Pharmocology of the Skin

Question 1

what are the 3 major routes of administration through the skin?

Answer 1

topical
transdermal
subcutaneous/depot

Question 2

what is topical administration used for?

Answer 2

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

Question 3

what routes are used for systemic effects?

Answer 3

transdermal

subcutaneous/depot

Question 4

name 6 other routes of epithelial drug administration

Answer 4

airways
bladder lining
conjunctival sac
nasal mucosa
rectum
vagina

Question 5

what is the stratum corneum?

Answer 5

keratin layer made of dead keratinocytes and corneocytes

most important barrier to drug penetration into/across skin

Question 6

what is the structure of the stratum corneum?

Answer 6

brick and mortar model
bricks = corneocytes containing aggregated keratin filaments
mortar = intercellular lipids (highly hydrophobic)

Question 7

describe the structure of the “bricks” in the brick and mortar model

Answer 7

corneocytes containing keratin filaments embedded in a filaggrin matrix surrounded by a cornified envelope
envelope is cross linked to adjacent corneocytes by corneodesmosomes

Question 8

how do drugs move across the stratum corneum?

Answer 8

most through the intercellular route through the hydrophobic lipids
some small molecules can travel through the corneocytes via the transcellular route but not many

Question 9

what sort of issues are topical drugs used to treat?

Answer 9

superficial skin disorders (psoriasis, eczema etc)
skin infections (antifungals, antibacterials etc)
itching
dry skin
warts

Question 10

what is a vehicle and what types can be used?

Answer 10

inactive substance in which the drug is dissolved to be applied
types = ointments, creams, gels, lotions, pastes, powders

Question 11

what determines the type of vehicle used?

Answer 11

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)

Question 12

how are transdermal drugs conventionally delivered? how is this quantified?

Answer 12

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

Question 13

what does ficks law show in terms of the importance of the vehicle?

Answer 13

concentration of drug in the vehicle and the partition coefficient (therefore rate of absorption) are highly dependant on the vehicle

Question 14

how can the choice of vehicle affect the rate of absorption of the drug? give 4 examples

Answer 14

1. lipophilic drug in lipophilic base = limited absorption as drug is just as happy in vehicle as in lipophilic skin
2. lipophilic drug in hydrophilic base = great absorption as drug is happier in hydrophobic skin than hydrophilic vehicle
3. hydrophilic drug in lipophilic base = limited absorption as drug doesn’t like lipophilic vehicle or hydrophobic skin
4. hydrophilic drug in hydrophilic base = no absorption

Question 15

what drives absorption of a drug from the vehicle into the skin?

Answer 15

only the dissolved drug
concentration gradient
undissolved drug doesn’t affect absorption

Question 16

what are excipients?

Answer 16

increase the solubility of the drug in its vehicle, increasing the concentration and therefore the absorption

Question 17

how can excess, undissolved drug in a vehicle affect the length of effectiveness and rate of delivery?

Answer 17

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

Question 18

why are topically applied drugs generally poorly absorbed? how can this be improved?

Answer 18

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

Question 19

why does hydration of the skin improve partitioning?

Answer 19

reduction in he barrier function of the stratum corneum due to reversible development of a pore pathway

Question 20

how can the nature of the skin influence absorption of topically applied drugs?

Answer 20

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

Question 21

how can the pharmaceutical preparation influence absorption of topically applied drugs?

Answer 21

drug concentration/properties
the drug salt (i.e different salt in same drug can change its effectiveness in certain environments - eg. hydrocortisone)
the vehicle

Question 22

how are glucocorticoids used in skin disease?

Answer 22

used topically in atopic eczema, psoriasis and pruritic

can be mild, moderate, potent or extremely potent depending on severity and site of disease

Question 23

what are the effects of glucocorticoids?

Answer 23

anti-inflammatory
immunosuppressant
vasoconstricting
anti-proliferating effects on keratinocytes and fibroblasts

Question 24

what can cause the penetration and potency of glucocorticoids to differ?

Answer 24

body site
state of skin
occlusion
vehicle
conc of drug
form of drug

Question 25

while short term low potency steroid use is safe, what are the adverse effects of using long term high potency steroids?

Answer 25

skin atrophy
systemic effects
spread of infection
steroid rosacea
stretch marks
steroid rebound - down regulation or desensitisation of receptors

Question 26

step 1 in glucocorticoid mechanism of action?

Answer 26

diffuse across the membrane

Question 27

step 2 in glucocorticoid mechanism?

Answer 27

encounter GR receptor in cytoplasm which is in association with heat shock protein meaning it cant move into nucleus

Question 28

step 3 in glucocorticoid mechanism?

Answer 28

GR binds to glucocorticoid and releases heat shock protein meaning it can move into the nucleus

Question 29

step 4?

Answer 29

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

Question 30

step 5?

Answer 30

this causes activation or depression of the transcription of the gene which alters mRNA and therefore the synthesis of certain proteins

Question 31

how are drugs delivered subcutaneously?

Answer 31

injection with needle inserted into adipose tissue just under skin
drug reaches systemic circulation by diffusion into capillaries or lymphatic vessels

Question 32

what are the advantages and disadvantages of subcutaneous drug delivery>

Answer 32

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

Question 33

advantages and disadvantages of skin administration of drugs?

Answer 33

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

Question 34

what is transdermal drug delivery and what is it suitable for?

Answer 34

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)

Question 35

what are the advantages and disadvantages of transdermal drug delivery?

Answer 35

advantages:
- steady rate of delivery
- avoids first pass metabolism
- rapid termination of action
- reduced dosage frequency
- convenient
disadvantages:
- few suitable drugs
- cost

Question 36

how can transdermal drug delivery be enhanced chemically?

Answer 36

adding enhancers like water or other solvents which increase permeability of skin

Question 37

how can transdermal drug delivery be enhanced physically?

Answer 37

iontophoresis - low voltage
electroporation - short bursts of high voltage
sonophoresis - Ultrasound
microneedles- punch holes in skin