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Drug Absorption Through the Skin: a Mixed Blessing

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Drug Absorption Through the Skin: a Mixed Blessing Arch Dis Child: first published as 10.1136/adc.62.3.220 on 1 March 1987. Downloaded from Archives of Disease in Childhood, 1987, 62, 220-221 Drug absorption through the skin: a mixed blessing Skin is a barrier that keeps body water in and micro- barrier properties to those of a child or adult. It is organisms and noxious chemicals out. Topical poorly developed in preterm infants, particularly drugs, the mainstay of treatment in dermatology, those with gestation less than 28 weeks.2 Such are applied in the hope and expectation that any infants have a very high transepidermal water loss percutaneous absorption will be minimal and that and readily absorb topically applied agents, some- systemic side effects will not occur. It is becoming times with disastrous consequences. Immaturity of apparent though that skin is not quite as imperme- the stratum corneum is only temporary. The ex- able as often believed. Undoubtedly, drugs can be trauterine environment triggers rapid maturation, absorbed through the skin and produce either so that by 2 or 3 weeks of age the skin has similar unwanted or intended systemic effects. barrier properties to that of a term infant. Mechanism of percutaneous absorption' Hazards of percutaneous absorption In 1886 Dr W Rayner, visiting medical officer at the The superficial layers of the epidermis, the stratum Marylebone Workhouse, London, reported an out- corneum, provide almost all the skin's barrier break of cyanosis in newborn infants. He found an properties. (The basal epidermal layers and the image of the workhouse stamp used for marking the underlying dermis are readily permeable-the often nappies imprinted on the buttocks and vulva of one used term 'transdermal absorption' is inaccurate.) of the infants and correctly deduced that something The stratum corneum is made up of layers of in the ink (an aniline dye) was being absorbed to overlapping cell plates containing the fibrous pro- cause cyanosis (methaemoglobinaemia). His mes- tein keratin. Most drug absorption is transcellular: it sage went unheeded and at least nine further copyright. is unlikely that noticeable absorption occurs be- outbreaks of methaemoglobinaemia caused by tween cells or through sweat pores and hair follicles. absorption of aniline dyes have been reported, with It is a passive diffusion process, the magnitude of considerable mortality. which will depend on the integrity and efficacy of Reports of other drugs and chemicals being the epidermal barrier but which will be influenced absorbed through the skin and causing toxic effects by the drug itself. Drugs with low molecular weight are numerous. Most involve dermatological prep- (below 800 daltons) with a high water and lipid arations and topical antiseptics, not surprisingly as http://adc.bmj.com/ solubility show the greatest penetration. The vehicle such agents are often liberally applied to large areas that contains the applied drug is important. So too is of the skin of infants. the degree of hydration of the stratum corneum: occluding the epidermis increases its water content, Dermatological preparations. Systemic effects from enhancing drug absorption. the absorption of topical steroids have often been reported. Most affected are young infants with Paediatric considerations extensive eczema treated with powerful fluorinated steroids. Effects range from adrenal suppression to on September 25, 2021 by guest. Protected Size. The smaller the child the larger the surface reduced growth and frank Cushingoid features. A area relative to body weight. Absorption of drugs solution of 1% hydrocortisone does not seem to depends on the surface area exposed, whereas produce these effects and is therefore safer in the distribution, metabolism, and excretion relate more treatment of eczema in infants. Many other topical to weight. Percutaneous drug absorption is there- agents have been reported to be absorbed through fore more important in a very low birthweight infant the skin, causing toxic systemic effects. Perhaps the than in an older child. most notable is the aminoglycoside neomycin, which is never used systemically because of ototoxicity. It Integrity of the epidermis. Percutaneous absorption is often used in the form of a triple antibiotic aerosol is greatly increased if the epidermal barrier is spray (with polymixin and bacitracin), which if used damaged or diseased. Young children with burns liberally on damaged skin can be absorbed. and infants with extensive skin disease (particularly eczema) are therefore at risk. Topical antiseptics. Hexachlorophene was widely used as a topical antiseptic for the prevention of Maturity of the epidermis. The stratum corneum is staphylococcal infection in the newborn. For 20 well developed in the term infant and has similar years it was common practice for infants to be 220 Arch Dis Child: first published as 10.1136/adc.62.3.220 on 1 March 1987. Downloaded from Drug absorption through the skin: a mixed blessing 221 bathed in it. Animal toxicology studies showed that Systemic effect. If a drug can exert its effects in central nervous system damage occurred, with a minute dosage the small amount absorbed through characteristic intramyelin oedema and vacuolation, the skin may be sufficient for systemic effect. A but it was assumed that it was safe in the newborn number of drugs can be administered to adults infant because blood concentrations were so low. through the skin-namely, nitroglycerine for an- Toxicity was only reported in infants with damaged gina, hyoscine for travel sickness, clonidine for or diseased skin. When preterm infants were hypertension, and oestrogens for replacement ther- studied, however, it was clear that absorption was apy (only nitroglycerin is available in the United much greater, and brain lesions identical to those Kingdom). The drug delivery system is in the form seen in poisoned animals were identified in 17 out of of an adhesive patch, containing (from the outside 248 infant autopsies.4 Common features of these 17 to the skin surface) an occlusive backing, a reservoir infants were prematurity and repeated exposure to of the drug, a microporous membrane, and an hexachlorophene. Tragic confirmation that hexa- adhesive. The microporous membrane is less chlorophene is neurotoxic after percutaneous permeable to the drug than the skin and is therefore absorption came when a French manufacturer rate limiting, releasing the drug in a controlled way. accidently marketed a batch of baby talcum powder Such a method of drug administration is not simply a that contained 6-3% hexachlorophene (it should curious gimmick. It is convenient, requiring less have contained none). Altogether 204 infants were frequent dosage than oral administration, produces poisoned, with an illness characterised by a severe more predictable and constant blood concentra- ulcerating nappy rash, fever, convulsions, and tions, can be taken by vomiting patients, and can be coma, of whom 36 died.5 removed at once. Unfortunately, most drugs given Iodine and alcohol cause local and systemic chronically to children (anticonvulsants, antibiotics, effects, and although chlorhexidene is thought to be and bronchodilators) require too high a dose to be safe it is certainly absorbed through the immature effective through the percutaneous route. skin. Poisoning from topical absorption of drugs and Where percutaneous treatment with drugs may copyright. chemicals should always be borne in mind by staff have a part to play is in the treatment of the preterm who care for infants below 28 weeks' gestation. The infant. Small size and immature skin mean that a skin is such a poor barrier that topical application is drug such as theophylline, which could not be given similar to oral administration. The very immature topically to a child, is readily absorbed and reaches infants are usually sick and often die; tragedies such therapeutic blood concentrations.7 Oral treatment as have happened to older infants could easily be with drugs in the small sick infant is unreliable and ascribed to natural illness and pass unnoticed. often contraindicated, while intravenous treatment requires skilled staff to establish and maintain it and http://adc.bmj.com/ Uses of percutaneous absorption is more hazardous and painful. Development of drug delivery systems that would enable preterm Drugs can be topically applied for local or systemic infants to be treated through the skin is an exciting effect.6 possibility. Local effect: The use of local anaesthetic cream is a References Montagna W, Van Scott EJ, Stoughton RB, eds. Pharmnacology welcome innovation. Usually, drugs like lignocaine on September 25, 2021 by guest. Protected antd the skini. Ncw York: Appleton-Century-Crofts, 1972. are poorly absorbed and do not produce local 2 Harpin VA, Rutter N. Barrier properties of the newborn anaesthesia. A new preparation, a eutectic mixture infant's skin. J Pediatr 1983;102:419-25. of 2-5% lignocaine and 2-5% prilocaine as an oil 3 Rayner W. Cyanosis in newly born children caused by aniline water emulsion, is absorbed appreciably when marking ink. Br Med J 1886;i:294. 4 Shuman RM, Leech RW, Aluord EC. Neurotoxicity of hexa- placed under an occlusive dressing. It produces very chlorophene in the human: 1. A clinicopathologic study of 248 good local anaesthesia in children. The cream children. Pediatrics 1974;34:689-95. (EMLA cream, Astra Pharmaceuticals Ltd) is Martin-Bowyer G, Lebreton R, Toga M. Stolley PD, Lock- particularly useful for children who need a vene- hart J. Outbreak of accidental hexachlorophene poisoning in France. Lanicet 1982:2i:91-5. puncture. Disadvantages are that it has to be applied Shaw JE, Urquhart J. Transdermal drug absorption: a nuisance an hour in advance and that the cream under the b>ecomes an opportunity. Br Med J 1981;283:875-6. occlusive dressing is rather messy and is expensive Evans NJ, Rutter N, Hadgraft J, Parr G. Percutaneous (about £1 a time), but these are outweighed by the administration of theophylline in the preterm infant. J Pediatr pain children are spared.
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