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Flashcards in Pharmacology Deck (23)
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1
Q

What is the single most important barrier to drug penetration?

A

Stratum corneum

2
Q

What does the stratum corneum consist of?

A

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

3
Q

What is the Brick and Mortar model?

A

Model of structure of Stratum Corneum

4
Q

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

A

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

5
Q

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

A

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)

6
Q

Describe penetration of the stratum corneum by drugs?

A

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

7
Q

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

A

Physicochemical properties of the drug, and clinical condition

8
Q

Describe the process of conventional transdermal drug delivery?

A

Passive process driven by diffusion

9
Q

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

A

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)

10
Q

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

A

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

11
Q

How is Km, the partition coefficient, described?

A

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

12
Q

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

A

Excipients such as propylene glycol used in glucocorticoids

13
Q

What physical and chemical factors can improve partitioning?

A

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

14
Q

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

A

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

15
Q

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

A

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

16
Q

Describe some features of the glucocorticoids

A

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

17
Q

Through what receptors do glucocorticoids signal?

A

Nuclear receptors (class 1), specifically GRalpha

18
Q

Describe the molecular mechanism of glucocorticoids

A

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

19
Q

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

A

Drug release membrane, occurs by diffusion across cutaneous barrier

20
Q

What factors of a drug make TBB a suitable choice?

A

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

21
Q

What chemical enhancement occurs in TDD?

A

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

22
Q

What agents are used in chemical enhancement of TDD?

A

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)

23
Q

What physical enhancement strategies occur in TDD?

A

Iontophoresis, electroporation, sonophoreiss, microneedles