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 &
1
st
-pass 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.