Vol. 22, No. 7July 2000
Refereed Peer Review
FOCAL POINTKEY FACTS
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Although topical drugs may beabsorbed in sufficient quantitiesto exert systemic pharmacologicand toxic effects, following a fewsimple protocols will significantlyreduce the incidence of adverseeffects.
Systemic Absorption of Topically AdministeredDrugs
Washington State University
Katrina Mealey, DVM, PhD
ABSTRACT:
A growing number of pharmaceutical agents are being designed for topical appli-cation to the skin and eyes. Drug absorption, defined as movement of a drug from the site ofadministration to the systemic circulation, is not desired. Instead, the intent of these agents isto maximize the concentration of the drug at the disease site while minimizing potential sys-temic adverse effects. Although this goal is achieved in most situations, systemic toxicity—inboth humans and animals—has been reported after topical administration of a number ofdrugs. As the number and variety of topical pharmaceutical agents on the market increase, therisk of systemic adverse effects will also rise. This article describes potential systemic adverseeffects resulting from topical application of drugs in animals and examines drugs that maycause systemic toxicity, the clinical signs of toxicity associated with these agents, and meth-ods that may be used to reduce systemic absorption of topical drugs.
P
harmacologic therapy of the eyes and skin offers several unique oppor-tunities. The topical route of application is especially appropriate formany diseases affecting these organs. In this article,
topical therapy
refersto drugs applied to the skin (including the external ear canal) and eyes(cornea and conjunctiva) with the intent of treating disease localized to theseareas. No other organ systems are as readily accessible for treatment and/orfor monitoring therapeutic efficacy. Additionally, this route of applicationgenerally allows for maximizing drug concentration at the desired site of ac-tion while minimizing the concentration of drug at other sites that may resultin adverse effects. Therefore, the concentration of active drug supplied inmany of these topical preparations is quite high relative to systemic doses of the same drug. A poor understanding of factors affecting the systemicbioavailability of these agents and the perceived safety level of topical drugpreparations may engender inappropriate prescribing practices and result inexcessive dosing. Consequently, sufficient amounts of a drug may be absorbedinto the systemic circulation to cause clinical signs of toxicity. Although thegeneral pharmacokinetic principles governing the use of drugs applied to theskin and eyes are the same as for oral and injectable preparations, specialproperties of these organs present unique opportunities and challenges fordrug delivery.
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The stratum corneum is the layerof the epidermis that providesthe most important barrier fortransdermal drug absorption.
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Unless the topical bioavailabilityof a drug is low, the doseadministered topically shouldnot exceed the systemic dose.
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Only a fraction of drug deliveredto the eye by a commercialophthalmic dropper actuallyremains in contact with thecornea and conjunctiva longenough to provide therapeuticeffects.
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Although blinking of the eyesactually increases the risk ofsystemic drug absorption afterapplication of an ophthalmicdrop, keeping the eyes closeddecreases systemic drugabsorption and increases theduration of drug contact withthe cornea and conjunctiva.
TRANSDERMAL DRUGABSORPTION
The physiologic function of the skin is to provide a two- way barrier between the body’sinternal and external environ-ments. The skin prevents theloss of water, electrolytes, andproteins from the body andprotects the body’s internalmilieu from physical, chemi-cal, and infectious environ-mental insults. Transdermaldrug absorption, therefore,necessarily involves transgres-sion of this barrier.The major variables influ-encing the degree of transder-mal drug absorption that may occur include the chemical characteristics of the drug,variables affecting the skin itself, and the nature of thevehicle containing the drug.
1
Lipid-soluble drugs withlow molecular weight formulated at high concentra-tions will be absorbed to a greater extent than will larg-er water-soluble drugs formulated at low concentra-tions. Many factors involving the skin itself affecttransdermal drug absorption. Healthy, intact skin gen-erally serves as an effective barrier to drug absorption,and diseased or denuded skin provides a minimal ob-stacle. The stratum corneum, the outermost layer of the epidermis, is the most important component of thisbarrier.
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In fact, the rate of drug absorption throughisolated stratum corneum is approximately equal to therate of absorption through whole skin.
1
Interestingly,this layer provides a functional barrier for both lipid-and water-soluble agents. Cells of the stratum corneum(keratinocytes) do not contain nuclei or cytoplasmic or-ganelles. Instead, they are filled with several hydrophilicproteins (such as keratin) that function as a barrier tolipid-soluble agents. The intercellular spaces of the stra-tum corneum contain an abundance of high-molecular- weight lipid molecules, which serve as a barrier to wa-ter-soluble agents (Figure 1). Thus, the stratum corne-umconsists of multiple layers of keratinocyte “bricks”(capable of repelling lipid-soluble agents) that are ce-mented together with a lipid matrix (capable of re-pelling water-soluble agents).Transdermal drug absorption also varies from onespecies to another
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and from one area of the body toanother.
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One probable reason for species differences indrug absorption is simply that the thickness of the stra-tum corneum differs among species. Another reasonmay be differences in the metabolic capacity of theskin.
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Regional variations indrug penetration occur simply because the thickness of thestratum corneum varies withanatomic location. Greaterdrug absorption would occur with an equivalent topical doseof a drug applied to the scro-tum or axillary region thanto the footpads or dorsal tho-racic region.
2
It is also impor-tant to remember that smalleranimals have a greater surfacearea:mass ratio than do largeranimals; therefore, an equiva-lent amount of drug appliedtopically results in a greatersystemic dose in smaller pa-tients.The vehicle within which a drug is contained greatly affects the rate and extent of transdermal drug absorp-tion. Examples of pharmaceutical vehicles include wa-ter, alcohol, dimethyl sulfoxide (DMSO), or morecomplex formulations such as ointments, lotions, gels,pastes, aerosols, or creams.
2
Vehicles have traditionally been considered pharmacologically inert, but many may provide therapeutic benefits in and of themselves(via moistening or drying effects). The nature of a vehi-cle may increase or decrease drug absorption by a num-ber of mechanisms (Table I). Many of these factorshave unpredictable effects on the pharmaceutical andpharmacokinetic properties of a particular drug, mak-ing it extremely difficult to predict the efficacy and po-tential toxicity of individual agents contained within anuntested, compounded formulation. Practitionersshould be aware that the responsibility of ensuring thesafety and efficacy of compounded products not ap-proved by the FDA resides solely with the veterinarianprescribing the drug. A simple example of a com-pounded product includes the formulation resultingfrom the addition of an injectable antimicrobial agentsuch as gentamicin or enrofloxacin solution to a com-mercial otic preparation. Unpredictable interactions of the vehicle within the commercial preparation may en-hance systemic absorption of the added drug, resultingin an increased risk of systemic toxicity.Pharmaceutical companies have exploited the con-cept of systemic absorption of topically applied drugsfor decades. The application of nitroglycerin ointmentto the skin results in rapid systemic venodilation,demonstrating both the rate and extent of systemicdrug absorption that can be achieved after topical ad-ministration. Fentanyl and several antiparasitic agents
Small Animal/Exotics
Compendium
July 2000
LIPID-SOLUBLE DRUGS
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STRATUM CORNEUM
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PHARMACEUTICAL VEHICLES
Figure 1—
Schematic drawing of the structure of the stra-tum corneum. Keratinocytes function as a barrier to lipid-soluble agents at the same time as the intercellular lipidmatrix functions as a barrier to water-soluble agents.
are formulated to be applied to the skin, undergo ab-sorption, and exert systemic effects. A number of otherdrugs have the potential to produce systemic effects inveterinary patients when applied topically. In these cas-es, however, this is not the desired effect.
Systemic Effects
Gentamicin-induced nephrotoxicity was diagnosedin a cat that was treated topically with injectable gen-tamicin solution.
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This patient had an infected, open wound that was lavaged with 10 ml of gentamicin solu-tion (50 mg/ml). Serum concentrations of gentamicinmeasured after renal failure was detected were six timesthe maximum recommended therapeutic concentra-tions. The cat was euthanized owing to progressiveazotemia. A similar incident involving a 40-kg rottweil-er occurred when a veterinarian lavaged a draining tract with gentamicin solution. Plasma concentrations of gentamicin in this dog greatly exceeded therapeuticconcentrations. This patient also developed acute renalfailure and required intensive medical management formany days but eventually recovered. Adverse effects re-sulting from topical administration of over-the-countermedications has also been documented.
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A 30-kg dogtreated for fleas with pennyroyal oil, obtained by theowner at a health food store, developed severe neuro-logic 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 ei-ther triamcinolone, fluocinonide, or betamethasone were applied to the skin once daily for 5 consecutivedays.
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Cortisol and corticotropin (ACTH) concentra-tions were determined in each dog before, during, andafter administration of the corticosteroid products. Allthree corticosteroids caused prompt and sustained pitu-itary–adrenocortical suppression within 2 days of treat-ment. One week after the last application of cortico-steroids, pre- and post-ACTH cortisol concentrationsremained suppressed in all corticosteroid-treated dogs.Two weeks after the last treatment, the pre-ACTH plas-ma cortisol concentrations of corticosteroid-treateddogs returned to normal ranges but the post-ACTHplasma cortisol concentrations remained suppressed. By 3 weeks after the last treatment, post-ACTH plasmacortisol concentrations of dogs treated with triamcin-olone acetonide had returned to normal ranges but re-mained suppressed in dogs treated with fluocinonideand 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 havethe potential to be absorbed through the skin and causesystemic effects. The anticancer agent 5-fluorouracilhas been reported to cause systemic effects after topicalapplication.
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Organophosphate and carbamate insecti-cides are formulated for topical use on dogs and cats tocontrol fleas, ticks, and mites. Systemic toxicities haveoccurred as a result of accidental exposure (i.e., whenproducts labeled for use on dogs are used on cats or when cattle products are used on small animals), mis-use (inappropriate dilution of dips), or excessive sensi-tivity.
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Decreasing Systemic Absorption
Factors that increase the risk of systemic adverse ef-
Compendium
July 2000Small Animal/Exotics
GENTAMICIN
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AZOTEMIA
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CORTICOSTEROIDS
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SYSTEMIC TOXICITIES
TABLEIEffect of Vehicle Characteristics on Transdermal Drug Absorption
Characteristic
High solubility of drug in vehicle Ability of vehicle to hydrate stratumcorneumStability of active ingredientin vehicleHigh concentration of soluble drugin vehiclePhysical and chemical interactionsof vehicle with skin
Effect on Absorption
DecreasedIncreasedIncreasedIncreasedIncreased ordecreased
Mechanism
If a drug has a higher affinity for the vehicle than forthe stratum corneum, diffusion will be decreasedHydration of stratum corneum increases permeability (i.e., ointments)Self-explanatory; stability of many compoundedveterinary drugs is unknown A high concentration of drug dissolved in vehicleprovides a “steep” concentration gradient down whichthe drug can diffuseThe best example is the ability of dimethyl sulfoxide toincrease transdermal absorption of many drugs by increasing permeability
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Systemic Absorption of Topically Administered Drugs
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