Dermatology of Department, University of California San Francisco, San Francisco, CA, USA

ABSTRACT

Esters of p-hydroxybenzoic acid (parabens) are the most widely used preservatives in cosmetic, pharmaceutical, and industrial products. However, since the 1960s, controversy has surrounded its use and safety as a potential cause of allergic contact dermatitis. Despite the cloud of suspicion that has hovered over parabens ever since, these ubiquitous compounds have withstood four decades of extensive skin testing conducted by a variety of organizations, both North American and European, and now, it seems parabens have shown to be one of the least sensitizing preservatives in commercial use. Of the very limited reports of paraben-induced allergic contact dermatitis, these cases are often attributable to the application of parabens on damaged skin.

Key Words:
parabens, allergic contact dermatitis, sensitization, allergen, patch test

Introduction

Esters of p-hydroxybenzoic acid (parabens) were first used in the 1920s as antibacterial and antifungal agents, however, not long after they were being incorporated as preservatives for foods, drugs, and cosmetics.¹ Parabens are popular preservatives found in creams, pastes, beauty products, glues, fats, and oils because, in addition to having a broad spectrum of antimicrobial activity, they are colorless, odorless, stable, and inexpensive.² Despite formulary advances, alternative preservatives to parabens for commercial topical applications remain limited. Since the 1960s, controversy has surrounded their use and safety with regards to allergic contact dermatitis. The concern over the possible hazards of topical parabens has yet to fully subside, which is a significant obstacle considering they are the most widely used preservatives in cosmetic, pharmaceutical, and industrial products.² As a result, apprehension over the possibility of paraben-induced allergic contact dermatitis persist.^3-7 The much publicized scrutiny not only questions their role as contact allergens, but also implicates them as potential endocrine disruptors, hence, herein we reexamine paraben contact allergy as a follow up to our lab’s previous overview.⁸ This review does not address the important but separate controversy regarding the possible endocrine disrupting effects of parabens and their metabolites, which is reviewed elsewhere.^9-12 A recent discussion by Kirchhof et al. discusses the more complex issue of parabens and their association with endocrine disruption.⁹

Review of Contact Sensitization Data

In 1968, Schorr and Epstein were among the first in the United States to express alarm that topical paraben use may induce allergic contact dermatitis.^13,14 Schorr did not find a high incidence of contact dermatitis from topical paraben application after patch testing 273 chronic dermatitis patients with 5% paraben in petrolatum. Schorr obtained a sensitization index of 0.8%, and cross-reactions were observed with methyl-, ethyl-, propyl-, and butylparaben.¹³ However, he believed the topical paraben danger was being underestimated because cosmetics and nonprescription drugs did not require a declaration of contents at the time. Due to the concerns expressed by Schorr, Epstein and others, the cosmetics industry began to develop and advertise paraben-free products in order to sidestep any consumer fears engendered by the recent reports.

Notwithstanding, the status of topical parabens in relation to skin hypersensitivity was soon to change again. In a study involving 397 healthy volunteers without significant dermatological issues, Marzulli et al. obtained a sensitization index of 0.3% with the Draize predictive test procedure using various concentrations of methyl- and propylparabens (up to 20%) in petrolatum.¹⁵ Contrary to the reservations held by many, these results indicate that the incidence of contact sensitization for parabens amongst healthy Americans is far below 1%.¹⁵ Moreover, around the same time, these results were bolstered by the clinical findings made by Fisher et al., which suggest that the sensitization rate is low overall (3% for a mix of 3 parabens tested in patients suspected of having allergic contact dermatitis to topical medications), especially when one considers how pervasive paraben use is.¹⁶ Moreover, the regulatory environment began to evolve at the same time— in 1973, the Cosmetic Ingredient Regulation directive began requiring the listing of all ingredients, both active and nonactive, on cosmetic packages and drug labels.¹⁷ This move directly addressed the concern of some that paraben hypersensitivity was under diagnosed because cosmetics and drugs did not require a declaration of content.

In 1972, the North American Contact Dermatitis Group sought to determine the relative frequency of positive paraben patch tests in dermatitis patients.¹⁸ Using a uniform patch test procedure, evaluations were performed on 1200 subjects in 10 geographic areas of the US and Canada; approximately 3% of the subjects were considered sensitized to parabens, which was a lower rate of reactivity than 15 other compounds. In fact, amongst the compounds tested, only one compound, cyclomethicone, had a lower rate of sensitization (2%). Considering paraben’s low index of sensitization (as determined by predictive and diagnostic tests as well as clinical impressions) and given the pervasiveness of parabens, its low overall toxicity, and the new requirements for labeling, Marzulli et al. in 1974 concluded that topical parabens did not constitute a significant hazard to the US public.⁸

Since then, numerous studies have been conducted to evaluate the link between topical parabens and allergic contact dermatitis. Over a period from 2001 to 2003, using data compiled by both the North American Contact Dermatitis Group (NACDG) and the European Environmental and Contact Dermatitis Research Group (EECDRG), Mirshahpanah et al. determined that the patch test positivity rate for parabens in an eczema population was 0.6% in the NACDG group and 1.2% in the EECDRG group.¹⁹ In its most recent report, the NACDG performed standardized patch testing on 4454 patients with suspected allergic contact dermatitis using a broad series of screening allergens. Findings included a 1.2% positive reaction rate to a mix of parabens, however, this percentage would have certainly been lower if individual paraben compounds were tested.²⁰ From 2001 to 2008, Svedman et al. tracked the contact allergy rates for the seven most common preservatives that were routinely tested in European centers representing the EECDRG.²¹ Compared to all the other preservatives, the paraben mix demonstrated the lowest level of contact allergy amongst patients referred with dermatitis (0.5-1%), whereas quaternium-15, imidazolidinyl urea, diazolidinyl urea, formaldehyde, methyldibromo glutaronitrile (MDBGN), and methylchloroisothiazolinone (MCI)/ methylisothiazolinone (MIT) all showed significantly higher rates of allergic contact dermatitis upon patch testing.

For the few patients demonstrating positive patch test reactions to parabens, it warrants consideration that compromised skin may react to parabens, while intact skin may not. This phenomenon is referred to as the “paraben paradox,” which hypothesizes that (1) patients who are sensitive to parabens often have falsenegative patch test reactions when the parabens are patch-tested on healthy skin, and (2) paraben patch test positive patients may be nonreactive when using paraben-containing products on normal intact skin, but may develop dermatitis when these same products are applied to damaged skin.²² In fact, most paraben allergies only develop when paraben-containing products are applied to skin with a compromised barrier function, common examples include leg ulcers and areas of dermatitis.²² Therefore, it follows that paraben-sensitive individuals do not usually develop allergic contact dermatitis when paraben-containing products are applied to healthy intact skin.

Conclusion

Despite the cloud that has surrounded paraben use since the late 1960s, this class of chemical preservatives has withstood four decades of extensive skin testing conducted by a variety of organizations, both North American and European. It now appears that parabens have proven to be one of the least allergenic preservatives on the market. In the limited documented examples of paraben-induced allergic contact dermatitis, these cases are often attributable to the application of parabens on damaged skin.

References

1. Sabalitschka T. Presentation of protein and carbohydrate containing substances. Swiss Prt. 1925 Mar;119:163.
2. Cashman AL, Warshaw EM. Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties. Dermatitis. 2005 Jun;16(2):57-66.
3. Duarte I, Antonio Jabur da Cunha J, Lazzarini R. Allergic contact dermatitis in private practice: what are the main sensitizers? Dermatitis. 2011 Jul-Aug;22(4):225-6.
4. Nardelli A, Morren MA, Goossens A. Contact allergy to fragrances and parabens in an atopic baby. Contact Dermatitis. 2009 Feb;60(2):107-9.
5. Zirwas M, Moennich J. Shampoos. Dermatitis. 2009 Mar-Apr;20(2):106-10.
6. Coloe J, Zirwas MJ. Allergens in corticosteroid vehicles. Dermatitis. 2008 Jan-Feb;19(1):38-42.
7. Pedersen S, Marra F, Nicoli S, et al. In vitro skin permeation and retention of parabens from cosmetic formulations. Int J Cosmet Sci. 2007 Oct;29(5):361-7.
8. Marzulli FN, Maibach HI. Status of topical parabens: skin hypersensitivity. Int J Dermatol. 1974 Nov-Dec;13(6):397-9.
9. Kirchhof MG, de Gannes GC. The health controversies of parabens. Skin Therapy Lett. 2013 Feb;18(2):5-7.
10. Boberg J, Taxvig C, Christiansen S, et al. Possible endocrine disrupting effects of parabens and their metabolites. Reprod Toxicol. 2010 Sep;30(2):301-12.
11. Witorsch RJ, Thomas JA. Personal care products and endocrine disruption: A critical review of the literature. Crit Rev Toxicol. 2010 Nov;40 Suppl 3:1-30.
12. Darbre PD, Harvey PW. Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. J Appl Toxicol. 2008 Jul;28(5):561-78.
13. Schorr WF. Paraben allergy. A cause of intractable dermatitis. JAMA. 1968 Jun 3;204(10):859-62.
14. Epstein S. Paraben sensitivity: subtle trouble. Ann Allergy. 1968 Apr; 26(4): 185-9.
15. Marzulli FN, Maibach HI. Antimicrobials: experimental contact sensitization in man. J Soc Cosmet Chem. 1973;24:399-421.
16. Fisher AA, Pascher F, Kanof NB. Allergic contact dermatitis due to ingredients of vehicles. A “vehicle tray” for patch testing. Arch Dermatol. 1971 Sep;104(3):286-90.
17. U.S. Food and Drug Administration. Code of federal regulations, Title 21. Part 701 Cosmetic labeling. Section 701.3 Designation of ingredients. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? CFRPart=701&showFR=1&subpartNode=21:7.0.1.2.11.1. Accessed: May 20, 2013.
18. Epidemiology of contact dermatitis in North America: 1972. Arch Dermatol. 1973 Oct;108(4):537-40.
19. Mirshahpanah P, Maibach HI. Relationship of patch test positivity in a general versus an eczema population. Contact Dermatitis. 2007 Mar;56(3):125-30.
20. Zug KA, Warshaw EM, Fowler JF Jr, et al. Patch-test results of the North American Contact Dermatitis Group 2005-2006. Dermatitis. 2009 May-Jun;20(3):149-60.
21. Svedman C, Andersen KE, Brandao FM, et al. Follow-up of the monitored levels of preservative sensitivity in Europe: overview of the years 2001-2008. Contact Dermatitis. 2012 Nov;67(5):312-4.
22. Askari SK, Warshaw EM. Parabens. Dermatitis. 2006 Dec;17(4):2 p following 214.

¹Department of Dermatology, Howard University College of Medicine, Washington, DC, USA
²Teikoku Pharma USA, Inc., San Jose, CA, USA
³Department of Dermatology, University of California, San Francisco, CA, USA

Conflict of interest: The authors have no conflicts of interest to declare.
ABSTRACT

Transdermal drug delivery allows for a constant rate of drug administration and prolonged action, which can be beneficial to elderly patients who are often polymedicated. Several studies have compared dermatopharmacokinetics in the young and elderly with conflicting results. Despite the potential limitations of age-related changes in skin factors and cutaneous metabolism, marketed transdermal products generally do not report age-related differences in pharmacokinetics. This overview discusses the current data, summarizes marketed product findings and highlights the importance of further studies to evaluate age-related dermatopharmacokinetics.

Key Words:
transdermal, elderly, dermatopharmacokinetics, percutaneous penetration, cutaneous metabolism

Introduction

The rate of growth of the older population (65 years old and over) has greatly exceeded the growth rate of the US population as a whole. According to the United States Census Bureau’s projections, about 1 in 8 Americans were elderly in 1994 and by the year 2030 it will increase to 1 in 5.¹ Furthermore, there has been a surge of interest in transdermal drug delivery to produce systemic effects. Transdermally delivered drugs include scopolamine, nitroglycerin, nicotine, clonidine, fentanyl, estradiol, testosterone, lidocaine, and oxybutynin. Recently, transdermal formulations have also been introduced for rivastigmine, rotigotine, selegiline, buprenorphine, granisetron, and methylphenidate. The current US transdermal market exceeds $3 billion annually.²

The advantages of percutaneous drug penetration over the oral route include circumvention of gastrointestinal absorption and hepatic first-pass metabolism (contrary to assumption, the skin also has a first-pass effect for some compounds), minimization of adverse effects secondary to peak plasma drug concentrations, and improved patient compliance. Additionally, percutaneous drug delivery harbors no risk of infection, which can be a complication with parenteral administration. Disadvantages include skin sensitivity and irritation by patches and the reservoir effect of skin, which allows for continued diffusion after patch removal. This overview provides a basis for understanding the effect of aging on dermatopharmacokinetics and discusses currently marketed transdermal products.

Dermatopharmacokinetics

Percutaneous absorption depends on passive diffusion across the stratum corneum, which has an excellent barrier function that undergoes structural and functional changes with increasing age. Typically, drugs that are candidates for percutaneous absorption must be pharmacologically potent and satisfy the following physicochemical properties when considering a formulation: aqueous solubility >1 mg/ml, lipophilicity 10<Ko/w (oil-water partition coefficient) <1000, molecular weight <500 Da, melting point <200°C, pH 5-9, and a dose deliverable <10 mg/day.³ Changes in the barrier properties of aged skin may have an impact on the type and amount of drugs that are able to undergo successful percutaneous absorption.

Substantial literature reviews in vivo percutaneous absorption in neonates and normal healthy adults.^4-8 However, the quantitative evaluation of skin barrier function has been minimally addressed in the elderly. Christophers and Kligman conducted studies in the 1960s that suggested the skin permeability in the elderly (>66 years old) was different from that of younger adults (<29 years old).⁹ In vitro studies using human cadaver skin demonstrated the permeability of fluorescein was seven times greater in skin from older than younger subjects. However, another in vitro study using skin from living subjects found no difference in the permeability of water between the two groups. They also conducted an in vivo study with 14C-testosterone applied to the backs of young and old subjects and found penetration to be greater in the younger (19-30 years) than the older (71-82 years) group over 24 hours.⁹ Furthermore, the absorption capability of the skin microcirculation was assessed by the clearance of intradermally injected radiolabeled sodium and was shown to be decreased in the elderly, suggesting that changes in the microcirculation occurred in the dermis of the elderly.⁹

DeSalva and Thompson reported contrasting results; they observed similar clearance rates of intradermally injected radiolabeled sodium administered in the face and hands of subjects 50 years of age or older, but the rates were slower in subjects 30 years of age or younger.¹⁰ However, when administered into the hand, the clearance of radiolabeled sodium was slower in subjects aged 71 years or older than subjects 60 years of age or younger.

Tagami measured the permeability of tetrachlorosalicylanilide (TCSA) across the stratum corneum in vivo and discovered that the permeation times of TCSA through the skin of both flexor and extensor forearm sites were significantly shorter in young (22-39 years) than in old (62-82 years) subjects. The TCSA penetration time took 2-2.5 hours in the former and about 1.5 hours in the latter. This was accomplished by stripping the stratum corneum at various time points after application and assaying for the TCSA via fluorescence.¹¹ The efficiency of cutaneous microcirculation was also assessed by the clearance of intradermally injected radiolabeled sodium. Clearance was unchanged between age groups for the extensor forearm, but significantly longer in aged (61-80 years) than in young (20-32 years) subjects for the midback area.¹¹

Roskos and colleagues made in vivo measurements of percutaneous absorption in young (18-40 years) and old (>65 years) subjects using standard radiotracer methodology with 14C-radiolabeled compounds.¹² Percutaneous absorption was quantified from urinary excretion profiles and corrected for incomplete renal elimination. Permeation of hydrocortisone, benzoic acid, acetylsalicylic acid, and caffeine was significantly lower in aged subjects, while the absorption of testosterone and estradiol was similar in the two groups (Table 1). This suggests that aging can affect percutaneous absorption in vivo and that relatively hydrophilic compounds are more sensitive, while highly lipophilic compounds may still be able to dissolve readily across the stratum corneum.

While the aforementioned studies indicate there are age-related differences in the percutaneous penetration and clearance of drugs, discrepancies abound. Some suggested greater absorption in the older subjects, others suggested greater absorption in younger subjects, and still others found no difference. Consequently, based on these studies, it is difficult to elucidate if the elderly are at increased risk secondary to altered percutaneous penetration. Furthermore, in practice, no significant differences in absorption of drugs from transdermal delivery systems have been demonstrated between young and old individuals.

Marketed Transdermal Products

Given the potential differences in skin from individuals of varying age, pharmacokinetics with transdermal delivery may be altered. Table 2 summarizes the available pharmacokinetic data reported in the US FDA’s New Drug Application (NDA) submissions and drug labels for transdermal products relative to the subjects’ age. As shown, in studies where the subject age was stratified relative to pharmacokinetic parameters, the majority of transdermal products do not report age-related differences in their pharmacokinetic profiles. The lack of age-related reports indicates that the skin, although the rate-limiting step for absorption, is not the major factor for observations of age-related effects. In other words, the skin in addition to other factors, including the active ingredient’s physiochemical characteristics and patch formulation components, determine whether a specific drug will have pharmacokinetic differences across age groups.

Discussion

Comorbid medical conditions in the elderly are often treated with polypharmacy, which may result in unwanted drugdrug interactions and adverse effects.¹⁴ Swallowing difficulty either as a symptom of the disease or secondary to aging is an additional consideration. Transdermal delivery of drugs may alleviate complications due to polypharmacy and swallowing difficulties while facilitating steady-state concentrations. Marketed transdermal products generally do not report agerelated differences in pharmacokinetics, suggesting that skin factors play a minor role in comparison to the drug’s chemistry and transdermal formulation.

Additional investigations may be beneficial in helping determine if the elderly should have different topical dosing regimens to ensure efficaciousness with minimal adverse effects. This is especially important for drugs that have a narrow therapeutic window, such as fentanyl and clonidine.¹⁵ Also, future studies would benefit from the inclusion of older subjects, as prior studies have largely focused on individuals younger than 70 years. Continued efforts should be directed at enhancing transdermal delivery design and predicting which topical drugs are likely to have altered pharmacodynamics in the elderly.

References

1. Day JC. Population projections of the United States, by age, sex, race, and Hispanic origin: 1993-2050. Washington, DC: US Department of Commerce, Bureau of the Census, 1993. (Current population reports; series P25, no. 1104).
2. Langer R. Transdermal drug delivery: past progress, current status, and future prospects. Adv Drug Deliv Rev. 2004 Mar 27;56(5):557-8.
3. Naik A, Kalia YN, Guy RH. Transdermal drug delivery: overcoming the skin’s barrier function. Pharm Sci Technolo Today. 2000 Sep 1;3(9):318-26.
4. Fisher LB. In vitro studies on the permeability of infant skin. In: Bronaugh RL, Maibach HI, eds. Percutaneous absorption. New York: Marcel Dekker, 1985; p213-22.
5. McCormack JJ, Boisits EK, Fisher LB. An in vitro comparison of the permeability of adult versus neonatal skin. In: Maibach HI, Boisits EK, eds. Neonatal skin: structure and function. New York: Marcel Dekker, 1982; p149-66.
6. Wilson DR, Maibach HI. An in vivo comparison of skin barrier function. In: Maibach HI, Boisits EK, eds. Neonatal skin: structure and function. New York: Marcel Dekker, 1982; p101-10.
7. Feldmann RJ, Maibach HI. Percutaneous penetration of steroids in man. J Invest Dermatol. 1969 Jan;52(1):89-94.
8. Feldmann RJ, Maibach HI. Absorption of some organic compounds through the skin in man. J Invest Dermatol. 1970 May;54(5):399-404.
9. Christophers E, Kligman AM. Percutaneous absorption in aged skin. In: Montagna W, ed. Advances in biology of the skin. Vol 6: Aging. Long Island City: Pergaman Press, 1965; p163-75.
10. DeSalva SJ, Thompson G. Na22Cl skin clearance in humans and its relation to skin age. J Invest Dermatol. 1965 Nov;45(5):315-8.
11. Tagami H. Functional characteristics of aged skin. Acta Dermatol Kyoto (English Edition). 1972;67:131-8.
12. Roskos KV, Maibach HI, Guy RH. The effect of aging on percutaneous absorption in man. J Pharmacokinet Biopharm. 1989 Dec;17(6):617-30.
13. Bucks DA, McMaster JR, Maibach HI, et al. Bioavailability of topically administered steroids: a “mass balance” technique. J Invest Dermatol. 1988 Jul;91(1):29-33.
14. Levy RH, Collins C. Risk and predictability of drug interactions in the elderly. Int Rev Neurobiol. 2007;81:235-51.
15. Nelson L, Schwaner R. Transdermal fentanyl: pharmacology and toxicology. J Med Toxicol. 2009 Dec;5(4):230-41.

¹Department of Dermatology, Howard University College of Medicine, Washington, DC, USA
²Teikoku Pharma USA, Inc., San Jose, CA, USA
³Department of Dermatology, University of California, San Francisco, CA, USA

ABSTRACT

Changes in the skin that occur in the elderly may put them at increased risk for altered percutaneous penetration from pharmacotherapy along with potential adverse effects. Skin factors that may have a role in age-related percutaneous penetration include blood flow, pH, skin thickness, hair and pore density, and the content and structure of proteins, glycosaminoglycans (GAGs), water, and lipids. Each factor is examined as a function of increasing age along with its potential impact on percutaneous penetration. Additionally, topical drugs that successfully overcome the barrier function of the skin can still fall victim to cutaneous metabolism, thereby producing metabolites that may have increased or decreased activity. This overview discusses the current data and highlights the importance of further studies to evaluate the impact of skin factors in age-related percutaneous penetration.

Key Words:
transdermal, elderly, dermatopharmacokinetics, percutaneous penetration, cutaneous metabolism

Introduction

Human skin changes with increasing age due to both intrinsic and extrinsic factors. Intrinsic skin aging is primarily determined by genetics and extrinsic aging (photoaging) is primarily caused by environmental exposure to ultraviolet light. In sun-exposed skin, these two processes of aging are superimposed. Age-related skin changes may affect the percutaneous penetration of drugs and ultimately their systemic absorption. Numerous physiological and biochemical changes within the skin have been identified, but it is not clear how these factors have a role, if any, in the degree of percutaneous penetration.¹

Changes that occur in aged skin include increased stratum corneum dryness,^2,3 reduction in sebaceous gland activity resulting in a decrease in skin surface lipids,⁴ flattening of the dermal-epidermal junction,^1,5 and atrophy of the skin capillary network resulting in a gradual attenuation of blood supply to the viable epidermis.⁶ This overview provides a basis for understanding the effect of skin aging on percutaneous penetration and discusses the individual skin factors and inherent cutaneous metabolism that may be contributing factors. While this is a relatively new and continually evolving area of investigation, we hope that the data consolidated here will serve as a stepping ground for future studies.

Skin Factors Affecting Age-related Percutaneous Penetration

Humans are exposed to drugs by the oral, pulmonary, or percutaneous routes through intentional or accidental means. The route of exposure as well as other factors can have an impact on the absorption of a drug and its resulting effects either locally or systemically. Percutaneous penetration of a drug occurs with its concentration on the skin’s surface as the main driving force for a series of partitioning and passive diffusion steps through the stratum corneum, underlying viable epidermis, dermis, and then finally into the circulatory of lymphatic system. Percutaneous penetration may occur through the intercellular, transcellular, and appendegeal routes. The intercellular route is thought to have a major role in drug penetration, which involves partitioning of the drug into the lipid laden extracellular regions of the stratum corneum. Lipophilic drugs diffuse through the lamellar acyl chains of the lipid, while hydrophilic drugs diffuse through the polar head groups of the lipid. The transcellular route involves the drug going through the corneocytes of the stratum corneum and the appendegeal route involves the drug entering the shunts of hair follicles and sebaceous and sweat glands, effectively bypassing the stratum corneum.

Percutaneous absorption of drugs can be affected by drug, exposure, and skin related factors. Drug-related factors include molecular weight, lipid solubility, water solubility, vehicle, irritancy, and other drugs that may serve as enhancers. Exposurerelated factors include drug concentration, duration, use of protective equipment, climate (temperature and humidity), and the matrix (e.g., soil). Skin-related factors include blood flow, pH, skin thickness, hair and pore density, and the content and structure of proteins, glycosaminoglycans (GAGs), water, and lipids (Table 1).^7,8 Cutaneous metabolism also has a role and will be covered in a separate section. The following sections serve as an overview for how some of these skin-related factors change as a function of increasing age. There is limited data available on how these age-related changes may directly or indirectly affect the percutaneous penetration of drugs.

As we review skin-related factors, keep in mind that percutaneous penetration varies depending on the regional site of the body.⁹ There is also considerable variability within a given site as well as within and between individuals, which can result in confounding factors.

Cutaneous Blood Perfusion

Cutaneous blood perfusion has been quantitatively studied in vitro using histologic sections stained for alkaline phosphatase or the CD31 antigen. The former is inversely correlated with the degree of blood perfusion and the latter is a marker for endothelial cells.^10,11 In vivo methods allow for three-dimensional visualization of cutaneous blood flow and include intravital capillaroscopy (native microscopy and fluorescein angiography), laser Doppler flowmetry (LDF), laser Doppler velocimetry, and photoplethysmography. Intravital capillaroscopy measurements of 26 subjects found a decrease in dermal papillary loops and little change in horizontal vessels with increasing age.¹⁰ Kelly and colleagues used LDF and found little difference in blood flow between young (18-26 years) and elderly (65-88 years) subjects; however, there were only 10 subjects in each group.¹⁰ Another LDF study of 201 people (10-89 years) revealed that areas with high blood flow, such as the lip, cushion of the third finger, nasal tip, and forehead, decreased with age while areas with initially low blood flow, such as the trunk, had no clear variation with age.¹² A photoplethysmographic study including 69 individuals (3-99 years) revealed significantly decreased capillary circulation in forehead skin with advancing age.¹³ Despite the many tools and techniques available, age studies are often conflicting in the area of blood flow. Overall trends indicate that blood flow may decrease with age, especially in photo-exposed areas. With topically applied drugs, a reduction in blood flow may enhance local delivery, but diminish systemic delivery.

pH

pH contributes to defense against microbiological or drug insults and plays a role in skin barrier homeostasis and stratum corneum desquamation.¹⁴ Instruments using a glass planar electrode are primarily used for pH measurement and they function based on a potential difference in H+ concentration between the skin surface and the solution (HgCl + KCl) contained in a reference electrode. Fluhr and colleagues measured 44 adults (21-44 years) and 44 of the adults’ children (1-6 years) and found no significant difference in pH between the two groups.¹⁵ However, another study involving 11 anatomic locations in 14 adults (26.7 ± 2.8 years) and 15 aged adults (70.5 ± 13.8 years) found pH was significantly higher in the aged group on the ankle and the forehead. Mean pH varied from 4.8 (ankle) to 5.5 (thigh) in the young group and from 5.0 (forehead) to 5.5 (abdomen) in aged individuals.¹⁶

Most drugs are weak organic acids or bases and exist in unionized and ionized forms in an aqueous environment. The unionized form is usually lipophilic and the ionized form is hydrophilic. The portion of the unionized form present is determined by the pH and the drug’s pKa (acid dissociation constant). When the pH is lower than the pKa, the unionized form of a weak acid predominates, but the ionized form of a weak base predominates. Thus, the skin’s pH can affect the amount of unionized drug available for percutaneous penetration. At present, it is unclear to what degree the skin’s pH changes with advancing age and more studies are needed in this area.

Skin Thickness

While the stratum corneum is generally accepted to maintain its thickness during aging,¹⁷ epidermal, dermal, and whole skin thickness changes are controversial. In vitro analyses of images taken from light, scanning electron, and transmission electron microscopies have been used to determine the thickness of various skin layers. Recently, confocal laser scanning microscopy (CSLM) has allowed for direct measurement of stratum corneum and epidermal thickness and is considered to be the “gold standard.” A CSLM study of 34 subjects (18-69 years) found that the epidermis on the arm thinned with increasing age.¹⁸ However, a study of 71 people (20-68 years) involved punch biopsies from the dorsal forearm, buttock, and shoulder found no significant difference in epidermal thickness associated with increasing age.¹⁹ Hull and colleagues used scanning electron microscopy to reveal that the corrugated papillary interface between the dermis and epidermis is visible up through the sixth decade and flattens thereafter.²⁰ Flattening may be associated with decreased proliferative potential and could affect percutaneous penetration.

Pulsed ultrasound has also been used for the determination of whole skin thickness. An ultrasound (B-mode) study of 40 subjects (25-90 years) found an increase in facial skin thickness with age.²¹ However, another ultrasound study showed thinning of forehead skin with age.²² Comparing skin layer thickness is challenging because of significant variation in measurements between individuals and between sites within each individual. The skin thickness of the eyelid is approximately 0.05 cm and that of the palm and sole is about 0.4 cm.²³ Note that percutaneous penetration is not exclusively a function of skin thickness. The skin on the sole or palm has a higher rate of diffusion than the skin of the forearm or abdomen, even though it is much thicker. Furthermore, hormonal differences (e.g., estrogen) during the aging process may confound studies of skin thickness.

Hair and Pore Density

Hair follicles and sebaceous and sweat glands represent an important shunt route into the skin for topical drugs. In vitro studies have demonstrated the importance of these skin appendages for percutaneous penetration by hydrophilic drugs.²⁴ The hair follicle infundibulum also has a large storage reservoir capacity, about 10 times more than the stratum corneum.²⁵ There may be a reduction in the amount of hair follicles with age, not only in the scalp, but also throughout the body. The mechanism for this hair follicle dropout is unclear, though it may be similar to the programmed hair follicle organ deletion that can occur in mice with age.²⁶ Sebaceous glands continually secrete sebum, which prevents the loss of water from the skin. In the elderly, sebaceous glands increase in size, but produce less sebum, which may contribute to xerosis. The number of sweat glands also decreases with age, but also shows variation between individuals after adjustment for age and sex.²⁷ All of these appendegeal changes may contribute to decreased percutaneous penetration in aged skin.

Proteins

Collagen comprises 70-80% of the dry weight of the dermis and is primarily responsible for the skin’s tensile strength. The rate of collagen synthesis, activity of post-translational enzymes, collagen solubility, thickness of collagen fiber bundles, and density of the collagen network all decrease in intrinsically aged skin.^28-30 However, extrinsically aged skin is characterized by collagen fibers that are fragmented, thickened, and more soluble.²⁸ The elastic fiber network occupies 2-4% of dermal volume and provides resilience and suppleness. Elastin is degraded slowly and accumulates damage with intrinsic aging; also, increased synthesis of abnormally structured elastin occurs in extrinsically aged skin.³¹ This leads to age-related accumulation of aberrant elastoic material, clumped in the papillary dermis. Age also leads to increased folding and decreased interaction of proteins with water, which may contribute to increased xerosis, and thus, decreased percutaneous penetration.³²

Glycoproteins (GAGs)

Most GAGs are present in human skin as hyaluronic acid and the proteoglycan family of chondroitin sulfates, including dermatan sulfate. Skin hydration is closely linked to the content and distribution of dermal GAGs, which can bind up to 1000 times their volume in water. Despite increased GAGs in extrinsically aged skin, these are abnormally deposited on elastoic material and cannot interact properly with water.³³ Brown and colleagues found that topical hyaluronic acid significantly enhanced the partitioning of both diclofenac and ibuprofen into human skin when compared to an aqueous control, pectin, and carboxymethylcellulose.³⁴ This suggests that GAGs, when allowed to interact with water, can enhance the percutaneous penetration of some drugs. The details of their interaction remain to be elucidated.

Water

In young skin, water is usually bound to proteins and is known as bound water, which is important for the structure and mechanical properties of proteins and their interactions. Water molecules not bound to proteins bind to each other and are found in a tetrahedron form. In aged skin, significantly more water is found in the tetrahedron form, which may result in delayed percutaneous penetration, especially for hydrophilic drugs.³⁵ Diridollou and colleagues utilized an active capacitance imaging system to investigate the hydration of dorsal and ventral forearm sites and, as expected, found skin dryness to increase with age.³⁶ Interestingly, they found ethnicity to be a significant factor with elderly African American and Caucasian women (>51 years) having increased skin dryness when compared to their Chinese or Mexican counterparts.

Lipids

Lipids form multilamellar sheets among the intercellular spaces of the stratum corneum and are critical to the stratum corneum’s mechanical and cohesive properties, allowing it to function as an effective water barrier. Lipid content appears to decrease with age, although the proportion of different lipid classes seems to remain fairly constant.^37,38 A study of 28 subjects (21-50 years) utilized high performance thin layer chromatography to separate lipid extracts from stratum corneum tape strippings and found a 30% decrease in the face, hands, and legs in older subjects.³⁹ However, Cua and colleagues studied 11 sites on 29 subjects and noted little relation between skin surface lipid content and age, except on the ankle, where the elderly demonstrated decreased lipid content.⁴⁰ These conflicting results may be due to significant regional variation within individuals they studied. It is generally accepted that percutaneous penetration is increased as the percentage of lipid weight in the stratum corneum is decreased. Both in vitro and in vivo studies have demonstrated enhanced percutaneous penetration following delipidization with polar and nontoxic solvents.⁴¹

Cutaneous Metabolism

The impact of cutaneous metabolism and how it changes as a function of increasing age is an area of growing interest on percutaneous drug delivery. Skin contains the major enzymes found in other tissues of the body. These enzymes have the ability to metabolize both endogenous drugs (e.g., hormones, steroids, and inflammatory mediators) and topically applied exogenous compounds (e.g., drugs, pesticides, and industrial and environmental agents). This cutaneous metabolism may result in activation of inert compounds to toxicologically active species, detoxification of toxicologically active drugs to inactive metabolites, conversion of active drugs to active metabolites, and activation of prodrugs. If transport through the epidermis is the rate limiting step and the metabolite is less hydrophobic than the parent compound, then percutaneous absorption of the metabolized compound could be faster than the parent compound, resulting in enhanced local and/or systemic toxicity. Examples of some drugs and compounds that undergo cutaneous metabolism are betamethasone 17-valerate, propranolol, nitroglycerin, theophylline, polycyclic aromatic hydrocarbons, butachlor, and atrazine.⁴²

The skin contains enzymes that undergo Phase 1 (e.g., oxidation, reduction, and hydrolysis) and Phase 2 (e.g., conjugation) reactions. Although the extent of cutaneous metabolism is modest when compared to hepatic metabolism (0.1-28% of the activities in the liver for Phase 1; 0.6-50% for Phase 2), it is important to consider the effect of cutaneous metabolism on percutaneous drug delivery.^43,44

Sotaniemi and colleagues measured cytochrome P-450 content in liver biopsy samples from 226 subjects and levels were found to be increased during the fourth decade, declined after 40 years to a level that remained unaltered up to 69 years, then declined further after 70 years.⁴⁵ Extrapolating this to the skin, one would expect cutaneous metabolism to follow a similar pattern with increasing age. While a study found a 15-25% decrease in the activity of most cutaneous enzymes,⁴⁶ other studies have reported no significant differences in relation to age.⁴⁷ Yamasawa and colleagues obtained skin biopsies from the abdomen of 63 subjects (1 month to 90 years) and enzyme activity was assayed using fluorometric methods. Fourteen enzymes, representative of the glycolytic pathway, tricarboxylic acid cycle, the transamination linkages between amino acid and carbohydrate metabolism, the pentose phosphate pathway, and fatty acid metabolism were studied. No significant differences in enzyme activity were observed in relation to age.⁴⁸

The effect of cutaneous metabolism on the biological response to topically applied drugs is only beginning to be investigated. Work has been directed towards the use of topical prodrugs and the design of molecules better able to transport across the stratum corneum and then undergo local enzymatic activation. This task is complicated since skin metabolism is difficult to measure in vivo without interference from systemic enzymes. In addition, certain cutaneous metabolic systems, such as cytochrome P-450, have relatively low activity when compared with the liver. Further research in this area requires a more specific quantitative understanding of the metabolic capabilities of human skin in vivo.

Conclusion

We are currently facing a dramatic demographic shift as the average age of the population steadily increases secondary to the baby boomer generation and advances in medicine allow for longer life expectancy. Consequently, it is crucial that we gain a better understanding of how age-related changes in the skin affect percutaneous drug penetration. Presently, studies focusing on dermatopharmacokinetics as a function of increasing age have conflicting results. If there is in fact a difference in percutaneous penetration between the young and the elderly, potential skin factors that may have a direct or indirect role have been outlined. Furthermore, cutaneous metabolism may provide an additional variable even if a drug is able to successfully navigate the barrier function of the skin. The crux of these evaluations is the assumption that individuals have similar pharmacodynamics, which may not be the case. In the future, metabolic phenotyping may be able to overcome inter-individual variation.

References

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3. Potts RO, Buras EM. In vivo changes in the dynamic viscosity of human stratum corneum as a function of age and ambient moisture. J Soc Cosmet Chem. 1985;36:169-76.
4. Pochi PE, Strauss JS, Downing DT. Age-related changes in sebaceous gland activity. J Invest Dermatol. 1979 Jul;73(1):108-11.
5. Lavker RM, Zheng PS, Dong G. Morphology of aged skin. Dermatol Clin. 1986 Jul;4(3):379-89.
6. Ryan TJ. Cutaneous circulation. In Goldsmith LA, ed. Biochemistry and physiology of the skin. Vol II. New York/Oxford: Oxford University Press; 1983:817-77.
7. Waller JM, Maibach HI. Age and skin structure and function, a quantitative approach (I): blood flow, pH, thickness, and ultrasound echogenicity. Skin Res Technol. 2005 Nov;11(4):221-35.
8. Waller JM, Maibach HI. Age and skin structure and function, a quantitative approach (II): protein, glycosaminoglycan, water, and lipid content and structure. Skin Res Technol. 2006 Aug;12(3):145-54.
9. Feldmann RJ, Maibach HI. Regional variation in percutaneous penetration of 14C cortisol in man. J Invest Dermatol. 1967 Feb;48(2):181-3.
10. Kelly RI, Pearse R, Bull RH, et al. The effects of aging on the cutaneous microvasculature. J Am Acad Dermatol. 1995 Nov;33(5 Pt 1):749-56.
11. Chung JH, Yano K, Lee MK, et al. Differential effects of photoaging vs intrinsic aging on the vascularization of human skin. Arch Dermatol. 2002 Nov;138(11):1437-42.
12. Ishihara M, Itoh M, Ohsawa K, et al. Blood flow. In: Kligman AM, Takase Y, eds. Cutaneous aging. Tokyo: University of Tokyo Press; 1988:167-81.
13. Leveque JL, Corcuff P, de Rigal J, et al. In vivo studies of the evolution of physical properties of the human skin with age. Int J Dermatol. 1984 Jun;23(5):322-9.
14. Rippke F, Schreiner V, Doering T, et al. Stratum corneum pH in atopic dermatitis: impact on skin barrier function and colonization with Staphylococcus aureus. Am J Clin Dermatol. 2004;5(4):217-23.
15. Fluhr JW, Pfisterer S, Gloor M. Direct comparison of skin physiology in children and adults with bioengineering methods. Pediatr Dermatol. 2000 Nov-Dec;17(6):436-9.
16. Wilhelm KP, Cua AB, Maibach HI. Skin aging. Effect on transepidermal water loss, stratum corneum hydration, skin surface pH, and casual sebum content. Arch Dermatol. 1991 Dec;127(12):1806-9.
17. Batisse D, Bazin R, Baldeweck T, et al. Influence of age on the wrinkling capacities of skin. Skin Res Technol. 2002 Aug;8(3):148-54.
18. Sandby-Moller J, Poulsen T, Wulf HC. Epidermal thickness at different body sites: relationship to age, gender, pigmentation, blood content, skin type and smoking habits. Acta Derm Venereol. 2003;83(6):410-3.
19. Branchet MC, Boisnic S, Frances C, et al. Skin thickness changes in normal aging skin. Gerontology. 1990;36(1):28-35.
20. Hull MT, Warfel KA. Age-related changes in the cutaneous basal lamina: scanning electron microscopic study. J Invest Dermatol. 1983 Oct;81(4):378- 80.
21. Pellacani G, Seidenari S. Variations in facial skin thickness and echogenicity with site and age. Acta Derm Venereol. 1999 Sep;79(5):366-9.
22. Gniadecka M, Jemec GB. Quantitative evaluation of chronological ageing and photoageing in vivo: studies on skin echogenicity and thickness. Br J Dermatol. 1998 Nov;139(5):815-21.
23. Maibach HI, Patrick E. Dermatotoxicology. In: Hayes WA, ed. Principles and methods of toxicology. 4th ed. Philadelphia, PA: Taylor and Francis; 2001:1039- 1046.
24. Essa EA, Bonner MC, Barry BW. Human skin sandwich for assessing shunt route penetration during passive and iontophoretic drug and liposome delivery. J Pharm Pharmacol. 2002 Nov;54(11):1481-90.
25. Lademann J, Richter H, Schaefer UF, et al. Hair follicles – a long-term reservoir for drug delivery. Skin Pharmacol Physiol. 2006;19(4):232-6.
26. Eichmuller S, van der Veen C, Moll I, et al. Clusters of perifollicular macrophages in normal murine skin: physiological degeneration of selected hair follicles by programmed organ deletion. J Histochem Cytochem. 1998 Mar;46(3):361-70.
27. Scobbie RB, Sofaer JA. Sweat pore count, hair density and tooth size: heritability and genetic correlation. Hum Hered. 1987;37(6):349-53.
28. Gniadecka M, Gniadecki R, Serup J, et al. Ultrasound structure and digital image analysis of the subepidermal low echogenic band in aged human skin: diurnal changes and interindividual variability. J Invest Dermatol. 1994 Mar;102(3):362-5.
29. Uitto J. Connective tissue biochemistry of the aging dermis. Age-associated alterations in collagen and elastin. Clin Geriatr Med. 1989 Feb;5(1):127-47.
30. Lavker RM, Zheng PS, Dong G. Aged skin: a study by light, transmission electron, and scanning electron microscopy. J Invest Dermatol. 1987 Mar;88(3 Suppl):44s-51s.
31. Bernstein EF, Chen YQ, Tamai K, et al. Enhanced elastin and fibrillin gene expression in chronically photodamaged skin. J Invest Dermatol. 1994 Aug;103(2):182-6.
32. Gniadecka M, Nielsen OF, Wessel S, et al. Water and protein structure in photoaged and chronically aged skin. J Invest Dermatol. 1998 Dec;111(6): 1129-33.
33. Bernstein EF, Underhill CB, Hahn PJ, et al. Chronic sun exposure alters both the content and distribution of dermal glycosaminoglycans. Br J Dermatol. 1996 Aug;135(2):255-62.
34. Brown MB, Hanpanitcharoen M, Martin GP. An in vitro investigation into the effect of glycosaminoglycans on the skin partitioning and deposition of NSAIDs. Int J Pharm. 2001 Aug 28;225(1-2):113-21.
35. Gniadecka M, Faurskov Nielsen O, Christensen DH, et al. Structure of water, proteins, and lipids in intact human skin, hair, and nail. J Invest Dermatol. 1998 Apr;110(4):393-8.
36. Diridollou S, de Rigal J, Querleux B, et al. Comparative study of the hydration of the stratum corneum between four ethnic groups: influence of age. Int J Dermatol. 2007 Oct;46 Suppl 1:11-4.
37. Roskos KV. The effect of skin aging on the percutaneous penetration of chemicals through human skin. Dissertation, University of California, San Francisco, CA, 1989.
38. Saint Leger D, Francois AM, Leveque JL, et al. Age-associated changes in stratum corneum lipids and their relation to dryness. Dermatologica. 1988;177(3):159-64.
39. Rogers J, Harding C, Mayo A, et al. Stratum corneum lipids: the effect of ageing and the seasons. Arch Dermatol Res. 1996 Nov;288(12):765-70.
40. Cua AB, Wilhelm KP, Maibach HI. Skin surface lipid and skin friction: relation to age, sex and anatomical region. Skin Pharmacol. 1995;8(5):246-51.
41. Menczel EM. Delipidization of the cutaneous permeability barrier and percutaneous penetration. In: Smith EW, Maibach HI, eds. Percutaneous penetration enhancers. 1st ed. Boca Raton, FL: CRC Press; 1995:383-92.
42. Bashir S, Maibach HI. Cutaneous metabolism of xenobiotics. In: Bronaugh RL, Maibach HI, eds. Percutaneous absorption: drugs-cosmetics-mechanismmethodology. 3rd ed. New York, NY: Marcel Dekker; 1999:65-80.
43. Kao J, Carver MP. Cutaneous metabolism of xenobiotics. Drug Metab Rev. 1990;22(4):363-410.
44. Hotchkiss SAM. Dermal metabolism. In: Roberts MS, Walter KA, eds. Dermal absorption and toxicity assessment. Vol 91. New York, NY: Marcel Dekker; 1998:43-101.
45. Sotaniemi EA, Arranto AJ, Pelkonen O, et al. Age and cytochrome P450- linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther. 1997 Mar;61(3):331-9.
46. Salfeld K. [On the problem of energy producing metabolism and amino acid metabolism in the aging skin. II. Enzymatic activity in the epidermis of adults of advanced age depending on the localization]. Arch Klin Exp Dermatol. 1966 May 27;225(1):93-100.
47. Ribuffo A. Metabolismo glicidico cutaneo nell’invecchiamento. In: Dinamico dell’invecchiamento della pelle. Italy: Minerva Medica; 1967:74-104.
48. Yamasawa S, Cerimele D, Serri F. The activity of metabolic enzymes of human epidermis in relation to age. Br J Dermatol. 1972 Feb;86(2):134-40.

Department of Dermatology, University of California at San Francisco,
San Francisco, CA, USA

ABSTRACT

Photosensitivity is defined as responsiveness to light exposure. For many common dermatologic drugs, proper storage conditions are essential for maintaining drug activity. Degradation and loss of activity can occur with exposure to light, temperature, and/ or moisture. For example, ketoconazole degrades after 24 hours of light exposure. In this article storage guidelines for common dermatology drugs are provided. We suspect that drug degradation is common due to improper storage and that improved patient instruction regarding storage will reduce degradation and alleviate some of the danger associated with improper storage and usage patterns.

Key Words:
drug storage; drug degradation; light sensitive; moisture sensitive; temperature
sensitive

Light can change the properties of different materials and products, and the number of drugs found to be photochemically unstable is steadily increasing. We define “photosensitivity” as the response that a compound shows to light exposure and includes not only degradation reactions, but also other processes, such as the formation of radicals, energy transfer, and luminescence.¹ Most are familiar with the traditional brown medicinal flask or the white pillbox; these offer adequate protection for most drug products during storage and distribution. Indeed, proper storage conditions are essential for the efficacy of many common
dermatologic drugs. In modern hospital pharmacies, drugs are often stored in unit-dose containers on an open shelf. In many cases, the protective market pack is removed; the inner container can be made of transparent plastic materials that offer little protection toward UV and visible radiation. The unprotected drug can then be exposed to fluorescent tubes and/or filtered daylight for several weeks or months before it is finally administered to the patient.

Drug efficacy depends on its stability, pH, correct chemical composition, and potency. Preservation of these characteristics require that many commonly used dermatologic drugs be kept in light-, temperature-, or moisture-free storage conditions. Indeed, itraconazole and erythromycin base are sensitive to all³ conditions. The most common consequence of drug photodecomposition is loss of potency with concomitant loss of therapeutic activity. Although less common, even less severe degradation can lead to problems. Adverse effects due to the
formation of minor degradation products during storage and administration have been reported.² In general, 2 aspects of drug photostability must be considered: in vitro and
in vivo stability.¹ Even if a drug product is shown to be photochemically inert, in the sense that it does not decompose during exposure to light, it can still act as a source of free radicals or form phototoxic metabolites in vivo.¹ Epstein and Wintroub suggested that patients who take certain dermatologic drugs and subsequently become exposed to light may develop phototoxic drug metabolites.³

Call for Renewed Vigilance in the Proper Storage of Drugs

Table 1 lists some commonly used dermatologic drugs that have special storage requirements; the general storage guidelines that follow provide an easy way to remember which drugs require special attention. The table was generated using The Pharmacopeia of the United States of America, 31st revision,⁴ Physicians’ Desk Reference at www.pdr.net,⁵ European Pharmacopeia,⁶ and British Pharmacopoeia 2007.⁷ An in-depth treatise on the effects of temperature, light, and moisture is provided by Rubinstein.⁸ Actual rates of degradation are not listed in these references, however, as this information is difficult to obtain because studies have not been done to determine degradation rates; most available information about degradation comes from studies that analyze the activity of the medicine.

Rates of Degradation

Studies with ketoconazole have shown that photodegradation occurs after 24 hours of UV light exposure.⁹ Following this, ketoconazole degradation products will peak at 4 minutes with high-resolution gas chromatography, while ketoconazole alone normally peaks at 6 minutes without the 4-minute degradation product peak. Acyclovir activity decreases after exposure to moisture, but the resulting rate of decline is unknown. Likewise, while terbinafine is light-sensitive, we only know that light exposure reduces its activity, although the activity loss-rate is also unknown.

Finally, expiration dates are used because the more time that passes from the initial issuance of the drug to the time when the drug is used will lead to degradation, not only because of its inherent activity, but also because of light exposure. In one Sudanese study, there was a 55% usage rate of old, unfinished drugs.10 Patients need clear instructions about the fact that old medications should be discarded or replaced once the expiration date passes. They should understand that it is not a cost-savings to use expired drugs, because they may not be effective and may even be harmful if degradation leads to the formation of toxic metabolites. Likewise, patients should receive clear storage instructions to avoid exposure to light, moisture, and temperature. While overworked doctors, nurses and pharmacists sometimes give hurried instructions, it is most important that patients be given clear directions.

For example, when patients are prescribed antibiotics, they should always be advised to complete the entire course of treatment. Despite these instructions, patients may not comply, assuming that the drug is no longer needed when they feel better and they may save any remaining medication for another time. This practice has led to the growth of drug-resistant strains of bacteria.^11-14 In other cases, unknowingly taking antibiotics previously associated with allergic symptoms can cause an allergic reaction.¹⁵

General Storage Guidelines

1. 1. Clarithromycin extended-release tablets: preserve in well closed containers, protected from light. Store at 25°C, excursions permitted between 15°C, and 30°C.
   2. All erythromycin preparations should be packaged and stored in tight containers.
   3. Tetracycline hydrochloride should be packaged and stored in tight, light-sensitive containers.
   4. Ketoconazole should be packaged and stored in wellclosed containers.
   5. Acyclovir should be packaged and stored in tight containers at room temperature, protected from light and moisture.
   6. Isotretinoin capsules should be packaged and stored in tight containers, protected from light, and stored at room temperature in a dry place.

Conclusion

The pharmacist receives training on appropriate drug labeling with respect to temperature, light, and humidity. Unfortunately, little literature exists that covers patient stored drug stability in well-lit, humid, non-air-conditioned areas. We suspect that drug degradation may be routine. Improved patient instruction may alleviate some of the danger associated with improper storage and usage patterns.

References

1. Tønnesen HH. Photostability of drugs and drug formulations, 2nd ed. Boca Raton, FL:CRC Press (2004).
2. de Vries H, Beijersbergen van Henegouwen GMJ, Huf FA. Photochemical decomposition of chloramphenicol in a 0.25% eyedrop and in a therapeutic intraocular concentration. Int J Pharm 20:265-71 (1984).
3. Epstein JH, Wintroub BU. Photosensitivity due to drugs. Drugs 30(1):42-57 (1985 Jul).
4. United States Pharmacopeia and National Formulary (USP 31-NF 26). Vol 2,3. Rockville, MD: United States Pharmacopeia Convention, pp. 1303, 1786-9, 2084-98, 2301-5, 2479-80, 2488-90, 3359-65 (2008).
5. Physicians’ Desk Reference. 62nd ed. Montvale, NJ: Thomson PDR (2008).
6. European Pharmacopoeia Commission. European Pharmacopoeia.
7. 6th ed. Strasbourg, France: Council of Europe (2007).
8. British Pharmacopoeia. London, UK: The Stationery Office (2007).
9. Duchene D, Vaution C, Glomot F. Cyclodextrins, their value in pharmaceutical technology. In: Rubinstein MH, editor. Pharmaceutical Technology – Drug Stability. Chichester, NY: Halsted Press;Ellis Horwood, pp. 9-23 (1989).
10. Staub I, Cruz AS, Pinto T, et al. Determinação da segurança biológica do xampu de cetoconazol: Teste de irritação ocular e avaliação do potencial de citotoxicidade in vitro. Revista Brasileira de Ciencias Farmaceuticas 43:301 (2007).
11. Yousif MA. In-home drug storage and utilization habits: a sudanese study. East Mediterr Health J 8(2-3):422-31 (2002 Mar-May).
12. World Health Organization: WHO model prescribing information. Geneva: World Health
    Organization (2001).
13. MayoClinic.com. Antibiotics: Use them wisely. At: http://www.mayoclinic.com/health/antibiotics/FL00075. Last accessed Dec 2008.
14. MD Consult. Antibiotic Resistance.
15. American College of Physicians. Antibiotic Resistance.
16. Karch AM, Karch FE. When it’s time to clean out the medicine cabinet. Am J Nurs 102(2):23 (2002 Feb).

University of California at San Francisco, San Francisco, USA

ABSTRACT

The elderly population is increasing and drug dosing requires special considerations for efficacy and decreasing toxicity. This overview provides algorithms for adjusting drug and dosage based on current evidence-based knowledge with emphasis on drugs prescribed in dermatological practice.

Key Words:
elderly, drug dosing, dermatological drugs

The proportion of elderly people in the general population continues to grow rapidly¹ and dermatological diseases are common in this group,² making drug dosage and administration particularly important. Furthermore, the elderly are vulnerable to adverse drug reactions (ADRs).³ Some dermatological drugs, such as methotrexate (MTX), may result in serious toxic effects in the elderly if the dosage is not reduced.⁴ Evaluating the factors that could influence drug pharmacokinetics and pharmacodynamics is worthwhile in order to improve drug treatment in this population.

Adverse Drug Reactions in the Elderly

Anti-Infective Agents

Infections are a common problem among the elderly, and anti-infective agents are frequently prescribed to them.⁵ In elderly patients, ADRs, as well as drug interactions, should be considered when selecting an anti-infective regimen. Common drug interactions with anti-infective agents involve macrolide antibacterials and fluoroquinolones.⁶

Erythromycin and troleandomycin are strong inhibitors of the cytochrome P450 enzyme CYP3A4, and may therefore be responsible for toxicity of coadministered drugs by decreasing their clearance (Table I).⁶ Example substrates of CYP3A4 include benzodiazepines, calcium channel antagonists, immunosuppressive agents (e.g., cyclosporin, tacrolimus [Protopic^®, Astellas]), and anticoagulants.⁷ Elderly patients receiving macrolides should be monitored for adverse events resulting from drug interactions.

Fluoroquinolones are antibacterials that are frequently used in infections affecting the elderly.⁸ One of the most important drug interactions of fluoroquinolones is the ability of ciprofloxacin (Cipro^®, Bayer) and enoxacin to inhibit the metabolism of theophylline by CYP1A2, resulting in theophylline accumulation and toxicity.⁶ Seizures may occur at therapeutic theophylline levels as a result of its additive effects on the central nervous system (CNS).⁶

Corticosteroids

Corticosteroids have adverse effects on many organ systems,⁹ ranging from those that are not necessarily serious (e.g., Cushingoid appearance), to those that are life-threatening (e.g., serious infections). Some of these adverse effects may be aggravated in the elderly. Patients receiving prednisolone 5–40mg/day for at least 1 year had a partial loss of explicit memory, and elderly patients may be more susceptible to memory impairment with less protracted treatment (Table 1).¹⁰ The risk of developing diabetes mellitus more than doubles in elderly patients who are newly initiated on oral corticosteroid therapy.¹¹

A higher risk for peptic ulcer disease was reported in corticosteroid users who were receiving nonsteroidal anti-inflammatory drugs (NSAIDs) concurrently (Table 1).¹² Those receiving NSAIDs and corticosteroids showed a risk for peptic ulcer disease 15 times greater than that of nonusers of either drug.¹²

Antihistamines

Elderly persons treated with first-generation histamine H1 receptor antagonists (antihistamines) may be at greater risk of adverse effects involving the CNS, such as sedation or impaired cognitive function.¹³

Diphenhydramine administration in hospitalized patients =70 years of age was associated with a higher risk of cognitive decline compared with nonexposed patients (Table 1).¹⁴ These findings strongly suggest caution when prescribing this drug to the elderly. Reports by Mann, et al. of sedation with second-generation antihistamines loratadine, cetirizine (Zyrtek^®, Pfizer), fexofenadine (Allegra^®, sanofi-aventis) and acrivastine (Sempra^®, GlaxoSmithKline) were infrequent, but this study did not focus on the elderly. Affrime et al.¹⁵ studied pharmacokinetics and adverse events of desloratadine (Aerius^®, Schering) in different age groups and suggested that no dosage adjustment of desloratadine is required in the elderly.

Immunobiological Agents

Three immunobiological agents have been approved by the US FDA for the treatment of moderate-to-severe psoriasis: alefacept (Amevive^®, Astellas), efalizumab (Raptiva^®, Genentech), and etanercept (Enbrel^®, Amgen Wyeth).¹⁶ A recent study found alefacept to be well tolerated and effective in elderly, obese, and diabetic patients with moderate-to-severe plaque psoriasis.¹⁷ Accidental injury, headache, and pharyngitis were among the most common adverse events. Infections were primarily colds, with no opportunistic infections being reported. In psoriatic patients =65 years of age treated with efalizumab, the overall rates of adverse events were comparable to those seen in patients < 65 years of age, although a higher rate of serious adverse events was observed in the older group.¹⁸

Table 1: Specific points on the effects of dermatological drugs prescribed for the elderly.

A recent study evaluated the safety profile of etanercept in patients with chronic, moderate-to-severe plaque psoriasis.19 Pooled safety results from the first 12 weeks of treatment suggest that short-term etanercept treatment is generally safe and well tolerated. No overall differences in safety were observed between older and younger patients.

Changes in Pharmacokinetics

Absorption

There appear to be no major alterations in intestinal drug absorption in the elderly.²⁰ However, percutaneous absorption of hydrocortisone, benzoic acid, acetylsalicylic acid, and caffeine was significantly lower in the elderly when compared with younger subjects, whereas absorption of testosterone and estradiol was not.²¹ These results suggest that aging can affect percutaneous drug absorption and that relatively hydrophilic compounds are particularly sensitive.

Physiological age-related changes in the skin may impair percutaneous drug absorption (see Table 2).²¹ The diminished lipid content of aged skin implies a diminished dissolution for percutaneous administered drugs, and the reduced water content may make aged skin less attractive to more hydrophilic compounds. Furthermore, comprised microcirculation may lead to poorer absorption capability.

Table 1: Specific points on the effects of dermatological drugs prescribed for the elderly.

Distribution

Changes in body composition in the elderly may lead to altered drug distribution. Lean body mass and total body water decrease with age, whereas fat as a percentage of body weight increases with age.^22,23 As a result, the volume of distribution is lower for hydrophilic drugs leading to potentially higher plasma concentrations. In contrast, the volume of distribution is higher for lipophilic drugs, often resulting in retention and prolonged half-life, as shown for hydroxyzine.24 When considering volume of distribution, elderly patients may have significantly reduced body weight,²⁵ which is a major risk factor for overmedication.²⁶

Drugs may be bound to plasma proteins with only the free fraction being pharmacologically active. The two plasma proteins to which drugs can bind are albumin and á-1-acid glycoprotein, and these may change with age.²⁷ Albumin levels tend to decrease with advancing age, whereas á-1-acid glycoprotein may increase.^28,29 Thus, the ratio of bound to free drug may be altered. However, the extent to which these changes in plasma protein binding are clinically relevant is controversial. Changes of >50% in the free fraction were documented for only a few drugs, such as naproxen, salicylates, and valproic acid,30 and greater drug elimination may counterbalance the increase in free drug concentration.³¹

Elimination

Decreased renal function can result in prolongation of the half-life of many drugs, which can accumulate to toxic levels if the dosage is not reduced.³² Thus, to avoid excessive drug dosing, renal function assessment is essential in elderly patients, especially when prescribing drugs with a low therapeutic index, such as MTX,³³ which is mainly eliminated by the kidney.³⁴ Studies have described a significant increase in its half-life in patients with impaired renal function, as defined by creatinine clearance (CLcr).^35,36 Patients with renal impairment have a higher overall rate of toxicity and are at higher risk of severe and respiratory toxicities than those with normal CLcr.⁴

Like MTX, the second generation antihistamine cetirizine is predominantly eliminated unchanged in the urine.³⁷ In elderly subjects with impaired renal function, the elimination half-life of cetirizine was significantly prolonged (i.e., an increase of 159% in patients with a mean CLcr of approximately 44mL/min) and apparent total body clearance was significantly reduced by 64%.³⁸ Therefore, Kaliner suggested that cetirizine dosage be reduced by 50% in patients with renal disease.¹³ Prescribing the second generation antihistamine fexofenadine may be considered in this setting, as the pharmacokinetics of fexofenadine are not affected by decreased renal function.³⁹

Renal function generally declines with age. Specifically, renal blood flow is reduced and tubular function is impaired, thus reducing the kidney’s ability to maintain homeostasis under stressful conditions.⁴⁰ The glomerular filtration rate (GFR), measured by creatinine clearance (CLcr), declines by approximately 30% between 30–80 years of age in about two thirds of the population.^41,42 It is important to remember, however, that CLcr provides only a rough estimate of the GFR because creatinine is also secreted in small amounts by the kidney.⁴³

CLcr can be estimated utilizing the Cockcroft and Gault equation44 by correcting the serum creatinine for age, sex, and weight:

Using this equation is probably the easiest way to estimate a patient’s renal function. However, CLcr estimated using this method can significantly differ from true CLcr, particularly in elderly patients.⁴⁵ Moreover, their serum creatinine might be lower because of lower muscle mass, and as a result, it might not rise significantly even when renal function is significantly impaired.⁴¹ This could lead to an overestimation of CLcr as has been shown by Goldberg and Finkelstein ⁴⁵.

CLcr measurement should be performed; however, even with this test, unreliable results are possible. Urine collection by patients might be incomplete, perhaps because of a forgotten urine specimen,⁴⁵ and CLcr might exceed the true GFR. An EDTA clearance or insulin clearance test should be performed, if available, because it provides a more accurate assessment of renal function.³³

Degrees of renal impairment can be classified as mild (GFR 20–50mL/min), moderate (GFR 10–19mL/min), or severe (GFR < 9mL/min) and therapeutic drug levels may be maintained either by reducing the dose, by increasing the interval between doses, or by doing both.³³

Metabolism

The hepatic clearance of many drugs is lower in the elderly, mainly because of a reduction in liver size of approximately 20%–40%⁴⁶ and a reduction in liver blood flow.⁴⁷ Drug metabolism proceeds via Phase I and Phase II reactions. While there may be changes in Phase I reactions with aging,48 Phase II reactions seem to be less affected.⁴⁹

Hepatic drug metabolism in the elderly is a controversial matter. Sotaniemi, et al.⁴⁸ showed a reduction of CYP-P450-linked drug metabolism by approximately 30% after 70 years of age in an investigation of CYP-P450 content and microsomal enzyme activity in the human liver. Conversely, other studies found no significant age-related differences in the activities and contents of human liver microsomal enzymes.^50,51

Drug-induced liver disease seems to occur more frequently in the elderly.⁵² For example, isoniazid-induced hepatitis, which is uncommon in younger age groups, occurred in approximately 2% of persons =50 years of age.⁵³ No studies have been published that evaluate whether elderly patients are more susceptible to potentially hepatotoxic drugs used in dermatological practice. However, caution may be indicated for this group.

Several commonly prescribed dermatological drugs, such as MTX, can potentially cause liver damage,⁵⁴ and the age at onset of therapy has been shown to be one risk factor.⁵⁵ Close attention should be paid to the recommendations for monitoring elderly patients taking MTX.

Itraconazole (Sporanox^®, Janssen Pharmaceutica) should be used with caution in patients with history of liver impairment.⁵⁶ Itraconazole users are at a higher risk of liver damage, which is associated with a cholestatic pattern of injury.^57,58 Although serious liver problems, including liver failure and death, are rare with the use of this drug,⁵⁸ liver function tests should be conducted in patients who have pre-existing hepatic dysfunction.⁵⁶

Severe hepatic injury with the use of acitretin (Soriatane^®, Connetics) has been reported,⁵⁷ but appears to be a rare side-effect of treatment with this drug. However, in patients with liver disease, the dose of acitretin should be reduced and liver function tests monitored closely.⁵⁸ Other potentially hepatotoxic drugs used in dermatology include agents such as tetracyclines, erythromycin, flucloxacillin, ketoconazole, azathioprine, synthetic androgens, and dapsone.⁵⁸

Changes in Pharmacodynamics

Pharmacodynamic considerations include receptor number and affinity, signal transduction mechanisms, cellular responses, and homeostatic regulation.⁵⁹ Sensitivity to certain drugs may be either increased or decreased in the elderly, e.g., sensitivity to benzodiazepines is greater in older patients,⁶⁰ as is the response to some opioids and anticoagulants.

Conversely, the elderly seem to be less responsive to certain â-adrenoceptor agonists and antagonists.²⁷ Simons, et al. studied H1-receptor sensitivity to hydroxyzine by measuring changes in suppression of histamine-induced wheal and flare and suggested an enhanced suppression of H1-receptor activity in the elderly.²⁴

Prescribing in the Elderly: General Considerations

How a drug is handled by the body may change in the elderly. Alterations in drug metabolism and elimination, and a higher prevalence of multidrug regimens make this population more susceptible to ADRs. What makes prescribing to the elderly even more challenging is the fact that they are known to tolerate a number of drugs less well, but they handle other drugs as well as younger individuals. In addition, drug response in the elderly shows a large inter-individual variability.31 There are no simple rules for prescribing that can apply to the elderly population in general; the right dosage must be determined for every elderly person individually.31 A general approach when prescribing drugs to this population would be to:

1. Start, when possible, with a small initial dose and titrate this dose to a clearly defined therapeutic response (dosage guidelines may help you find out about initial dosage reduction).
2. Reduce the number of drugs administered simultaneously as much as possible.
3. Take a careful drug history.
4. Check for possible ADRs or drug interactions.^27,31,32

Noncompliance with drug therapy regimens is a common reason for hospital admission for elderly patients.61 Risk factors include the patients’ inability to recall their medication regimen, medication costs, using several physicians, polypharmacy, and complicated drug regimens.⁶¹ Cognitive impairment and physical dependency are additional risk factors for poor medication management in this group.⁶² To enhance drug management in the elderly, it is crucial to simplify the drug regimen as much as possible, e.g., try to use drugs that can be taken at the same time of day.³²

Conclusions

Some commonly prescribed dermatological drugs such as MTX and cetirizine are likely to be eliminated more slowly in the elderly. Dosage reduction is recommended not only with these agents, but with any drug that is predominantly eliminated by the kidney. Potentially hepatotoxic drugs such as MTX, itraconazole, and acitretin should be used with caution in the elderly, and liver function tests should be performed when these drugs are given in order to lower the risk of hepatotoxicity. Absorption of percutaneously administered drugs may be lowered in the elderly and altered distribution may lead to prolonged half-life, as shown for hydroxyzine, or to a higher plasma concentration of hydrophilic drugs. Further research is needed in order to determine how specific dermatological drugs are handled by the elderly so that pharmacotherapy in this part of the population can be improved.

*Modified with permission from: Drugs Aging 23(3):203-15 (2006).

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