Pharmacology and Skin Flashcards by Olivia McNee

What are the major routes of drug administration via skin?

Topical
Transdermal
Subcutaenous

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What is the most important barrier to drug penetration into the skin?

Stratum corneum

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What are the bricks in the brick and mortar model?

Corneocytes containing keratin aggregated filaments embedded in a filaggrin matrix surrounded by a cornfield envelope

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What is the mortar in the brick and mortar model?

Multiple bilayers or lamellar structures of intercellular lipids

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What can the lamellar structures provide for drugs?

Reservoir for lipid-soluble drugs (e.g. topical corticosteroids)

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What are vehicles for drugs?

Ointment 
Cream
Gel
Lotion
Pastes
Powders

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What dictates the choice in vehicle?

physiochemical properties of the drug

2. the clinical condition

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Conventional transdermal drug delivery is a ….. process driven by…..

passive

diffusion

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What describes the rate of absorption?

Fick’s law

J=KpCv

Kp=permeability concentration
Cv=concentration of a drug in the vehicle

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What can affect the rate and extent of absorption of a topically applied drug in a vehicle?

Dissolved concentration of the drug in a vehicle

Maximising drug partitioning

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How can you alter the absorption of a drug via drug partitioning?

lipophilic drug in a lipophilic base is soluble in both the vehicle and the skin and partitions between the two
lipophilic drug in a hydrophilic base is more soluble in the skin and partitions readily and preferentially to it
a hydrophilic drug in a lipophilic base has limited solubility in both the vehicle and the skin and partitions into it to a limited extent
a hydrophilic drug in a hydrophilic base is soluble in the vehicle but not the skin and remains on the surface of it

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What can enhance the solubility of a drug?

Including excipients (propylene glycol)

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How do drug patches provide a constant rate of delivery?

dissolved drug is removed by absorption into and across the skin its free is concentration in the patch is maintained by undissolved drug solubilizing- this can maintain a fairly constant soluble concentration that drives the rate of absorption

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How can you prevent water loss in the skin?

choice of vehicle- ointment

Cling film

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How does increased partitioning occur?

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

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How does the nature of the skin influence the absorption of topically applied drugs?

-site of application, permeability can be roughly ranked as;
nail &laquo_space;palm/sole < trunk/extremities < face/scalp < scrotum

hydration of the skin
integrity of the epidermis

What is more potent hydrocortisone butyrate or hydrocortisone acetate?

Hydrocortisone butyrate

What is most active vehicle for bethametasone valerate?

More active as an oitment than a cream

What are glucocorticoids used for?

Treatment of atopic eczema, psoriasis and pruritus

What effects do glucocorticoids have?

possess anti-inflammatory, immunosuppressant and vasoconstriction effect and anti-proliferating actin upon keratinocytes and fibroblasts

What does glucocorticoid penetration, potency and clinical effect vary with?

Body site
State of skin
Occlusion
Vehicle 
Concentration
form of drug

What serious effects can higher potency steroids have when used long term?

steroid rebound (probably due to GRalpha down-down-regulation)
skin atrophy (that may not be totally reversible)
systemic effects (HPA axis depression due to systemic absorption)
spread of infection (due to immune suppression of the skin)
steroid rosacea (skin reddening and pimples of facial skin)
production of stretch marks (striae atrophica) and small superficial dilated blood vessels (telangiectasia)

Describe the mechanism of action of glucocorticoids

glucocorticoids signal via nuclear receptors (class 1), specifically GRalpha 
glucocorticoids are lipophilic molecules- enter cells by diffusion across the plasma membrane 
within the cytoplasm, they combine with GRalpha producing dissociation of inhibitory HSP. the activated receptor translocates to the nucleus aided by importins
within the nucleus activated monomers assemble into homodimers and bind to glucocorticoid response elements int the promotor region of specific genes
the transcription of specific genes is either switched on or off to alter mRNA levels and the rate of synthesis of mediator proteins

Describe subcutaneous delivery of a drug?

drug delivery by a needle (inserted into the fatty (adipose) tissue just beneath the surface of the skin)

How do drugs delivered via the subcutaneous route reach the targets?

diffusion into either (i) capillaries or (ii) lymphatic vessels (particularly high molecular weight compounds

Wha are the advantages of subcutaneous drug administration?

- absorption is relatively slow (advantageous/disadvantaegous) due to poor vascular supply - route of administration for many protein drugs (e.g. insulin) - suitable for administration of oil-based drugs (steroids) -can be used to introduce a depot of drugs under the skin which is very slowly released into the circulation (particularly contraceptive steroids) and antipsychotic drugs relatively simple and painless

What are the disadvantages 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, for example by the intestine and liver liver and potential toxicity to those organs - drug absorption can be terminated rapidly (with the caveat that some drug may have accumulated in the skin) - intact skin is a water-tight barrier- only a limited number of drugs can diffuse across the epidermis to read the superficial capillaries of the dermis to be systemically available at an effective concentration

How is drug absorption partially controlled in TDD?

drug release membrane- occurs by diffusion across cutaneous barrier

What drugs are most suitable for TDD?

(i) low molecular weight (ii) moderately lipophilic (iii) potent (iv) of relatively brief half-life

What are the advantages of TDD?

-steady rate of drug delivery, decreased dosing frequency, avoidance of first-pass metabolism, rapid termination of action (if t1/2 is short) -user friendly, convenient, painless, increased patient compliance/concordance disadvantages

What are the disadvantages of TDD?

relatively few suitable drugs allergies cost

What are some examples of drugs delivered by TDD?

nicotine GTN fentanyl estradiol

How could TDD be chemically enhanced?

enhancers interact with the lipid matrix of the stratum corneum to increase permeability, mainly to drugs that already cross the skin relatively well water, solvents (ethanol) and surfactants (sodium dodecyl sulphate)

How could TDD be physically enhanced?

lontophoresis Electroporation Sonophoresis microneedles

What is iontophoresis?

application of low voltage electrical pulses to the skin via a surface electrode over a prolonged period of time can drive low molecular mass molecules of the same charge through the skin. Has been clinically used to deliver lidocaine and fentanyl for pain relief

What is electroporation?

very brief high voltage pulses lead to pore formation. has the potential for the deliver of hydrophilic and changed molecule into the ski

What is sonophoresis?

use of ultrasound to increase skin permeability is under investigation for the delivery of some protein drugs (e.g. insulin)

What are micro needles?

typically 0.1 to 1mm in length- punch microscopic holes in the skin, largely experimental to date