Pharmacology and the Skin Flashcards
Major routes by which the skin is used for drug administration?
Topical - laargely for a LOCAL EFFECT, but also to treat underlying tissues
For systemic effects (often prolonged):
Transdermal
Subcutaneous/depot
What is the single most important barrier to drug penetration?
Stratum corneum
Structure of the stratum corneum?
Consists of CORNEOCYTES (hardened, dead, keratinocytes) surrounded by intercellular lipids forming 10-30 sheets of tissue that are constantly shed (desquamated) and renewed
Describe the “Brick and Mortar” model of the stratum corneum
Bricks - corneocytes containing aggregated keratin filaments embedded in a matrix of filaggrin surrounded by a cornified cell envelope that is highly cross-linked; adjacent corneocytes are held together by CORNEODESMOSOMES
Mortar - multiple bilayers of lamellar structures of intercellular lipids, i.e: cholesterol, free fatty acids; highly hydrophobic and can act as a reservoir for lipid-soluble drugs
Two routes through the stratum corneum?
Intercellular route - highly convoluted and tortuous but also very hydrophobic; local/systemic effects of a drug require penetration of the stratum corneum (occurs largely via the intercellular route and normally only allows diffusion of small, hydrophobic drugs)
Transcellular route - diffusion across corneocytes
Describe corneodesmosomes
Corneocytes express proteins, desmocollin and desmoglein (held in place by keratin intermediate filaments), which bind to eachother
Vehicles of topical drug administration?
Ointments Creams Gels Lotions Pastes Powders
2 factors affecting the choice of vehicle?
- Physiochemical properties of the drug
2. Clinical conditions
Examples of scenarios where drugs are applied topically?
Superficial skin disorders, e.g: psoriasis and eczema (glucocorticoids and retinoids)
Skin infections, e.g: viral, bacterial, funal and parasitic (anti-virals/biotics/fungals/parasitic classes)
Itching (anti-histamines)
Dry skin (moisturising agents)
Warts (keratolytic agents, e.g: salicylic acid)
How does conventional transdermal drug delivery occur?
PASSIVE process that is driven by diffusion; the rate of absorption/flux (J) is described by Fick’s Law
Equation for Fick’s Law to calculate the rate of absorption?
J = KpCv
Kp - permeability coefficient
Cv - conc. of drug in the vehicle
Describe Kp (permeability coefficient) in more detail
Embodies factors relating to:
The drug
The barrier
The interactions between the two
Km is the partition coefficient (not the Michaelis constant); Dd is the diffusion coefficient and L is the length of the diffusion pathway:
J = (DKm / L)Cv
Why is this equation clinically important?
Cv and Km are highly dependent upon the vehicle
Important factors in the determination of the vehicle of the drug?
Solubility of the drug in the vehicle (Cv)
Maximising the movement/partitioning of the drug from vehicle to the stratum corneum (Km) - drug must escape from vehicle and enter the outermost layer of the stratum corneum
How is Km described?
Equilibrium solubility of the drug in the stratum corneum relative to its solubility in the vehicle
How do different types of drugs in different bases cross the membrane?
Lipophilic drug in lipophilic base so Km is low; tends to remain in vehicle and little crosses the skin
Lipophilic drug in hydrophilic base; the base drives drug across membrane so there is a high Km; a lot of drug across the skin
Hydrophilic drug in lipophilic base; the base provides the driving force but the drug is hydrophilic so there is little absorption
Hydrophilic drug in hydrophilic base; the drug stays in the base and will not cross the membrane
How does solubility influence the driving force for absorption?
Only the soluble fraction provides the driving force for absorption; as soluble drug crosses the membrane, more drug dissolves
What are excipients?
Inclusion of excipients in the vehicle can enhance solubility and enhance absorption; these are molecular agents that increase drug solubility so there is a higher free drug conc.
Examples inc. DMSO, which is a better excipient than EMLA
What is an advantage of transdermal drug delivery?
Rate of drug delivery is constant and prolonged, with the net effect being a smooth Cpss
What factors improve partitioning?
Hydration of the skin by occlusion (this prevents water loss), e.g: using an ointment, cling film, will increase drug absorption
Inclusion of excipients, which will increase the solubility of hydrophobic drugs
How does increased partitioning result?
Reduction in the barrer function of the stratum corneum , due possibly to the reversible development of a pore pathway
Factors that influence absorption of topically applied drugs?
Nature of the skin, i.e: thickness of the stratum corneum at different sites of application, hydration of the skin and integrity of the epidermis
Drug/pharmaceutical preparation:
Drug conc. / physiochemical properties
Drug SALT, e.g: hydrocortisone butyrate far more potent that hydrocortisone acetate
Vehicle (must be specified and not substituted)
Topical uses of glucocorticoids in dermatology?
Widely used (topically) in the treatment of atopic eczema; they possess anti-inflammatory, immunosuppressant and vasoconstricting effects and anti-proliferating action (upon keratinocytes and fibroblasts)
How does glucocorticosteroid penetration, potency and clinical effect vary?
Body site, e.g: thickness of the stratum corneum
State of the skin, e.g: lower potency in children/certain body sites
Occlusion
Vehicle:
Affects potency (bioassays show ointment > cream/lotion)
Affects compliance
Conc. of drug
Form of drug, e.g: 1% hydrocortisone acetate (mild) compared to 0.1% hydrocortisone butyrate (potent)
Via which receptors do glucocorticoids signal?
NUCLEAR receptors, specifically GRα
Molecular mechanism of action of glucocorticoids?
Lipophilic molecules enter cells by diffusion across the plasma membrane
Within the cytoplasm, they combine with GRα, producing dissociation of inhibitory heat shock proteins; activated receptor translocates to the nucleus aided by “importins”
Within the nucleus, activated receptor monomers assemble into homodimers and bind to glucocorticoid response elements (GRE) in the promoter region of specific genes
Transcription of specific genes is either switched ON or OFF to alter mRNA levels and rate of synthesis of mediator proteins
What is the subcutaenous route of administration?
Drug delivered by a needle into the adipose tissue just beneath the skin; drug reaches the systemic circulation by diffusion into either capillaries, or lymphatic vessels
Advantages of the subcutaneous route of administration?
Absorption is relatively slow due to poor vascular supply (may be advantageous/disadvantageous)
Route of administration for many protein drugs
Suitable for administration of oil-based drugs
Can be used to introduce a depot of drug under the skin that is very slowly released into the circulation
Relatively simple and painless
Disadvantages of subcutaneous drug administration?
Injection volume limited
Why is the skin an attractive route of drug administration for a systemic effect?
Application is simple and non-sterile
Potentially allows for a Cpss of drug to be achieved over a prolonged period of time
Avoids first-pass metabolism, e.g: by the intestine and lvier and potential toxicity to those organs
Drug absorption may be rapidly terminated
Difficulty with using skin as a route of drug administration for a systemic effect?
Intact skin is a water-tight barrier and only a limited no. of drugs diffuse across the epidermis to reach the superficial capillaries of the dermis to be systemically available at an effective conc.
Describe transdermal drug delivery (TDD)
Drug is usually incorporated into an adhesive patch applied to the epidermis
What drugs is TDD more suitable for?
Low molecular weight
Moderately lipophilic
Potent OR
Of relatively brief half-life
Advantages of TDD?
Steady rate of drug delivery
Decreased dosing frequency
Avoidance of first-pass metabolism
Rapid termination of action (if t1/2 is short)
User friendly, convenient, painless (increased patient compliance/concordance)
Disadvantages of TDD?
Relatively few drugs suitable for TDD
Allergies
Cost
Examples of TDD drugs?
Nicotine, GTN, fentanyl, estradiol
Strategies to enhance TDD?
Chemical enhancement - enchancers interact with the lipid matrix of the stratum corneum to increase permeability (mainly to drugs that already cross the skin reasonably well)
Advantages of chemical enhancement of TDD?
Low cost
Can be incorporated into vehicles
Disadvantages of chemical enhancement of TDD?
Skin irritation/toxicity
Not effective for highly soluble drugs, or macromolecules
Agents for chemical enhancement of TDD?
Water - prolonged occlusion causes increased hydration of the stratum corneum and the formation of a “PORE” PATHWAY
A variety of solvents, e.g: ethanol, and surfactants
