Absorption from the respiratory tract

The alveoli, which enables the lung to

carry out its primary function of
rapidly supplying oxygen to the body
and removing carbon dioxide.

The pulmonary alveolus is lined with

a single layer of epithelial cells
forming an extremely thin barrier
between alveolar air and an
interstitium richly supplied with
capillaries

Total air-blood is only 0.5 to 1 µm

thick

In the skin = 40 to 100 µm

In man, the number of alveoli → 300 to 400 million

A total surface area of about 200 m2

The pulmonary capillaries have a surface area of about 90 m2

All these factors combine to make the lungs the most effective
absorptive area of the body.

}
Materials inhaled as gasses
Cross the alveolar epithelium and enter
the blood
Vapors of volatile liquids

Gases as a rule are small molecules of relatively high lipid solubility.

This rapid absorption is a desirable feature of gases like nitrous oxide and
cyclopropane or volatile liquids like ether when they are used to produce general
anesthesia.

It can be disastrous when the inspired air contains poisonous gases or vapors
like carbon monoxide or gasoline fumes.

Chemicals can also be inhaled.

Soluble chemicals can be absorbed anywhere along the respiratory tract.

the size, the rate of solution of chemical, its rate of absorption

the size, the rate likelihood of its reaching the alveoli

Particles larger than 10 µm in diameter are usually completely removed

before leaving the nasal passages.
 Pollens

}
Smoke are examples of substances
Industrial dusts with particle sizes below 10 µm
Fumes in diameter.
Bacteria
Viruses
Various aerosol preparations

Insoluble particles are dangerous only they reach alveoli

excreted by ciliary movement

or removed by the phagocytic white cells.

 Absorption through the skin

Functions of the skin:

1- as a protective covering for the body
2- helps prevent excessive water loss
3- as a mechanism for excreting several different waste materials
4- as an aid in regulating the temperature of the body
5- as an instrument whose sensory nerve ending receive impulses
from the outside environment
6- as a depot in which reserve nutrients are stored
Cornified or keratinized stratified squamous epithelium is found in
the outermost layer of the skin. The cornified layer is composed of
many dead, scaly cells.

The protective barrier function of the skin is mainly related with the cells of
cornified layer.

The cells of cornified layer contain less phospolipid, lipid and water than
those of other epithelia and unique in being densely packed with the
complex protein keratin.
Absorption through the skin is ordinarily extremely slow processes and carried
out by passive diffusion.

Although the skin is an effective barrier against the transport of almost all
substances, letting no molecule through readily, it is a perfect barrier to very
few substances.

Heavy metals (like mercury) can be absorbed to some degree through the skin.

Many accidentally exposed foreign chemicals can be absorbed through the

skin.
When drugs are purposely applied to the skin, they are expected to produce
their desired effects only in the local area of administration

Nasal drops
Intravaginal jellies
Local anesthetics

However, there may be absorption of drugs leading to systemic effects,

sometimes causes serious side effects

Tannic acid (used in the treatment of burns)

produces toxic effects on the kidney

 Absorption from subcutaneous sites

Subcutaneous injections of drugs bypass the barrier of the epidermis since

they are placed below the dermis.

Only barrier to entry into the systemic circulation is the wall of the capillary.

It is composed of endothelial cells, and it is the endothelial tissue which forms

the barrier to solute movement into as well as out of the circulation.

{
For lipid soluble substance by their
The rates of a absorption into oil/water partition coefficients
capillaries are determined
For lipid-insoluble substances by their
molecular size
The rate of capillary blood flow is the major factor in determining rate of entry
into the circulation.

The more vascular the subcutaneous area, the greater the rate of absorption
Sometimes the rate of absorption to increase the effect by decreasing
rate of blood flow through the area

Local anesthetics used for tooth contains an agent capable of decreasing

the diameter of the blood vessels at the site of injection.

The rate of absorption by preparing special preparations which release

small amounts of drug continuously over a period of time.

Insulin (produce systemic effect) is prepared in this way

 Absorption from intramuscular sites

Intramuscular injections are usually made

into the muscle of buttock or the upper
arm.

The intramuscular route permits the

administration of more irritating drugs and
of larger volumes of solutions than can not
be tolerated subcutaneously.

The barrier to absorption from muscles is also capillary wall.

The rate of absorption from muscle and subcutaneous areas appear to be

about the same when the muscles are at rest.

During exercise, since rate of absorption is dependent on rate of blood

flow, drugs would gain access to the general circulation more rapidly from
intramuscular than from subcutaneous sites.

During exercise additional vascular channels are opened.

The intramuscular route can be used to introduce drugs into the body slowly as
well as rapidly.

Alteration of physical state of the drug

deposited in muscles

it goes into solution gradually

making small fractions of the dose available for absorption

over an extended period.

Special microcrystalline suspension of penicillin can be given as an

example.
 Intravenous Administration

The placement of a drug into the bloodstream, usually into a vein of the arm.

The intravenous route completely eliminates the process of absorption and

thus represents the most rapid means of introducing drugs into the body.

In the treatment of emergencies and when absolute control of the amount of

drug administered is essential.
It requires the greatest amount of skill.

Introduction of particulate matter or air may produce embolism which may

prove fatal.

Drugs should never be introduced directly into the blood stream unless
specifically indicated.

Intravenous route of drug administration is of greatest value in emergencies

when speed is vital.

The amount of drug administered can be controlled with an accuracy not

possible by any other procedure.

The intravenous route may also be used for drugs which are too irritating to
be injected into other tissues without causing pain and tissue damage.

Drugs that would be destroyed by chemical reactions before reaching the

bloodstream are also given intravenously.
 Distribution

Once a solute has reached the bloodstream, it usually must traverse one or
more biologic barriers in order to reach its ultimate site of action.

Its accessibility to this is determined initially

1- by its ability to cross the capillary wall
2- then by the blood flow through the site
3- and finally, if the drug acts intracellularly, by its rate of
passage across cells.

The sequence of movement of a solute in the process of its distribution is

the reverse of that involved in its absorption.
 Capillary Permeability

The tissue covering the surface of

internal cavities of the body is
endothelium.

Individual cells comprising the

endothelium overlap each other at their
margins but are not closely
approximated as are epithelial cell.

In capillaries, this lining is one cell thick and is continuous throughout the
closed passages.

However, in the liver, the smallest channels of the circulation, called

sinusoids, are even simpler than capillaries.
These sinusoids lack a complete endothelial lining, and their wall are at
least in part, nonexistent.
Small lipid-soluble molecules like gases pass into, and consequently out of the
capillary so expeditiously that equilibrium on both sides of the vessel wall is
reached almost instantenously.

[Drug] [Drug]

Lipid soluble Lipid soluble

The lipid/water partition coefficient is the most important factor in

determining differences in rates among compounds
The rate at which any molecule diffuses across the capillary endothelium at
all sites except the brain is greater than its rate a passage across epithelial
tissue.

At both types of tissues this diffusion occurs across the cellular membrane.

Water-soluble molecules, and water itself, also readily traverse the

capillary wall, but at rates slower than compounds with lipid solubility.

Molecular size is the major determinant of the rate of transcapillary

movement:

Smaller the water-soluble molecule, the faster its rate of diffusion.

Even relatively large molecules like proteins are able to penetrate the
capillary endothelium very slowly.
Relatively small water-soluble molecules cross the capillary at rates
directly proportional to their concentration gradients.

Low High

In contrast, the driving force for movement of large water-soluble

substances appears to be the hydrostatic pressure exerted by the blood.

The pressure of the blood on the arterial end of the capillaries is normally
higher than that of the venous end.
It is this pressure gradient between the two ends of the capillary bed
that largely accounts for the transcapillary movement of high molecular-
weight compounds like protein.

Proteins

Hydrostatic pressure

In the liver and kidney the capillaries present less of barrier to the movement
of molecules of all sizes than do capillaries elsewhere.
 The kidney is the organ chiefly responsible for the
excretion of water-soluble compounds.

The liver not only manufactures many proteins for

use by the body but also receives most substances
absorbed from the small intestine before they
distributed.

The increased rate of permeability in kidney is related with two factors:

1- the capillaries associated with the initiation of urine formation contain large
pores in the membrane of the endothelial cell itself.
2- the hydrostatic pressure within these capillaries is very high compared with
many other capillary beds.

Diffusion is supplemented by transcapillary filtration through the pores.

In the liver the increased permeability relates mainly to the greater rate of
translocation of large molecules.

Since hepatic sinusoids lack a complete endothelial lining, large molecules even
large proteins, can enter and leaves the blood flowing through the liver more
readily than the blood flowing through other tissues of the body.
 Magnitude of distribution

Blood capillary is a relatively

effective barrier only to large
molecules

When a macromolecular compound is injected intravascularly, it is almost

completely retained in the extracellular fluid of the circulation – the plasma-
since its size also prevent entry the blood cells.

The action of the heart and the turbulence of the uneven blood flow
through various vessels quickly mixes the agent with the circulating
plasma.
70 kg man the volume of plasma is approximately 3 L

The quantity of drug is diluted to 100 (initial unit)

3

A drug which is unable to cross the capillary wall has

a volume of distribution equal to plasma-water.

The volume of distribution of a drug capable of

readily traversing the capillary endothelium will be
greater than that of plasma-water.

Let us, specify an ideal situation in which the drug is

1- a free solute, unbound to any tissue components
2- unchanged by any chemical reactions of the body
3- not eliminated during the period of distribution.

Drug
enters the circulation
(mixed into plasma-water)
It will diffuse
The concentration
1- its molecular size
gradient drive the drug
2- lipid solubility
across capillary wall
3-degree of
ionization

The drug will be distributed from plasma The movement of drug will
to the extracellular fluid of all parts of the continue until no longer a
body (if we assume, the permeability gradient between the inside
chracateristics of capillaries are identical and outside of capillaries
all over the body)
 The rate at which the drug concentration in the extracellular fluid of a particular
site reaches this point of equibrium will depend on the number of capillaries.
The richer the vascularity, the greater the blood flow and more rapid the
distribution of drug from plasma to extravascular interstitial fluid.
Tissue Blood Flow (L/min) Tissue mass (% of total body weight)
Blood 5.4 8.0
Rapidly perfused
Brain 0.75 2.0
Liver 1.55 3.5
Kidney 1.2 0.5
Heart 0.25 0.5
Less rapidly perfused
Muscle 0.8 48
Skin 0.4 6.5
Poorly perfused
Fat 0.25 14
Skeleton 0.2 17

Average rates of blood flow through some organs of the body in relation to their mass.

A drug will appear in the extracellular fluid of organs like liver, kidney and brain more
rapidly than in that of tissues like fat.
Ideal condition the concentration of drug in all extracellular water, including
plasma-water will reach the same level.

When this equilibrium is attained, the quantity of drug that originally entered
the bloodstream will be diluted into about 12 lt.

3 lt (plasma water) + 9 lt (extravascular interstitial fluid) = 12lt

A drug which can readily leave the capillaries but which can not enter cells will
have a volume of distribution equal to the total extracellular fluid.

100
12 lt
If the drug is capable of traversing the cell membrane, it will move
from the extracellular space into the fluid within the cell.

The concentration of drug will be diluted by a volume equal to that of the

total intracellular water of all cells (approximately 28 lt) + the total
extracellular fluid

100 units
40 lt

Total water content of the body

Consequently, a drug which can readily pass all biologic barriers will
have a volume of distribution equal to the total water content of the
body