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Getting to know your dermatology drugs

Getting to know your dermatology drugs

Retinoids

The term vitamin A refers to a group of compounds that are necessary for cellular differentiation, organ development and production of the visual pigment in the retina. These compounds also influence immune function and have some anti-inflammatory activity. Except in the retina, the main active form is probably all-trans retinoic acid (tretinoin), the level of which in the cell is dependent on complex interconversions with closely related analogues and various binding and storage proteins. Retinoic acid receptor (RAR) subtypes mediate its effects. There are other receptors, eg retinoic acid receptor (RXR), which bind an isomer, 9-cis retinoic acid. This incompletely understood system is utilised therapeutically by administration of the following agents generically termed retinoids.

Tretinoin is used topically in the treatment of acne and other skin disorders.

Isotretinoin (13-cis retinoic acid) is a stereoisomer of all-trans retinoic acid, which probably acts by conversion to it but has less toxicity. It is given orally in the treatment of cystic acne. Like all vitamin A analogues it is teratogenic, but in contrast to etretinate and acitretin relatively rapid elimination permits the safe initiation of pregnancy from 1 month after stopping the drug.

Etretinate is a synthetic retinoid. It is absorbed after oral administration to the extent of about 50%. It is a prodrug, being an ethyl ester of the active acid acitretin. Etretinate is stored in fat and cleared very slowly from the body over months. It is teratogenic and the very long, but undefined duration of its continued presence in the body after discontinuation of dosing imposes the need to avoid pregnancy. The arbitrarily mandated period for this is 2 years.

Acitretin is an active metabolite of etretinate. It is has been used orally in the treatment of psoriasis and disorders of keratinisation such as severe ichthyosis. It is metabolised more rapidly than etretinate but unfortunately there is some conversion to that long-lasting ester. This esterification step is enhanced by alcohol and thus alcohol consumption during and for a period after treatment with acitretin will increase the subsequent risk to a pregnancy. The necessity to avoid pregnancy after stopping acitretin is therefore for 2 years as for etretinate.

More recent potent synthetic analogues known as arotinoids (adapalene and tazarotine) differ more markedly in structure from retinoic acid. They bind to retinoic acid receptors with different affinities for the different subtypes. Future developments may produce agents with selective activity and consequent reduced toxicity.

In Australia, oral retinoids can only be prescribed by dermatologists.

All systemic retinoids have substantial toxicity manifested as:

           cheilitis

           dryness of nose, eyes and face

           scaling of palms and soles and softening of nails

           loss of hair

           joint and muscle pain and headache

           hypertriglyceridaemia

           hypercholesterolaemia and reduced high-density lipoprotein cholesterol

           photosensitivity.

Most significantly, they are teratogenic and must not be used in women who may conceive. Because of prolonged retention of etretinate in the body, pregnancy should be prevented for 2 years after the drug is ceased. A similar caution applies to acitretin since it is in part metabolised to etretinate. Comprehensible, practical advice on the need and means for fertility control is essential.

Calcipotriol

Calcipotriol is an analogue of 1,25-dihydroxy cholecalciferol, the active form of vitamin D. It shares with the vitamin affinity for an intracellular receptor, combination with which reduces epidermal proliferation and inhibits interleukin 1 and T cell function. It is used topically as an ointment or cream in local treatment of plaque psoriasis. Adverse effects include erythema and irritation. The theoretical possibility of hypercalcaemia, renal calculi and ectopic calcification due to absorption is not a practical problem unless it is applied to large areas of inflamed skin. It should not be used on the face or flexures.

Corticosteroids

The naturally occurring hydrocortisone has anti-inflammatory and immunosuppressive effects, which are useful in treating many skin disorders. Modifications of the hydrocortisone molecule have produced a large number of agents with varying anti-inflammatory potency, which may be used systemically or topically.

The potency of topically applied corticosteroids is assayed by the degree of vasoconstriction they produce when applied under an occlusive dressing. This depends on the concentration used, the intrinsic activity of the compound and its ability to penetrate the barrier of the epidermis which may be influenced by the vehicle in which it is applied. This assay permits topical corticosteroid preparations to be arranged in groups with equivalent potency in the assay. Such a ranking corresponds in a general way with clinical effectiveness although the correspondence is only approximate and leaves room for individual preference.

Adverse effects of topical corticosteroids may be due to local effects on the skin at the site of application or to systemic response to absorbed drug. The former consists of loss of dermal collagen (leading to skin atrophy, striae, fragility and easy bruising), telangiectasia and perioral dermatitis. Their intensity is proportional to the therapeutic effect and thus increases with the potency of the preparation.

Penetration of corticosteroid to the dermis is greater on the face, the scrotum and where conditions mimic application under occlusion, ie flexures and intertriginous areas. The use of the more potent corticosteroids on these sites therefore carries greater risk of local damage and should be avoided. With greater potency, there is increased risk of rebound on withdrawal and of tachyphylaxis.

Absorption of more potent agents applied to large areas may cause suppression of the hypothalamic pituitary axis and other usual complications associated with systemic corticosteroid administration.

Antihistamines

This term applies to competitive antagonists at the histamine H1-receptor. They may be classified according to chemical structure but a more practical division is into sedating and nonsedating groups, the latter owing this property to exclusion by the blood-brain barrier. Some agents have substantial antimuscarinic activity.

Choice of drug in this class will depend largely on whether some degree of central nervous system (CNS) depression is desirable, eg in suppressing itch, or is an undesirable accompaniment of the antihistaminic action. They have important but limited uses in dermatology, especially in urticaria and as antipruritics.

Antimicrobial agents

Skin infections may require treatment with a range of antibiotics but only those with a particular dermatological use will be considered here. For a more general discussion see Principles of antimicrobial use.

Topical administration favours development of resistance in skin flora and is prone to cause hypersensitivity in the patient. It should thus be employed with caution especially for agents with important indications by systemic routes of administration.

Mupirocin is a valuable topical antibiotic which is not used systemically. It is active mainly against Gram-positive aerobes, including most strains of staphylococci and streptococci. However, the emergence of high-level mupirocin-resistance in methicillin-resistant Staphylococcus aureus (MRSA) has been reported in Western Australia.

Topical mupirocin is used in the treatment of bacterial skin infections such as impetigo and infected dermatitis. Nonmacrogol based formulations are used intranasally to eradicate staphylococcal carriage.

Tetracycline itself has a very broad-spectrum but acquired resistance is common in many species of organisms.

Modifications of the basic molecule has produced many drugs, including doxycycline and minocycline, which have longer half-lives and greater potency on a weight basis but do not differ appreciably in spectrum and exhibit cross-resistance.

All tetracyclines cause some gastrointestinal symptoms and may lead to photosensitivity. They damage enamel of unerupted teeth and should not be given to children under 8 years. They should be avoided in pregnancy for the same reason but also because of the rare occurrence of hepatic necrosis in pregnant women. Except for doxycycline and minocycline they are renally excreted, and may accumulate in renal failure and further aggravate renal impairment. Minocycline is particularly prone to cause dizziness and ataxia but such symptoms can occur with others of the group and they can rarely cause benign intracranial hypertension. Minocycline in particular can cause abnormal pigmentation of mucosae and of tissues, including scars. As with all broad-spectrum antibiotics, overgrowth of resistant organisms occurs, particularly fungi in the case of tetracyclines.

They are frequently used in treatment of acne where, like other antibiotics in this indication, they probably act by suppressing proliferation of Propionibacterium acnes. The rationale for use in rosacea is uncertain. Tetracyclines also have anti-inflammatory effects, mediated by inhibition of neutrophil chemotaxis and phagocytosis and suppression of granuloma formation, and possibly a direct effect on vascular endothelium, which may be beneficial in a variety of skin conditions

Erythromycin is a macrolide active against Gram positive organisms and some anaerobes. It is used both topically (as a 2% gel or solution) and systemically in treatment of acne and rosacea. This antibiotic is suitable for use in pregnancy, see Drug use in pregnancy and breastfeeding.

Clindamycin is active against Propionibacterium acnes. It is used topically as a lotion or gel in acne and rosacea. Oral administration carries a risk of producing pseudomembranous colitis.

Metronidazole is active against anaerobes but not Propionibacterium acnes. It is administered topically in rosacea but the mode of its action is unknown, although there is some evidence that metronidazole is effective against the Demodex mite.

Dapsone, a sulphone for treatment of leprosy, and sulfapyridine, a sulfonamide, are used in dermatology for anti-inflammatory effects in a variety of inflammatory skin conditions. Dapsone is of specific value in dermatitis herpetiformis and is used in such noninfective inflammatory conditions as pyoderma gangrenosum, pemphigus and bullous pemphigoid. Dapsone, in the doses employed, has a considerable incidence of haemolysis (especially in glucose-6-phosphate dehydrogenase (G6PD) deficiency), methaemoglobinaemia and rash. Rarer adverse consequences are blood dyscrasias, severe skin reactions, hepatitis, fever and malaise, which may occur alone or as part of a generalised hypersensitivity reaction.

Antifungal agents

Topical application of antifungal agents is effective for superficial cutaneous infections but is not for those involving hair or nails.

There is a large number of agents used in this way. Imidazole derivatives bifonazole, clotrimazole, econazole, miconazole and ketoconazole have a broad-spectrum of antifungal activity achieved by inhibition of ergosterol synthesis and consequent disruption of the fungal membrane. After topical application they efficiently reach keratinocytes but there is no appreciable systemic absorption. Topical imidazole preparations can be irritating but local sensitisation is uncommon.

Tolnaftate is a thiocarbamate active against dermatophytes but not Candida species. Its mode of action is unknown.

Terbinafine is an allylamine, which inhibits ergosterol synthesis at an earlier stage than the azoles. It is fungicidal for dermatophytes, and is also active against Pityrosporum species but less clearly useful against Candida species.

Nystatin and amphotericin are polyenes active against Candida species but not dermatophytes. Various other compounds such as undecenoic acid and the keratolytics benzoic acid and salicylic acid are used to treat tinea. Amorolfine is a morpholine with a broad-spectrum, which inhibits ergosterol synthesis at different sites to other antifungals. It is used as a lacquer painted onto abraded nails once or twice weekly for 6 to 12 months to treat onychomycosis.

Systemic administration of antifungals is employed to treat deep-seated infections and those involving nail and hair. The imidazole, ketoconazole was the first orally active azole but has been largely superseded by the triazoles (itraconazole and fluconazole) due to the rare occurrence of liver damage, inhibition of androgen synthesis and interactions with many drugs due to inhibition of the cytochrome P450 (3A4) pathway. The triazoles are absorbed after oral administration. Both are effective against Candida species but itraconazole is more active against filamentous fungi.

Terbinafine, an allylamine, is well absorbed when given by mouth and concentrates in the stratum corneum, including the nail bed. Gastrointestinal disturbance occurs in approximately 5% of patients and rare adverse effects include hepatitis, toxic epidermal necrolysis, blood disorders and a reversible loss of taste.

Griseofulvin was the first orally effective agent against dermatophytes. It is less effective than the azoles and allylamines but is much cheaper. It is poorly soluble and absorption is assisted by preparations with very small particle size or by ingesting with a fatty meal. It is taken up by keratinocytes and exerts a fungistatic action in the stratum corneum which continues in hair and nails. It must be given for sufficient time for the quiescent but viable spores in the keratin to be shed. It is inactive against Candida species.

Antimalarial agents

Chloroquine and hydroxychloroquine are used as immunomodulating agents in lupus erythematosus and other connective tissue disorders. Their mode of action in these diseases is unknown. The most alarming adverse effect is a dose-related permanent retinopathy, and regular monitoring by an ophthalmologist is necessary, see Points on eye testing and antimalarials. They are category D drugs and their use should be avoided in pregnancy, see Drug use in pregnancy and breastfeeding.

Antiviral agents

Aciclovir is an analogue of guanosine that is phosphorylated preferentially by herpes simplex viral thymidine kinase to then inhibit the DNA polymerase. It may be administered topically, or systemically by oral or intravenous routes. When taken orally, it is poorly and variably absorbed. Its prodrug, valaciclovir, is its L-valyl ester which is much better absorbed after hydrolysis, resulting in higher and more reliable blood levels of aciclovir and permitting less frequent dosing. Famciclovir is a prodrug of penciclovir, which has the same mode of action as aciclovir. Penciclovir is also administered topically. They are all generally well tolerated.

Cytotoxics and immunosuppressants

Some representatives of this group of drugs have an important role in management of skin conditions.

Azathioprine is converted in the body to 6-mercaptopurine, an inhibitor of purine synthesis and an immunosuppressant. It also has potent anti-inflammatory properties. It is used alone or in combination with other agents, usually corticosteroids. Toxicity is mainly due to bone marrow suppression, although this is less than with agents such as cyclophosphamide. Gastrointestinal upset is common and may necessitate discontinuation of therapy. Hypersensitivity reactions, including shock, have been reported.

Cyclophosphamide is a nitrogen mustard analogue which is converted to the active metabolite in the body where it exerts its immunosuppressant effects by interfering with DNA synthesis and function in B and T cells. It may be a more effective immunosuppressant than azathioprine, but this is associated with greater toxicity.

Cyclosporin is a potent inhibitor of T-cell activation and proliferation. It is variably absorbed after oral administration and extensively metabolised predominantly by CYP3A4, an isoform of the hepatic cytochrome P450 enzymes. Use of high doses should be guided by monitoring of blood levels. The main toxicity is reversible renal impairment and hypertension. Its place in dermatology is in the treatment of a wide variety of inflammatory conditions such as psoriasis, atopic dermatitis, lichen planus and bullous pemphigoid, but the difficulties in its use and the reversibility of benefit on ceasing administration markedly limit the circumstances warranting its use.

Methotrexate is an inhibitor of dihydrofolate reductase. It is well absorbed after oral dosing of up to 25mg/m². It is not metabolised to any extent and elimination depends on renal excretion so caution and perhaps dosage adjustment is needed in the presence of renal impairment. Toxicity due to bone marrow depression and mucositis is less likely in dermatological applications than when higher doses are used but regular monitoring with blood counts is necessary. Prolonged intake leads to hepatic fibrosis and this requires liver function to be included in the monitoring. Liver biopsy is necessary for early detection and characterisation of this complication but whether this is justified and how often it should be performed is controversial. Methotrexate is valuable in treatment of severe unresponsive psoriasis.

Hydroxyurea blocks pyrimidine synthesis. It causes much more short-term bone marrow depression than methotrexate, necessitating frequent blood counts.

Thalidomide is not generally available but is an inhibitor of tumour necrosis factor and has found a use in a number of inflammatory conditions despite its notoriety.

Bleomycin has antitumour, antibacterial and antiviral activity. It binds to DNA, causing strand scission and elimination of pyridine and purine bases. Intralesional injections are used in the treatment of unresponsive warts, although the mechanism of action is not known.

Fluorouracil is an analogue of uracil and, after activation, it inhibits thymidylate synthase. It is used by topical application for solar keratoses. Used in this way, adverse effects are limited to local irritation, but this may be severe and experience in its use is necessary.

Imiquimod is an immune response modifier. It is used topically in the treatment of external genital warts, but has no direct antiviral activity.

Psoralens

The psoralens constitute a group of photosensitising agents, which are used in conjunction with exposure to ultraviolet (UV) radiation to treat psoriasis and some other conditions. They absorb radiation in the wavelength range 320 to 335nm, the lower ultraviolet A (UVA), but the details of the mechanism producing photosensitivity are not known.

Methoxsalen (8-methoxypsoralen) is the only psoralen currently available in Australia. It is used as an oral preparation and also as a lotion for local application in treatment of vitiligo or in a bath before exposure to UV radiation. Maximal photosensitivity is produced 1 to 2 hours after oral administration, but sensitivity persists for 8 to 12 hours.

Excessive exposure to UVA can result in erythema and blistering. There is increased incidence of squamous cell carcinoma after chronic use. Protection of the eyes from UV light is necessary while photosensitivity persists.

Minoxidil

Minoxidil is a potent vasodilator. Its systemic use to treat hypertension is limited by tachycardia, fluid retention and the undesired stimulation of hair growth. Minoxidil is used as a local application to the scalp where it acts as a nonspecific hair growth stimulant, probably by prolonging the anagen phase. This persists only while treatment is continued.

Antiandrogens

These have a role in hirsutism, androgenic alopecia and in acne. They should all be avoided in pregnancy.

Spironolactone is a potassium-sparing diuretic which, independent of that property, is a weak antagonist of androgen receptor binding and an inhibitor of androgen biosynthesis.

Spironolactone should not be administered to patients with renal failure due to the potential for potassium retention. The patient’s potassium status should be checked prior to commencing therapy and on an annual basis thereafter.

Cyproterone acetate is a synthetic corticosteroid with progestational and antiandrogen actions. The latter is due to competition at the dihydrotestosterone receptor and at high doses to inhibition of androgen synthesis. It may be used in treatment of hirsutism and paradoxically of alopecia of the androgenetic type.

Flutamide is not a steroid but potently competes at the androgen receptor.

Finasteride inhibits the conversion of testosterone to dihydrotestosterone by the type II 5-alpha-reductase enzyme, which is present on hair follicle cells, thus reducing the influence of androgens. Consequently, it has a role in androgenetic alopecia in men since it does not alter the effect of androgen on the testes and hypothalamic-pituitary function.

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