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Pharmacokinetics I
PERCUTANEOUS
KINETICS
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Human skin consists of 3 layers
1) epidermis
2) Dermis 3) subcutaneous fat
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The epidermis is non vascular,
multilayered, outer region of the skin.
The most superficial layer of the epidermisis the stratum corneum, which is
composed of several layers of dead
keratinized cells.
The stratum carneum is generally
recognized as the principal skin barrier to
loss of water and to entry of foreign
substances. 4
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The dermis or true skin is a highly vascular
region.
Drugs penetrating to this region are likelyto reach the systemic circulation.
The vascularity of the dermis should
produce a sink condition such that drug
concentration is very much less than that
present on the skin surface
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One study found that salicylate levels in
the muscle adjacent to the site of topical
application of triethanolamine salicylatewere 20 times higher than after oral
administration of a dose of aspirin that
produced blood levels 10 to 100 times
greater than those after topical dosing..
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These results suggest that topical
application of analgesics may provide
relief of local pain and discomfort withoutsystemic side effects.
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The site of application and the state of the
skin plays an imp role in percutaneous
absorption of drugs.
For eg: variation in the percutaneous
penetration of hydrocortisone has been
observed in man.
Absorption is rapid in regions with large or
numerous hair follicles.
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Hydrocortisone penetrates the scalp and
forehead much more readily than it
penetrates the ventral surface of the
forearm.
Absorption is decreased in some regions
of skin having thickened stratum
corneum(eg: the foot).
Absorption from the palm, which has a
fairly thick stratum corneum and no hair
follicles 9
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The scrotum provides almost no barrier to
the absorption of hydrocortisone.
A recent study examined thepercutaneous absorption of sodium
benzoate, caffeine, benzoic acid and
aspirin applied to different sites.
Skin permeability varied substantially,
depending both on the properties of the
drug and on the site of application.10
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Whatever the compound applied, the
forehead was about twice as permeable
as the arm or abdomen.
Application behind the ear produced
intermediate results.
Cuts, diper rash, inflammation, mild burns,
or any other condition in which the stratum
corneum is damaged or destroyed
promotes the absorption of drugs through
the skin. 11
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Studies in patients with mycosis fungoides
indicate that the percutaneous absorption
of the antineoplastic drug carmustine
through affected skin is much greater than
through uninvolved skin.
This excess hydration makes it easier for
the chemicals or medicines to permeateyour skin.
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Cutaneous T cell lymphoma (CTCL) is a
class of non-Hodgkin's lymphoma, which
is a type of cancer of the immune system.
Unlike most non-Hodgkin's lymphomas
(which are generally B-cell related), CTCL
is caused by a mutation of T cells. The
malignant T cells in the body
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Stripping the skin with cellophane tape
until it removes the stratum carneum and
causes damage to the upper layers of
epidermis.
Stripped skin showed a fourfold increase
in the penetration of hydrocortisone
compared with intact skin.
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Hydration of the skin, by soaking in water
or by occluding the skin surface with an
impermeable material such as plastic film,
alters the barrier characteristics of the
stratum carneum and promotes drug
absorption.
Occlusion also increases thepercutaneous absorption of testosterone.
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Certain lipophillic ointment bases may
retard water loss from skin and promote
hydration and drug absorption.
Aging and environmental factors lead to
dehydration of the skin can retard drug
absorption.
Environmental temperature can affect the
hydration of the stratum carneum as well
as the local blood flow.16
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The absorption of a topically applied
cholinesterase inhibitor from the cheek in
normal male persons increased 8 times
when the persons were exposed to
increasing temperatures ranging from -
18C to 46C.
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The chemical form of the drug and the
vehicle can have an important influence on
percutaneous absorption.
For eg: the efficacy of fluocinalone
acetonide in inflammatory dermatoses
(eczema and psoriasis) strongly depends
on the vehicle.
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An ointment formulation of 0.025%
fluocinolone acetonide dissolved in
propylene glycol and dispersed in soft
paraffin was compared with 0.025%
microcrystalline drug suspended in soft
paraffin.
The ppn containing drug dissolved, rather than suspended, in the ointment was
significantly more effective in both eczema
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And psoriasis patients
The percutaneous absorption of
betamethasone17-benzoate has beenstudied in patients with skin disorders
following application of either a gel or a
cream.
Betamethsone concentration in plasma
and inhibition of plasma cortisol were
significantly greater following the use of
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The gel rather than the cream.
The incorporation of certain chemicals
such as dimethyl l sulfoxide (DMSO) intotopical formulations has been advocated
to enhance penetration.
Invitro and invivo studies suggest that
DMSO enhances the percutaneous
absorption of many drugs, possibly by
producing structural changes in the skin,
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Such as swelling of the stratum corneum.
Other agents have also been studied as
³potential enhancers´.One report presents the results of the
vasoconstrictior assay following
application of betamethasone 17-benzoate
with different enhancing agents.
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For eg: propylene glycol with oleic acid,
propylene glcol with azone, and dimethyl
formamide, among other agents,
increased steroid bioavailability
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hexachlorophene is very useful as a
topical anti-infective, anti-bacterial agent,
often used in soaps and toothpaste. It is
also used in agriculture as a soil fungicide,
plant bactericide
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Hexachlorophene products can be lethal
from percutaneous (through the skin)
absorption. Children may be specifically
susceptible. Hexachlorophene (6.3%) was
added to ³baby powder´ in France due to a
manufacturing error. It, or possibly
contaminating dioxins, causedencephalopathy and ulcerative skin
lesions. 36 of 204 exposed children died
within a few days of exposure25
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A 2% topical minoxidil, used in severe
hypertension, is now available for the
treatment of male pattern baldness.
2-4% of a dose applied to the scalp is
absorbed.
Based on these findings application of a
2% lotion twice a day to entire scalp may
provide a systemic dose of about
2mg/day. This is less than the
recommended oral adult antihypertensive26
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Dose of 10-40mg/day
Short term use of minoxidil has resulted in
minimal decrease in B.P in normotensivepatients; whether topical minoxidil has a
hypotensive effect on patients with
hypertension is not clear.
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There is now considerable interest in the
topical application of drugs intended for
systemic effects.
This route of administration may be useful
for drugs with low bioavailability after oral
administration due to first pass
metabolism.
It may be particularly useful for short
acting drugs since p..absorption tends to28
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Be slow, and prolonged effects may be
realized.
Eg: topical preparations of nitroglycerin, acompound with low oral bioavailability and
a short duration of action.
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A transdermal patch is a medicated
adhesive patch that is placed on the skin
to deliver a specific dose of medication
through the skin and into the bloodstream.
An advantage of a transdermal drug
delivery route over the other routes such
as oral, topical, intravenous,intramuscular, etc. is that the patch
provides a controlled release of the
medication into the patient.30
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A 21mg dose Nicoderm CQ patch
applied to the left arm
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Contraceptive patch
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Clonidine tablets and
transdermal patches
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The highest selling transdermal patch in
the United States is the nicotine patch,
which releases nicotine in controlled doses
to help with cessation of tobacco smoking
Estrogen patches are sometimes
prescribed to treat menopausal symptoms
as well as post-menopausal osteoporosis.
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Other transdermal patches for hormone
delivery include the contraceptive patch
and testosterone patches for both men
(Androde) and women (Intrinsa).
Nitroglycerin patches are sometimes
prescribed for the treatment of angina.
Transdermal scopolamine is commonly
used as a treatment for motion sickness.[4]
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The anti-hypertensive drug Clonidine is
available in transdermal patch form under
the brand name Catapres.
Vitamin B12 may also be administered
through a transdermal patch.
Cyanocobalamin, a highly stable form of
vitamin B12, is compatible withtransdermal patching.
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Rivastigmine, an Alzheimer's treatment
medication, was released in patch form in
2007, under the brand name Exelon[
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Factors influencing percutaneous
absorption of drugs
1) drug release from dosage form: drug
present in the dosage form should reach
the skin surface at an adequate rate and in
sufficient concentration
2) drug concentration in the formulation:
the more the concn of drug in the
formulation, the greater the rate of drugabsorption through the skin.
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3) drug oil/water partition coefficient: the
greater the solubility of a drug in oil, the
greater its percutaneous absorption.
However, the aqueous solubility of a drug
determines the concentration presented to
the absorption site.
4) surface area: more drug is absorbedthrough percutaneous absorption when
the drug is applied to a larger surface
area.39
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5) site of application: p.absorption is to be
greater when the drug is applied to the
skin with a thin layer than with one that is
thick.
6) Hydration of the skin:
7) Nature of the vehicle used: in general
vehicles that cause hydration of the skin
improve the p. absorption of drugs.
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8) rubbing or inunction: the amount of
rubbing in or inunction of the topical
application will have a bearing on the
amount of drug absorbed; the longer the
period of inunction, the greater the
absorption.
9) contact period: the longer the time of contact of a dosage form with the skin, the
greater will be the absorption of the drug.41
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10) Permeation enhancers: DMSO,
propylyne glycol, azone are found to
enhance the p.absorption of drugs by
disrupt the net work of the horny layer.
11) other factors: absorption of drugs
through numerous hair follicles, rapid
absorption from a damaged skin due tolack of stratum corneum, therefore injuries,
rashes, mild burns, rashes, inflammation
promote drug absorption.42
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