• Pharmacokinetics of the skin • Topical preparations:Vehicles for presenting drugs to the skin; Emollients, barrier preparations and dusting powders;Topical analgesics; Antipruritics; A
Trang 1Drugs and the skin
SYNOPSIS
This account is confined to therapy directed
primarily at the skin.
• Pharmacokinetics of the skin
• Topical preparations:Vehicles for presenting
drugs to the skin; Emollients, barrier
preparations and dusting powders;Topical
analgesics; Antipruritics; Adrenocortical
steroids; Sunscreens
• Cutaneous adverse drug reactions
• Individual disorders: Psoriasis.Acne,
Urticaria, Skin infections
It is easy to do more harm than good with
potent drugs, and this is particularly true in
skin diseases Many skin lesions are caused by
systemic or topical use of drugs, often taking
the form of immediate or delayed
hypersensitivity.
Pharmacokinetics
The stratum corneum (superficial keratin layer) is
both the principal barrier to penetration of drugs into
the skin and a reservoir for drugs; a corticosteroid
may be detectable even 4 weeks after a single
application
Drugs are presented in vehicles, e.g cream,
ointment, and their entry into the skin is determined
by the:
• rate of diffusion of drug from the vehicle to the surface of the skin (this depends on the type of vehicle, see below)
• partitioning of the drug between the vehicle and the stratum corneum (a physicochemical feature
of the individual drug) and
• degree of hydration of the stratum corneum (hydration reduces resistance to diffusion of drug)
Vehicles (bases1) are designed to vary in the extent to which they increase the hydration of the stratum corneum; e.g oil-in-water creams promote hydration (see below) Some vehicles also contain substances intended to enhance penetration, e.g squalane (p 306)
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, the scalp, the face until on the scrotum and vulva absorption is very high
Where the skin is damaged by inflammation, burn or exfoliation, 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) Serious systemic toxicity can result from use of occlusive dressing over large areas
A drug readily diffuses from the stratum corneum into the epidermis and then into the dermls, where
1 The chief ingredient of a mixture.
Trang 2it enters the capillary microcirculation of the skin,
and thus the systemic circulation There may be a
degree of presystemic (first-pass) metabolism in the
epidermis and dermis, a desirable feature to the
extent that it limits systemic effects
Transdermal delivery systems are now used to
administer drugs via the skin for systemic effect
(see p 109)
Topical preparations
It is convenient to think of these under the following
headings:
• Vehicles for presenting drugs to the skin
• Emollients, barrier preparations and dusting
powders
• Topical analgesics
• Antipruritics
• Adrenocortical steroids
• Sunscreens
• Miscellaneous substances
VEHICLES FOR PRESENTING DRUGS
TO THE SKIN
The formulations 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
Lotions or wet dressings
Water is the most important component Wet
dressings are generally used to cleanse, cool and
relieve pruritus in acutely inflamed lesions, especially
where there is much exudation, e.g atopic eczema
The frequent reapplication and the cooling effect of
evaporation of the water reduce the inflammatory
response by inducing superficial vasoconstriction
Sodium chloride solution 0.9%, or solutions of
astringent2 substances, e.g aluminium acetate lotion,
or potassium permanganate soaks or compresses of
approx 0.05%, can be used The use of lotions or
2 Astringents are weak protein precipitants, e.g tannins, salts
of aluminium and zinc.
wet dressings over very large areas can reduce body temperature dangerously in the old or the very ill
Shake lotions, e.g calamine lotion, are essentially
a convenient way of applying a powder to the skin (see Dusting powders, p 301) with additional cooling due to evaporation of the water They are contraindicated when there is much exudate because crusts form Lotions, after evaporation, sometimes produce excessive drying of the skin, but this can be reduced if oils are included, as in oily calamine lotion
Creams
These are emulsions either of oil-in-water (washable; cosmetic 'Vanishing' creams) or water-in-oil The water content allows the cream to rub in well A cooling effect (cold creams) is obtained with both groups as the water evaporates
Oil-in-water creams, e.g aqueous cream (see emul-sifying ointment, below), mix with serous discharges and are especially useful as vehicles for water-soluble active drugs They may contain a wetting (surface tension reducing) agent (cetomacrogol) Aqueous cream is also used as an emollient (see below) Various other ingredients, e.g calamine, zinc, may
be added to it
Water-in-oil creams, e.g oily cream, zinc cream, behave like oils in that they do not mix with serous discharges, but their chief advantage over ointments (below) is that the water content makes them easier
to spread and they give a better cosmetic effect They act as lubricants and emollients, and can be used on hairy parts Water-in-oil creams can be used as vehicles for lipid-soluble substances A dry skin is mainly short of water, and oily substances are needed to provide a barrier that reduces evaporation of water, i.e the presence of oils contributes to epidermal hydration
Ointments
Ointments are greasy and are 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
Trang 3they 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:
Water-soluble ointments include mixtures of
mac-rogols and polyethylene glycols; their consistency can
be varied readily They are easily washed off and
are used in burn dressings, as lubricants and as
vehicles that readily allow passage of drugs into the
skin, e.g hydrocortisone
Emulsifying ointment is made from emulsifying
wax (cetostearyl alcohol and sodium lauryl sulphate)
and paraffins Aqueous cream is an oil-in-water
emulsion of emulsifying ointment
Nonemulsifying ointments do not mix with water
They adhere to the skin to prevent evaporation and
heat loss, i.e they can be considered a form of
occlusive dressing (with increased systemic absorption
of active ingredients); skin maceration may occur
Nonemulsifying ointments are helpful in chronic
dry and scaly conditions, such as atopic eczema,
and as vehicles; they are not appropriate where
there is significant exudation They are difficult to
remove except with oil or detergents and are messy
and inconvenient, especially on hairy skin Paraffin
ointment contains beeswax, paraffins and cetostearyl
alcohol
Collodions
Collodions are preparations of cellulose nitrate
(pyroxylin) dissolved in an organic solvent The
solvent evaporates rapidly and the resultant flexible
film is used to hold a medicament, e.g salicylic
acid, in contact with the skin They are irritant and
inflammable and are used to treat only small areas
of skin
Pastes
Pastes, e.g zinc compound paste, are stiff,
semi-occlusive ointments containing insoluble powders
They are very adhesive and give good protection to
circumscribed lesions, preventing spread of active
ingredients to surrounding skin Their powder
content enables them to absorb a moderate amount
T O P I C A L P R E P A R A T I O N S
of discharge They can be used as vehicles, e.g coal tar paste, which is zinc compound paste with 7.5% coal tar Lassar's paste is used as a vehicle for dithranol in the treatment of plaque psoriasis
EMOLLIENTS, BARRIER PREPARATIONS AND DUSTING POWDERS
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
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, cal-amine) The barrier preparations are useful in protecting skin from discharges and secretions (colostomies, napkin rash) but they 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 the victims3 They may consist of titanium oxide in an ointment base with colouring appropriate to the site and the patient
Dusting powders, e.g zinc starch and talc,4 may
3 In the UK, the Red Cross offers a free cosmetic camouflage service through hospital dermatology departments.
4 Talc is magnesium silicate It must not be used for dusting surgical gloves as it causes granulomas if it gets into wounds
or body cavities.
Trang 4cool by increasing the effective surface area of the
skin and they reduce friction between skin surfaces
by their lubricating action Though usefully
absor-bent, they cause crusting if applied to exudative
lesions They may be used alone or as a vehicle for,
e.g fungicides
Gels or jellies are semisolid colloidal solutions or
suspensions used as lubricants and as vehicles for
drugs They are sometimes useful for treating the
scalp
TOPICAL ANALGESICS
Counterirritants and rubefacients are irritants
that stimulate nerve endings in intact skin to relieve
pain in skin (e.g postherpetic), viscera or muscle
supplied by the same nerve root All produce
inflammation of the skin which becomes flushed,
hence rubefacients They are often effective though
their precise mode of action is unknown
The best Counterirritants are physical agents,
especially heat Many drugs, however, have been
used for this purpose and suitable preparations
containing salicylates, nicotinates, menthol, camphor
and capsaicin (depletes skin substance P) are also
available
Topical NSAIDs (see p 290) are used to relieve
musculoskeletal pain
Local anaesthetics Lidocaine and prilocaine are
available as gels, ointments and sprays to provide
reversible block of conduction along cutaneous
nerves (see p 422) Benzocaine and amethocaine
(tetracaine) carry a high risk of sensitisation
Volatile aerosol sprays, beloved by sportspeople,
produce analgesia by cooling and by placebo effect
ANTIPRURITICS
Mechanisms of itch are both peripheral and central.
Impulses pass along the same nerve fibres as those
of pain, but the sensation experienced differs
qualitatively as well as quantitatively from pain In
the CNS endogenous opioid peptides are released
and naloxone can relieve some cases of intractable
itch Local 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 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 (Ha receptor), especially chlor-phenamine and hydroxyzine orally, are used for their sedative or anxiolytic effect (except in urticaria); they should not be applied topically over a prolonged period for risk of allergy
In severe pruritus, a sedative antidepressant may also help The itching of obstructive jaundice may
be relieved by androgens but they may increase the jaundice If obstruction is only partial, colestyramine and phototherapy can be useful 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 Firm pressure with a finger may relieve the itch A vicious cycle can be set up in which itching provokes scratching and scratching leads to skin lesions which itch, as in lichenified eczema Covering the lesion or enclosing it in a medicated bandage so as to prevent any further scratching or rubbing may help
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 antipruritic, probably by weak local anaesthetic action
Calamine and astringents (aluminium acetate, tannic
acid) may help Local anaesthetics do not offer any long-term solution and since they are liable to sensitise the skin they are best avoided; lignocaine
is least troublesome in this respect Topical doxepin
Trang 5T O P I C A L P R E P A R A T I O N S
can be helpful in localised pruritus, but extensive
use induces sedation; like other topical antihistamines
it induces allergic contact dermatitis
Crotamiton, an acaricide, is reputed to have a
specific but unexplained antipruritic action, although
it is irritant
Pruritus ani is managed by attention to hygiene,
emollients, e.g washing with aqueous cream, and a
weak corticosteroid with antiseptic/anticandida
application used as briefly as practicable (some cases
are a form of neurodermatitis) Secondary contact
sensitivity, e.g to local anaesthetics, is common
ADRENOCORTICAL STEROIDS
Actions Adrenal steroids possess a range of actions
(see p 664) 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 this 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 steroids 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
Cortico-steroids are most useful for eczematous disorders
(atopic, discoid, contact) and other inflammatory
conditions save those due to infection Dilute
corticosteroids are useful in psoriasis (see p 309)
Adrenal steroids of highest potency are reserved for recalcitrant dermatoses, e.g lichen simplex, lichen planus, nodular prurigo and discoid lupus ery-thematosus
Topical corticosteroids are of no use for urticarial conditions and are contraindicated in infection, e.g fungal, herpes, impetigo, scabies, because the infection will exacerbate and spread Where ap-propriate, an adrenal steroid formulation may include
an antimicrobial, e.g miconazole, fusidic acid, in infected eczema
Topical corticosteroids should be applied sparingly ('Marmite rather than marmalade') The 'finger tip unit'5 is a useful guide in educating patients (see Table 16.1)
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
• Use for symptom relief and never prophylactically
• Choose the appropriate therapeutic potency (see Table 16.2), i.e 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, i.e a water-based cream for weeping eczema, an ointment for dry scaly conditions.
• Use a combined adrenal steroid/antimicrobial formulation if infection is present.
• Advise the patient to apply the formulation very thinly, just enough to make the skin surface shine slightly.
• Prescribe in small but adequate amounts so that serious overuse is unlikely to occur without the doctor knowing, e.g weekly quantity by group (Table 16.2): very potent 15 g; potent 30 g; others 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.
Choice Corticosteroids are classified according to
their therapeutic potency (efficacy), i.e according to
both drug and % concentration (see Table 16.2)
5 The distance from the tip of the adult index finger to the first crease.
16
Trang 6TABLE 16.1 Finger tip unit dosimetry for topical
corticosteroids
Age
3-6 months
1 -2 years
3-5 years
6-10 years
Adult
Face/
Neck
1
1.5
1.5
2
2.5
Arm/
Hand
1 1.5 2 2.5 Arm — 3 Hand— 1
Leg/
Foot
1.5 2 3 4.5 Foot — 2 Leg—6
Trunk (front)
1 2 3 3.5 7
Trunk (back, including buttocks) 1.5 3 3.5 5 7
TABLE 16.2 Topical corticosteroid formulations
conventionally ranked according to therapeutic
potency
Very potent Clobetasol (0.05%) [also formulations of
diflucortolone (0.3%), halcinonide]
Potent Beclomethasone (0.025%) [also
formulations of betamethasone, budesonide, desonide, desoxymethasone, 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, desoxymethasone, fluocinolone (0.00625%), fluocortolone, fluandrenolone, hydrocortisone plus urea (see p 307)]
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 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, 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
clo-trimazole When the infection is eliminated the
corticosteroid may be continued alone
Intralesional injections are occasionally used to
provide high local concentrations without systemic effects in chronic dermatoses, e.g hypertrophic lichen planus and discoid lupus erythematosus Adverse effects Used with restraint topical cortico-steroids are effective and safe Adverse effects are more likely with formulations ranked therapeutically
as very potent or potent in Table 16.2
• Short-term use Infection may spread.
• Long-term use Skin atrophy can occur within
4 weeks and may or may not be fully reversible
It reflects loss of connective tissue which also causes striae (irreversible) and generally occurs
at sites where dermal penetration is high (face, groins, axillae)
Other effects include: local hirsutism; perioral dermatitis (especially in young women) responds
to steroid withdrawal and may be mitigated by tetracycline by mouth for 4-6 weeks; depigmentation
(local); 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 furcate are rapidly metabolised following cutaneous absorption which may reduce the risk of systemic toxicity Suppression
of the hypothalamic/pituitary axis readily occurs 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.6 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
for-6 Kelly C J et al 2001 Raised cortisol excretion rate in urine and contamination by topical steroids British Medical Journal 322: 594.
Trang 7T O P I C A L P R E P A R A T I O N S
mulation, may cause allergic contact dermatitis and
the possibility of this should be considered where
expected benefit fails to occur
SUNSCREENS
(Sunburn and Photosensitivity)
Ultraviolet (UV) solar radiation consists of:
• UVA (320-400 nanometres): causes skin aging
(damage to collagen) and probably skin cancer
• UVB (290-320 nm): is 1000 times more active
than UVA, acutely causes sunburn and tanning,
and chronically skin cancer and skin aging
• UVC (200-290 nm) is prevented, at present, from
reaching the earth at sea level by the
stratospheric ozone layer, though it can cause
skin injury at high altitude
Protection of the skin
Protection from UV radiation is effected by:
Absorbent sunscreens These organic chemicals
absorb UVB and UVA at the surface of the skin
(generally more effective for UVB)
UVB protection: aminobenzoic acid and
aminobenzoates (padimate-O), cinnamates,
salicylates, camphors
UVA protection: benzophenones (mexenone,
oxybenzone), dibenzoylmethanes
Reflectant sunscreens Inert minerals such as
titanium dioxide, zinc oxide and calamine act as a
physical barrier to UVB and UVA: they are
cos-metically unattractive but the newer micronised
preparations are more acceptable
The performance of a sunscreen is expressed as
the sun protective factor (SPF) which refers to UVB
(UVA is more troublesome to measure and the
protection is indicated by a star rating system with
4 stars providing the greatest) A SPF of 10 means
that the dose of UVB required to cause erythema
must be 10 times greater on protected than on
unprotected skin The SPF should be interpreted
only as a rough guide; consumer use is more
haphazard and less liberal amounts are applied to
the skin in practice Sunscreens should protect against
both UVB and UVA Absorbent and reflectant
components are combined in some preparations The washability of the preparation (including removal by sweat and swimming) is also relevant to efficacy and frequency of application; some penetrate the stratum corneum (padimate-O) and are more persistent than others
Uses Sun screens are no substitute for light-impermeable clothing and sun avoidance They are, however, beneficial in protecting those who are photosensitive due to drugs (below) or to disease, i.e for photodermatoses such as photosensitivity dermatitis, polymorphic light eruption, cutaneous porphyrias and lupus erythematosus Methodical use of sunscreens appears to reduce the incidence of squamous cell carcinoma in vulnerable individuals The lower lip receives a substantial dose of UV but may be neglected when a sunscreen is applied (specific lip-blocks are available) Sunscreens can cause allergic dermatitis or photodermatitis (but not titanium dioxide, though its vehicle may) Treatment of mild sunburn is usually with a lotion such as oily calamine lotion Severe cases are helped by topical corticosteroids NSAIDs, e.g indometacin, can help if given early, by preventing the formation of prostaglandins
Photosensitivity
Drug photosensitivity means that an adverse effect occurs as a result of drug plus light, usually UVA; sometimes even the amount of ultraviolet radiation from fluorescent light tubes is sufficient
Systemically taken drugs that can induce photo-sensitivity are many Of the drug groups given below, those most commonly reported are:7
antimitotics: dacarbazine, vinblastine antimicrobials: demeclocycline, doxycycline,
nalidixic acid, sulphonamides
antipsychotics: chlorpromazine, prochlorperazine cardiac arrhythmic: amiodarone
diuretics: frusemide (furosemide),
chlorothiazide, hydrochlorothiazide
fibric acid derivatives, e.g fenofibrate hypoglycaemic: tolbutamide
' Data from The Medical Letter 1995 37: 35.
Trang 8nonsteroidal anti-inflammatory: piroxicam
psoralens (see below).
Topically applied substances that can produce
photosensitivity include:
pam-aminobenzoic acid and its esters (used as
sunscreens)
coal tar derivatives
psoralens from juices of various plants (e.g.
bergamot oil)
6-methylcoumarin (used in perfumes, shaving
lotions, sunscreens)
There are two forms of photosensitivity:
Phototoxicity, like drug toxicity, is a normal effect
of too high a dose of UV in a subject who has been
exposed to the drug The reaction is like severe
sunburn The threshold returns to normal when the
drug is withdrawn Some drugs, notably NSAIDs,
induce a 'pseudoporphyria', clinically resembling
porphyria cutanea tarda and presenting with skin
fragility, blisters, and milia on sun-exposed areas,
notably the backs of the hands
Photoallergy, like drug allergy, is a cell-mediated
immunological effect that occurs only in some
people, and which may be severe with a small dose
Photoallergy due to drugs is the result of a
photo-chemical reaction caused by UVA in which the drug
combines with tissue protein to form an antigen
Reactions may persist for years after the drug is withdrawn;
they are usually eczematous
Systemic protection, as opposed to application of
drug to exposed areas, should be considered when
the topical measures fail Antimalarials such as
hydroxychloroquine may be effective for short periods
in polymorphic light eruption and in cutaneous
lupus erythematosus
Psoralens (obtained from citrus fruits and other
plants), e.g methoxsalen, are used to induce
photo-chemical reactions in the skin After topical or
systemic administration of the psoralen and
sub-sequent exposure to UVA there is an erythematous
reaction that goes deeper than ordinary sunburn
and that may reach its maximum only after 48 h
(sunburn maximum is 12-24 h) Melanocytes are
activated and pigmentation occurs over the following week This action is used to repigment areas of disfiguring depigmentation, e.g vitiligo in black-skinned persons
In the presence of UVA the psoralen interacts with DNA, forms thymine dimers, and inhibits DNA synthesis Psoralen plus UVA (PUVA) treatment is used chiefly in severe psoriasis (a disease charac-terised by increased epidermal proliferation), and cutaneous T cell lymphoma
Severe adverse reactions can occur with psoralens
and ultraviolet radiation, including increased risk
of skin cancer (due to mutagenicity inherent in their action), cancer of the male genitalia, cataracts and accelerated skin aging; the treatment is used only
by specialists
Chronic exposure to sunlight induces wrinkling
and yellowing due to the changes in the dermal connective tissue Topical retinoids are widely used in an attempt to reverse some of these tissue changes
MISCELLANEOUS SUBSTANCES Keratolytics are used to destroy unwanted tissue,
including warts and corns Great care is obviously necessary to avoid ulceration They include trichloracetic acid, salicylic acid and many others Resorcinol and sulphur are mild keratolytics used
in acne
Squalane is a saturated hydrocarbon insoluble in
water but soluble in sebum It therefore penetrates the skin and is a vehicle for delivery of agents; it is water repellent and is used for incontinence and prevention of bed sores It appears in mixed formulations
Salicylic acid may enhance the efficacy of a topical
steroid in hyperkeratotoic disorders
Tars are mildly antiseptic, antipruritic and they
inhibit keratinisation in an ill-understood way They are safe in low concentrations and are used in psoriasis Photosensitivity occurs There are very many preparations, which usually contain other
Trang 9C U T A N E O U S A D V E R S E D R U G R E A C T I O N S
substances, e.g coal tar and salicylic acid ointment;
it is sometimes useful to add an adrenal steroid
Ichthammol is a sulphurous tarry distillation
product of fossilised fish (obtained in the Austrian
Tyrol); it has a weaker effect than coal tar
Zinc oxide provides mild astringent, barrier and
occlusive actions
Calamine is basic zinc carbonate that owes its pink
colour to added ferric oxide It has a mild astringent
action and is used as a dusting powder and in shake
and oily lotions It is of limited value
Urea is used topically to assist skin hydration, e.g
in ichthyosis
Insect repellents, e.g against mosquitoes, ticks,
fleas, such as deet (diethyl toluamide), dimethyl
phthalate These are applied to the skin and repel
insects principally by vaporisation They must be
applied to all exposed skin, and sometimes also to
clothes if their objective is to be achieved (some
damage plastic fabrics and spectacle frames) Their
duration of effect is limited by the rate at which they
vaporise (skin and ambient temperature), by washing
off (sweat, rain, immersion) and by mechanical
factors causing rubbing (physical activity) They can
cause allergic and toxic effects, especially with
prolonged use About 10% is absorbed Plainly the
vehicle in which they are applied is also important,
and an acceptable substance achieving persistence
of effect beyond a few hours has yet to be developed
But the alternative of spreading an insecticide in
the environment causing general pollution and
indiscriminate insect kill is unacceptable Selective
environmental measures against some insects, e.g
mosquitoes, are sometimes feasible
Benzyl benzoate may be used on clothes; it
resists one or two washings
the same drug may produce different rashes in different people
Irritant or allergic contact dermatitis is eczematous
and is often caused by antimicrobials, local ana-esthetics, topical antihistamines, and increasingly commonly by topical corticosteroids It is often due
to the vehicle in which the active drug is applied, particularly a cream
Reactions to systemically administered drugs are
commonly erythematous, like those of measles, scarlatina or erythema multiforme They give no useful clue as to the cause They commonly occur during the first 2 weeks of therapy, but some immu-nological reactions may be delayed for months Patients with the acquired immunodeficiency syndrome (AIDS) have an increased risk of adverse reactions, which are often severe
Though drugs may change, the clinical problems remain depressingly the same: a patient develops a rash; he is taking many different tablets; which, if any, of these caused his eruption, and what should
be done about it? It is no answer simply to stop all drugs, though the fact that this can often be done casts some doubt on the patient's need for them in the first place All too often potentially valuable drugs are excluded from further use on totally inadequate grounds Clearly some guidelines are needed but no simple set of rules exists that can cover this complex subject 8
The following questions should be asked in every case:
• Can other skin diseases be excluded?
• Are the skin changes compatible with a drug cause?
• Which drug is most likely to be responsible?
• Are any further tests worthwhile?
• Is any treatment needed?
These questions are deceptively simple but the answers are often difficult
Cutaneous adverse drug
reactions
DRUG-SPECIFIC RASHES
Despite great variability, some hints at drug-specific
Drugs applied locally or taken systemically often
cause rashes These take many different forms and
8 Hardie R A, Savin J A1979 British Medical Journal: 1935, to whom we are grateful for this quotation and classification.
Trang 10or characteristic rashes from drugs taken systemically,
can be discerned, as follows:
Acne and pustular: e.g corticosteroids,
androgens, ciclosporin, penicillins
Allergic vasculitis: e.g sulphonamides, NSAIDs,
thiazides, chlorpropamide, phenytoin, penicillin,
retinoids
Anaphylaxis: x-ray contrast media, penicillins,
ACE inhibitors
Bullous pemphigoid: frusemide (and other
sulphonamide-related drugs), ACE inhibitors,
penicillamine, penicillin, PUVA therapy
Eczema: e.g penicillins, phenothiazines.
Exanthematic/maculopapular reactions are the
most frequent; unlike a viral exanthem the eruption
typically starts on the trunk; the face is relatively
spared Continued use of the drug may lead to
erythroderma They commonly occur at about the
ninth day of treatment (or day 2-3 in previously
exposed patients), although onset may be delayed
until after treatment is completed; causes include
antimicrobials, especially ampicillin,
sulphonamides and derivatives (sulphonylureas,
frusemide (furosemide) and thiazide diuretics)
Morbilliform (measles-like) eruptions typically
recur on rechallenge
Erythema multiforme: e.g NSAIDs,
sulphonamides, barbiturates, phenytoin
Erythema nodosum: e.g sulphonamides, oral
contraceptives, prazosin
Exfoliative dermatitis and erythroderma: gold,
phenytoin, carbamazepine, allopurinol, penicillins,
neuroleptics, isoniazid
Fixed eruptions are eruptions that recur at the
same site, often circumoral, with each
administration of the drug: e.g phenolphthalein
(laxative self-medication), sulphonamides, quinine
(in tonic water), tetracycline, barbiturates,
naproxen, nifedipine
Hair loss: e.g cytotoxic anticancer drugs,
acitretin, oral contraceptives, heparin,
androgenic steroids (women), sodium valproate,
gold
Hypertrichosis: corticosteroids, ciclosporin,
doxasosin, minoxidil
Lichenoid eruption: e.g p-adrenoceptor blockers,
chloroquine, thiazides, frusemide (furosemide),
captopril, gold, phenothiazines
Lupus erythematosus: e.g hydralazine, isoniazid,
procainamide, phenytoin, oral contraceptives, sulfazaline
Purpura: e.g thiazides, sulphonamides,
sulphonylureas, phenylbutazone, quinine Aspirin induces a capillaritis (pigmented purpuric dermatitis)
Photosensitivity: see above.
Pemphigus: e.g penicillamine, captopril,
piroxicam, penicillin, rifampicin
Pruritus unassociated with rash: e.g oral
contraceptives, phenothiazines, rifampicin (cholestatic reaction)
Pigmentation: e.g oral contraceptives (chloasma
in photosensitive distribution), phenothiazines, heavy metals, amiodarone, chloroquine (pigmentations of nails and palate, depigmentation
of the hair), minocycline
Psoriasis may be aggravated by lithium and
antimalarials
Scleroderma-like: bleomycin, sodium valproate,
tryptophan contaminants (eosinophila-myalgia syndrome)
Serum sickness: immunoglobulins and other
immunomodulatory blood products
Stevens-Johnson syndrome and toxic epidermal
necrolysis:9 e.g anticonvulsants, sulphonamides, aminopenicillins, oxicam NSAIDs, allopurinol, chlormezanone, corticosteroids
Urticaria and angioedema: e.g penicillins, ACE
inhibitors, gold, NSAIDs, e.g aspirin, codeine
Recovery after withdrawal of the causative drug
generally begins in a few days, but lichenoid reactions may not improve for weeks
Diagnosis The patient's drug history may give clues Reactions are commoner during early therapy (days) than after the drug has been given for months Diagnosis by readministration of the drug (challenge)
is safe with fixed eruptions, but not with others, particularly those that may be part of a generalised effect, e.g vasculitis Patch and photopatch tests are useful in contact dermatitis, for they reproduce the causative process but should be performed only by those with special experience Fixed drug eruptions can sometimes be reproduced by patch testing with the drug over the previously affected site
9 Roujeau C-J et al 1995 New England Journal of Medicine 333:1600