Pharmacology and skin Flashcards
What are the major routes of drug administration via the skin ?
- Topical (largely for local effect)
- Transdermal (for systemic effects)
- Subcutaneous/depot (for systemic effects)
Drug administration via the skin can be used to treat systemic [via transdermal drug delivery (TDD) or subcutaneous/depot], as well as skin disease - T/F?
True
What is an advantage of topical administration ?
Allows a relatively high local concentration of drug, but minimises adverse systemic effects
What layer is the single most important barrier to drug penetration ?
The strateum corneum as both local and systemic effects of drugs require penetration of the stratum corneum
What does the stratum corneum consist off ?
Consists of corneocytes (hardened, dead, keratinocytes) surrounded by intercellular lipids forming sheets of tissue that are constantly shed (desquamated) and renewed.
Adjacent corneocytes are held together by corneodesmosomes.
Multiple bilayers of lamellar structures of intercellular lipids (i.e. ceramides, cholesterol, free fatty acids). Highly hydrophobic and can act as a reservoir for lipid-soluble drugs (e.g. topical corticosteroids).
Think of the corneocytes as the bricks and the intracellular lipids as the mortor
How do drugs penetrate the stratum corneum ?
Two ways - Intracellular route and transcellular route
The intracellular route is the most common.
What is meant by topical route of administration ? and give some examples of vehicles used topically
Drug applied directly to the surface of the skin
Some examples include:
- ointments
- creams
- gels
- lotions
- pastes
- powders
What is the difference between topical and transdermal administration ?
The terms are often used interchangeabley but topical is meant to have an effect as the site of administration whereas transdermal medications are absorbed through the skin or mucosal membranes but are intended to have a systemic rather than local effect.
What is Ficks law of diffusion ?
The amount of gas that moves across a sheet of tissue in unit time is proportional to the area of the sheet but inversely proportional to its thickness
What is the equation for rate of absorption of topically/transdermal medications ?
J = KpCv
- J = rate of absorption
- Kp = permeability coefficient
- Cv = concentration of drug in vehicle
Refer to formula sheet for more.
What are the factors influencing the absorption of topical/transdermal medications ?
Conventional transdermal drug delivery is a passive process, driven by diffusion and rate of absorption is described by ficks law of diffusion.
The vehicle is a factor which absorption of the drug is highly dependant on. Also the factors described in ficks law e.g. area and thickness affecting diffusion
Why are topically applied drugs generally poorly absorbed ?
Because only a small fraction paritions into the stratum corneum
List some of the physical and chemical factors which can improve partitioning
- Hydration of the skin by occlusion (prevention of water loss from the skin) - can be done by using cling film or maybe an ointment over a cream
- Inclusion of excipients which also increase the solubility of hydrophobic drugs
- Integrity of the epidermis
- Site of application different parts of the body have varying thickness of the stratum corneum
- Drug concentration / physicochemical properties
- the vehicle
What is an excipient?
An inactive substance that serves as the vehicle or medium for a drug or other active substance.
List some of the features that glucocorticosteroids potency and clinical effect varies with
Body site
- e.g. thickness of stratum corneum (keratin layer)
State of the skin
- e.g. lower potency in children/certain body sites
Occlusion
Vehicle
- affects potency - bioassays (vasoconstriction) show ointment > cream/lotion
- affects compliance
Concentration of drug
Form of drug:
- 1% hydrocortisone acetate = mild
- 0.1% hydrocortisone butyrate = potent
What is the mechanism of action of glucocorticoids ?
- Enter cells by diffusion across the plasma membrane
- In the cytoplasm the combine with GR(alpha) causing dissociation of inhibitory heat shock proteins
- The activated receptor translocates to the nucleus aided by ‘importins’
- In the nucleus activated receptors monomers assemble into homodimers and bind to glucocorticoid response elements (GRE) in the promotor region of specific genes
- Transcription of specific genes is switched on or off
- This alters mRNA levels and rate of synthesis of mediator proteins
Glucocorticoids = yellow, receptors = blue
Glucocorticoids signal via nuclear receptors - mainly what one ?
GRalpha
Describe what subcutaneous route of administration is
Drug delivered by a needle [inserted into the fatty (adipose) tissue just beneath the surface of the skin]
How does the drug reach the systemic circulation if it is administered subcutaneously ?
By diffusion into either (i) capillaries, or (ii) lymphatic vessels
What are the advantages of subcutaneous drug administration ?
- Relatively simple and painless
- Absorption is relatively slow (advantageous/disadvantageous) due to poor vascular supply
- Route of administration for many protein drugs (e.g. insulin
- Suitable for administration of oil-based drugs (e.g. steroids)
- Can be used to introduce a depot of drug under the skin
What is the main disadvantage 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 (when drug is applied topically)
- Potentially allows for a steady-state plasma concentration (Cpss) of drug to be achieved over a prolonged period of time
- Avoids first pass metabolism
- Drug absorption can be terminated rapidly
However only a limited number of drugs are able to diffuse across the epidermis to reach the superficial capillaries of the dermis to be systemically available at an effective concentration
Describe transdermal drug delivery
- Drug is usually incorporated into an adhesive patch applied to the epidermis
- Drug absorption is (partially) controlled by a drug release membrane
What are some of the advantages and disadvantages of transdermal drug delivery ?
Advantages:
- Steady rate of drug delivery
- User friendly, convenient, painless - patient compliance / concordance
Disadvantages:
- Relatively few drugs suitable for TDD, allergies, cost
Give a couple examples of drugs adminstered transdermally ?
Nictonine and GTN patches
What are enhancers and what do they do ?
Enhancers interact with the lipid matrix of the stratum corneum to increase permeability mainly to drugs that already cross the skin reasonably well
e.g. water, some solvents - eithanol etc
What are the advantages and disadvantages of enhancers ?
Advantages:
- low cost
- can be incorporated into vehicles, or conventional patches
Disadvantages:
- skin irritation/toxicity
- not effective for highly water soluble drugs, or macromolecules
