Pharmacokinetics

Lecture 1
Pharmacokinetics
Pharmacokinetics refers to what the body does to a drug, whereas pharmacodynamics
describes what the drug does to the
body. Four pharmacokinetic properties determine the onset, intensity,
and the duration of drug action
• Absorption: First, absorption from the site of administration permits
entry of the drug (either directly or indirectly) into plasma.
• Distribution: Second, the drug may then reversibly leave the bloodstream
and distribute into the interstitial and intracellular fluids.
• Metabolism: Third, the drug may be biotransformed by metabolism by
the liver or other tissues.
• Elimination: Finally, the drug and its metabolites are eliminated from
the body in urine, bile, or feces.
Using knowledge of pharmacokinetic parameters, clinicians can design
optimal drug regimens, including the route of administration, the dose,
the frequency, and the duration of treatment.
ROUTES OF DRUG ADMINISTRATION
A. Enteral
B. Parenteral
C. Other
ABSORPTION OF DRUGS
Absorption is the transfer of a drug from the site of administration to the
bloodstream. The rate and extent of absorption depend on the environment
where the drug is absorbed, chemical characteristics of the drug,
and the route of administration (which influences bioavailability). Routes
of administration other than intravenous may result in partial absorption
and lower bioavailability
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
1. 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
are absorbed 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.
2. 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.
3. 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 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 is
saturable. Active transport systems are selective and may be competitively
inhibited by other cotransported substances.
4. Endocytosis and exocytosis: This type of absorption is used
to transport drugs of exceptionally large size across the cell
membrane. Endocytosis involves engulfment of a drug by the cell
membrane and transport into the cell by pinching off the drugfilled
vesicle. Exocytosis is the reverse of endocytosis. Many
cells use exocytosis to secrete substances out of the cell through
a similar process of vesicle formation. Vitamin B12 is transported
across the gut wall by endocytosis, whereas certain neurotransmitters
(for example, norepinephrine) are stored in intracellular
vesicles in the nerve terminal and released by exocytosis
Factors influencing absorption
1. Effect of pH on drug absorption: Most drugs are either weak
acids or weak bases. Acidic drugs (HA) release a proton (H+),
causing a charged anion (A?) to form: HA _H+ + A?
Weak bases (BH+) can also release an H+. However, the protonated
form of basic drugs is usually charged, and loss of a proton
produces the uncharged base (B): BH+ _B + H+
A drug passes through membranes more readily if it is uncharged
. Thus, for a weak acid, the uncharged, protonated
HA can permeate through membranes, and A? cannot. For
a weak base, the uncharged form B penetrates through the cell
membrane, but the protonated form BH+ does not. Therefore, the
effective concentration of the permeable form of each drug at its
absorption site is determined by the relative concentrations of the
charged and uncharged forms. The ratio between the two forms
is, in turn, determined by the pH at the site of absorption and by
the strength of the weak acid or base, which is represented by
the ionization constant, pKa . [Note: The pKa is a measure
of the strength of the interaction of a compound with a proton.
The lower the pKa of a drug, the more acidic it is. Conversely, the
higher the pKa, the more basic is the drug.] Distribution equilibrium
is achieved when the permeable form of a drug achieves an equal
concentration in all body water spaces.
2. Blood flow to the absorption site: The intestines receive much
more blood flow than the stomach, so absorption from the intestine
is favored over the stomach. [Note: Shock severely reduces blood
flow to cutaneous tissues, thereby minimizing absorption from SC
administration.]
3. Total surface area available for absorption: With a surface rich
in brush borders containing microvilli, the intestine has a surface
area about 1000-fold that of the stomach, making absorption of the
drug across the intestine more efficient.
4. Contact time at the absorption surface: If a drug moves
through the GI tract very quickly, as can happen with severe diarrhea,
it is not well absorbed. Conversely, anything that delays the
transport of the drug from the stomach to the intestine delays
the rate of absorption of the drug. [Note: The presence of food
in the stomach both dilutes the drug and slows gastric emptying.
Therefore, a drug taken with a meal is generally absorbed more
slowly.]
5. Expression of P-glycoprotein: P-glycoprotein is a transmembrane
transporter protein responsible for transporting various
molecules, including drugs, across cell membranes (Figure 1.9).
It is expressed in tissues throughout the body, including the
liver, kidneys, placenta, intestines, and brain capillaries, and is
involved in transportation of drugs from tissues to blood. That is, it
“pumps” drugs out of the cells. Thus, in areas of high expression,
P-glycoprotein reduces drug absorption. In addition to transporting
many drugs out of cells, it is also associated with multidrug
resistance