PENATALAKSANAAN

HIPERPIGMENTASI

DEWA AYU SWASTINI

FARMASI FMIPA UDAYANA

Disampaikan dalam Webinar Nasional Kefarmasian Kamis, 23 Desember 2021

Berdasarkan Tipe, Warna
kulit manusia dapat
dibagi menjadi lima:
• Hitam → Negroid : tipe V
• Coklat → Melanesia : tipe IV
• Merah → Indian : tipe III
• Kuning → Mongoloid : tipe II
• Putih → Kaukasoid : tipe I

Yang menentukan warna kulit

tersebut : pigmen Melanin +
Hemoglobin + Betacaroten
Caucasian skin Asian skin Black skin

MELANIN
 Melanosom
Organela di melanosit
tempat berlangsungnya
sintesis melanin

Melanosit Sumber: Bolognia

Sumber: Bleehen S.S.
Stratum basalis
epidermis -Sel berdendrit
Sumber: Virtualmedicalcentre
-Dendrit mencapai berbagai lapisan epidermis
• 1. Sun (UVA/UVB rays,
environmental damages, free
radicals)

• 2. Hormones (internal unbalance,

pregnancy, menopause)

• 3. Inflammation (blemishes, acne,

injury, laser treatment, heat,
medical & chemical procedures)

• 4. Oral Medications (diuretics,

birth control pills, antibiotics, anti-
depressants, ...)

• 5. Alcohol (aftershave, colognes,

perfumes)
Biosintesis Melanin (Chang, 2009).
Proses distribusi dan transfer melanosom
ke keratinosit di sekitar melanosit.

Produksi /sintesis melanin

di dalam melanosom di melanosit
 KELAINAN PIGMENTASI

Hipopigmentasi Hiperpigmentasi

Pigmentasi coklat Lain-Lain

Vitiligo
Albinisme
Sindrom Alezandrini
Sindrom Chediak- Melanoderma
Melanosis Hemokromatosis
Higashi Pasca Radang
Piebaldism Melasma Acne Likopenemia
Leukoderma Lentiginosis Karotenosis
Luka bakar
Inkontinensia Efelid
Pigmenti Lentigo Senilis Pasca Inf. Bakteri Panu coklat
Melanosis Riehl
 Faktor etiologi utama:
Genetik, Sinar matahari, Hormonal
Berdasarkan letak melanin di kulit:
Sinar Ultra Violet
Hormon (estrogen,
Tipe Epidermal Tipe Dermal
progesteron, MSH)
warna coklat,batastegas warna abu-abu kebiruan, Tipe campuran
Genetik
batastidak tegas
Obat (minosiklin,
sitostatik)
Ras
Kosmetika
Idiopatik

Pipi, hidung (pola Malar), dagu (pola Mandibular),

pelipis, dahi, alis, bibir atas (pola Centrofacial)
- Bercak-bercak kecil, coklat terang
- Pada kulit yang terpajan sinar matahari
- Timbul pada individu berkulit putih

Timbul pada usia kanak-kanak / remaja,

dan mengalami regresi dengan
bertambahnya usia

↑ Melanin di lapisan basal epidermis

Makulacoklat/ coklat kehitaman berbentuk
bulat atau polisiklik Lentiginosis: keadaan
timbulnya lentigo dalam jumlah banyak, di
tempat terbuka
: wajah , leher , lengan dan tungkai bwh
Etiologi
Bertambahnya jumlah Melanosit
(proliferasi fokal) pada dermoepidermal
junction.
Pertama kali oleh Riehl sebagai dermatitis akibat fotosensitivitas
Pruritus, eritema dan pigmentasi yang meluas secara perlahan
wanita dewasa

Gejala Klinis : - pigmentasi coklat muda à coklat tua

dahi,belakang telinga dan sisi leher
- telangiektasis + hiperemia
Etiologi à Mgkn o.k. semprotan Perfume di leher &
muka yang terpajan oleh sinar matahari
Fotosensitizer : derivat Tar, Fragrance pada kosmetika
 Hiperpigmentasi pascainflamasi
Inflamasi

→lekotrien, prostaglandin, →Interleukin-1,

tromboksan IL-6, TNF-α

↑ Sintesis melanin
↑Proliferasi dendrit
↑ Transfer melanin
melanosit
ke keratinosit

Epidermis
Deposit melanin di Pigmentasi coklat
kehitaman

Dermis – melanofag di dermis

Pigmentasi abu-abu kebiruan
Hiperpigmentasi pascainflamasi
Pasca Acne
Pasca Luka Bakar
Pasca infeksi bakteri
Pasca Dermatitis kontak
 PENATALAKSANAAN TERAPI
➢ Onset hiperpigmentasi: kongenital,
masa kanak-kanak- bintik-bintik
kehamilan-melasma
➢ Durasi
➢ Gejala sistemik: penyakit adrenal,
hipertiroidisme, diabetes
➢ Riwayat obat- obat, suplemen
➢ Paparan tanaman
➢ Paparan sinar matahari
✓ Mengidentifikasi dan mengobati penyakit
sistemik
✓ Hentikan obat/tanaman yang mengganggu
✓ Rawat kondisi peradangan yang
mendasarinya - jerawat, lupus
✓ Kesadaran matahari- hindari sinar matahari,
tabir surya
✓ Agen pencerah kulit topical
✓ Dermabrasi kulit
✓ Laser
 UV Penanganan Hiperpigmentasi Kulit
Radikal • Menghindari sinar matahari
Hormonal • Tabir surya
• Hindari pengaruh hormonal
• Proteksi mekanis
transkripsi
Hambat transkripsi tirosinase • Antioksidan
tirosinase
•Bahan depigmentasi : • Antiinflamasi
retinoid, berbagai herbal
Hambat aktivitas tirosinase
Tirosin
Bahan depigmentasi : hidrokuinon, arbutin, asam azeleat,
Tirosinase asam kojik, aloesin

Hambat transfer melanosom

melanin •Bahan depigmentasi : niasinamid, kedelai, vitamin C
Transfer
•Peeling kimia : asam glikolik, TCA, asam salisilat
Deposit •Laser ablatif : CO2
melanin •Laser non-ablatif : NdYAG 532 nm
Kulit epidermal
Deposit
melanin •Laser non-ablatif : NdYAG 1064 nm
dermal
 Percepat pergantian epidermis : deskuamasi
➔ chemical exfoliators: lactic acid retinol derivative
retinol-like glucosamine derivatives

• UV stimulates keratinocytes & can break their DNA ➔

keratinocytes look for protection → “ask” the melanocyte to
produce melanin to be used as a “cap” for the next time
keratinocytes are exposed to UV

➢under UV: activated the cytokines → alpha MSH

melanin formation depends on → the generation of
free radical species
➢➔ The down-regulation of POMC will stop the communication
❑ KatalisROS : copper & oxygen
• Tyrosinase isa copper-containing enzyme:
o Ex. Kojic acid → chelating the copper
(melanocyte stimulating hormone) & endothelin are released
→Pro-opio melano cortin (POMC) released by the
keratinocytes
between keratinocyte & melanocyte
o Undecylenoyl phenylalanine → act as alpha-MSH
antagonist

✓ Many antioxidants have skin-brightening properties: o Ascophyllum nodosum extract is an algae extract → block
scavenging free radicals that can be a precursor to hyperpigmentation endothelin adhesion to the membrane of the melanocyte
4
o Sea Daffodil (Pancratium Maritimum ) ------Inhibiting POMC
❑ In the nerves: nerves → stimulate the melanocytes ↑the dendricity: via a peptide: Substance P→ activate
substance P
receptors → ↑the # of dendrites in the melanocytes➔ neuro-whitening…
extract of Pancratum maritimum (white sea lily or sea daffodil): down-regulate POMC & ↓the stimulation from

Inhibit
melanin
tranfers and
inflammation

• reduces the lenght of

dendrites
• reduces the synthesis of the
Inhibiting receptor TacR1 for
POMC Substance P
❖ especially in darker skin types ➔ inflammation can exacerbate melasma Latanoprost & Bimatoprost: analogues of PGF2
→ ∆ pigment of the iris & the
eyelid
- → stimulating eyelash growth ➔ should be used
Prostaglandins: with
↑ caution by those with darker skin types & those
PGF2 with history of melasma & others..

-
Inflammation tyrosinase skin pigmentation

Histamine
released from mast cells ↑the production of eumelanin rather > pheomelanin
prevent inflammation

➔ inhibit histamine release block histamine action

Antioxidants: especially flavonoids Famotidine: blocking H2 receptors → suppressed the ↑melanogenesis

effects on→ TNF- B inducible nitric oxide synthase expression * but antagonists of H1 & H3 do not have any 5effect
inhibition of cyclooxygenase.
Fairness Industry
Cantik = Putih
• Queen
Cleopatra -milk
• Chinese -
ground pearl
• Ancient
Romans - lead
• Japanese -Bird
dropping
• Indians-
Turmeric paste
 
1-1 Sunscreens  ▪2-4 competitive inhibitors: Arbutin &
1-2. Anti Oxidants  4 MSK
o ex. ascorbic acid derivatives ▪2-5 inhibit tyrosinase maturation or
o plant extracts: licorice root synthesis: magnolignan : + induces
extracts: contain glabridin metallothionein: antioxidant pr (copper-
1-3. Melanin-stimulating hormone 2-1 chelating)
(MSH, melanotropin) 2-2 Metal Chelators
o AA→ ergo-thioneine:
copper chelator
3-1 
o ellagic acid
o kojic acid.

▪2-3 Microphthalmia-associated transcription factor (MITF) →

transcription factor for tyrosinase (TYR) & tyrosinase-related protein 1
(TYRP1) ➔ down-regulate MITF gene ➔ the tyrosinase is not
activated: water extract of an alga (Dictyopteris membranacae)
▪ 3-2: AHAs & kertolytic Enz.s (ex, papaya & bromalein)→
exfoliate
surface SCcells ➔ promote brighter, more even-tone complexion

 Melanocyte-cytotoxic agents
 SunScreens/ UV absorber

➢ Meskipun perlindungan matahari tidak secara langsung mengganggu proses pembentukan pigmen →
membantu memblokir radiasi UV membatasi paparan sinar matahari membentuk eritema → adalah
pemicu utama melanosit untuk memproduksi melanin

➢ sangat penting untuk melihat hasil & mempertahankan hasil dari bahan aktif pencerah kulit

➢ Dalam keratinosit → batasi komunikasi antara keratinosit & melanosit...

menerapkan tabir surya UVA/UVB foto-stabil spektrum luas fisik/kimiawi secara teratur saat terkena
radiasi UV

➢ pakaian pelindung: anyaman serat penyerap UV menjadi pakaian pelindung topi bertepi lebar kemeja
lengan Panjang celana penggunaan kacamata pelindung UV

➢ berlindung di tempat teduh saat sinar matahari paling kuat antara jam 10 pagi & 4 sore Cari
perlindungan di dalam ruangan atau setidaknya di tempat yang teduh
 Skin Lightening & Whitening/Skin Bleaching
❑SkinLightening& Whitening/Skin Bleaching:
umum digunakan Hydroquinon. Satu satunya zat aktif pemutihkulit yang disetujui FDA
➢Bahan aktif pencerah kulit (menurut FDA) z a t y a n g d i r a n c a n g u n t u k memutihkan atau
mencerahkan area terbatas kulit yang mengalami hiperpigmentasi of hyperpigmented skin dengan menekan
pembentukan melanin
➢SkinBrightening:formulasi yang mencerahkan warna kulit yang tidak merata & mengadung bahan alternatif HQ
atau lainnya → bahan alami, peptoda, dan vitamin dll

• Istilah“tyrosinase inhibitor” telahdigunakansecara luas dipasaranuntukmendefinikanbahanaktif pencerahkulit

❖not all skin-brighteningingredients directly interfere with the catalyzing of the tyrosinaseenzyme.

❑ The labeling of the product contains→

• a statement of the indications : “For the gradual fading or lightening of dark discolorations/spots/areas/freckles/age spots.”

• + contain the appropriate warningsidentified by the FDA.

❖ term used to describe alternatives is “skin brightening,” or you can say it helps to promote a more even skin tone
22
 1a. Hydroquinon
✓ ProdukOTC ]≤ 2% peresepan (4%) sediaan yang ada (2% - 10%)
> 2% → lebih iritasi→ side effects: kulit kemerahan
✓ inhibit melanin production: by inhibiting tyrosinas cytotoxicity to
melanocytes
✓ Digunakan untuk PIH & melasma.
✓ Baik digunakan tunggal kadang dikombinasikan dengan
tretinoin, glycolic acid, kojic acid & azelaic acid.
✓ Penggunaan jangka Panjang, ≥ 6 bulan, kadang diperlukan

exogenous ochronosis: a simptomatik blue-black macules pada area

Safety of HQ …?!
pemaparan ]→ hiperpigmentasi permanen
o Menghambat homogentisic acid oxidase kulit➔ the akumulasi lokal
homogentisic acid → berpolimerisasi membentuk ochronotic pigment
o Terjadi pada penggunaan jangka panjang ≥ 4%
o Lebih sering pada kulit gelap
skin rashes & nail discoloration → resolved by simply discontinuing HQ use
using a test site first to determine the presence of allergy
taking “hydroquinone holidays” every 3 months.
23
 1b.Mequinol
• 4-Hidroksianisol , turunan dari
Hidrokuinon
• Kurang iritasi
• Menghambat Tirosinase
• Digunakan dalam konsentrasi 2-4%
• Digunakan dalam kombinasi dengan
tretinoin
• Lebih aman & efektif pada jenis kulit
gelap

2% mequinol with 0.01% tretinoin → effective in the

treatment of solar lentigines + compared with those of
3% HQ
 2. Flavonoids
• aFlavonoids & flavonoid-like memhasilkan derajad berbeda sebagai tyrosinase inhibition…

• Beberapa komponenjuga menghambatmelanin production pada jalur berbeda dari inhibisi tyrosine 



• Diklasifikasi menjadi 6 groups: flavanols, flavones, flavonols, flavanones, isoflavones, anthocyanidins

➢antioxidant properties directly inhibit tyrosinase

• + mild inhibition;

2.1 Resveratrol → the hydroxy stilbene derivative group of • ++ moderate inhibition;

flavonoids • +++ strong inhibition;


• ?, not enough studies performed to rank.



➢Resveratrol induces depigmentation also by →

➢ ↓microphthalmia-associated transcription factor (MITF) 
➢ tyrosinase promoter activity

❖ oxy-resveratrol & gnetol → more efficient tyrosinase inhibitors >
resveratrol 14

2.2 Piceatannol (PICE) (Flavonoids)

▪ PICEkomponen fenolik turunan resveratrol, ditemukan pada grapes & red

wine.

➢anti-oxidative------ melanogenesis

o Aloesin (Flavonoids) → naturally derived from aloe vera

o Pycnogenol (Flavonoids) from pine bark extract

✓ protecting against UV-induced pigmentation (➔ as a photo-protective

complement to sunscreens)

✓ melasma

✓ ↓the inflammatory sunburn reaction & immuno-suppression

26
 3.3 Green Tea

• 4 major polyphenolic catechins in fresh leaves of the green tea plant Camellia sinensis:
have large amounts
• ECG[(–)-epicatechin-3-O-gallate] GCG[(–)-gallocatechin-3-O-gallate] of green tea

• EGCG[(–)-epigallocatechin-3-O-gallate] EGC[(–)-epigallocatechin]

➢ Anti-oxidant, anti-inflammatory, competitively inhibiting tyrosinase

➢ GTPs → modulate biochemical pathwaysimportant in cell proliferation, inflammatory responses, responses of tumor promoters

➢ especially potent @ suppressing the carcinogenic activity of UV radiation, exerting broad protection against other UV-mediated responses
(ex. Sunburn), immuno-suppression, & photoaging

➢ EGCG→ inhibit melanin synthesis by ↓MITF & tyrosinase protein levels

• There are 2 major challenges for the topical use in humans:

• (1) establishing a standard formulation & delivery systems that ensure the stability of these easily oxidized antioxidants

• (2) ↑epidermal penetration of these hydrophilic agents into human skin.

27
3.4 Silymarin
• a naturally-occurring polyphenolic flavonoid or flavonolignans compound derived from the
seeds of the milk thistle plant Silybum marianum.

• The main component of silymarin is silybin (silibinin) → its most biologically active
constituent for anti-Oxidant, anti-inflammatory, anti-carcinogenic properties.

• Topical application of silybin prior to, or immediately after, UV irradiation → strong

protection against UV-induced damage in the epidermis , silybin enhances UVB-induced
apoptosis & acts as a UVB damage sensor to confer its biologic action.

• Chemoprotective activity against skin cancer, inhibit UV-induced NF-B activation in

keratinocytes

➢→ free radical scavenging & a modulation of intracellular GSHcontent.

• ➔ silymarin may favorably supplement sunscreen protection & provide additional anti
photo- carcinogenic protection

• oral supplements
28
3.5 Ellagic acid (Flavonoids)

• a polyphenol, for whitening @ 0.5%.

• is isolated from strawberries, green tea, eucalyptus, geranium

➢The mode of action: copper chelation tyrosinase inhibitor prevent UV-induced pigmentation

❖ more effective than> kojic acid or arbutin safer than > HQ: it affects melanogenesis without cytotoxic reaction

3.6 GENTISIC ACID

• derived from genetian roots.

➢inhibitory effect on tyrosinase.

• methyl gentisate → more effective > the free acid

❖ HQ is less effective & more cytotoxic to melanocytes < methyl gentisate.

3.7 Arbutin → consists of a molecule of HQ bound to glucose

• present in the leaves of pear trees, wheat & bearberry… Competitive tyrosinase inhibitors

3.8 Paper Mulberry or Mulberry Extract (Broussonetia papyrifera)

18
3.9 Hydroxy-coumarins

➢directly interact with tyrosinase inhibited melanogenesis & intracellular glutathione (GSH) synthesis in
melanocytes

• a combined treatment of hydro-coumarins & 𝜶tocopherols → ↑the hypo-pigmenting effect by a free radical-
scavenging mechanism.

3.10 Kojic Acid (≈ 1% )

➢suppresses tyrosinase activity → mainly by chelating copper ➔ whitening effect on the skin

❖ in cosmetic products →↑the product’s shelf life through its preservative & antibiotic actions

• usually used twice daily for 1-2 months or until the patient achieves the desired effect

contact allergy have a high sensitizing potential ---di Jepang dilarang

• Ex. containing 10% glycolic acid 2%HQ 2%kojic acid.

• derivativesof kojic acid → ↑penetration into the skin➔ ↑efficiency through

3.11 Licorice Extract

• Glabridin (Glycyrrhiza glabra) → the main ingredient of licorice extract that affects
skin…
• → treat dermatitis eczema pruritus cysts skin irritation

• inhibitstyrosinase activity
• inhibition of superoxide anion production & cyclooxygenase activity ➔ anti-inflammatory agent
• ex. licochalconeA— an oxygenated retrochalcone...

✓ glabridin exhibits a superior depigmenting effect compared to HQ.

• Licochalone → + treating rosacea

3.12 Emblicanin

• Emblica in an extract from the edible Phyllantus emblica fruit ➔ 100% natural

• The key components → tannins emblicanin A, emblicanin B.

✓ Have efficacy comparable to HQ & kojic acid----but without provoking similarly harmful side effects
20
 3.MELANOSME-TRANSFERINHIBITORS

3. 1 Niacinamide / nicotinamide

• is the biologically active amide of vitamin B3

➢ anti-inflammatory anti-oxidant immunomodulatory properties

➢ inhibit the transfer of melanosomes to epidermal keratinocytes ➔ improve unwanted facial pigmentation

• Ex. 5% niacinamide formulation used twice daily for 8 weeks

• by 3.5%niacinamide + retinyl palmitate

3.2 Soy

• soy contains isoflavones → have anti-oxidant properties & confer cancer-preventing benefits

• The PAR-2→ regulate the ingestion of melanosomes by keratinocytes

➢ inhibit PAR-2 activation ➔ induce skin depigmentation

• depigmentingactivity capacity to prevent UV-induced pigmentation

21
 4. Melanocyte-cytotoxicagents
4.1 Azelaic Acid

• a naturally-occurring saturated di-carboxylic acid

• a useful adjunct in the treatment of post-inflammatory pigment alteration (PIPA).

−
➢ ՜ the energy production &/or DNA synthesis of hyperactive melanocytes

➢ partially antit-tyrosinase activity (competitive inhibitor)

➢ in part inhibitory action on neutrophil-generated ROS: is a scavenger of OH° & inhibits oxyradical toxicity ➔ ↓
oxidative tissue injury @sites of inflammation & in melanin formation.

✓ AAis even more effective > topical HQ for patients with melasma, without the latter’s side effects 

• ex. (azelaic acid 20% cream + glycolic acid 15% or 20% lotion) is as effective as 4% HQ cream

• In the US, topical azelaic acid isavailable by prescription → 15%gel (rosacea), 20%cream (acne)

 The use for hyperpigmentation is off-label

• is well tolerated → adverse effects generally limited to mild local cutaneous irritation.

4.2 N-Acetyl-4-S-cysteaminyl phenol (NACP)

is a melano cytotoxic agent consisting of phenolic & catecholic compounds with potent depigmenting properties
22
 4.3 Monobenzone

• The monobenzyl ether @ a concentration of 20%

• used in vitiligo patients to permanently depigment the skin surrounding depigmented areas when re-pigmentation is not
feasible & the depigmented areas are disfiguring.

➢ metabolized inside cells into quinine → acts by permanently damaging the melanocytes.

• applied 2-3 times daily on pigmented skin → depigmentation beginning around 6-12 months of treatment.

 Transfer of the agent can occur to anyone who touches the medication ➔ contact with others should be avoided for up to
3h after application.
Potential side effects→ contact dermatitis conjunctival melanosis, skin lightening in untreated areas possibility
of an unwanted re-pigmentation starting from follicular melanocytes the need for lifelongtotal photo-protection

Because this agent is cytotoxic to melanocytes, it must be stressed that after de-pigmentation therapy with this agent, future
attemptsat re-pigmentation treatment

23
 5. ANTIOXIDANTS
➢Antioxidants → anti-aging anti-carcinogenic anti-inflammatory activities ↓pigmentation that occurs after exposure to UV light
(➔ treatment of melasma, In vitiligo: anti-oxidants may affect melanin production)

➢Anti-oxidants (ex, GSH, a naturally-occurring anti-oxidant involved in regulating melanin synthesis) → inhibit or delay
hyperpigmentation

• comparison of normal melanocytes ↔ melanocytes from vitiligo patients: levels in the vitiligo patients: lower catalase activity &
higher vitamin E& ubiquinone (CoQ10) ➔ an imbalance in the anti-oxidant status & ↑the intracellular peroxide levels

❖ some anti-oxidants ↑skin pigmentation ➔ the individual properties of each anti-oxidant should be considered before using them to ↓
skin pigmentation ➔ the indiscriminate use of these compounds should be weighed with caution.

Each anti-oxidant & its effects should be considered separately & it should not be assumed that all anti-oxidants will inhibit
melanogenesis → an opposite effect seems to be possible in some cases & unexpected hyper-pigmentation can occur.
• ex, quercetin, an extract of onion, is a tyrosinase inhibitor in vitro; however, this flavonol is a strong inductor of melanogenesis in
normal & malignant human melanocytes, & in reconstituted 3D human epidermis models.

• Glycyrrhizin → popular anti-oxidant frequently used to inhibit tyrosinase → stimulate melanogenesis in B16 melanoma cells.
35
 4.1 Vitamin C/ ascorbic acid

• found in citrus fruits & green leafy vegetables...

−
➢՜ melanin formation: ↓oxidized melanin → ↓o-DOPAquinone back to DOPA

➢has anti-oxidant properties stimulate collagen synthesis

 problems with stability & their utility is questionable…

• the packaging of these products limits UV & air exposure from rapidly oxidizing vitamin C

✓ Magnesium-L-ascorbyl-2- phosphate (VC-PMG), 2%, → is a stable derivative of ascorbic acid →

significant lightening effect

percutaneous absorption of VC-PMG is marginal → is a charged molecule, making it difficult to traverse

the SC.

tetra-iso palmitoyl ascorbic acid (use level 3%) → oil-soluble form of vitamin Cis easier to use &
prevents UV- induced skin pigmentation through its anti-oxidative properties

Other forms of vitamin C: vitamin C-ethyl …

36
 4.2 Vitamin E

• Tocopherol employs 4 homologues (𝛼,𝛽,𝛿,& 𝛾)→ differing # & positions of the methyl groups in the chromatin ring.

✓ Oral intake of vitamin E(𝛼-tocopherol or 𝛼-T) → effective for the treatment of facial hyperpigmentation, especially in
combination
with vitamin C.

▪ 𝜶-tocopheryl ferulate (composed of 𝛼-T & ferulic acid) → inhibit tyrosine hydroxylase activity in an indirect manner.

✓ stronger inhibitor of melanin formation > arbutin & kojic acid.

• ameliorate & prevent facial hyperpigmentation induced by UV radiation → inhibiting tyrosinase + anti-oxidant
mechanisms

▪ 𝛾-Tocopherol (𝛾-T) → suppress the expression of tyrosinase melanoma cells.

▪ Tocopheryl di-methyl glycinate (TDMG) → a novel tocopherol derivative

• 𝛾–TDMG HCl → a hydrophilic 𝜸-T derivative → convertsto the anti-oxidant 𝜸-T in skin greater BA> 𝜸-T itself

• significant skin lightening (0.5%) ∶ inhibition of the melanin synthesis & preventing photo-induced skin pigmentation
37
 4.3 Alpha Lipoic Acid / thioctic acid

• its reduced form di-hydro lipoic acid (DHLA) → both strong anti-oxidants.

• DHLA slightly stronger anti−oxidant activity by reacting with superoxide & hydroxyl radicals.

• 𝜶−lipoic acid → universal anti-oxidant: is both water & fat soluble ➔ act in the lipid cell
membrane
& the aqueous compartment of the cell.
−
the activation of NF-B transcription factor modulating the cellular response to UV radiation
preventing UV-induced oxidative injury inhibits tyrosinase: chelating copper suppressing

DOPAquinone-derivative formation ↑intracellular GSHlevels (↑its de novo synthesis) ➔ ↓UV

radiation sensitivity

➢Both lipoic & DHLAs→ block the expression of MITF ➔ inhibiting tyrosinase expression & activity

➢Na Zn di-hydro lipoyl histidinate (DHLHZn) → covalently react with DOPAquinone ➔ competitive
inhibitory effect on DOPAchrome formation ➔ effective skin lightening agent.

report on contact dermatitis to 𝜶− lipoic acid.

38
 5. OTHERAGENTS
5.1 𝜶-Hydroxy Acids (AHA) & 𝜷-Hydroxy Acid (BHA)
• Ex. Glycolic Acid → very versatile peeling agent minimal complications used in 20-70%

• lacticAcid
✓ People with virtually any skin type can be candidates for AHA& BHApeels

• they exert different effects on the epidermis & the dermis...

• In the epidermis: diminished corneocyte cohesion ➔ more rapid desquamation of the pigmented keratinocytes → the newly
formed keratinocytes will contain less pigment ↑the keratinocyte turnover rate ➔ shortening the cell cycle.

• In melanoma cells AHAs also directly inhibit tyrosinase activity.

✓ glycolic acid peels→ minimal adverse effects for the treatment of PIH

• lactic acid → treat melasma + ↓pigmentation

 When treating PIPA with peels, it is initially important to use lower concentrations of AHA

& slowly ↑the strength to avoid irritating the skin, causing even more hyperpigmentation.
✓ The use of topical HQ preparations pre-& post-peel ↓the chances of aggravating PIPA.
 5.2 Retinoids

✓ lipophilic vitamin Aderivatives → easily penetrate the epidermis.

➢directly influencing melanocytes indirectly modulating melanogenesis

➢Topical retinoids directly affect melanogenesis via tyrosinase, TRP-1 & -2 expression.

𝒊𝒏
𝒉
𝒊𝒃
𝒕
➢ detoxification of toxic species ➔ ↑the melano-cytotoxic effect of depigmenting agents.

➢By accelerating the cell turnover of epidermal keratinocytes → promote ↓melanosome transfer to the keratinocytes
➔ induces desquamation ➔ accelerated loss of melanin in the SC.

➢ induce dispersion of keratinocyte pigment granules ➔ a uniform distribution of melanin content in the epidermis + ↓the
cohesiveness of corneocytes

✓ Indirectly: changes in the SCmay facilitate the penetration of other/additional depigmenting agents into the epidermis & ↑
their B.A
➔ ↑depigmentation

• Tretinoin (Retin-A™, Renova™, Avita™) (0.05- 0.1%) → used to treat PIPA& melasma

• It is frequently employed as an adjuvant in the treatment of pigmentation disorders

40
• The topical retinoid tazarotene (Avage™, Tazorac™) → improve irregular hyper-pigmentation associated with
photoaging

✓ Adapalene (Differin Gel™0.1% and 0.3%) is a potent synthetic retinoid → had significantly fewer side effects.

• Oral 0.05% isotretinoin → not statistically significant results in treating Thai patients with melasma.

The side effects of retinoids: dryness irritation scaling: signs of a damaged skin barrier ➔ This condition allows for
other agents to
more readily penetrate into the skin & ↑efficacy (ex., with HQ)

➢It is advisable to add a corticosteroid to retinoid therapy to mitigate irritation.

• the combination consisting of 0.1% tretinoin+ 5% HQ+ 0.1% dexamethasone → the Kligman formula → treat
melasma.

41
5.3 Resorcinol

• Resorcinol is isomeric with cathecol & HQ.

• This bacteri-cidal agent is soluble in water, ether, & alcohol.

• Use: PIH + melasma acne secondary indications: sun-damaged skin freckles

should not be used in pregnancy or in darker skin types (IV–VI).

the possibility of an allergic reaction has a skin sensitization potential ➔ testing

the agent: applying to the retro auricular area a few days before using it as a peel.

➢4-substituted resorcinols → have potent tyrosinase inhibitory ability.

• isopentyl group derivative in position 6 of resorcinol (NKO-09), with a more potent

depigmenting effect > HQ : inhibiting tyrosine hydroxylation & DOPAoxidation.

▪ Rucinol (4-n-Butyl resorcinol): @ 0.3%

➢ inhibitory effect on both tyrosinase & tyrosinase-related protein (TRP)-1 & -2

42
 5.4 Octa-decene dioic Acid (ODA)
• is a skin-whitening agent with a similar structure to azelaic acid.

➢is a PPAR-𝛾(peroxisome proliferator-activating receptor ) agonist → the stimulate PPAR

• PPARsare members of the nuclear receptor superfamily, regulating important cellular
functions: cell proliferation &
differentiation, + inflammatory responses.
• 3 subtypes of PPAR(designated 𝛼,𝛽& 𝛾) are expressed in human melanocytes.

➢The binding to PPARleads to reduced melanin production through ↓synthesis of tyrosinase

mRNA.

5.5. Linoleic acid:

• Linoleic acid (LA) is an unsaturated omega-6 fatty acid called 18:2 (n-6).

• can be obtained from hydrolysis of vegetals (ex. Safflowe evening primrose kukui seed oils).

• Linoleic acid (omega-6) is located in the cell membranes

➢ can ↓the tyrosinase level accelerate tyrosinase degradation ➔ less melanin being produced➔
whitening
43
• @ 0.1%
 5.6 Pyruvic Acid

• is an alpha-keto-acid with keratolytic, anti-microbial, sebo-static properties

• + stimulate new collagen production & elastic fiber formation.

↑skin elasticity ↓skin wrinkling
• treatment of acne effectively ↓the pigmentation in melasma

✓ No side effects, such as persistent erythema or PIH, were observed.

5.7 Tranexamicacid:

• Tranexamic acid is a drug used to treat melasma

inhibit
➢ UV-induced hyperpigmentation, & melanocyte activity (lightening skin)

• In people with melasma, or dark spots → the pigment-suppressing abilities of tranxemic acid works
best on localized areas of irregular melanin distribution.

➢Tranexamic acid prevents the binding of plasminogen (originating from endothelial cells)
to keratinocytes → a possible mechanism for melasma treatment.

Tranexamic acid cetyl ester HCl → The mode of action is similar to the tranexamic acid used by Shiseido
44
 5.8 4-Methoxy potassium salicylate (4 MSK):

➢tyrosinase inhibition

5.9 Adenosine mono-phosphate (AMP) di-Na salt: @ 3%

➢This AMP salt acts as a fuel to the cells ➔ produce more energy ➔
↑epidermal turnover & the cells containing melanin will exfoliate faster ➔ ↓
the melanin content in the skin.

5.10 Magnolignan (Di-propyl bi-phenyl-2,2’-di-ol): @ 0.5%

• belongs to the family of poly phenols looks like the magnolol of magnolia.

• Magnolignan retards or slowsdown the maturation of tyrosinase.

5.11 rhododendrol/ 4-(4-Hydroxy phenyl)-2-butanol (4-

HPB) :

➢a competitive inhibitor of tyrosinase.

5.12 Chamomilla extract

✓ Dosis 0.5%
 anti-inflammatory the mechanism does not involve tyrosinase
➢ cells communicate with each other & once activated by UVB, the keratinocytes produce alpha-MSH & endotheline
→ bind to specific receptors in the SC & activate the melanocytes
➢ → Chamomille extract acts as an antagonist of this receptor ➔ ↓the “call” for melanin production.

5.13 Bovine placenta

• long used along with the use of vitamin C& its derivatives.

• The main source of placental extract was bovine

• it could also come from porcine origin→ recently used to replace the bovine due to the BSEissue (The form of
this disease in humans is the Creutzfeldt Jakob Disease)

➢ the mode of action of placental extract → ↑cell turnover to remove the melanin from the upper layers of the skin or the
role of high concentrations of minerals & amino acids, to ↓melanin synthesis
 5.15 Sea daffodil Extract
• Pancratium Maritimum is a flower that blooms in the harsh
environment of the Mediterranean region

• Products combined with brightening ingredients such as

niacinamide, soybean seed extract, glasswort extract, vitamin
C, and curcuma longa (turmeric).

• Mechanism :
✓Inhibiting POMC
✓Inhibit melanin tranfers and inflammation
✓reduces the lenght of dendrites
✓reduces the synthesis of the receptor TacR1 for
Substance P
 5.16 N-Acetyl Glucosamine

▪ Gula amino yang merupakan prekursor asam

Hyaluronic
▪ Menghambat glikosilasi tyrosinase Digunakan dalam
konsentrasi 2% saja atau dalam kombinasi dengan
niacinamide
▪ Dapat ditoleransi dengan baik dengan iritasi ringan-
sedang
▪ Aman dan berkhasiat dalam pengobatan
hiperpigmentasi sekunder akibat paparan sinar
matahari
 Chemical peels

• Sendiri atau dalam kombinasi dengan agen pencerah kulit

• Kurangi diskromia dan PIH
• Superficial -Glycolic -20-70% conc, salicylic,
lactic acid
Modifikasi Jessner, Yellow Peel
• Kedalaman Sedang- TCA 15-35%
• Kulit dalam- Fenol
• Mengurangi iritasi. Gunakan sunscreen
• Pra-perawatan- tretinoin, HQ, asam alfa hidroksi
 Laser Therapy

• 1064nm QS (Nd:YAG) laser

• margin keamanan yang lebih besar
• hasil memuaskan
• Lebih aman pada orang berkulit gelap
• Ablatif pecahan & non ablatif penggunaan
kosmetik pasca prosedur
• IPL pada lesi berpigmen
• PIH yang diinduksi laser
• pra perawatan dengan pencerah kulit agen
untuk mengurangi risiko PIH
 51
Laser Therapy
▪ Selective photothermolysis
▪ Melanin mengabsorpsi laser → panasnya merusak sel → • Nyeri
melanin lisis • Inflamasi
(Kemerahan,
bengkak)
• Gatal
• Blistering
• Hipopigmentasi /
hiperpigmentasi
• Lebam