The mechanism of action of 5-FU has been covered previously.

The topical formulation of this drug is used in the treatment of actinic and solar keratosis and superficial basal cell carcinoma.  It is usually applied twice daily.

The side effects of Efudex® include pain, pruritus, hyperpigmentation, irritation, inflammation, and burning.  This is more pronounced upon exposure to sunlight, ultraviolet light, or the use of occlusive dressings.

The clinical response to Efudex® occurs in four (4) distinct phases.

1) Early inflammation -- erythema
2) Severe inflammation -- burning, stinging, vesiculation
3) Disintegration -- erosion, ulceration, necrosis, pain, and crusting
4) Healing
The first three phases usually occur during the initial 2-6 weeks of application.  Patients should be warned that these effects will occur and that they represent the beneficial actions of the drug.  The healing phase may require anywhere from 2 weeks to 2 months.
 

These agents are anti-mitotics and act in a manner similar to the epipodophyllotoxin anti-neoplastics.

Podophyllum is used in the treatment of epitheliomatosis and condylomata acuminata (venereal warts).

Local side effects include irritation, redness and burning.  Systemic toxicity includes neuropathies, nausea and vomiting, and lethargy.  NOTE that the podophyllum resin preparations are often suspended in tincture of benzoin.  Patients should be careful to allow the application to dry before allowing the skin to assume its natural position.  Otherwise, adhesion (gluing) to skin surface may occur.

Application

Podophyllum resin -- should be applied daily.  The lesions will blanch, become dry and decrease in size.

Condylox® -- should be applied twice daily for three days and then allow a four day holiday.  This regimen may be repeated for up to 4 weeks of treatment.  Application is made with a cotton applicator to an area less than 10 cm² and using less than 0.5 ml of the preparation.  The clinical response resembles that described above for the resin.

Coal Tar Preparations -- Coal Tar Extract (Fotofar®), 30% Whole Coal Tar (Zetar®), Anthralin (Lasan®)
Mechanism of Action -- These agents decrease mitosis and rate of proliferation of epidermal cells by decreasing DNA synthesis.

Coal tar is used primarily in the treatment of chronic psoriasis.  They are contraindicated in acute flare-ups of psoriasis, since their systemic absorption would be increased.

Side effects include excessive irritation, hypersensitivity, and photosensitivity.  Additionally, exposure to sunlight will increase the risk of cancer as an extension of the pharmacologic effect of the preparation.  They may also discolour nails and white or grey hair.  Systemic absorption may cause nephrotoxicity, hepatoxicity, or cancer.

Application -- Apply a protective layer of petrolatum around the lesion.  Then apply a thin film of the preparation to the lesion (the petrolatum protects unaffected skin).  Application is usually at bedtime, with the drug being washed off the next morning.  Application should be made wearing rubber gloves to limit absorption.  Staining of fabrics (i.e. bedclothes) may occur.

Mechanism of Action -- Inhibit the enzymatic oxidation of tyrosine and other melanocyte reactions to decrease melanin formation, therefore causing depigmentation.

Hydroquinone is used primarily to depigment hyperpigmented skin and is indicated for the treatment of freckles and senile lentigines (liver spots or age spots).  Its actions are reversible.  Monobenzone is used to achieve final depigmentation in vitiligo, which is characterised by acquired (possibly autoimmune state) damage to melanocytes, causing loss of skin pigmentation.

Side effects include dryness and fissuring of skin (especially paranasal and intraorbital areas), erythema, and stinging.  Protection from the sun is essential (may be pro-carcinogenic).

Application -- Do not apply to irritated, denuded, or damaged skin.  A small test dose should be applied (often behind the ear).  If no reaction (vesicles, itching, inflammation) occurs withing 24 hr, then the patient may use (note that a small amount of redness is acceptable and does not preclude use of the compound).  If no reaction occurs, the patient should apply the medication twice daily.  If no improvement is seen within 2-3 months, the medication should be discontinued.

Vitamin A Derivatives (Retinoids)

Mechanism of Action -- The retinoids act via a typical thyroid/steroid receptor complex that results in the expression of specific genetic actions (protein synthesis).  The consequences of these actions include decreased cohesiveness of follicular epithelium, decreased sebum production, and prevention of keratinisation, all of which may contribute to decreased comedone formation.

Tretinoin (Retin-A®) -- Topical retinoid

Side Effects -- Warmness, tingling, increased risk of sunburn (water-based sunblocks should be used if the patient is going to be exposed to UV radiation), and hyperpigmentation.  Note that acne may acutally worsen during the first 2-3 weeks of therapy (extrusion of oils as a result of decreased keratinisation).  Once a good response is seen, the frequency of application may be decreased.  Counsel patients to "rest" the skin prior to application (wait after washing or exposure to sun, wind, or cold) to decrease the risk of side effects.
 
Adapelene (Differen®) -- Topical and typical retinoid
Less likely to cause skin irritation (may be due to gel base), but essentially the same as Retin-A®

Azelaic Acid (Azelex®) -- Natural product derived from whole grain cereals and animal products
It is anti-microbial and keratolytic.  It is presumed to work in a fashion similar to the retinoids.  It produces less scaling and redness (although initial burning and stinging may occur) than Retin-A®.  It may produce some hypopigmentation as a side effect.
 
Isotretinoin (Accutane®) -- A systemic retinoid, approved only for recalcitrant cystic acne.  It is also used (unapproved) for the treatment of xeroderma pigmentosum and following squamous cell carcinoma. Systemic retinoic acid derivatives are also demonstrating efficacy in the treatment of adult T cell leukaemias.
Side effects include headache, nausea, vomiting, visual disturbances, pseudotumour cerebri (benign intracranial hypertension), papillœdema (especially with tetracyclines), photosensitivity, corneal opacity (cataracts), decreased night vision, and decreased contact lens tolerance.  Accutane® may increase serum triglycerides (ethanol potentiates this effect), and may cause hepatotoxicity (usually reversible, obtain baseline liver enzyme levels) and arthralgia.

Accutane® is contraindicated in pregnancy due to the risk of birth defects (hydrocephalus; microcephaly; micropenna, loss of external auditory canals, and other ear abnormalities; cleft palate, cardiovascular, and thymus abnormalities).  Note that many physicians will not dispense Accutane® unless oral contraceptive therapy is included in the patient's regimen.  Also note that patients should NOT give blood within thirty days of taking Accutane®, due to detectable levels that may exert adverse effects in the recipient of the donated blood.
 

Etretinate (Tegison®) -- A systemic retinoid that is used in psoriasis.  Its warnings and precautions are the same as those for isotretinoin.

Alitretinoin (Panretin®) -- A topical retinoid used in the treatment of Kaposi's sarcoma.  Side effects are similar to the other retinoic acid derivatives.  NOTE that patients with T-cell lymphoma are less responsive.  The recommended dose is applied twice daily, but application may increase or decrease dependent upon the patient.  Also NOTE that if the patient has more than 10 new lesions monthly or if systemic lesions appear, then alitretinoin therapy is inappropriate.

Casein (Travase® Ointment)
Fibrinolysin/Deoxyribonuclease (Elase® Powder, Ointment)
Granulex® Spray --
Trypsin (enzyme)
Balsam Peru (capillary bed stimulant, to improve blood flow)
Castor Oil (protective covering, delay premature dessication and cornification of forming skin to improve epithelialisation)

These agents are indicated as adjuncts to wound care with biochemical debridement following second and third degree burns, decubitus ulcers, incisional trauma, pyogenic wounds, and ulcers secondary to peripheral vascular disease.

Application -- A moist environment is necessary for the action of some of these compounds.  Also, note that antiseptics may inactivate the enzymes in these preparations.  Rinse and clean the area well prior to application.  Physically debride any tissue from the wound prior to application.  The preparation should be applied to an area extending 1/4 to ½ inch beyond the wound at least once daily.  NOTE that frequency and NOT quantity of application is the major determinant of efficacy.  Cleaning and debridement should precede each application.