Dermatology MedChem (Sikazwe) Flashcards
Terms:
UVR PUVA Mab TNF IgG1
Ultra Violet Radiation Psoralen + UVA Monoclonal antibody Tumor Necrosis Factor Recombinant human immunoglobulin
VIS wavelength of ___-___ nm
400-700
UVA:
- wavelength of ___ (or ___) to ___
UltraViolet A
- 315 (or 320) to 400
UVB:
- wavelength of ___ to ___ (or ___)
UltraViolet B
- 280 to 315 (or 320)
Topical agents (9)
- Emollients
- Tars
- Anthralin
- Psoralen (Topical/Oral)
- Corticosteroids
- Vitamin D3 Analogs
- Retinoids (Topical/Oral)
- Macrolide
- Immunosuppressants
Systemic agents (2 major)
- Biologicals
- Non-Biologicals
Non-Biological Systemic agents (3)
- Methotrexate
- Cyclosporine
- Mycophenolate
TOPICALS - Emollients
________ - mostly H2O emulsions (prevent skin H2O loss)
- ________ (most effective, ___ Carbons)
- Lanolin (odorus, wool grease)
- Silicone based (hypoallergenic & non-comedogenic)
- _________: straight chain structure
- _________: a pentameric cyclic structure
Emollients
- Petrolatum, >25
- Silicone based:
- Dimethicone
- Cyclomethicone
TOPICALS - Tars
MOA unknown, but may have ____-_________ activity
____ Tar (e.g. Neutrogena T-Gel ®)
- Mixture of phenols, PAHs & heterocyclic compounds
- May be used with ___
- Photosensitizer
Non-photosensitizers (2):
- ________ Tar
- ________ Tar
anti-proliferative
Coal Tar
- UVB
- Shale Tars (Ichthammol)
- Wood Tars
TOPICALS - Anthralin or Dithranol (e.g. Psoriatec):
- Have ____-_________ properties
- A _____________ derivative of anthracene
- ________ paste (anthralin + ZnO + parrafin + salicylic acid)
MOA: Generates free ________ (oxygen super anion)
- anti-proliferative
- hydroxyanthrone
- Lassar’s
radicals
Topicals: Psoralens
- classified as _____________
8-Methoxypsoralen (Methoxsalen, 8-MOP)
*5-Methoxypsoralen (Bergapten, 5-MOP)
*4,5’,8-trimethylpsoralen (Trioxsalen, TMP)
furanocoumarins
Topicals: Psoralens
- Psoralen + UVA light (315-400nm) = PUVA:
MOA:
________ binding to __________ in DNA,
↓ of DNA synthesis (antiproliferative)
Covalent… pyrimidines
Topicals: Psoralens
ADMET (8-MOP)
- Potently Inhibits ___ ___ (key for Caffeine, Nicotine metabolism)
- “_________ based inhibition” or “_______ inhibition”
- CYP 2A6
- Mechanism, or suicide
Topicals: Glucocorticoids
- produced in…
- adrenal cortex
Topicals: Glucocorticoids
SAR: \_\_ keto ↑ glucocorticoid activity \_\_\_ β-keto ↑ activity \_\_-\_\_ db ↑ activity \_\_-\_\_ db ↑ activity \_\_\_ _-substituent ↑ activity
__ and/or __ __________, ↑ both lipophilicity & potency, prevent oxidation of Ketone
- C3 keto
- C17 β-keto
- C1-C2 db
- C4-C5 db
- C11 O-
- C6 and/or C9 halogenation
Topicals: Glucocorticoids
Potency rankings for topical glucocorticoids: Based on (3):
- Super-potent (e.g., _________ _________ _.__% cream & ointment)
- Potent (e.g., _________ ___________ _.__% cream & ointment)
- Medium potency (e.g., ________ ________ .% cream)
- Low potency (e.g.,_________ ______ .% & _% creams & ointments)
Based on:
1) chemical structure;
2) delivery vehicle;
3) % conc. in formulation
- Clobesterol proprionate 0.05%
- Betamethasone dipropionate 0.05%
- Betamethasone valerate 0.1%
- Hydrocortisone acetate 0.5% & 1%
Topicals: Vitamin D Analogs….
Calcitriol (Rocaltrol ®)
Calcipotriene (Dovonex ®)
Uses (2)
1) bone health;
2) Antiproliferatives
Topicals/Orals: Retinoids
- Normalize ___________ & ____________
Topical agent(s): \_\_\_\_\_\_\_\_\_ - Acetylenic retinoid
Oral Agents (2)
- keratinization & proliferation
Tazarotene (Tazorac ®)
Acitretin (Soriatane ®)
Isotretinoin (Accutane ®)
Topicals: Immunosuppressants
__________ ________ - ↓ release of inflammatory __________ from mast cells
- Pimecrolimus (Elidel ®) - ______ skin protein binding
- Tacrolimus (FK-506, Protopic ®)
Note: Both are ____ penetrating into skin
Calcineurin inhibitors
cytokines
- higher;
less
Systemic agents: Non-Biologicals
Methotrexate or MTX (Folex, Mexate):
- Antiproliferative - Inhibits __________ _________ (DHFR) - ________ DNA/RNA synthesis
- Immuno-suppressant & Anti-inflammatory effects
- Dihydrofolate Reductase
inhibits
Systemic agents: Non-Biologicals
Methotrexate or MTX (Folex, Mexate):
SAR
- ______ ring, p-Amino Benzoic Acid, Glutamic Acid
- Aromaticity of the _______ ring should be maintained for ________
- Aromatic _-alkylation ↓ activity
- _-___ is essential for activity
- Pteridine,
- pteridine, activity
- N-
- N-CH3
Systemic agents: Non-Biologicals
Methotrexate or MTX (Folex, Mexate):
ADMET
Absorption: PO variable due to __________
Distribution: 50-70% bound; DDIs - displaced by ______ drugs (sulfonamides, salicylates, etc.)
Metabolism: 7-OH-MTX
Elimination: 80 % (______)
Toxicity: e.g. acute renal toxicity ….. _________ precipitation in urine (hydration/ urine alkalinization can help)
A: ionization D: acidic M: 7-OH-MTX E: urine T: 7-OH-MTX
Systemic agents: Non-Biologicals
Cyclosporine:
- A “______” Immunosuppressant
- Activated by complexation with _________ receptor
- Inhibits _________ ________ & T-cell production
- 11 Amino Acid cyclic peptide
- prodrug
- ciclophilin
- calcineurin phosphatase
Systemic agents: Non-Biologicals
Mycophenolate:
- A “_______” Immunosuppressant
- Rapidly forms ___ after PO or IV
MPA = ___________ _____:
- Potent, selective, non-competitive & reversible inhibitor of _____
- Inhibits _- & _-___________ proliferation
- Inactivated by phenolic Glucuronidation to ____
- prodrug
- MPA
= Mycophenolic Acid
- IMPDH
- T- & B-lymphocytes
- MPAG
Acne Overview:
4 major components:
Treatment Goals (4)
components:
- Increased sebum production
- Excessive follicular keratinization
- Bacterial (P. acnes) growth
- Inflammation
treatment goals:
- Normalize follicular keratinization
- Decrease sebaceous gland activity
- Decrease P. acnes colonization
- Decrease inflammation
Acne Treatment Agents (4)
- Keratolytics
- Retinoids
- Hormones
- Antibiotics
Acne:
Keratolytics (4)
- Glycolic Acid (AHA)
- Salicylic Acid
- Sulfur
- Benzoyl peroxide
Acne: Keratolytics
SAR:
- ____ group(s)
- __ group on the carbon _____ to –COOH group
- COOH
- OH, alpha
Acne: Keratolytics
Glycolic Acid
- An ____-hydroxy acid
- Hydrophylic Acid
- Higher concs.- for deeper skin peels
- Metabolized to ______ ____
- alpha-
- to oxalic acid
Acne: Keratolytics
Salicylic Acid
- Promotes __________ (shedding)
- More _________ than glycolic acid
- May be irritating, but is generally well tolerated
- desquamation
- lipophylic
Acne: Keratolytics
Sulfur (monotherapy or mixtures)
S + Sulfacetamide (Plexion ®, Avar ®)
S + Zinc Oxide
MOA
– Unclear, but …..Sulfur reacts with _______ on skin cells to produce ___ which degrades keratin
- cysteine, H2S
Acne: Keratolytics
Benzoyl peroxide:
(e. g. Oxy-10 ®, Clearsil ®, ProActive ®)
- Has _________ effects - Propionibacterium Acnes
- Is absorbed in the skin & forms ________ ____
- Benzoic acid – rapidly excreted in ______
- antibiotic
- benzoic acid
- urine
Acne: Retinoids
\_\_\_\_\_\_\_\_\_ - Derivatives of Vitamin \_\_ (retinol) - Act via retinoid receptors: \_\_\_ (alpha, beta, gamma) and \_\_\_ 1- Anti-\_\_\_\_\_\_\_\_\_ properties 2- Anti-\_\_\_\_\_\_\_\_\_ properties 3- ↓ \_\_\_\_\_ production
Retinoids
- A1
- RAR and RXR
1- inflammatory
2- proliferative
3- sebum
Acne: Retinoids Biosynthesis
Beta-Carotene
to
Retinal \_\_\_\_\_\_
to
ATRA \_\_\_\_\_\_\_\_\_
SAR:
- The acid form is active at retinoid _______ (-____ group is essential)
- 1st & 2nd gen. retinoids are _______
- 3rd gen. retinoids are _______
Retinol
Isotretinoin
SAR:
- receptors, (-COOH)
- polyenes
- polyaryls
Acne: Retinoids 1st generation
_________ (Vitamin A1) - parent compound
___-_____ retinoic acid - 1st retinoid for acne
__-___ retinoic acid - Geometric isomer of Tretinoin
Retinol
All-Trans
13-cis
Acne: Retinoids 2nd generation
- Etretinate (Tegison ®):
- _____ _____ Prodrug
- T1/2 (___ ____) - highly lipophilic
- Removed from U.S. market in 1998 due to teratogenicity
- ______ Therapeutic Index
- *Acitretin (Soriatane ®):
- ______ form of Etretinate
*
- Ethyl Ester
- 120 days
- Narrow
- *
- Active
Acne: Retinoids 3rd generation
*Adapalene (Differin ®)
1st ________ retinoid
Lipophilic
Tazarotene (Tazorac ®) Tazarotenic Acid (active metabolite)
synthetic
Acne: Retinoids 3rd generation
ADMET:
Tazarotene Low systemic \_\_\_\_\_\_\_\_\_ – low sytemic \_\_\_\_ \_\_\_\_\_\_ - rapidly metabolized - short t1/2 - Do not accumulate in \_\_\_\_\_ \_\_\_\_\_\_\_ - Equally excreted in \_\_\_\_\_ and \_\_\_\_\_
absorption
side effects
- fatty tissue
- urine and feces
Acne: Hormones (OCs)
OCs work on _________ triggers of acne:
Hormonal adjunct therapy in females (2)
hormonal
- Ethinyl Estradiol & Norgestimate (Ortho Tri-Cyclen Lo®)
- Ethinyl Estradiol & Drospirenone (Yasmin®, Yaz®)
Hormones: Antiandrogens
Steroidal AA: _____________
Non-Steroidal AA:
1.
2.
Both estrogenic/anti-androgenic agents regulate _________ ______ and prevent _______ _______ production
Spironolactone (Aldactone)
- Flutamide (Eulexin)
- Ketaconazole
androgen levels
excess sebum
Wrinkles (Fine/coarse) & pigmentary changes in the skin due to (3)
1) UVR
2) Smoking
3) Xenobiotic insult
Sunscreens (UVA/UVB)
Physical Sunscreens -
Topical preparations include (2)
Notes:
- Are broad spectrum (UVA & UVB)
- _____ - do not irritate the skin
- Available in ________ formulations
- Reflect, scatter & absorb UVR on skin
- Zinc Oxide (ZnO)
- Titanium Dioxide (TiO2)
- inert
- micronized
Chemical sunscreens: (organic) compounds that absorb UVR UVA (315-400 nm) Absorber(s): Dibenzoylmethanes Avobenzone Absorbs the full spectrum of UVA Rapidly degraded by UVA
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