Pharmacology-4 PHL 425 Third Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

Pigmentation Disorders, Chloasma (Melasma) Melasma is an acquired irregular light- to dark-brown hyperpigmentation that occurs in sun-exposed areas of the skin, most often on the face and results from exposure to sunlight Clinically, It is characterized by macular hyperpigmentation of the face. Intensity (light or dark brown or even black) depends largely on the skin phototype of the patient Melasma etiological factors include: Genetic background: There is a genetic predisposition to melasma Exposure to UV radiation Pregnancy (melasma gravidarum, the mask of pregnancy): Overproduction of melanin induced by hormonal factors and amplified by the sun The pigmentation often fades a few months after delivery Hormonal therapies (e.g., estrogen oral contraceptive drugs) Photosensitizing drugs e.g., NSAIDs, thiazides, sulfonamides, sulfonylureas and antiepileptic medications such as diphenylhydantoin (phenytoin) Scented or deodorant soaps and cosmetics (a phototoxic reaction) The mechanism of the disease is unknown, but all cases are associated with sun exposure

Chloasma, contd. Epidemiology, Course & Prognosis It is well known that sun-exposed skin of the face contains significantly more epidermal melanocytes than the rest of the body Melasma is characterized by epidermal hyperpigmentation, possibly caused both by an increased number of melanocytes and by an increased activity of melanogenic enzymes leading to dermal changes caused by solar radiation Melasma skin has more melanin in the whole epidermis, including the stratum corneum, whereas in normal skin the melanin pigment is mostly confined to the basal layer Thus, an increased synthesis of melanosomes in the melanocytes, and increased transfer and decreased degradation of melanosomes in the keratinocytes, are suggested to be essential for the development of melasma Epidemiology, Course & Prognosis Epidemiology of chloasma in females is more than in males; about 10% of patients with melasma are men It appears in all racial types, but occurs more frequently in those persons (from Asia, the Middle East, South America) with Fitzpatrick skin phototypes IV to VI who live in areas of high UV; sun exposure deepens these hyperpigmented areas Melasma may disappear spontaneously over a period of months after delivery or after cessation of contraceptive hormones. Melasma may or may not return with each subsequent pregnancy In men, melasma rarely fades Avoiding the sun keeps the condition from worsening

Chloasma, contd.

Management of Chloasma (melasma) Management approaches include: Avoiding the sun keeps the condition from worsening Discontinuing hormonal contraception Use broad-spectrum very high protection sunscreen of reflectant type Alternatively, use a make-up containing sunscreen Treatment depends on whether the pigmentation is epidermal or dermal Only epidermal pigmentation responds to treatment A variety of therapies are available: Hydroquinone (HQ) Topical retinoids such as tretinoin Azelaic acid Salicylic acid cream Glycolic acid and lactic acid, as chemical peels Topical corticosteroids to decrease the irritation caused by depigmenting agents

Management of Chloasma (melasma), HQ The most popular depigmenting agent is hydroquinone (dihydroxybenzene; HQ) introduced for clinical use since 1961 Due to its strong depigmenting activity, HQ has been considered as a reference standard in evaluating depigmenting agents HQ exerts its effects mainly in melanocytes with active tyrosinase activity, such as epidermal hyperactivated melanocytes MOA of HQ: Considering its analogy to melanin precursors, HQ may act as an alternative substrate for tyrosinase, competing for tyrosine and dopa oxidation Thus, it acts by blocking the synthesis of melanin by inhibition of tyrosinase; the enzyme responsible for conversion of tyrosine to melanin Following oxidation, HQ generates quinones and ROS, leading to oxidative damage to membrane lipids and alteration of membrane-bound proteins, such as tyrosinase Other putative mechanisms include: Covalent binding to histidine or interaction with coppers at the active site of tyrosinase Alteration of melanosome formation and structure, and melanization extent Increase of melanosomal degradation rate within keratinocytes Inhibition of RNA and DNA synthesis in melanocytes Destruction of melanocytes

Management of Chloasma (melasma) In addition to its use for the treatment of chloasma, HQ is used for the treatment of excessive freckling Topical hydroquinone (3% solution and 4% cream) usually results in temporary lightening, whereas the monobenzyl ether of hydroquinone (MEH; MBEH) causes irreversible depigmentation (the clinical use is limited to obtain a generalized depigmentation in patients with diffuse vitiligo) Under no circumstances should MBEH or the other ethers of hydroquinone be used in the treatment of melasma because these drugs can lead to a permanent loss of melanocytes with the development of a disfiguring spotty leukoderma, even at sites distant from those of application (percutaneous absorption) Because of the hazard of long-term treatments with HQ (e.g., mutagenesis and tumorigenesis in animals), the use of HQ in cosmetics has been banned by the European Committee and formulations are available only by prescription of physicians and dermatologists HQ may cause local irritation, inflammation (Allergic dermatitis) HQ may also act on normal melanocytes

Management of Chloasma (melasma) Tretinoin (retinoic acid [RA]) exert its depigmenting effects by: Inhibiting tyrosinase by inhibiting the enzyme’s transcription Inhibiting dopachrome conversion factor (Dopachrome tautomerase), with a resulting interruption of melanin synthesis Induction of desquamation (shedding of the outer layers of the skin) Concentrations ranging from 0.05% to 0.1% have been used and the associated side effects are erythema and peeling in the area of application; postinflammatory hyperpigmentation has also been reported Because it is teratogenic, RA cannot be used during pregnancy Triple fixed combination therapy HQ 4%, RA 0.05% and fluocinolone acetonide (FA) 0.01% is more effective than either agent alone

Management of Chloasma (melasma) Azelaic acid (AZA): It is a straight-chain saturated dicarboxylic acid that has been shown to be effective in the treatment of melasma AZA inhibits tyrosinase activity and may also interfere with DNA synthesis and mitochondria activity in hyperactive and abnormal melanocytes ( antiproliferative and cytotoxic effects on these melanocytes) It is not able to induce depigmentation on normally pigmented skin, freckles, senile lentigines and nevi, suggesting its selective anti-proliferative and cytotoxic action on abnormal melanocytes Topical AZA (15–20%) is efficacious in the treatment of melasma AZA has been also demonstrated to be effective in the treatment of acne vulgaris It has no major side effects. However, slight burning, itching, redness skin may occur The only problem of melasma treatment with AZA is that its therapeutical response is rather slow In order to improve this aspect, combined therapies with other agents, particularly compounds capable of accelerating desquamation have been evaluated AZA 20% plus tretinoin 0.05 or 0.1% has been shown to be more effective than AZA alone

Melasma, Freckles, Lentigo and Nevus There are centrofacial, malar and mandibular patterns of melasma, whereas freckles typically appear on the cheeks around the eyes and across the bridge of the nose.    Lentigines (commonly called liver spots or age spots), typically darker than freckles and round or oval in shape, may arise on any part of the skin or mucous membranes as isolated findings or, when multiple, associated with various genetic syndromes. Merck Lentigines: Lentigines (singular: lentigo) are flat, tan to brown oval spots. They are commonly due to chronic sun exposure (solar lentigines; sometimes called liver spots) and occur most frequently on the face and back of the hands. They typically first appear during middle age and increase in number with age. Medicinenet: Lentigines (singular: lentigo) comes from the Latin word for lentil and is the medical term for certain types of darker freckles and sunburn freckles. Lentigines tend to be darker than the common freckle and do not usually fade in the winter. This kind of spot is referred to as lentigo simplex. Although occasionally lentigines are part of a rare genetic syndrome, for the most part they are just isolated and unimportant spots. Nevus (or naevus, plural nevi or naevi, from nævus, Latin for "birthmark") is the medical term for sharply-circumscribed[1] and chronic lesions of the skin. These lesions are commonly named birthmarks and moles. Nevi are benign by definition tumour like but nonneoplastic hamartoma of skin. A vascular naevus is a localised capillary rich area of the skin (strawberry birthmark, sometimes the much more extensive port wine stain)

Management of Chloasma (melasma) Other therapeutic approaches: Dermabrasion: It is a technique that uses a wire brush or a diamond wheel with rough edges (called a burr or fraise) to remove the upper layers of the skin. The brush or burr rotates rapidly, taking off and leveling (abrading or planing) the top layers of the skin It is a relatively safe and highly effective means for curing melasma However, it is a relatively invasive technique and damage to the melanocytes may increase pigment production and darken the melasma Laser treatment: It is an acronym for Light Amplification by Stimulated Emission of Radiation Lasers are sources of high-intensity monochromatic coherent light that can be used for the treatment of various dermatologic conditions The initial results are encouraging but repigmentation is the rule rather than the exception