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.

Fig. 17.1 Principal pathways operating during topical drug delivery.

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:

• Physicochemical features: lipophilic drugs can utilise the intracellular route because they readily cross cell walls, whereas hydrophilic drugs principally take the intercellular route, diffusing in fluid-filled spaces between cells.

• Molecular size: most therapeutic agents suitable for topical delivery measure 100–500 Da.

Drugs are presented in vehicles (bases ¹), 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.

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.

Emollients and barrier preparations

Emollients

hydrate the skin, and soothe and smooth dry scaly conditions. They need to be applied frequently as their effects are short lived. There is a variety of preparations but aqueous cream, in addition to its use as a vehicle (above), is effective when used as a soap substitute. Various other ingredients may be added to emollients, e.g. menthol, camphor or phenol for its mild antipruritic effect, and zinc and titanium dioxide as astringents.³

Barrier preparations

Many different kinds have been devised for use in medicine, in industry and in the home to reduce dermatitis. They rely on water-repellent substances, e.g. silicones (dimethicone cream), and on soaps, as well as on substances that form an impermeable deposit (titanium, zinc, calamine). The barrier preparations are useful in protecting skin from discharges and secretions (colostomies, nappy rash), but are ineffective when used under industrial working conditions. Indeed, the irritant properties of some barrier creams can enhance the percutaneous penetration of noxious substances. A simple after-work emollient is more effective.

Silicone sprays and occlusives, e.g. hydrocolloid dressings, may be effective in preventing and treating pressure sores. Masking creams (camouflaging preparations) for obscuring unpleasant blemishes from view are greatly valued by patients.⁴ They may consist of titanium oxide in an ointment base with colouring appropriate to the site and the patient.

Topical analgesics

Counterirritants and rubefacients

are irritants that stimulate nerve endings in intact skin to relieve pain in skin (e.g. post-herpetic), viscera or muscle supplied by the same nerve root. All produce inflammation of the skin, which becomes flushed – hence the term ‘rubefacients’. The best counterirritants are physical agents, especially heat. Many compounds have been used for this purpose and suitable preparations contain salicylates, nicotinates, menthol, camphor and capsaicin. Specific transient receptor potential (TRP) cation channels involved in sensory perception in skin can be stimulated by these drugs. The moderate heat receptor TRPV1 is sensitive to capsaicin as well as moderate heat (42–52°C), whereas TRPM8 is stimulated specifically by temperatures below 26°C and by menthol.

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.

Generalised pruritus

In the absence of a primary dermatosis it is important to search for an underlying cause, e.g. iron deficiency, liver or renal failure, and lymphoma, but there remain patients in whom the cause either cannot be removed or is not known. Antihistamines (H₁-receptor), especially chlorphenamine and hydroxyzine orally, are used for their sedative or anxiolytic effect (except in urticaria); they should not be applied topically over a prolonged period because of risk of allergy. In severe pruritus, a sedative antidepressant may also help.

The itching of obstructive jaundice might be relieved by the anion exchange resin colestyramine, an endoscopically placed nasobiliary drain, or phototherapy with ultraviolet B light. Naltrexone offers short-term relief of the pruritus associated with haemodialysis.

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.

Pruritus ani

is managed by attention to any underlying disease, e.g. haemorrhoids, parasites, and hygiene. Emollients, e.g. washing with aqueous cream and a weak corticosteroid with antiseptic/anticandida application, may be used briefly to settle any acute eczema or superinfection. Some cases are a form of neurodermatitis, and an antihistamine with anti-anxiolytic properties, e.g. hydroxyzine, or a low-dose sedative antidepressant, e.g. doxepin, and mirtazapine, may be helpful. Secondary contact sensitivity, e.g. to local anaesthetics, must be considered.

Adrenocortical steroids

Actions

Adrenal steroids possess a range of actions, of which the following are relevant to topical use:

• Inflammation is suppressed, particularly when there is an allergic factor, and immune responses are reduced.

• Antimitotic activity suppresses proliferation of keratinocytes, fibroblasts and lymphocytes (useful in psoriasis, but also causes skin thinning).

• Vasoconstriction reduces ingress of inflammatory cells and humoral factors to the inflamed area; this action (blanching effect on human skin) has been used to measure the potency of individual topical corticosteroids (see below).

Penetration into the skin is governed by the factors outlined at the beginning of the chapter. The vehicle should be appropriate to the condition being treated: an ointment for dry, scaly conditions; a water-based cream for weeping eczema.

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.

Table 17.1 Fingertip unit dosimetry for topical corticosteroids (distance from the tip of the adult index finger to the first crease)

Guidelines for the use of topical corticosteroids

• Use for symptom relief and not prophylactically.

• Choose the appropriate therapeutic potency (Table 17.2), e.g. mild for the face. In cases likely to be resistant, use a very potent preparation, e.g. for 3 weeks, to gain control, after which change to a less potent preparation.

• Choose the appropriate vehicle, e.g. a water-based cream for weeping eczema, an ointment for dry, scaly conditions.

• Prescribe in small but adequate amounts so that serious overuse is unlikely to occur without the doctor knowing, e.g. weekly quantity by group (see Table 17.2): very potent 15 g; potent 30 g; other 50 g.

• Occlusive dressing should be used only briefly. Note that babies’ plastic pants are an occlusive dressing as well as being a social amenity.

• If it’s wet, dry it; if it’s dry, wet it. The traditional advice contains enough truth to be worth repeating.

• One or two applications a day are all that is usually necessary.

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.