity of tained on the surface of the cornea and drains through
gentamicin used to lavage the wound should therefore the nasolacrimal ducts. Increased tear production and
not exceed 18 mg in a 12-hour period. Furthermore, blinking enhance nasolacrimal drainage. When the lids
when considering concomitant drug therapies, the fact are closed during the blink reflex, muscular contrac-
that the patient is receiving gentamicin, or other drugs tions dilate the upper part of the lacrimal sac and com-
that might interact with gentamicin, should be taken press the lower portion. Thus tears are aspirated into
into account. Aminoglycoside antibiotics should not be the sac, and fluid that has collected in the lower part of
administered to this patient by any other route, nor the lacrimal sac is forced down the nasolacrimal duct.
should other potentially nephrotoxic drugs such as As the lids open, muscular relaxation causes the col-
furosemide or NSAIDs be administered because they lapse of the upper part of the lacrimal sac, squeezing
are additive risk factors for gentamicin-induced fluid into the lower portion. In this way, the act of
nephrotoxicosis. A similar protocol should be followed blinking exerts a suction-force-pump action in remov-
for other topically administered drugs to minimize the ing excess fluid from the surface of the cornea and con-
likelihood of adverse effects. junctiva and promotes drainage into the nasolacrimal
Because of its lipophilic nature, the stratum corneum system.13
2,12
may act as a reservoir for many drugs. Consequently, Normal tear volume in humans is approximately 7
the local half-life may be sufficiently long to allow µl14 (tear volume in dogs and cats has not been report-
once-daily application. In humans, for example, once- ed). The human eye can hold a maximum volume of 30
daily application of corticosteroid preparations is as ef- µl if the subject is not allowed to blink; however, with
fective as are multiple applications in most circum- blinking only about 10 µl can be retained.14 Commer-
2
stances. Direct access to the skin may predispose the cial eyedrops deliver a volume of 25 to 50 µl per drop.15
patient to frequent topical applications, increasing the Thus when a drop is applied to the eye, a significant
risk of systemic adverse effects. Because broken or portion is lost through overflow onto the eyelids,
abraded skin is an ineffective barrier, drugs applied to through the nasolacrimal system, and into the nasal mu-
such areas should be expected to achieve higher con- cosa. The nasal mucosa is supplied with a rich capillary
centrations within the systemic circulation. network that is easily penetrated by most drugs. Venous
drainage of the nasal mucosa occurs through the maxil-
OPHTHALMIC DRUG ABSORPTION lary vein, which empties into the external jugular vein.
Although there are several routes of ocular drug ad- Drug 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 pos-
sible pathways may be followed (Figure 2). Absorption Systemic Effects
of a drug through the corneal and conjunctival epitheli- Several ophthalmic drugs used in veterinary medicine

NEPHROTOXIC DRUGS ■ LIPOPHILIC NATURE ■ NASAL MUCOSA ■ HEPATIC METABOLISM


Compendium July 2000 Small Animal/Exotics

COMPENDIUM
ON CONTINUING EDUCATION
have been reported to cause systemic toxicity. Phenyle-
phrine is an α−adrenergic sympathomimetic amine. It
F O R T H E P R A C T I C I N G V E T E R I N A R I A N ®

is used ophthalmologically for its ability to vasocon- Veterinary Technician reprints also available
strict conjunctival vasculature and for inducing maxi-
mal pupillary dilation prior to ocular surgeries. System- 2001 PRICE SCHEDULE*
ically, phenylephrine causes peripheral vasoconstriction 2 4 8 12 16
with a resultant increase in diastolic and systolic blood Quantity pages pages pages pages pages
pressures. In one report, three dogs scheduled for cataract Black & White
surgery were treated topically with phenylephrine, flur- 100 $ 108 $ 204 $ 416 $ 604 $ 784
500 152 296 616 896 1,156
biprofen, atropine, and prednisolone.16 Each dog devel- 1000 208 412 868 1,260 1,628
oped arterial hypertension, with systolic, diastolic, and 5000 636 1,264 2,828 4,076 5,160
mean arterial pressures ranging from 170 to 205, 90 to 10,000 1,172 2,332 5,280 7,596 9,572
112, and 123 to 148 mm Hg, respectively (normal val- Color
ues do not exceed 160 systolic, 100 diastolic, and 120 100 $ 972 $1,408 $2,856 $4,180 $5,380
500 1,152 1,612 3,112 4,704 6,040
mm Hg mean). Systemic doses of phenylephrine as a 1000 1,264 1,840 3,428 5,260 6,852
pressor agent range from 0.01 to 0.1 mg/kg. The doses 5000 2,328 3,600 7,140 10,672 12,168
these dogs received for ocular effects were estimated to 10,000 3,280 5,792 10,640 16,704 18,812
be 50 to 367 times greater than the intravenous dose *Price includes UPS Ground Shipping to one location.

required to increase arterial pressure by 50% in anes- ORDER FORM


thetized dogs. The use of ocular adrenergic agents is Quantity _____________ ❏ Black & White ❏ Color
contraindicated in humans receiving monoamine oxi- ❏ With Review Questions ❏ Without Review Questions
dase inhibitors or tricyclic antidepressants because of
Author _________________________________________
the potential for severe drug interactions. The risk of
such an interaction in animals may increase as these Title of Article ___________________________________
classes of drugs are used more frequently for their be- ______________________________________________
havior-modifying properties. From Vol. _________________ No. ______________
Glucocorticoids are one of the most frequently used
❏ Compendium ❏ Veterinary Technician
topical ophthalmic medications in veterinary medicine.
These drugs are used to treat conditions such as bleph- ❏ Payment Enclosed (All payments must be in US funds drawn
on a US branch of a US bank.)
aritis, conjunctivitis, episcleritis, keratitis, iritis, and
uveitis. Systemic effects associated with ophthalmic glu- ❏ Purchase Order Attached
cocorticoid use have been reported in dogs.17,18 In one Contact Person ___________________________________
case, polymyopathy was reported to result from chronic Phone __________________________________________
ophthalmic administration of a 0.1% dexamethasone
preparation.17 Topical ophthalmic use of both dexa- SHIP TO:
methasone and prednisolone (1% prednisolone acetate) NAME
in dogs was reported to cause elevations in liver enzymes
(alkaline phosphatase and alanine aminotransferase), al- COMPANY OR PRACTICE

tered hepatic glycogen metabolism resulting in marked ADDRESS


glycogen accumulation in hepatocytes, and suppression
of the hypothalamic-hypophysis-adrenocortical axis.17,18 CITY STATE ZIP

Systemic absorption has been documented to occur BILL TO:


following topical ophthalmic administration of at- NAME
ropine,19 cyclosporine (in rabbits),20 and timolol21 in an-
imals. In one study, atropine sulfate 1% solution was COMPANY OR PRACTICE

administered topically to the left eyes of 19 dogs for 14 ADDRESS


days and tear production in both eyes was monitored
before, during, and after treatment. Although atropine CITY STATE ZIP

was applied to the left eye only, tear production signifi- Detach and Mail to: Reprints Department
cantly decreased in both eyes. Three weeks after the last Veterinary Learning Systems
treatment, tear production remained significantly de- 275 Phillips Boulevard
creased compared with baseline values in both treated Trenton, NJ 08618
No telephone calls accepted.
and untreated eyes.19 In another study,16 cyclosporine

GLUCOCORTICOIDS ■ TEAR PRODUCTION


Small Animal/Exotics Compendium July 2000

2% eyedrops were administered to rabbits at a dosage may also pose a threat to individuals who work with
of one drop every 12 hours for 5 days or one drop ev- veterinary patients. Because of its venodilating effects,
ery 6 hours for 10 days. Low cyclosporine concentra- topical nitroglycerin paste is used to treat cardiogenic
tions were detected in plasma. Although there are no pulmonary edema.25 Because nitroglycerin paste is read-
reports of systemic absorption or systemic side effects ily absorbed transdermally, individuals working with
of cyclosporine in dogs, routine use of topical cy- this drug should wear nonpermeable gloves. Al-
closporine for treatment of keratoconjunctivitis sicca in trenogest is an orally administered synthetic progesta-
dogs had been somewhat limited. A commercially for- tional agent indicated for estrus synchronization in
mulated veterinary product containing cyclosporine mares. The solution can be absorbed transdermally, and
was recently introduced; therefore, ophthalmic admin- the manufacturer recommends that pregnant women
istration of cyclosporine is likely to increase. and individuals with hormone-responsive tumors or
Timolol (β1 and β2 antagonist) is used topically to treat other diseases adversely affected by progesterone-type
glaucoma. This drug reduces intraocular pressure by in- hormones do not handle the product. Rarely, topical
hibiting aqueous humor formation by the ciliary body.15 exposure to chloramphenicol has resulted in aplastic
The recommended dose of ophthalmic timolol in dogs anemias in humans.26
and cats is one drop of 0.5% solution two to three times Dimethyl sulfoxide is a chemical that, during the
daily.22 The actual quantity of timolol delivered in one course of its use as an agricultural solvent, was discov-
drop (50 µl) is 0.25 mg. The oral dose of timolol for ered to alleviate arthritic pain.27,28 It soon became wide-
dogs is 0.5 to 5 mg three times daily.23 Because the oral ly and promiscuously used for the topical treatment of
bioavailability of timolol is only 50%, owing to first-pass a variety of inflammatory conditions. The discovery of
hepatic metabolism, a single ophthalmic dose of timolol DMSO-induced lens opacities in animals resulted in
approaches the systemic dose. Systemic effects resulting termination of these uses.29–31 DMSO is rapidly ab-
from ophthalmic timolol in dogs reportedly include de- sorbed through intact skin and has a remarkable capaci-
creased heart rate and blood pressure.21 These effects may ty to enhance transdermal absorption of many other
lead to decompensation of congestive heart failure in sus- chemicals and drugs.32–35 Topical use of DMSO in hu-
ceptible patients. Several deaths in human asthmatic pa- mans has been reported to cause photophobia, distur-
tients have occurred after topical administration of timo- bances in color vision, headache, nausea, diarrhea, and
lol as a result of severe bronchoconstriction.24 local inflammatory reaction (believed to result from the
drug’s ability to degranulate mast cells).27,36 Rubber
Decreasing Systemic Absorption gloves should be worn when handling this drug.
Systemic absorption of ophthalmic medications can Organophosphates are routinely used in small animal
be reduced by following a few simple procedures. Over- veterinary hospitals for the topical treatment of fleas,
flow of drug into the nasolacrimal system can be mini- ticks, and mites. Frequently, the same few individuals
mized by instilling only one drop of medication. If in one veterinary clinic are repeatedly exposed to these
more than one drop is deemed necessary, the second agents (i.e., the same person bathes and dips all ani-
drop should be administered a minimum of 10 minutes mals). Chronic exposure to organophosphates can re-
after the first one in order to avoid overflow into the sult in headaches, gastrointestinal disturbances, and
nasolacrimal system. Prevention of drug entry into the central nervous system signs.37 Personnel working with
nasolacrimal system can be accomplished by occluding these chemicals should wear protective clothing (e.g.,
the lacrimal ducts with gentle fingertip pressure over water-impermeable aprons, long gloves).
the medial aspect of the lower eyelid. Keeping the lids
closed allows for greater retention of instilled ocular CONCLUSION
medication. Larger volumes are retained and no fluid Topically administered medications are generally well
enters the lacrimal sac when the lids are closed, result- tolerated in veterinary patients. However, they have
ing in greater delivery of drug to the eye with conse- been documented to cause adverse effects in dogs and
quent reductions in system drug concentrations. Ad- cats. Because of the perceived high margin of safety of
herence to these techniques will not only help prevent these drugs, neither the clinician nor the owner may as-
systemic absorption of ophthalmic drugs but will also sociate drug administration with an adverse systemic ef-
increase therapeutic efficacy. fect. Veterinarians should be aware of the potential for
systemic adverse effects associated with any topically ap-
PREVENTING UNINTENTIONAL plied drug, particularly when the drug is used chronical-
HUMAN EXPOSURE ly or when the patient has concurrent medical condi-
Systemic absorption of topically administered drugs tions (e.g., cardiac, endocrine, or respiratory disease)

TIMOLOL ■ DIMETHYL SULFOXIDE ■ ORGANOPHOSPHATES


Compendium July 2000 Small Animal/Exotics

that may be exacerbated by topical drug administration.


Drug interactions involving topically applied medica-
tions should be considered for patients receiving other
medications, and the patients should be monitored ac-
cordingly. This article discussed adverse effects associat-
CALL
ed with topical administration of several drug classes,
but certainly other drugs and routes of exposure also
have the potential to cause toxicity in veterinary pa-
FOR
tients. Increased awareness of the potential complica-

PAPERS

I
tions resulting from topical drug administration should
allow for improved client education and better monitor-
ing of patients, minimizing the risk of iatrogenic disease.

REFERENCES
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1140–1145. days after submission. Contact
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mate insecticide toxicoses, in Bonagura JD (ed): Kirk’s Cur-
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and suspensions: Problems and advantages, in Edman P
(ed): Biopharmaceutics of Ocular Drug Delivery. Boca Raton,
FL, CRC Press, 1993, pp 27–42.
Small Animal/Exotics Compendium July 2000

15. Fraunfelder FT, Meyer SM: Systemic side effects from oph- 27. Jacob SW, Wood DC: Dimethyl sulfoxide (DMSO): Toxi-
thalmic timolol and their prevention. J Ocular Pharm cology, pharmacology, and clinical experience. Am J Surg
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16. Pascoe PJ, Ilkiw JE, Stiles J, Smith EM: Arterial hyperten- 28. Gorog P, Kovacs IB: Antiarthritic and antithrombotic effects
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dogs. JAVMA 205(11):1562–1564, 1994. 243:91–97, 1975.
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192(1):73–75, 1988.
30. Heywood R: Drug-induced lenticular lesions in the dog. Br
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ure, in Bonagura JD (ed): Kirk’s Current Veterinary Therapy Dr. Mealey is affiliated with the Department of Clinical Sci-
of Small Animal Practice, XII. Philadelphia, WB Saunders ences, College of Veterinary Medicine, Washington State
Co, 1995, pp 713–721. University, Pullman. She is a Diplomate of the American
26. Fernandez-de-Sevilla T, Alegre J, Vallespi T, et al: Adult College of Veterinary Internal Medicine and the American
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College of Veterinary Clinical Pharmacology.
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