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540 exam III- transdermal
transdermal
73
Biology
Graduate
11/15/2012

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Term
iontophoresis (electrophoresis)
Definition
implies the delivery of ionic (charged) drugs in the body by the use of electric current (single digit volts)
Term
does iontophoresis hurt?
Definition
no its painless from minutes to hous
Term
what are examples of iontophoresis
Definition
local dermal anesthesia (lidocaine) icorticosteroids (products) and Glucowatch
Term
what is iontophoresis useful for?
Definition
proteins/peptide drugs
Term
Electroportation
Definition
charge breaks down lipid barriers and permits passive transport of ordinarily impermeable molecules.
Term
Which barrier does electroportation affect?
Definition
SC barrier
Term
What is the type of voltage and how long for electroportation?
Definition
use of high voltage and short time treatment (hundreds of volts for microseconds)
Term
How does electroporation change the phenotype of electroporation?
Definition
creates new aqueous pores across the stratum corneum
Term
examples of electroporation?
Definition
few model compounds such as heparin, calcein, and vaccines
Term
Sonophoresis
Definition
lipid bilayer disordering and convection, this eliminates lag time
Term
therapeutic frequency of ultrasound?
Definition
1-3 MHz
Term
what does sonophoresis do to lag time?
Definition
eliminates lag time
Term
mech involving ultrasound?
Definition
- thermally enhanced diffusion
-structural changes by mechanical oscillations and cavitation (=1/ultrasound frequency)
-cavitation (formation of vapor bubbles of a flowing liquid in a region where the pressure of the liquid falls below its vapor pressure)
-convective transport through hair follicles
Term
Is the pro-drug approach therapeutically active?
Definition
Nope
Term
Pro-drug: explain lipophilicity compared to parent drug
Definition
This drug is more lipophillic than the parent drug (increase in permeability and partitioning through the skin)
Term
How does the pro-drug produce therapeutically active drug in biological environment
Definition
Bioconversion by hydrolysis or enzymatic degradation.
Term
What is the most important epidermis barrier to chemical penetration?
Definition
Stratum corneum (layer of dead, flattened keratinocytes)
Term
The three types of penetration pathways
Definition
intracellular, intercellular, follicular
Term
What are the two main types of dermal delivery?
Definition
Topical delivery (ointments and creams) and systemic delivery
Term
What are the two main types of topical delivery? and what are they used to treat?
Definition
surface epithelium and appendages (dry skin, surface infections) , lower epidermis/dermis (infections and inflammation)
Term
Functions of the skin
Definition
Thermoregulation (termperature control)
Barrier to pathogens and foreign chemicals (sloughing)
Protection against massive loss of water (50M)
Protection against physical abrasion and UV radiation.
Term
What are the five layers of the epidermis?
Definition
stratum corneum layer (keratin layer, glycine/alanine and disulfide bonds)
stratum lucidum
Stratum granulosum
stratum spinosum
stratum germinativum
Term
Is the epidermis vascular or avascular?
Definition
avascular
Term
what is the turnover of epidermis?

where is the highest turnover? the lowest?
Definition
21-28 days

highest turnover is the scalp, the lowest turnover is at the toes
Term
What is the average thickness of the epidermis?
Definition
100 micrometers
Term
what is the percent that is needed of moisture for the epidermis?
Definition
10% to remain soft and supple
Term
what is the average thickness of the stratum corneum?
Definition
10 micrometers
Term
where are blocks of keratin embedded in the stratum corneum?
Definition
in the extracellular lipids
Term
are the cells in the stratum corneum alive?
Definition
they are flattened, dead cells with no nucleus
Term
Which layer is the major barrier towards permeation of water and other molecules?
Definition
the stratum corneum
Term
explain the layout of exracellular lipids of the stratum corneum
Definition
arranged in bilayers that form sheets
Term
Explain the vascular and nerve supply in the dermis
Definition
contains a rich blood supply, lymphatic vessels, and nerve endings
Term
explain the speed of diffusion of drugs through the dermis
Definition
drugs quickly diffuse through this area
Term
Explain elastin fiber layouts in the dermis
Definition
elastin fibers are loosely arranged in all directions and give elasticity to the skin
Term
What types of cells and tissues/nerves are involved in the dermis?
Definition
the dermis containes nerves, sweat glands, and origin of hair follicles

cell types: mast cells, fibroblasts (synthesis of collagen and elastin), Langerhan cell (allergic response), schwann cells
Term
What are types of skin appendages?
how much % do they occupy of the total skin?
Definition
arectir pili muscle
hair follicle
sebaceous glands
sweat glands

skin appendages occupy only 0.1% of the total skin surface
Term
what is a sebaceous glands associated with?
Definition
associated with a hair follicle
Term
which hormone is the sebaceous gland dependent on?
Definition
testosterone
Term
When is there an enormous increase in sebaceous gland
Definition
increases activity in puberty
Term
what is the function of the sebaceous gland. where do they discharge sebum?
Definition
Discharge sebum into the hair follicle

essentially an oil:
protect against the penetration of foreign chemicals
antibacterial and fungicidal: fatty acid esters (ph5)
Barrier against loss of water (role duplication by commercial dry skin products)
Lubricant, providing slip
Term
What are eccrine glands?
Where are eccrine glands?
Definition
These are sweat glands. they are distributed over all of the body (palms and soles)
Term
Eccrine glands- what do they have?
Definition
lactic acid
Term
What kind of stimulation do eccrine cells respond to?
Definition
thermal and CNS stimulation
Term
What are apocrine glands and when do they develop?
Definition
They are hormonal glands. They are associated with sexual development and do not appear until puberty
Term
what kind of substance is secreted from apocrine glands?
Definition
milky, fatty secretion. This is the development of body odor (by bacteria decomponsition of the contents of sweat (acid and dead cell debris)
Term
Where are apocrine glands located?
Definition
found in relatively small numbers in the underarm area, on the abdomen, and the genito-anal region
Term
Where the melanocytes located?
Definition
they are every 4th cell in epidermal-dermal interface (basale layer)
Term
what do melanocytes do?
Definition
They synthesize and distribute melainin (a dark polymer capable of absorbing UV radiation)
Term
What do langerhan cells do?
Definition
uptake and processing of antigenic material
Term
thickness of the:

stratum corneum

dermis

erythrocyte membrane

Leukocyte membrane
Definition
stratum corneum: 4X10^-3

dermis: 2X10^-2

erythrocyte membrane: 5X10^-7

Leukocyte membrane: 1X10^-6
Term
Diffusivites of:

stratum corneum

dermis

erythrocyte membrane

Leukocyte membrane
Definition
stratum corneum:4.2X10-10

dermis: 2X10^-6

erythrocyte membrane: 6.5X10^-9

Leukocyte membrane: 2.8X10^-9
Term
What are the pathways of drug permeation through skin?
Definition
Transcellular (accross the cell membrane)

Paracellular (between cells or intercellular junctions)

Transappendageal(hair follicles and glands)
Term
Mechanism of drug absorption through the skin. What is fick's first law of diffusion?
Definition
dM/dt= (DKAdelta C)/h

dM/dt= steady state flux across stratum corneum

D- diffusion coefficient or diffusivity of drug molecules

K- partition coefficient of drug between the skin and formulation

delta C- drug concentration gradient across the stratum corneum

h= thickness of the stratum corneum
Term
How do you find the flux of the solute?
Definition
Js= (Dm*Km delta c)/h

Js= flux of a solute
Km= partition coefficient between vehicle and skin
Dm- diffusion coefficient of drug in skin
h- membrane thickness
Term
How do you find the permeability coefficient of drug in skin?
Definition
Pm=(Dm*Km)/h

Pm= permeability coefficient of drug in the skin

Dm= diffusion coefficient of drug in skin

Km= partition coefficient between vehicle and skin
Term
Absorption of the drug is affected by:
Definition
Cs- concentration of drug in vehicle

h- thickness of barrier

D- mobility of drug molecule in the barrier

k- relative solubility of the drug

A- contact surface area of vehicle
Term
General rules for diffusion through the skin
Definition
-small hydrophilic, polar molecules are rate-controlled by the stratum corneum
-small hydrophobic molecules are controlled by their partitioning from the stratum corneum into the lower epidermal layers
-diffusion decreases with increasing molecular size(limit about 1000 daltons)

- occluding the skin results in an increase in hydration of the stratum corneum and increase permeability
-damage destroys the barrier properties of the stratum corneum
Term
What are physiological factors affecting transdermal F?
Definition
-stratum corneum
-anatomic site
-skin metabolism (cytochrome p450)
-skin hydration
-age: premature neonates (<30 weeks)
-desquamation (shedding)
Term
What are formulations factors affecting trasdermal F?
Definition
-o/w partition coefficient of drug
-size and charge of drug
-contact time
-drug concentration
-active surface area of the transdermal delivery system
-penetration enhancers (surfactants)
Term
Where is the highest site of drug permeation? Lowest?
Definition
highest- post auricular, then the back

the lowest is the thigh
Term
what are methods to modify SC?
Definition
hydration, chemical enhancers, thermal passive
Term
What are passive (diffusions) method?
Definition
Methods to modify SC (hydration, chemical enhancers, thermal passive)
Term
What are sc poration methods
Definition
mechanical or electrically-driven methods
Term
What are electrically-driven methods?
Definition
sonophoresis, thermal poration, radio frequency poration, ionophoresis, electroporation
Term
what are mechanical methods?
Definition
Microstructure array, SC removal, high velocity particles/liquids
Term
What is the generally impermeable principle barrier of the skin?
Definition
the stratum corneum
Term
What part of a drug does the permeability of transdermal systems correlate to?
Definition
-water solubility
-Mw (size)
-oil/water partition coefficient
Term
Transdermal systems are useful for which kinds of drugs?
Definition
-low dose requirement
-high skin permeability
Term
Why do we use transdermal systems for systemic drug administration?
Definition
-bypass first-pass effect (eg estradiol)
-reduce side effects by more controlled release
-reduced inter-and intra-patient variability
-increased patient compliance with fewer dosing events- self-administration
-easy to apply and remove
Term
What are marketed transdermal products?
Definition
scopolamine- antinausea
nitroglycerine-angina
clonidine- hypertension
fentanyl- analgesic
testosterone- cancer
nicotine- smoking cessation
estradiol- post-menapausal conditions
ethinyl estradiol/norelgestromin- contraception.
Term
physiochemical and PK properties of transdermally administered drugs
Definition
1-octanol-water partition coefficients
2- total clearance
3-biological half-life
4- base form of the drug
Term
Disadvantages of TDDS
Definition
-lipophilic (moderately) drugs with low MW only
-potent drugs only (<10mg/day)
-drugs with short half-lives only
-atopic dermatitis @ the site of application is possible (by the drug or adhesive)
-Lag time to reach steady state (2-6 hours in some cases)
-skin damage due to adhesion (elderly)
-expensive
-excess drug content in patches (proper disposal)
Term
Types of transdermal DDS
Definition
adhesive patches (SC regulates drug absorption)

reservoir (membrane) controlled system

matrix controlled system
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