Pharmacology Flashcards
What are the main routes of drug administration via the skin?
Topical, transdermal, subcutaneous/depot
Which methods of drug administration via the skin are useful for systemic drug effects?
Transdermal and subcutaneous/depot injections
What epithelial routes of drug administration exist? (excluding those involving the skin)
Airways, bladder/intravesicle, conjunctival sac, nasal mucosa, rectum and vagina
What is the main advantage of epithelial drug administration?
High local concentration of the drug giving a strong local effect but minimal systemic effect
What is the structure of the keratin layer?
Corneocytes surrounded by intercellular lipids in lamellar structures (brick and mortar model)
What is the most pharmacologically relevant layer of the skin in terms of drug delivery?
Keratin layer
How are corneocytes held together?
Intercellular corneodesmosomes
What are intercellular lipids composed of? What ratio is this in?
Ceramides, cholesterol, free fatty acids. 1:1:1
What are the different routes of drug transport through the keratin layer of the skin? What is the most common route?
Intercellular (most common) and transcellular.
Normally only small, hydrophobic drugs may pass through the skin. T/F
True
How can you increase the permeability of the skin to drugs?
Breaking down corneodesmosomes
Intercellular lipids can act as a reservoir for the storage and slow release of lipophilic drugs. T/F
True
What are the topical treatments for superficial skin disorders?
Glucocorticoids and retinoids
What are the topical treatments for skin infections?
Antivirals, antibacterials, antifungals and antiparasitics
What is the topical treatment for pruritis?
Antihistamines
What is the topical treatment for dry skin?
Moisturising agents
What is the topical treatment for warts?
Keratinolytics
What are the vesicles used for topical drugs?
Ointments, creams, gels, lotions, pastes and powder
What factors are important for deciding the vesicle of a topical drug?
Physiochemical properties and clinical condition
What is Fick’s law?
J (the rate of absorption) = Kp (the permeability coefficient) x Cv (concentration of drug in the vehicle/concentration gradient)
What does Kp consist of?
[Km (the partition coefficient) x D (the diffusion coefficient)]/ L (length of the diffusion pathway)
Why is Fick’s law clinically important?
Km (the partition coefficient) and Cv (concentration of drug in the vehicle) are dependent on the choice of vehicle
The best drugs for topical absorption are lipophilic/hydrophilic and dissolved in a hydrophilic/lipophilic base
Lipophilic and hydrophilic
What can increase absorption of a topical drug?
Inclusion of excipients in the drug vehicle can increase drug solubility and so absorption
The inclusion of excess, non-dissolved drug in topical applications (e.g transdermal patches) can be useful for what reason?
As the dissolved drug is absorbed by the skin the undissolved drug can migrate into the vehicle, therefore providing a fairly constant delivery rate
Which physical and chemical factors can improve drug partitioning?
Hydration of the skin (occlusion - vehicle choice or clingfilm)
Excipients which increase solubility
Reducing the barrier function of the keratin layer increases drug partitioning. T/F
True
Rank the thickness (and so lack of permeability) of different areas of the skin
Nails > palm/sole > trunk/extremities > face/scalp > scrotum
What factors relating to the skin influence the absorption of topically applied drugs?
Skin thickness, skin hydration and integrity of the epidermis
What factors improve the hydration of the skin in relation to drug absorption?
Vehicle choice and occlusive dressings
Moist/weeping skin, dry skin and hairy skin will all have different vehicle choices respectively. T/F
True
What factors relating to the drug influence the absorption of topically applied drugs?
Drug concentration, physiochemical properties of the drug, the drug salt, the vehicle
Glucocorticoids are used in the treatment of atopic eczema. T/F
True
What are the effects of topical glucocorticoids?
Anti-inflammatory, immunosuppressant, vasoconstricting & anti-proliferative against keratinocytes & fibroblasts
What are the UK catagories of topical glucocorticoids?
Mild, moderate, potent and very potent
Are adverse affects of glucocorticoids more likely with topical or oral administration?
Oral
Is hydrocortosone acetate or butyrate the more potent of the two?
Hydrocortosone butyrate is potent (the other is mild)
Describe the molecular mechanism of action of glucocorticoids
Glucocorticoids are lipophilic and so diffuse across the cell membrane > in the cytoplasm they combine with GR-alpha receptors > inhibitory heat shock proteins then dissociate > the receptors, now activated, translocates to the nucleus with the help of importins > monomeric receptors join into homodimers > homodimers bind to glucocorticoid response elements in the promotor regions of genes > specific genes are either transactivated or transrepressed > the rate of protein synthesis is altered
What is the process subcutaneous drug delivery?
A needle is inserted into the skin to the depth of the adipose tissue
How do drugs delivered by subcutaneous injection reach the systemic circulation?
Diffusion into capillaries or lymphatics (if high molecular weight)
What are the advantages and disadvantages of subcutaneous drug delivery?
Advantages: -slow absorption -useful for protein drugs (e.g insulin) -useful for oil-based drugs (e.g steroids) -useful for introducing depot of drugs -simple procedure -painless Disadvantages: -limited injection volume
Why is subcutaneous drug absorption relatively slow?
Poor vascular supply
What are the reasons that the cutaneous route of drug administration may be desirable for systemic drug delivery?
- Easy & non-sterile application (topical only)
- Steady-state plasma concentration can be achieved relatively easily
- Avoidance of first pass metabolism
- Drug absorption can be terminated easily
What is the difficulty with subcutaneous drug administration when there is a desired systemic effect?
The skin is a tight barrier that only a few drugs can diffuse through at a reasonable concentration
What is transdermal drug delivery?
Drug is incorporated into a patch applied to the skin allowing drug to diffuse across the epidermis at a rate controlled by the drug release membrane
What features do drugs delivered by transdermal patches usually possess?
Low molecular weight, lipophilic, potent & possessing a short half life
What are the advantages and disadvantages of transdermal drug delivery?
Advantages: -steady drug delivery rate -decreased dosing frequency -avoids first pass metabolism -can terminate drug delivery rapidly -easy & painless to apply -patients very compliant Disadvantages: -tendency for allergic reaction -few drugs suitable -expensive
What chemical strategy can be used to increase transdermal drug delivery?
Inclusion of chemical enhancers which increase the permeability of the lipid matrix of the keratin layer
What are the advantages and disadvantages of chemical enhancers?
Advantages:
-low cost
-easily incorporated into vehicles or patches
Disadvantages:
-may irritate skin
-not useful for highly water soluble drugs/macromolecules
What are some examples of chemical enhancers?
Water, solvents (e.g ethanol) and surfactants (e.g sodium dodecyl sulphate)
Why is water a good chemical enhancer?
Prolonged occlusion causes increased hydration of the keratin layer and the formation of a pore pathway
What are some physical strategies that can increase transdermal drug delivery?
Iontophoresis, electroporation, sonophoresis and microneedles
What is iontophoresis? What drugs is it used for?
Low voltage electrical pulses are applied to the skin over a long period of time driving low molecular weight drugs of the same charge through the skin. Lidocaine and fentanyl
What is electroporation?
Short lasting high voltage pulses being applied to the skin causing the formation of pores. Delivers hydrophilic and charged drugs to the skin
What is sonophoresis?
The use of ultrasound to increase skin permeability
What are microneedles?
Very small needles which punch microscopic holes in the skin
