Principles of Pharmacology: Chapter 3 Pharmacokinetics

A successful drug must be able to cross the physiologic barriers that limit the
access of foreign substances to the body. Drug absorption may occur by a # of
mechanisms that are designed either to exploit or to breach these barriers. After
absorption, the drug uses distribution systems w/in the body to reach its target
organ in an appropriate concentration. The drugs ability to access its target is
also limited by several processes which fall broadly into 2 categories: metabolism
(the body inactivates the drug thru enzymatic
degradation) & excretion (drug is eliminated
form the body).
o ADME: absorption, distribution,
metabolism, excretion.
At all times, free drug in the systemic
circulation is in equilibrium w/ tissue reservoirs,
plasma proteins, & the target site (which
usually consists of receptors); only the fraction
of drug that binds to specific receptors will
have a pharmacologic effect.
The hydrophobic core of a biological membrane presents the major barrier to drug
transport.
In the absence of other factors, a drug will enter a cell until the intracellular &
extracellular concentrations of the drug are equal.
o The rate of diffusion depends on the concentration gradient of the drug
across the membrane & on the thickness, area & permeability of the
membrane.
In vivo, additional factors affect the ability of a drug to enter cells: ionic, pH &
charge gradients across the membrane.
o pH trapping: depends on the drugs acid
dissociation constant (pKa) & the pH gradient
across the membrane.
o In the example: If drug is a weak acid, in the
highly acidic environment of the stomach, it is
largely protonated. The protonated, neutral form
of the drug is able to diffuse across the gastric
mucosal barrier in the blood. B/c the blood
plasma has a pH of 7.4 the vast majority of the
drug is no deprotonated (negatively charged) & is
no longer able to diffuse across the lipid bilayers of the gastric mucosa & the
drug is effectively trapped in the plasma.
The central nervous system (CNS) is particularly well insulated from foreign
substances. The blood-brain barrier uses specialized tight junctions to prevent the
passive diffusion of most drugs from the systemic to the cerebral circulation.
Drugs designed to act in the CNS must either be sufficiently small & hydrophobic
to traverse biological membranes easily or use
existing transport proteins.
Bioavailability, or the fraction of administered drug
that reaches the systemic circulation, may depend
on the route by which the drug is administered, the
chemical form of the drug, & a # of patient-specific factors.

An intravenously administered drug is immediately available in circulation. The

drug is then distributed to other body compartments & eliminated by first-order
kinetics.
o The definition of bioavailability is based on the fact that most drugs reach
their molecular & cellular sites of action directly from the systemic
circulation.
o Intravenous bioavailability be definition is 1.0
The total amount of drug reaching the systemic circulation can be quantified by
integrating the area under the curve (AUC) of the plasma drug concentration
versus time plot.
Enteral drug administration (drug by mouth) is the simplest of drug routes. An
orally administered drug must be stable during its absorption across the
gastrointestinal tract epithelium.
o Gastrointestinal epithelial cell junctions make paracellular transport across
an intact epithelium difficult. Ingested substances must traverse the cell
membrane at both apical & basal surfaces before entering the blood.
o In general, hydrophobic
& neutral drugs cross
cell membranes more
efficiently than
hydrophilic or charged
drugs, unless the
membrane contains a
carrier molecule that
facilitates the passage of
hydrophilic substances.
o All orally administered
drugs are subjected to
first-pass metabolism in the liver.
Parenteral administration is introduced directly into the systemic circulation,
cerebrospinal fluid, vascularized tissue, or some other tissue space, immediately
overcomes barriers that can limit the
effectiveness of orally administered drugs.
Administration of drugs across the mucous
membrane can potentially provide rapid
absorption, low incidence of infection,
convenience of administration & avoidance of
harsh gastrointestinal environments & 1stpass metabolism.
o The mucous membranes are highly
vascular, permitting the drug to enter
the systemic circulation rapidly & to
reach its target organ.
Transcutaneously administered drugs are
absorbed from the skin & subcutaneous
tissues directly into the blood. This route of
administration is ideal for drugs that must be
slowly & continuously administered over
extended periods.
A large &/or rapidly administered dose creates a high local concentration of a drug
which creates a large concentration gradient b/w the site of administration & the

surrounding tissue which drives the distribution of the drug into the nearby tissue.
Any factor that decreases the concentration gradient at the site of administration
will diminish the driving force of the gradient & decrease the amt of drug that is
distributed. Regional blood flow has the greatest effect b/c the drug molecules
crossing into that compartment are rapidly removed. This effect maintains the
drug concentration at a low level in the
compartment, allowing the driving force for
entry of new drug molecules into the
compartment to remain high.
Absorption of the drug is a prerequisite for
establishing adequate plasma drug levels, but
the drug must also reach its target organ in
therapeutic concentrations to have the desired
effect on a pathophysiologic process.
o Organs & tissues vary widely in their
capacity to take up different types of drugs
& in the proportion of systemic blood flow
they receive.
The volume of distribution (Vd) describes the
extent to which a drug partitions b/w the plasma & tissue compartments.
o A drug that is taken up in large quantities by tissues will be largely removed
from the circulation at steady state. Thus, for drugs of equal potency, a drug
that is more highly distributed among body tissues generally requires a
higher initial dose to establish a therapeutic plasma concentration than does
a drug that is less highly distributed.
The capacity of muscle & adipose tissue to bind a drug increases the tendency of
the drug to diffuse form the blood into nonvascular compartments, but this
tendency can be counteracted to some extent by plasma protein binding of the
drug.
o Plasma protein binding tends to reduce the availability of a drug for diffusion
or transport into the drugs target organ b/c, in general, only the free or
unbound form of the drug is capable of diffusion across membranes.
Most drugs are distributed rapidly from the systemic circulation (intravascular
compartment) to other compartments in the body. This distribution phase results
in a sharp decrease in the plasma drug concentration
shortly after intravenous administration of a drug
bolus.
o Even after the drug equilibrates among its tissue
reservoirs, the plasma drug concentration
continues to decline b/c of drug elimination from
the body.
o Plasma drug concentration decreases more
slowly during the elimination phase, in part due
to a reservoir of drug in the tissues that can
diffuse back into the blood to replace the drug that has been eliminated.
o Immediately after intravenous administration of a drug, the plasma drug
concentration declines rapidly as the drug distributes from the vascular
compartment to other body compartments. This rapid decline is followed by
a slower decline as the drug is metabolized & excreted from the body.
Biotransformation: modifications by hepatic enzymes chemically modify a variety
of substituents on drug molecules, thereby either rendering the drugs inactive or

facilitating their elimination. Biotransformation reactions are classified into 2

types: (1) oxidation/reduction reactions & conjugation/hydrolysis reactions.
o Oxidation/reduction reactions modify the chemical structure of a drug.
o Conjugation/hydrolysis reactions hydrolyze a drug or conjugate a drug to a
large, polar molecule in order to inactivate or enhance the drugs solubility &
excretion.
o Oxidation/reduction & conjugation/hydrolysis reactions enhance the
hydrophilicity of a hydrophobic drug & its metabolites, enabling such drugs
to be excreted along a final common pathway.
Renal blood flow comprises about 25% of total systemic blood flow, ensuring the
kidneys are continuously exposed to any drug found in the blood. The rate of drug
elimination thru the kidneys depends on the balance of drug filtration, secretion &
reabsorption rates.
o Only free drug form is filtered into the renal tubule. Therefore, renal blood
flow, glomerular filtration rate, & drug binding to plasma protein all affect the
amt of drug that enters the tubule @ the glomerulus. Enhancing blood flow,
increasing glomerular filtration rate, & decreasing plasma protein binding
cause a drug to be excreted more rapidly.
o Drugs may be (1) filtered @ the renal glomerulus, (2) secreted into the
proximal tubule, (3) reabsorbed from the tubular lumen & transported back
into the blood, & (4) excreted in the urine.
Drug reabsorption plays an important role in biliary excretion. B/c the bile duct
enters the gastrointestinal tract in the duodenum, such drugs must pass thru the
length of the small & large intestine before being eliminated. The drugs undergo
enterohepatic circulation, in which they are reabsorbed in the small intestine &
subsequently retained in the portal & then systemic circulation.
The clearance of a drug is the pharmacokinetic parameter that most significantly
limits the time course of action of the drug at its molecular, cellular, & organ
targets.
o Defined as the rate of elimination of the drug from the body relative to the
concentration of the drug in plasma.
o Defined also as the rate at which plasma would have to be cleared of the
drug to account for the observed kinetics of change of the total amount of
drug in the body, assuming that all the drug in the body is present at the
same concentration as that in the plasma.
The rate of drug metabolism & excretion by an organ is limited by the rate of blood
flow to that organ. The majority of drugs demonstrate first-order kinetics when
used in standard therapeutic doses; that is, the amt of drug that is metabolized or
excreted in a given unit of time is directly proportional to the concentration of drug
in the systemic circulation at that time.
o Drug elimination typically follows first-order kinetics. The rate of drug
elimination increases as the plasma drug concentration increases, until the
elimination mechanisms become saturated & reach a maximal elimination
rate.
By decreasing the concentration of active drug in the blood, drug metabolism &
excretion shorten the time during which a drug is capable of acting on a target
organ.
The elimination half-life of a drug is defined as the amount of time over which the
drug concentration in the plasma decreases to of its original value.

o Knowledge of a drugs elimination half-life allows the clinician to estimate the

frequency of dosing required to maintain the plasma concentration of the
drug in the therapeutic range.
o Hepatic, cardiac, & renal failure can each lead to a decreased ability to
inactivate or eliminate a drug, & thereby increase the elimination half-life of
the drug.
The basic principles of pharmacokinetics absorption, distribution, metabolism, &
excretion influence the design of an optimal dosing regimen for a drug.
o Absorption determines the potential route(s) of administration & helps to
determine optimal drug dose.
o Therapeutic dosing of a drug seeks to maintain the peak (highest) plasma
drug concentration below the toxic concentration, & the trough (lowest) drug
concentration above the minimally effective level.
o Optimal dosing regimens typically maintain the steady-state plasma drug
concentration w/in the
therapeutic window for
that drug. B/c steady
state is reached when
the rate of drug input is
equal to its output, the
steady-state drug
concentration is
affected by drug
bioavailability,
clearance, dose, &
dosing interval (the
frequency of
administration).
Loading dose: after
administration of a drug by
any route, the plasma
concentration of the drug initially increases.
o In the absence of a loading dose, 4-5 elimination half-lives are required for
the tissue distribution & plasma concentration of a drug to reach steady
state.
Maintenance dose: once steady-state drug concentrations are achieved in the
plasma & the tissues, subsequent doses need to replace only the amt of drug that
is lost thru metabolism & excretion.
Saturation kinetics (zero-order kinetics): the bodys capacity to eliminate the drug
may become saturated at therapeutic drug concentrations. Continued
administration of drug results in rapid drug accumulation in the plasma & drug
concentrations may reach toxic levels.