Pharmacology

Question 1

What is the single most important barrier to drug penetration?

Answer 1

Stratum corneum

Question 2

What does the stratum corneum consist of?

Answer 2

Corneocytes surrounded by intercellular lipids forming 10-30 sheets of tissue (typically 20) that are constantly shed and renewed

Question 3

What is the Brick and Mortar model?

Answer 3

Model of structure of Stratum Corneum

Question 4

What are the bricks in the Brick and Mortar model of the stratum corneum??

Answer 4

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

Question 5

What is the mortar in the Brick and Mortar model of the stratum corneum?

Answer 5

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)

Question 6

Describe penetration of the stratum corneum by drugs?

Answer 6

Occurs largely via intercellular route and normally allows only diffusion of small, hydrophobic drugs

Question 7

What is the choice of vehicle dictated by in the topical route of drug administration?

Answer 7

Physicochemical properties of the drug, and clinical condition

Question 8

Describe the process of conventional transdermal drug delivery?

Answer 8

Passive process driven by diffusion

Question 9

How is the rate of absorption described regarding topical drug administration?

Answer 9

Rate of absorption (or flux, J) is described by Fick’s law J = KpCv, where Kp is the permeability coefficient and Cv is the concentration of drug in the vehicle (the latter being a simplification of the concentration gradient across the barrier)

Question 10

What factors does the permeability coefficient of a topically applied drug relate to, and why are they clinically important?

Answer 10

The drug, the barrier and their interactions: Km, the partition coefficient; D, the diffusion coefficient; and L, the length of the diffusion pathway. Important as Cv (concentration of drug in vehicle) and Km are highly dependent upon vehicle

Question 11

How is Km, the partition coefficient, described?

Answer 11

The equilibrium solubility of the drug in the stratum corneum relative to its solubility in the vehicle

Question 12

What’s inclusion in the vehicle of topical drugs can enhance solubility and enhance absorption?

Answer 12

Excipients such as propylene glycol used in glucocorticoids

Question 13

What physical and chemical factors can improve partitioning?

Answer 13

Hydration of skin by occlusion - achieved by choice of vehicle (e.g. ointment vs creams), cling film. Inclusion of excipient

Question 14

What factors regarding the nature of the skin can influence of topically applied drugs?

Answer 14

Site of application (thickness of stratum corneum). Permeability roughly ranked as: nail

Question 15

What factors regarding the drug/pharmaceutical preparation can influence of topically applied drugs?

Answer 15

Drug concentration/physicochemical properties, drug salt (hydrocortisone butyrate more potent than hydrocortisone acetate), vehicle (should be specific and not substituted)

Question 16

Describe some features of the glucocorticoids

Answer 16

Widely used in atopic eczema, possess anti-inflammatory, immunosuppressant and vasoconstricting effects and anti-proliferating action upon keratinocytes and fibroblasts. Various formulations. Less likely to have adverse effects when topical

Question 17

Through what receptors do glucocorticoids signal?

Answer 17

Nuclear receptors (class 1), specifically GRalpha

Question 18

Describe the molecular mechanism of glucocorticoids

Answer 18

Enter cells by diffusion. Combine with GRalpha, production dissociation of inhibitory HSPs. Activated receptor translocates to nucleus aided by transportins. Within nucleus monomers assemble into homodimers, bind to glucocorticoid response elements in promote region. Transcription of specific genes switched on/off (transactivated/repressed) to alter mRNA levels and rate synthesis of mediator proteins

Question 19

In transdermal drug delivery what is drug absorption partially controlled by?

Answer 19

Drug release membrane, occurs by diffusion across cutaneous barrier

Question 20

What factors of a drug make TBB a suitable choice?

Answer 20

Drugs that are low mw, moderately lipophilic, potent, relatively brief half life

Question 21

What chemical enhancement occurs in TDD?

Answer 21

Enhancers interact with lipid matrix of stratum corneum to increase permeability, mainly to drugs that already cross skin reasonably well.

Question 22

What agents are used in chemical enhancement of TDD?

Answer 22

Water- prolonged occlusion (via topical formulation or patch causes increased hydration of stratum corneum and formation of pore pathway), variety of solvents (e.g. ethanol) and surfactants (e.g. sodium dodecyl sulphate)

Question 23

What physical enhancement strategies occur in TDD?

Answer 23

Iontophoresis, electroporation, sonophoreiss, microneedles