Pharmacology: Skin

Retinoids in Dermatology ....................................................................................................................................................... 2

Principles of Topical Therapy .................................................................................................................................................. 3
 Retinoids in Dermatology
 Sun exposure makes you wrinkled later in life; retinoids can help
 Current definition: any molecule that binds to / activates retinoic acid receptors & activates transcription of
retinoic-acid-responsive genes to result in specific biological processes

Nomenclature
 Β-carotene is basically two vitamin A molecules (all-trans retinol)
hooked together; processed to yield all-trans retinol in vivo

Oxidative changes:
 all-trans retinol (vitamin A) all-trans retinaldehyde  all-trans
retinoic acid via oxidation

Esterification for storage & transport through blood

 add a fatty acid, e.g. palmityl acid, & esterify in enterocyte to get
retinyl palmitate. Ship it through the blood, store it in the liver,
then oxidize it in target cell to use

Inactivated by CYP450 hydroxylation (adds an –OH on the 4’carbon of all-trans retinoic acid)

Function: Retinoid Receptors

Retinoids originally classified based on structure, biologic activity: now based on binding to retinoid receptors
Retinoid receptors:
 Zinc-finger receptors in nucleus (e.g. RAR, RXR)
o After oxidation from ester form, retinoid binds binding protein, translocated to nucleus, binds receptor
o heterodimerize when ligand (retinoid) bound
o DNA-binding domain can then bind DNA & affect target gene expression of mRNAs  effector function
 Majority of receptors are RXRs (can bind hormones, not just retinoic acid)

Many retinoids now look nothing like RAs but just bind the receptors
 (STILL HAVE THE SAME EFFECT ALTHOUGH STRUCTURE DIFFERENT – if you bind the receptor, effect is same!)
 Reduce wrinkling, etc.

What do retinoids do?

 Dermis is 90% collagen (mostly type I); usually a balance between synthesis & destruction
 Fibroblasts make matrix molecules (e.g. collagen); extracellular enzymatic processing involved
o Collagen assembled thermodynamically, then crosslinked
 In photoaged skin you make less collagen (can see on immunostaining)
o UV light: ↑matrix metalloprotease activity, ↓ procollagen synthesis
 Retinoids help restore collagen production (varies person/person)

Results may vary

 Principles of Topical Therapy
 Think of stratum corneum like a “brick wall” built through a programmed series of events, keeping water & stuff
out, with keratohyaline granules tied together by cell-cell adhesions. How can you get through it?

It’s hard to get drugs through the skin in a reliable manner: Lots of variables
 status of skin (damaged?)  partition coefficient (if molecule likes to stay in its
 location (groin≫eyelids≫chest for absorption) vehicle, it won’t leave)
 concentration  diffusion coefficient (how fast?)
 liphophilicity (more is better)  metabolism
 MW (smaller better)  dermal vascular/lymph flow?

What to order: vehicles

 Lotions (Sprays): alcohol/water solutions, e.g. scalp How much to order?
 Creams: oil in water, good acceptance (feels better) 30g = one application
o Always preferred by pts except when they’re dry/scaly to the whole body
 Ointments: more occlusive but greasy (pts don’t like)
o For dry scaly skin in non-occlusive intertriginous area (greasy: not for hands)

Corticosteroids: Actions Pharmocoeconomics 101

1. Anti-inflammatory (a.k.a. things you already knew)
2. Immunosuppressive  Generic drugs are cheaper
3. Vasoconstrictive  Buying in bulk is cheaper
4. Antiproliferative o if you need a lot, buy a lot

Topical steroids (mild to strong): Hydrocortisone < triamcinalone < fluocinonide < clobetasol
 Balance efficacy with side effects; don’t put on groin or eyelids! Can be expensive!

Occlusion: get better penetration by “hydrating the bricks” & loosening up that “mortar”
 Principle: ↑ hydration + ↑ temp = ↑ absorption
 Can use saran wrap, baggies, cordran tape, vinyl suits, shower caps, whatever
 Can cause problems in topical steroid occlusion so be careful (infections, hot, itchy, etc)

Systemic steroids
 If you’re going to use them, use an adequate dose;
 Give at 7AM & 4PM if itchy, NOT before sleep (interferes with circadian rhythms)
 Taper BID to QD in AM 1st, then to alternate day slowly
 Can consider alternate drugs too
Key Points
1. Everything you put on
Treating an itch
the skin gets absorbed to
 COLD (ice cube, not hot shower – feels good but then bad afterwards)
some degree
 Lotions (evaporate; feels good)
2. Absorption ↑ in
 Dry? Lube it up with Vaseline diseases skin (↓ barrier
 Atarax / sedating antihistamines but don’t use with driving or drinking function)
 other therapies too (UV light – but avoid systemic corticosteroids) 3. As skin gets better from
drug, absorption
Wet dressings: for wet, weeping lesions, cooling/antipruritic/debridement decreases
 Keep moist for 30 min QID, don’t allow to dry
 Continuous wet soaks: good for debridement/cleansing, macerates necrotic tissue
 Can use Kerlex/saran wrap, re-wet q4h with asepto syringe