Pharmocology of the Skin Flashcards
what are the 3 major routes of administration through the skin?
topical
transdermal
subcutaneous/depot
what is topical administration used for?
applied to surface of skin for local effect but also to treat underlying disease
good for local effect as it achieves high conc of drug only at desired site without systemic disease
what routes are used for systemic effects?
transdermal
subcutaneous/depot
name 6 other routes of epithelial drug administration
airways bladder lining conjunctival sac nasal mucosa rectum vagina
what is the stratum corneum?
keratin layer made of dead keratinocytes and corneocytes
most important barrier to drug penetration into/across skin
what is the structure of the stratum corneum?
brick and mortar model
bricks = corneocytes containing aggregated keratin filaments
mortar = intercellular lipids (highly hydrophobic)
describe the structure of the “bricks” in the brick and mortar model
corneocytes containing keratin filaments embedded in a filaggrin matrix surrounded by a cornified envelope
envelope is cross linked to adjacent corneocytes by corneodesmosomes
how do drugs move across the stratum corneum?
most through the intercellular route through the hydrophobic lipids
some small molecules can travel through the corneocytes via the transcellular route but not many
what sort of issues are topical drugs used to treat?
superficial skin disorders (psoriasis, eczema etc)
skin infections (antifungals, antibacterials etc)
itching
dry skin
warts
what is a vehicle and what types can be used?
inactive substance in which the drug is dissolved to be applied
types = ointments, creams, gels, lotions, pastes, powders
what determines the type of vehicle used?
the type of drug (eg. hydrophobic drug will dissolve in hydrophobic vehicle like ointment, hydrophilic drug will dissolve in hydrophilic vehicle like lotion)
and the clinical condition of skin (dry vs weeping etc)
how are transdermal drugs conventionally delivered? how is this quantified?
passive diffusion as the conc of drug in the vehicle > conc of drug in the skin described by ficks law: J = KpCv - J = rate of absorption - Kp = permeability coefficient Cv = concentration of drug in vehicle
what does ficks law show in terms of the importance of the vehicle?
concentration of drug in the vehicle and the partition coefficient (therefore rate of absorption) are highly dependant on the vehicle
how can the choice of vehicle affect the rate of absorption of the drug? give 4 examples
- lipophilic drug in lipophilic base = limited absorption as drug is just as happy in vehicle as in lipophilic skin
- lipophilic drug in hydrophilic base = great absorption as drug is happier in hydrophobic skin than hydrophilic vehicle
- hydrophilic drug in lipophilic base = limited absorption as drug doesn’t like lipophilic vehicle or hydrophobic skin
- hydrophilic drug in hydrophilic base = no absorption
what drives absorption of a drug from the vehicle into the skin?
only the dissolved drug
concentration gradient
undissolved drug doesn’t affect absorption
what are excipients?
increase the solubility of the drug in its vehicle, increasing the concentration and therefore the absorption
how can excess, undissolved drug in a vehicle affect the length of effectiveness and rate of delivery?
as undissolved drug is removed and absorbed into skin, the conc in vehicle decreases so more undissolved drug can now dissolve, replacing the lost drug and maintaining the concentration and therefore the rate of absorption for longer
used in nicotine patches
why are topically applied drugs generally poorly absorbed? how can this be improved?
only a small fraction partitions into the stratum corneum and enters the deeper layers of the skin
can be improved by hydration of the skin by reducing water loss from skin - can be achieved by use of oily vehicle (ointment) or cling film
why does hydration of the skin improve partitioning?
reduction in he barrier function of the stratum corneum due to reversible development of a pore pathway
how can the nature of the skin influence absorption of topically applied drugs?
thickness of stratum corneum at site of application (drug less effective at thick stratum corneum like sole of foot compared to face)
hydration of the skin
integrity of epidermis (trauma, inflammation, moist/weeping, dry, hairy) can all influence choice of vehicle, even for cosmetic reasons in case of hair
how can the pharmaceutical preparation influence absorption of topically applied drugs?
drug concentration/properties
the drug salt (i.e different salt in same drug can change its effectiveness in certain environments - eg. hydrocortisone)
the vehicle
how are glucocorticoids used in skin disease?
used topically in atopic eczema, psoriasis and pruritic
can be mild, moderate, potent or extremely potent depending on severity and site of disease
what are the effects of glucocorticoids?
anti-inflammatory
immunosuppressant
vasoconstricting
anti-proliferating effects on keratinocytes and fibroblasts
what can cause the penetration and potency of glucocorticoids to differ?
body site state of skin occlusion vehicle conc of drug form of drug
while short term low potency steroid use is safe, what are the adverse effects of using long term high potency steroids?
skin atrophy systemic effects spread of infection steroid rosacea stretch marks steroid rebound - down regulation or desensitisation of receptors
step 1 in glucocorticoid mechanism of action?
diffuse across the membrane
step 2 in glucocorticoid mechanism?
encounter GR receptor in cytoplasm which is in association with heat shock protein meaning it cant move into nucleus
step 3 in glucocorticoid mechanism?
GR binds to glucocorticoid and releases heat shock protein meaning it can move into the nucleus
step 4?
GR receptor/glucocorticoid complex binds with another complex of the same kind forming a homodimer which then binds to steroid response elements in promoter region of specific genes
step 5?
this causes activation or depression of the transcription of the gene which alters mRNA and therefore the synthesis of certain proteins
how are drugs delivered subcutaneously?
injection with needle inserted into adipose tissue just under skin
drug reaches systemic circulation by diffusion into capillaries or lymphatic vessels
what are the advantages and disadvantages of subcutaneous drug delivery>
Advantages:
slow absorption due to poor vascular supply
good for protein drugs (insulin) and oil based drugs (steroids)
can be used for drug depots which are slowly released into circulation
disadvantages:
- injection volume limited
advantages and disadvantages of skin administration of drugs?
advantages:
- simple, non-sterile application
- steady state plasma conc over long time
- avoids first pass metabolism so non-toxic to liver/intestines
- absorption can be quickly terminated
disadvantages:
- skin is water tight so only few drugs can penetrate through to dermis
what is transdermal drug delivery and what is it suitable for?
drug incorporated into adhesive patch applied to epidermis and absorption is controlled by drug release membrane (diffusion across cutaneous barrier)
suitable for LMW, lipiphilic, potent and short half life drugs
(eg - nicotine, GTN, fentanyl)
what are the advantages and disadvantages of transdermal drug delivery?
advantages: - steady rate of delivery - avoids first pass metabolism - rapid termination of action - reduced dosage frequency - convenient disadvantages: - few suitable drugs - cost
how can transdermal drug delivery be enhanced chemically?
adding enhancers like water or other solvents which increase permeability of skin
how can transdermal drug delivery be enhanced physically?
iontophoresis - low voltage
electroporation - short bursts of high voltage
sonophoresis - Ultrasound
microneedles- punch holes in skin
