Pharmacology of Skin Flashcards
What are the major routes of drug administration via the skin?
Topical (for local effects), Transdermal and Subcutaneous (for systemic effects)
What are some other epithelial routes?
Airways, bladder, conjunctival sac, nasal mucosa, rectum, vagina
What is a major advantage of topical drug application?
Allow for relatively high concentration of drug, but minimise adverse systemic effects
What layer of the skin is the most important barrier to drug penetration?
The stratum corneum
What does the stratum corneum consist of?
Corneocytes surrounded by intercellular lipids forming 10-30 sheets of tissue that are constantly shed and renewed
What are corneocytes made of?
Hardened dead keratinocytes
How many sheets of intercellular lipids are typically found in the stratum cornea?
20
What are corneocytes embedded in and what is this surrounded by in the stratum corneum?
Embedded in a filaggrin matrix surrounded by a cornified cell envelope (cross linked to adjacent corneocytes by corneodesmosomes)
What do corneocytes contain?
Aggregated keratin filaments
What are some examples of intercellular lipids?
Ceramides, cholesterol, free fatty acids
What benefit do the intercellular lipids convey for the stratum corneum in terms of drug application?
Highly hydrophobic so can act as a reservoir for lipid-soluble drugs
What makes up the “bricks and mortar” model of the stratum corneum?
Bricks=corneocytes
Mortar=multiple layers of lamellar structures of intercellular lipids
What are the two routes that drugs can use to move through the stratum corneum?
Intercellular route (most common) and the transcellular route
What do both local and systemic effects of drugs require to act?
Movement through the stratum corneum (normally only allows diffusion of small hydrophobic drugs)
How are topical drugs applied?
Directly on to the skin
What are some conditions that are commonly treated with topical drugs?
Superficial skin disorders (glucocorticoids,retinoids), skin infections (antivirals/bacterials/fungals/parasitics), itching (antihistamines), dry skin (moisturisers), warts (kerolytics)
What dictates the choice of vehicle used for a drug treatment?
Physiochemical properties of the drug and the clinical condition
What drives conventional transdermal drug delivery?
Diffusion (passive process)
What is the equation for rate of absorption (or flux)?
J=KpCv (Fick’s law)
What is Kp?
Permeability coefficient
What is Cv?
Concentration of drug in the vehicle (simplification of concentration gradient across barrier)
What does Kp embody?
Factors that relate to the drug and the barrier as well as their interactions: Km (partition coefficient), D (diffusion coefficient), L (length of diffusion pathway)
What is the other way to write J=KpCv?
J= (DKm/L)Cv
Why is Fick’s law clinically relevant?
Cv and Km (and thus J), are highly dependent on the vehicle
What important factors must be considered when choosing a vehicle?
The dissolved concentration of the drug (Cv) and maximising the movement of the drug from vehicle into the stratum corneum (Km)
How does a lipophilic drug in a lipophilic base act?
Soluble in both the vehicle and the skin, and partitions between the two
How does a lipophilic drug in a hydrophobic base work?
More soluble in the skin and partitions readily and preferentially into it
How does a hydrophilic drug in a lipophilic base act?
Limited solubility in both the vehicle and the skin, and partitions into it to a limited effect
How does a hydrophilic drug in a hydrophilic base act?
Soluble in the vehicle but not the skin, and remains on the surface of it
Which fraction of the drug drives absorption?
Only the fraction of the drug within the vehicle that is solubilised (e.g the drug that has dissolved)
Including what in the vehicle can enhance solubility?
Excipients (e.g propylene glycol added to hydrophobic glucocorticoids) enhance solubility and enhance absorption
What does including excess non-dissolved drug to transdermal patches do?
Increases duration of effectiveness and provides a constant rate of delivery
How does undissolved drug maintain the rate of absorption in transdermal patches?
The concentration of free drug is maintained by the undissolved drug solubilising which maintains a fairly constant soluble concentration which drives absorption
Why are topically applied drugs generally poorly absorbed?
Only a small fraction partitions into the stratum corneum and enters the deeper layers of the skin
What are some physical and chemical factors which can improve partitioning?
Hydration of the skin by occlusion (prevention of water loss-achieved by choice of vehicle or cling film), inclusion of excipients (also increases solubility of hydrophobic drugs)
How does the development of a pore pathway impact partitioning?
Increases partitioning results by reducing the barrier function of the stratum corneum
How does the nature of the skin influence absorption?
Site of application (thickness of stratum corneum), hydration of skin (vehicles/occlusive dressings), integrity of epidermis (e.g infection, inflammation)
What is the ranking of the areas of the skin according to their ability to absorb drugs, from least to most absorptive?
Nail, palm/sole, trunk/extremities, face/scalp, scrotum (if applicable)
What are some ways the pharmacological preparation and the drug itself can influence absorption?
Dug concentration, physiochemical properties, the drug salt, the vehicle
What are some conditions that use glucocorticoids in their treatment?
Atopic eczema, psoriasis, pruritis
What properties do glucocorticoids have?
Anti-inflammatory, immunosuppressant, vasoconstricting, anti-proliferating action upon keratinocytes and fibroblasts
What factors influence the penetration, potency and clinical effects of glucocorticoids?
Body site, state of skin, occlusion, vehicle, concentration and form of drug
Is short term use of glucocorticoids usually safe?
Yes-if low potency steroid
What are some adverse effects of long term use of high potency steroids?
Steroid rebound (due to GRalpha down regulation), skin atrophy, systemic effects, spread of infection, steroid rosacea, striae atrophica, telangiectasia)
What is a systemic effect of long term glucocorticoid use?
HPA axis depression due to systemic absorption
What is steroid rosacea?
Skin reddening and pimples of facial skin
What is striae atrophica?
Stretch marks
What is telangiectasia?
Small superficial dilated blood vessels
What type of receptor do glucocorticoids use for signalling?
Nuclear receptors (class 1), specifically GRalpha
What kind of molecule are glucocorticoids and what does this allow them to do?
Lipophilic molecules so enter cells by diffusion across the plasma membrane
What do glucocorticoids do once they are in the cytoplasm?
Combine with GRalpha producing dissociation of inhibitory heat shock protein
Where does the receptor move to from the cytoplasm after it has been activated by glucocorticoids?
Translocates to the nucleus aided by importins
What do the activated receptors do once they are within the nucleus?
Activated receptor monomers assemble into homodimers and bind to glucocorticoid response elements (GRE) in the promoter region of specific genes
What does the binding of GREs in the promoter regions do to the genes?
The transcription of specific genes is either transactivated or transrepressed to alter mRNA levels and the rate of mediator protein synthesis
How are subcutaneous drugs delivered?
Drug delivered by needle-inserted into adipose tissue just beneath surface of skin
How do drugs delivered subcutaneously reach the blood?
Reaches systemic circulation by diffusion into capillaries or lymphatics vessels (particularly high molecular weight compounds)
What are the advantages of subcutaneous drug delivery?
Absorption relatively slow due to poor vascular supply, route of administration for many protein drugs, used to introduce depot of drug under skin that is very slowly into the circulation, simple and painless
What is the disadvantage of subcutaneous drug delivery?
Limited injection volume
Why is the skin used to deliver drugs?
Simple and non-sterile application, allows for a steady state plasma concentration of drug to be achieved over a prolonged period of time, drug absorption can be terminated rapidly, avoids first pass metabolism
What is the issue with using the skin as a mode of drug delivery?
Intact skin is a water tight barrier=only limited number of drugs diffuse across the epidermis to reach the superficial capillaries of the dermis to be systemically available at an effective concentration
How is transdermal drug delivery normally carried out?
Drug is incorporated into adhesive patch and applied to the epidermis
How is drug absorption controlled in transdermal drugs delivery?
Partially controlled by a drug release membrane which occurs by diffusion across cutaneous barrier
What kind of drugs are suitable for transdermal delivery?
Low molecular weight, moderately lipophilic, potent, relatively brief half life
What are the advantages of transdermal delivery?
Steady state of drug delivery, decreased dosing frequency, avoidance of first pass metabolism, rapid termination of action, convenient, painless
What are the disadvantages of transdermal delivery?
Relatively few drugs suitable, allergies, cost
What are some drugs that are delivered via the transdermal route?
Nicotine, GTN, fentanyl, estrachol
What are some chemical methods for enhancing transdermal delivery?
Enhancers are added to interact with the lipid matrix of the stratum corneum to increase permeability, mainly to drugs that already cross the skin well
What are the advantages of chemical enhancers being added to transdermal drugs?
Low cost, incorporated into vehicles or conventional patches
What are the disadvantages of chemical enhancers being used in transdermal drugs?
Skin irritation/toxicity, not effective for highly water soluble drugs or macromolecules
What are some examples of chemicals used as enhancers in transdermal drugs?
Water (prolongs occlusion to cause increased hydration of stratum corneum and formation of pore pathway), solvents (ethanol), surfactants (sodium dodecyl sulphate)
What are some physical ways of enhancing transdermal drug delivery?
Iontophoresis, Electroporation, Sonophoresis, Microneedles
What happens in Iontophoresis?
Low voltage electrical pulses applied to the skin via a surface electrode over a prolonged period of time, driving a low molecular mass molecule through the skin
What occurs during Electroporation?
Very brief high voltage pulses lead to pore formation and has potential to allow delivery of hydrophilic and changed molecules
What is Sonophoresis?
Use of ultrasound to increase skin permeability
What are microneedles?
Typically 0.1-1mm in length, punch microscope holes in skin
What is the water content of different vehicles, from highest to lowest?
Lotions, creams, ointments, gels, pastes, powders
