Pharmacokinetics
To produce its characteristic effects,
a drug must be present in appropriate
concentrations at its sites of action.
Pharmacokinetics is the study of what
the body does to foreign substances. It
looks at how the human body absorbs,
distributes and eliminates drugs. The
effect of a particular drug depends upon
the following:
- Amount of drug administered
- Extent and rate of absorption
- Extent and rate of distribution
- Binding and localization in tissues
- Metabolism (bio-transformation)
- Excretion.
The absorption, distribution,
metabolism and excretion of a drug all
involve its passage across cell
membranes.
Factors affecting drug transfer
The following properties of the drug
and the membrane will influence the
transfer of a drug across cell
membranes.
- Molecular size and shape of the drug
- Solubility at the site of absorption
- Chemical characteristics of the drug
- Manner of administration (oral,
injection, or inhalation)
Barriers to drug movement may be a
single layer of cells (intestinal
epithelium) versus several layers of
cells (skin). For example, aspirin would
not be absorbed through the skin if you
ground it up and put it on your arm,
whereas it would easily be absorbed
through the small intestine.
Drug absorption, bioavailability and
bioequivalence
Absorption is the phenomenon of a drug
leaving its site of administration and
the extent to which it is absorbed by
the body.
Bioavailability
Bioavailability is a term used to
indicate the amount of a drug that
reaches the target site. For example, a
drug that is absorbed from the stomach
and intestine will pass through the
liver before it reaches the circulatory
system. If the drug is metabolized in
the liver or excreted in the bile, some
of the active drug will be destroyed
before it can reach the general blood
circulation and be distributed to its
site of action.
If the metabolic capacity of the liver
for a given drug is great,
bioavailability will be substantially
decreased. This is called the first pass
effect. The decrease in availability of
the drug is a function of the anatomical
site from which absorption occurs, as
well as other physiological and
pathological conditions. The choice of
dosage and the manner of administration
must be based on an understanding of
these conditions.
Bioequivalence
Pharmaceutical formulations of a drug
are termed "chemically equivalent" if
they meet the chemical and physical
standards established by scientific
experts, and governmental or other
regulatory agencies.
Drugs are said to be "biologically
equivalent" if they yield similar
concentrations of drug in blood and
tissues.
Drugs are deemed "therapeutically
equivalent" if they produce equal
therapeutic effect at the target site.
Pharmaceutical preparations that are
chemically equivalent but not
biologically or therapeutically
equivalent are said to differ in their
bioavailablity. The reasons for
differing bioavailability include:
- Differences in crystal form of the
drug
- Particle size of the drug
- Other physical characteristics of
the drug that are not rigidly
monitored and controlled in
formulation or manufacture.
These factors usually affect the rate
and extent of absorption, and usually
only apply to oral dosages.
Factors that modify absorption
The factors that affect absorption of a
drug are:
- Drug solubility: Drugs come in
different forms, namely aqueous
solutions, oils, gases, suspensions,
and solids;
- Rate of dissolution (for solids);
- Local conditions at the site of
absorption, particularly in the
gastrointestinal tract;
- Stomach contents;
- Concentration of the drug. Generally
high concentrations are absorbed more
rapidly than low concentrations;
- Circulation to the site of
absorption. For instance, increased
blood flow due to massage or local
application of heat enhances
absorption of a drug, whereas
decreased blood flow produced by
vasoconstrictors (agents that narrow
blood vessels), shock, or other
disease factors can slow absorption;
- The area of the absorbing surface to
which a drug is exposed helps
determine the rate of drug absorption.
Drugs are absorbed very rapidly in
regions with large surface areas such
as the lungs and the intestines. The
absorbing surface is determined
largely by the route of
administration.
All of these factors can have
considerable impact on the effectiveness
of a drug and its potential to cause
toxic reactions.
Routes of administration
There are several ways to administer
drugs enumerated below. The method
chosen is usually a function of the
following considerations:
- Convenience
- Desired rapidity and duration of
action
- Availability of sterile preparations
- Drug's solubility
- Absorption characteristics of the
drug
- Onset of action
1 Oral ingestion (enteral)
This is the most common route of
administration. It is also the safest,
most convenient and economical. But it
has disadvantages, the most signficant
of which include:
- Emesis (vomiting) as a result of
irritation to the gastrointestinal
tract
- Destruction of some drugs as a
result of digestive enzymes or acidic
nature of the stomach
- Irregularities in absorption or
propulsion of the drug in the presence
of food or other drugs
- Necessity for cooperation by the
patient
- The enzymes of the gastrointestinal
tract, the intestinal flora, or the
liver may metabolize drugs before they
reach the general blood circulation.
Absorption from the gastrointestinal
tract is governed by the following
factors:
- Surface area at the site of
absorption
- Blood flow to the site of absorption
- Physical state of the drug at the
site of absorption
- Concentration of the drug at the
site of absorption
Drugs that are destroyed by gastric
juices or that cause gastric irritation
are sometimes administered in a dosage
form with a coating that prevents
dissolution in the acidic gastric
contents.
Some enteric-coated preparations of a
drug may also resist being dissolved in
the intestine. This too would limit the
amount of a drug that is absorbed.
The rate of absorption of a drug
administered as a tablet or other solid
dosage form is partly dependent on the
location of absorption and the rate at
which it is dissolved in
gastrointestinal fluids.
Controlled release
This factor is the basis for the
so-called controlled release,
time-release or sustained release
preparations. They are designed to
produce slow, uniform absorption of a
drug for 8-12 hours or longer. Potential
advantages include:
- Reduction in the frequency of
administration
- Maintenance of the therapeutic
effect overnight
- Decreased incidence of undesired
effects by the elimination of peaks in
drug concentration that often occur in
other dosage forms.
Not all controlled release preparations
work reliably. For example:
- The dissolution rate may be
irregular due to technical
manufacturing problems
- There may be variations in gastric
acidity and emptying, intestinal
motility and other physiological
factors that modify drug absorption
- Slow absorption from the
gastro-intestinal (GI) tract is often
incomplete and erratic
Drugs required for a brief therapeutic
effect should not be in the controlled
release form. Also, controlled release
forms would not be used for drugs with a
long duration of effect. In controlled
release preparations the total dose may
be several times the dose of the
conventional form and faulty release of
the entire amount at once could lead to
toxic reactions, even death.
2 Injection (parenteral)
Parenteral administration has
advantages over oral administration. For
example:
- Necessary for certain drugs to be
absorbed in an active form
- Absorption is usually faster and
more predictable than for oral
administration
- Effective dose can be more readily
determined
- For emergency therapy, if patient is
unconscious, uncooperative or unable
to retain anything given orally
However, injection of drugs also has
disadvantages:
- Possibility for infection
- Pain may accompany the injection
- Difficult to perform self-injection
for self-medication
- Expense (injectable form is usually
costlier)
Here are the different ways to inject a
drug:
2.1 Intravenous - direct
injection into a vein
- Absorption via the gastro-intestinal
tract is bypassed with potentially
immediate effects
- Valuable for emergency use
- Permits titration of dosage (dosage
can be accurately predicted because
there is no loss of drug through
absorption in gastro-intestinal tract)
- Suitable for large volumes and can
be used for diluting irritating
substances (eg. morphine and other
analgesics administered in a saline
solution in an intravenous drip)
- Increased risk of adverse effects
- Solutions must be injected slowly
- This method is unsuitable for oily
solutions or insoluble substances
2.2 Subcutaneous - injection
beneath the skin
- Slow and sustained release over a
few hours into the surrounding blood
vessels
- Insulin is given this way
- Can only be used for drugs that are
not irritating to tissue
2.3 Intramuscular - direct
injection into a muscle
- Can provide prompt absorption, from
aqueous solution
- Slow and sustained absorption from
repository preparations
- Suitable for moderate volumes, oily
solutions, and some irritating
substances.
2.4 Intra-arterial - direct
injection into an artery
- Localizes effect in a particular
tissue or organ
- Very dangerous
- Can be used to administer diagnostic
agents
2.5 Intrathecal - direct
injection into the spinal subarachnoid
space (membrane covering the brain and
spinal cord).
2.6 Intraperitoneal - direct
injection into the peritoneal cavity
- Large surface area for absorption.
- First pass hepatic losses are
possible.
- Danger of infection; this type of
injection is usually performed in the
laboratory
3 Topical application
Drugs are applied to mucous membranes
in the eyes, colon, vagina, nose and
skin. Absorption occurs rapidly. Few
drugs readily penetrate skin. Absorption
through skin can be enhanced by
suspending the drug in an oily solution
and rubbing the resulting preparation
into the skin (inunction).
4 Sublingual administration
(oral mucosa)
Absorption from the oral mucosa (under
the tongue) has special importance for
certain drugs, even though the surface
area in this location is small.
Nitroglycerine is effectively
administered in this fashion.
5 Rectal administration
The rectal route is often used when
vomiting precludes oral ingestion or
when the subject is unconscious. It
should be noted, however, that rectal
absorption is often irregular and
incomplete and many drugs cause
irritation of the rectal mucosa.
6 Pulmonary administration
Drugs administered as gases penetrate
the cell linings of the respiratory
tract easily and rapidly. Anaesthetic
gases have small molecular sizes and
high fat solubility. They are absorbed
almost as fast as they are inhaled,
because contact between blood and the
lung membrane is close. This process is
almost as efficient as intravenous
injection.
Despite this knowledge about the rapid
absorption of gases through the lungs,
very little information is available
about the pulmonary absorption of drugs
other than those administered as gases.
Cigarettes and marijuana are examples
of such administration, since nicotine
and tars in cigarettes and cannabinoids
in marijuana are not gases but particles
carried in smoke.
Although many drugs appear to be
absorbed readily when inhaled as sprays,
aerosols, smokes, or dusts, knowledge of
the extent and rate of absorption is
incomplete.
Because of the ultrasensitivity of the
lung tissue to foreign substances,
administration of drugs by inhalation
should probably not be widely adopted.
Distribution of Drugs
Once absorbed, a drug is distributed
throughout the body by means of the
circulation of the blood. The
distribution of most drugs in the body
is far from even. This complicates the
efforts to correlate blood levels and
the pharmacological effects of the drugs
used.
- Some drugs tend to bind to blood
elements
- Some drugs dissolve more readily in
body fat depots
- A few drugs have a strong tendency
to locate in bone
Drugs must be very fat soluble to enter
the brain. It is generally true that
high blood drug levels yield
correspondingly greater pharmacological
effects.
Even though a drug is in the
bloodstream it must pass across various
barriers to reach its site of action.
Only a very small proportion of the
total amount of drug in a body at any
one time is in direct contact with the
specific cells that produce the
pharmacological effect. Most of the drug
is to be found in areas of the body
remote from the drug's site of action.
In the case of psychoactive drugs, most
of the drug is to be found outside the
brain and is therefore not directly
contributing to the pharmacological
effect.
Drug that has accumulated in a given
tissue may serve as a reservoir that
prolongs drug action in that same tissue
or at a distant site reached through
circulation.
Distribution by the heart and blood
The heart pumps approximately
6 litres of blood per minute. With
only 6 litres of blood in the
circulatory system, the entire blood
volume circulates in the body about once
every minute.
Once a drug is absorbed into the blood,
it is quite rapidly (usually within this
1 minute circulation time) distributed
throughout the circulatory system. The
following cycle of events describes the
circulation of a drug within the human
body.
The drug is taken orally passing
through the mouth, throat and esophagus
into the stomach. Once in the stomach it
is subjected to the acidic conditions of
the stomach and eventually allowed to
pass into the small intestine after the
pyloric sphincter (valve at the base of
the stomach) opens.
The drug in the intestine comes in
contact with the intestinal mucosa
(lining of the intestine) and is
absorbed into the blood stream via the
portal vein. This vein carries the
recently absorbed drug to the liver and
empties into the vena cava which carries
the blood returning to the heart from
the rest of the body.
This blood, containing carbon dioxide
returns to the right side of the heart
and is circulated to the lungs by the
pulmonary artery, where it is purified
by exchanging the carbon dioxide for
oxygen. The purified blood returns to
the left side of the heart by the
pulmonary vein. After leaving the heart,
the purified blood is circulated to the
remainder of the body by large arteries.
About one-third of the blood goes to the
brain; the remainder goes to the rest of
the body.
The aorta is the largest artery in the
body and supplies blood to the lower
extremities and all of the organs in the
abdomen. The carotid artery is the major
artery supplying blood to the brain.
10 billion capillaries
Once the blood is in the major arteries
it flows to smaller and smaller arteries
eventually arriving at the capillaries.
There are about 10 billion capillaries
in the body.
Drug circulation in capillary blood can
now diffuse into the interstitial fluid
surrounding the cells. If the drug is
able to penetrate the cell wall, it can
enter the cell and start its effect.
After some time, the drug can leave the
cell, passing through the cell wall,
enter the interstitial fluid, and pass
into the capillary blood leaving the
cell area.
The capillary blood flows into larger
and larger veins, terminating in the
vena cava. At this point, the cycle
begins anew.
A normal, lean 150 pound man contains
approximately 41 litres of water (58% of
total body weight). Therefore, if 41
litres represents the total body water
and 6 litres of this represent the
volume of the circulating blood, the
remaining 35 litres of water must be in
the body tissues.
This water is not isolated from the
blood, for fluids and drugs are
transferred between the blood and body
fluids, in and around the cells of the
body. Therefore, drugs are diluted not
only by the blood, but also by body
tissues, since virtually all drugs can
move out of the bloodstream and into the
fluid that closely surrounds the cells
of the body tissues. If the drug is
capable of penetrating the cells, it
will be further diluted by the
intracellular fluids.
Protein-bound drugs
Another factor that can limit
distribution is that many drugs may
actually become bound firmly to proteins
contained in the blood. Since blood
proteins can be very large, they are
unable to leave the bloodstream and are
confined to the blood vessels. Such a
protein bound drug is prevented from
reaching the cells of the body tissue.
This might appear to render it useless.
If the drug's site of action is outside
the blood vessels (in the brain for
example), its binding would decrease its
effectiveness. However if the drug's
site of action is directly on blood
cells, such a binding might augment its
action.
Warfarin is used to prevent blood
clots. This drug is almost completely
bound and is therefore confined inside
the blood vessels. Since the drug acts
directly on blood cells to stop clots
from forming, this confinement is
useful. The more common situation is
that only small amounts of a drug are
bound to blood proteins and the
distribution of a drug may be more
general.
There may be unequal distribution among
different parts of the body. Protein
bound drug is confined to the blood
stream. Drugs not bound to protein but
soluble in water and insoluble in fat
easily pass out of the bloodstream into
the extracellular fluid but not into the
intracellular fluid. An unbound drug
which is soluble in both water and fat
will move easily through to the
intracellular fluid.
Thiopental, a commonly used anesthetic,
will cause a person to pass out within
seconds when injected intravenously
because it is extremely soluble in fat,
so it can rapidly leave the bloodstream
and pass into the cells of the brain,
where it quickly depresses the brain and
causes unconsciousness. LSD is another
example of a drug that readily
penetrates brain cells.
Many drugs are distributed throughout
the body in an unequal manner and the
concentration of a drug may be higher in
one organ than in another. It is also
important to note, however, that the
organ with the highest concentration of
the drug is not necessarily the organ
most affected by that drug. With respect
to thiopental, most of this drug, in the
body of a patient awakened from
anesthesia, will be found in body fat
and muscle. The effect of this drug is
not on muscle or body fat. Any drug that
remains in the body, but elsewhere than
its site of action is considered to be
inactive until it is redistributed.
Blood capillaries
Drug molecules are distributed
throughout the body by means of the
circulation of blood and are distributed
fairly evenly within a minute or so
after they enter the blood stream.
Most drugs, however, are not confined
to the bloodstream, because they can be
exchanged back and forth across the
capillaries.
Capillaries are tiny cylindrical tubes
with walls formed by a thin layer of
cells tightly packed together and
surrounded (for structural rigidity) by
a thin membrane.
Each cell is separated from the others
by minute passageways, called pores,
which connect the interior of the tube,
the capillary, with the body tissues
around it. The pores have a very small
diameter but are larger than most drugs.
Since it is only in the capillaries that
drugs are exchanged between blood and
body cells, the capillaries must be
small, to bring water and essential
nutrients into close contact with the
surrounding cells.
The capillaries are so small that only
one red blood cell at a time can squeeze
through a given capillary and fluid
readily diffuses through both the
ceiling lining and the water filled
pores.
Since most drugs are smaller than the
pores, even the least fat soluble drug
is able to pass out of the capillaries
into the surrounding tissue.
The rate at which drug molecules enter
specific tissues of the body depends on
two factors:
- The rate of blood flow through the
tissue
- The ease with which drug molecules
pass through the capillary membranes
Blood flow is greatest to the brain and
much poorer to the bones, joints and fat
deposits. Drug distribution, all else
being equal, would follow a similar
pattern.
Some capillaries have special
properties that may further limit the
rapid and free diffusion of a drug into
the brain.
Blood-brain barrier
The passage of drugs into the central
nervous system (CNS) is a special aspect
of cellular penetration and is a unique
example of the unequal distribution of
drugs.
The brain constitutes only 2% of the
body weight and yet under resting
conditions it receives 16% of the blood
pumped by the heart. The brain is the
organ most richly supplied with blood.
The average rate of blood flow to the
brain is approximately 10 times that to
the resting muscles.
Since the distribution of drugs to the
various areas of the body is largely
dependent upon the blood flow to the
tissue, one might expect that drugs
would pass very rapidly from the blood
to the brain.
Indeed, some compounds (thiopental) do
reach the brain very quickly, but many
enter brain tissue only slowly, if at
all. The decreased permeability of the
capillaries of the brain has a
structural basis and is frequently
called the blood-brain barrier.
The blood-brain barrier can be bypassed
if the drug is injected into the
cerebrospinal fluid.
Placental barrier
Among all the membrane systems in the
body, the placenta is unique. It
separates two human beings with
different genetic compositions,
physiological responses, and
sensitivities to drugs. The fetus
receives essential nutrients and
eliminates metabolic waste products
through the placenta without depending
on its own organs, many of which are not
yet functioning.
This dependence of the fetus on the
mother places the fetus at the mercy of
the placenta when foreign substances,
such as drugs, appear in the mother's
blood. Pregnant women can present
dangers to their fetus by taking drugs,
or exposing themselves to toxic
substances in food, cosmetics, household
chemicals and in the environment.
The effects of drugs on the fetus are
of two major types:
Early in pregnancy, when the limbs and
organs are being formed, drugs may
induce structural abnormalities:
teratogenesis. The best example of this
was thalidomide. Later in pregnancy and
during delivery, drugs may induce
respiratory problems in the newborn.
In general, the mature placenta
consists of a network of vessels and
pools of maternal blood into which
protrude treelike or fingerlike villi
containing the blood capillaries of the
fetus.
Oxygen and nutrients move from the
mother's blood to that of the fetus
while carbon dioxide and other waste
products move from the fetal to the
maternal blood.
The membranes separating fetal blood
from maternal blood in the intervillous
space resemble cell membranes found
elsewhere in the body.
Fat-soluble substances move across
readily while fat-insoluble substances
don't transfer as smoothly. This is of
interest, since late in pregnancy and at
the time of delivery, most anesthetic
liquids and gases and most pain
relieving agents penetrate both the
blood-brain barrier and the placental
barrier very well.
Anesthetic agents and narcotic
analgesics may be found in fairly high
concentrations in the newborn infant. We
are all aware of stories about
withdrawal symptoms in infants born to
addicted mothers.
Biotransformation - metabolism
Once it enters the body, a drug divides
into two parts, the part that remains
unchanged and the part that changes. It
can be eliminated from the body in both
of these states -- as the drug
administered and as the new chemical
entities.
The amount of drug eliminated in a
particular state depends on the nature
of the drug, the dose, the route of
administration, and the physiological
characteristics of the user.
The process by which drugs are changed
into different chemical compounds is
called metabolism. The new substances
that are produced are called
metabolites.
Drugs are metabolized by compounds
called enzymes. These are sophisticated
proteins which act as catalysts in a
chemical reaction. Most drug metabolism
occurs in the liver, but enzymes in the
gastrointestinal tract, lung and blood
also assist in this breakdown process.
Conversion
The conversion of fat-soluble drugs to
water soluble substances may involve
several chemical steps, each step
yielding a slightly more soluble
substance, for eventual excretion by the
kidneys. One drug can therefore yield
many different metabolites.
As the drug becomes progressively less
fat-soluble, it simultaneously loses its
ability to cross the blood-brain
barrier, and loses its strength in the
brain.
Many intermediate metabolites are less
potent than the parent drug, while
others are completely devoid of
pharmacological activity. Some drugs are
pharmacologically more active than the
parent drug. Metabolites are also
capable of producing a completely
different activity from the parent drug.
Repeated drug exposure can cause enzyme
systems to increase in number, resulting
in a faster metabolic rate. A more rapid
rate of conversion can lead to increased
intensity and speedier effect if the
original substance was inactive and the
metabolites active. It can also result
in decreased intensity and duration of
effect if the original drug was active
and the metabolites inactive.
Many drugs are fat (lipid) soluble, or
weak organic acids or bases and are not
readily eliminated from the body.
Advantage may sometimes be taken of
drug-metabolizing enzymes by
administering an agent in an inactive
form as a prodrug. In this case the
metabolism creates the active species.
If drug metabolites are active,
termination of action takes place by
further biotransformation or by
excretion of the active metabolite in
the urine.
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