Drugs and the skin

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Chapter 17 Drugs and the skin

Dermal pharmacokinetics

Human skin is a highly efficient self-repairing barrier that permits terrestrial life by regulating heat and water loss while preventing the ingress of noxious chemicals and microorganisms. A drug applied to the skin may diffuse from the stratum corneum into the epidermis and then into the dermis, to enter the capillary microcirculation and thus the systemic circulation (Fig. 17.1). The features of components of the skin in relation to drug therapy, whether for local or systemic effect, are worthy of examination.

The principal barrier to penetration resides in the multiple-layered lipid-rich stratum corneum. The passage of a drug through this layer is influenced by its:

Drugs are presented in vehicles (bases1), designed to vary in the extent to which they increase hydration of the stratum corneum; e.g. oil-in-water creams promote hydration (see below). Increasing the water content of the stratum corneum via occlusion or hydration generally increases the penetration of both lipophilic and hydrophilic materials. This may be due to an increased fluid content of the lipid bilayers. The stratum corneum and stratum granulosum layers become more similar with hydration and occlusion, thus lowering the partition coefficient of the molecule passing through the interface. Some vehicles also contain substances intended to enhance penetration by reducing the barrier properties of the stratum corneum, e.g. fatty acids, terpenes, surfactants. Encapsulation of drugs into vesicular liposomes may enhance drug delivery to specific compartments of the skin, e.g. hair follicles.

Absorption through normal skin varies with site. From the sole of the foot and the palm of the hand it is relatively low; it increases progressively on the forearm, trunk, head and neck; and on the scrotum and vulva absorption is very high. Where the skin is damaged by inflammation, burn or exfoliation, barrier function is reduced and absorption is further increased.

If an occlusive dressing (impermeable plastic membrane) is used, absorption increases by as much as 10-fold (plastic pants for babies are occlusive, and some ointments are partially occlusive). Systemic toxicity can result from use of occlusive dressing over large areas.

Transdermal delivery systems are now used to administer drugs via the skin for systemic effect; the advantages and disadvantages of this route are discussed on page 88.

Vehicles for presenting drugs to the skin

Dermatological formulations tend to be classified by their physical properties. The formulations below are described in order of decreasing water content. All water-based formulations must contain preservatives, e.g. chlorocresol, but these rarely cause allergic contact dermatitis.

Ointments

Ointments are greasy and thicker than creams. Some are both lipophilic and hydrophilic, i.e. by occlusion they promote dermal hydration, but are also water miscible. Other ointment bases are composed largely of lipid; by preventing water loss they have a hydrating effect on skin and are used in chronic dry conditions. Ointments contain fewer preservatives and are less likely to sensitise. There are two main kinds:

Solid preparations

Solid preparations such as dusting powders, e.g. zinc starch and talc,2 may cool by increasing the effective surface area of the skin and they reduce friction between skin surfaces by their lubricating action. Although usefully absorbent, they cause crusting if applied to exudative lesions. They may be used alone or as specialised vehicles for, e.g., fungicides.

Antipruritics

Mechanisms of itch are both peripheral and central. Itch (at least histamine-induced itch) is not a minor or low-intensity form of pain. Cutaneous histamine injection stimulates a specific group of C fibres with very low conduction speeds and large fields, distinct from those that signal pain. Second-order neurones then ascend via the spinothalamic tract to the thalamus. In the central nervous system, endogenous opioid peptides are released (the opioid antagonist naloxone can relieve some cases of intractable itch). Itch signalling appears to be under tonic inhibition by pain. If pain after histamine injection is reduced by opioid then itch results and, if pain is ablated by lidocaine, itch sensation increases. Prolonged inflammation in the skin may lead to peripheral and central sensitisation, thus leading non-itchy stimuli to be reinterpreted as itch.

Liberation of histamine and other autacoids in the skin also contributes and may be responsible for much of the itch of urticarial allergic reactions. Histamine release by bile salts may explain some, but not all, of the itch of obstructive jaundice. It is likely that other chemical mediators, e.g. serotonin, progesterone metabolites, endogenous opioids and prostaglandins, are involved.

Localised pruritus

Scratching or rubbing seems to give relief by converting the intolerable persistent itch into a more bearable pain. A vicious cycle can be set up in which itching provokes scratching, and scratching leads to infected skin lesions that itch, as in prurigo nodularis. Covering the lesion or enclosing it in a medicated bandage so as to prevent any further scratching or rubbing may help. Multiple intralesional triamcinolone injections and thalidomide may be used in recalcitrant cases of prurigo nodularis.

Topical corticosteroid preparations are used to treat the underlying inflammatory cause of pruritus, e.g. in eczema. A cooling application such as 0.5–2% menthol in aqueous cream is temporarily antipruritic.

Calamine and astringents (aluminium acetate, tannic acid) may help. Local anaesthetics do not offer any long-term solution and, as they are liable to sensitise the skin, they are best avoided. Topical doxepin can be helpful in localised pruritus but extensive use induces sedation and may cause allergic contact dermatitis.

Adrenocortical steroids

Uses

Adrenal corticosteroids should be considered a symptomatic and sometimes curative, but not preventive, treatment. Ideally a potent steroid (see below) should be given only as a short course and reduced as soon as the response allows. Corticosteroids are most useful for eczematous disorders (atopic, discoid, contact), whereas dilute corticosteroids are especially useful for flexural psoriasis (where other therapies are highly irritant). Adrenal corticosteroids of highest potency are reserved for recalcitrant dermatoses, e.g. lichen simplex, lichen planus, nodular prurigo and discoid lupus erythematosus.

Topical corticosteroids should be applied sparingly. The ‘fingertip unit’5 is a useful guide in educating patients (Table 17.1). The difficulties and dangers of systemic adrenal steroid therapy are sufficient to restrict such use to serious conditions (such as pemphigus and generalised exfoliative dermatitis) not responsive to other forms of therapy.

Guidelines for the use of topical corticosteroids

Table 17.2 Topical corticosteroid formulations conventionally ranked according to therapeutic potency

Potency Formulations
Very potent Clobetasol (0.05%); also formulations of diflucortolone (0.3%), halcinonide
Potent Beclometasone (0.025%); also formulations of betamethasone, budesonide, desoximetasone, diflucortolone (0.1%), fluclorolone, fluocinolone (0.025%), fluocinonide, fluticasone, hydrocortisone butyrate, mometasone (once daily), triamcinolone
Moderately potent Clobetasone (0.05%); also formulations of alclometasone, clobetasone, desoximetasone, fluocinolone (0.00625%), fluocortolone, fluandrenolone
Mildly potent Hydrocortisone (0.1–1.0%); also formulations of alclomethasone, fluocinolone (0.0025%), methylprednisolone

Important note: the ranking is based on agent and its concentration; the same drug appears in more than one rank.

Choice

Topical corticosteroids are classified according to both drug and potency, i.e. therapeutic efficacy in relation to weight (see Table 17.2). Their potency is determined by the amount of vasoconstriction a topical corticosteroid produces (McKenzie skin-blanching test6) and the degree to which it inhibits inflammation. Choice of preparation relates both to the disease and the site of intended use. High-potency preparations are commonly needed for lichen planus and discoid lupus erythematosus; weaker preparations (hydrocortisone 0.5–2.5%) are usually adequate for eczema, for use on the face and in childhood.

When a skin disorder requiring a corticosteroid is already infected, a preparation containing an antimicrobial is added, e.g. fusidic acid or clotrimazole. When the infection has been eliminated, the corticosteroid may be continued alone. Intralesional injections are used occasionally to provide high local concentrations without systemic effects in chronic dermatoses, e.g. hypertrophic lichen planus and discoid lupus erythematosus.

Other effects include:

local hirsutism; perioral dermatitis (especially in young women), which responds to steroid withdrawal and may be mitigated by tetracycline by mouth for 4–6 weeks; depigmentation (local); monomorphous acne (local). Potent corticosteroids should not be used on the face unless this is unavoidable. Systemic absorption can lead to all the adverse effects of systemic corticosteroid use. Fluticasone propionate and mometasone furoate are rapidly metabolised following cutaneous absorption, which may reduce the risk of systemic toxicity. Suppression of the hypothalamic–pituitary axis occurs readily with overuse of the very potent agents, and when 20% of the body is under an occlusive dressing with mildly potent agents.

Other complications of occlusive dressings include infections (bacterial, candidal) and even heat stroke when large areas are occluded. Antifungal cream containing hydrocortisone and used for vaginal candidiasis may contaminate the urine and misleadingly suggest Cushing’s syndrome.7

Applications to the eyelids may get into the eye and cause glaucoma.

Rebound exacerbation of the disease can occur after abrupt cessation of therapy. This can lead the patient to reapply the steroid and so create a vicious cycle.

Allergy. Corticosteroids, particularly hydrocortisone and budesonide, or other ingredients in the formulation, may cause allergic contact dermatitis. The possibility of this should be considered when expected benefit fails to occur, e.g. varicose eczema.

Sunscreens (sunburn and photosensitivity)

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