Download PHL 425 3rd Lecture S

Pharmacology-4 PHL 425
Third Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
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
 exposure to UV radiation
 pregnancy (melasma gravidarum, the mask of pregnancy)
 hormonal therapies (e.g., oral contraceptive drugs)
 photosensitizing drugs e.g., NSAIDs, thiazides, sulfonamides,
sulfonylureas and antiepileptic medications such as
diphenylhydantoin (phenytoin)
 The mechanism of the disease is unknown, but all cases are associated with sun
exposure
Chloasma, contd.
 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
Management of Chloasma (melasma)
 Treatment depends on whether the pigmentation is epidermal or dermal. Only
epidermal pigmentation responds to treatment
 Topical corticosteroids have been included in several clinical trials for the treatment
of melasma to decrease the irritation caused by depigmenting agents
 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
 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
Inhibition of RNA and DNA synthesis in melanocytes
Alteration of melanosome formation and structure, and melanization extent
Increase of melanosomal degradation rate within keratinocytes
Destruction of melanocytes
Management of Chloasma (melasma)
 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
 Tretinoin (retinoic acid [RA]) inhibits tyrosinase by inhibiting the enzyme’s
transcription. It also inhibits dopachrome conversion factor, with a resulting
interruption of melanin synthesis. In addition, RA reduces hyperpigmentation through
the induction of desquamation
 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
 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)
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 (irritation!) and 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
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