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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



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



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



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



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



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



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



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



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



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



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



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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