Once
the drug is administered through one of several available routes, four
pharmacokinetic properties determine the speed of onset of drug action, the
intensity of the drug`s effect, and the duration of drug action.
1.
ABSORPTION
Absorption
is the transfer of a drug from its site of administration to the bloodstream
with no change via one of several mechanisms. The rate and efficiency of
absorption depend on both factors in the environment where the drug is absorbed
and the drugs chemical characteristics and route of administration. The extent
of absorption is determined with bioavailability.
It is the amount of an administered drug that becomes available for
pharmacological activity after the absorption in the target tissue. For IV delivery, absorption is
absolute. Drug delivery by other routes may result in only partial absorption
and, thus, lower bioavailability.
A. Mechanisms of
absorption of drugs from the GI tract
Depending
on their chemical properties, drugs may be absorbed from the GI tract by
passive diffusion, facilitated diffusion, active transport, or endocytosis.
a. Passive diffusion:
The driving force for
passive absorption of a drug is the concentration gradient across a membrane
separating two body compartments. In other words, the drug moves from a region
of high concentration to one of lower concentration. Passive diffusion does not
involve a carrier, is not saturable, and shows a low structural specificity.
The vast majority of drugs gain access to the body by this mechanism.
Water-soluble drugs penetrate the cell membrane through aqueous channels or
pores, whereas lipid-soluble drugs readily move across most biologic membranes
due to their solubility in the membrane lipid bilayers.
b. Facilitated
diffusion:
Other agents can enter the cell through specialized
transmembrane carrier proteins that facilitate the passage of large molecules.
These carrier proteins undergo conformational changes, allowing the passage of
drugs or endogenous molecules into the interior of cells and moving them from
an area of high concentration to an area of low concentration. This process is
known as facilitated diffusion. It does not require energy, can be saturated,
and may be inhibited by compounds that compete for the carrier.
c. Active transport:
This mode of drug
entry also involves specific carrier proteins that span the membrane. A few
drugs that closely resemble the structure of naturally occurring metabolites
are actively transported across cell membranes using these specific carrier
proteins. Energy-dependent active transport is driven by the hydrolysis of adenosine
triphosphate. It is capable of moving drugs against a concentration gradient,
from a region of low drug concentration to one of higher drug concentration.
The process shows saturation kinetics for the carrier, much in the same way
that an enzyme-catalyzed reaction shows a maximal velocity at high substrate
levels where all the active sites are filled with substrate. Active transport
systems are selective and may be competitively inhibited by other cotransported
substances.
d. Endocytosis and
exocytosis:
These types of drug delivery systems transport drugs of
exceptionally large size across the cell membrane.
2.
DISTRIBUTION
Drug
distribution refers to the Reversible Transfer of a Drug between the Blood and
the Extra Vascular fluids and tissues of the body (for example, fat, muscle,
and brain tissue). Distribution is a Passive Process, for which the driving
force is the concentration gradient between the blood and Extra vascular
tissues. The
Process occurs by the Diffusion of Free Drug until equilibrium is established.
As the Pharmacological action of a drug depends upon its concentration at the
site of action, so distribution plays a significant role in the Onset,
Intensity, and Duration of Action. The extent of distribution is measured by Volume of Distribution (Vd). It is a hypothetical volume of body
fluid that would be required to dissolve the total amount of drug needed to
achieve the same concentration as that found in the blood. Distribution of a
drug is not uniform throughout the body because different tissues receive the
drug from plasma at different rates and to different extent.
3.
METABOLISM
The
kidney cannot efficiently eliminate lipophilic drugs that readily cross cell
membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble agents must first be metabolized
into more polar (hydrophilic)
substances in the liver using two general sets of reactions, called Phase I and Phase II reactions.
Phase I:
Phase I reactions
convert lipophilic molecules into more polar molecules by introducing or
unmasking a polar functional group, such as –OH or –NH2. Phase I metabolism may
increase, decrease, or leave unaltered the drugs pharmacologic activity.
Reactions include oxidation, reduction and hydrolysis.
Phase II:
This phase consists
of conjugation reactions. If the metabolite from Phase I metabolism is
sufficiently polar, it can be excreted by the kidneys. However, many Phase I
metabolites are too lipophilic to be retained in the kidney tubules. A
subsequent conjugation reaction with an endogenous substrate, such as
glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in
polar, usually more water-soluble compounds that are most often therapeutically
inactive.
4.
ELIMINATION
Elimination
is the irreversible loss of the hydrophilic or polar drug, or food molecules
from the body. Elimination of drugs from the body requires the agents to be
sufficiently polar for efficient excretion. Removal of a drug from the body
occurs via a number of routes, Kidny, liver, and lungs, the most important
being through the kidney into the urine.
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