Chapter 1: Pharmacokinetics Flashcards
Routes of drug administration
Enteral
Parenteral
The parenteral route introduces drugs directly into the systemic cir-
culation. Parenteral administration is used for drugs that are poorly absorbed from the GI tract (for example, heparin) or unstable in
the GI tract (for example, insulin). Parenteral administration is also
used if a patient is unable to take oral medications (unconscious
patients) and in circumstances that require a rapid onset of action.
In addition, parenteral routes have the highest bioavailability and
are not subject to first-pass metabolism or the harsh GI environ-
ment. Parenteral administration provides the most control over the
actual dose of drug delivered to the body. However, these routes
of administration are irreversible and may cause pain, fear, local
tissue damage, and infections. The three major parenteral routes
are intravascular (intravenous or intra-arterial), intramuscular, and
subcutaneous (Figure 1.3).
1. Intravenous (IV): IV injection is the most common parenteral
route. It is useful for drugs that are not absorbed orally, such as
the neuromuscular blocker rocuronium. IV delivery permits a
rapid effect and a maximum degree of control over the amount
of drug delivered. When injected as a bolus, the full amount of
drug is delivered to the systemic circulation almost immediately. If
administered as an IV infusion, the drug is infused over a longer
period of time, resulting in lower peak plasma concentrations and
an increased duration of circulating drug levels. IV administration
is advantageous for drugs that cause irritation when administered
via other routes, because the substance is rapidly diluted by the
blood. Unlike drugs given orally, those that are injected cannot be
recalled by strategies such as binding to activated charcoal. IV
injection may inadvertently introduce infections through contami-
nation at the site of injection. It may also precipitate blood con-
stituents, induce hemolysis, or cause other adverse reactions if
the medication is delivered too rapidly and high concentrations are
reached too quickly. Therefore, patients must be carefully moni-
tored for drug reactions, and the rate of infusion must be carefully
controlled.
2. Intramuscular (IM): Drugs administered IM can be in aque-
ous solutions, which are absorbed rapidly, or in specialized
depot preparations, which are absorbed slowly. Depot prepara-
tions often consist of a suspension of the drug in a nonaqueous
vehicle such as polyethylene glycol. As the vehicle diffuses out
of the muscle, the drug precipitates at the site of injection. The
drug then dissolves slowly, providing a sustained dose over an
extended period of time. Examples of sustained-release drugs
are haloperidol (see Chapter 11) and depot medroxyprogester-
one (see Chapter 26).
3. Subcutaneous (SC): Like IM injection, SC injection provides
absorption via simple diffusion and is slower than the IV route. SC
injection minimizes the risks of hemolysis or thrombosis associ-
ated with IV injection and may provide constant, slow, and sus-
tained effects. This route should not be used with drugs that cause
tissue irritation, because severe pain and necrosis may occur.
Drugs commonly administered via the subcutaneous route include
insulin and heparin.
Others
Other
1. Oral inhalation: Inhalation routes, both oral and nasal (see
discussion of nasal inhalation), provide rapid delivery of a drug
across the large surface area of the mucous membranes of the
respiratory tract and pulmonary epithelium. Drug effects are
almost as rapid as those with IV bolus. Drugs that are gases (for
example, some anesthetics) and those that can be dispersed in
an aerosol are administered via inhalation. This route is effective
and convenient for patients with respiratory disorders (such as
asthma or chronic obstructive pulmonary disease), because the
drug is delivered directly to the site of action, thereby minimizing
systemic side effects. Examples of drugs administered via inha-
lation include bronchodilators, such as albuterol, and corticoste-
roids, such as fluticasone.
2. Nasal inhalation: This route involves administration of drugs
directly into the nose. Examples of agents include nasal decon-
gestants, such as oxymetazoline, and corticosteroids, such as
mometasone furoate. Desmopressin is administered intranasally
in the treatment of diabetes insipidus.
3. Intrathecal/intraventricular: The blood–brain barrier typically
delays or prevents the absorption of drugs into the central nervous
system (CNS). When local, rapid effects are needed, it is neces-
sary to introduce drugs directly into the cerebrospinal fluid. For
example, intrathecal amphotericin B is used in treating cryptococ-
cal meningitis (see Chapter 42).
4. Topical: Topical application is used when a local effect of the drug
is desired. For example, clotrimazole is a cream applied directly to
the skin for the treatment of fungal infections.
5. Transdermal: This route of administration achieves systemic
effects by application of drugs to the skin, usually via a transder-
mal patch (Figure 1.4). The rate of absorption can vary markedly,
depending on the physical characteristics of the skin at the site
of application, as well as the lipid solubility of the drug. This route
is most often used for the sustained delivery of drugs, such as
the antianginal drug nitroglycerin, the antiemetic scopolamine, and
nicotine transdermal patches, which are used to facilitate smoking
cessation.
6. Rectal: Because 50% of the drainage of the rectal region
bypasses the portal circulation, the biotransformation of drugs by
the liver is minimized with rectal administration. The rectal route
has the additional advantage of preventing destruction of the drug
in the GI environment. This route is also useful if the drug induces
vomiting when given orally, if the patient is already vomiting, or if
the patient is unconscious. [Note: The rectal route is commonly
used to administer antiemetic agents.] Rectal absorption is often
erratic and incomplete, and many drugs irritate the rectal mucosa.
Figure 1.5 summarizes the characteristics of the common routes
of administration.
ABSORPTION OF DRUGS
Passive diffusion
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 (Figure 1.6).
1. Passive diffusion: The driving force for passive absorption of
a drug is the concentration gradient across a membrane sepa-
rating two body compartments. In other words, the drug moves
from a region of high concentration to one of lower concentra-
tion. 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 pene-
trate 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.
Facilitated diffusion
Facilitated diffusion: Other agents can enter the cell through spe-
cialized 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 con-
centration 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.
Active transport
Active transport: This mode of drug entry also involves spe-
cific 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 com-
petitively inhibited by other cotransported substances.
Endocytosis and exocytosis
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 drug-
filled 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 neurotrans-
mitters (for example, norepinephrine) are stored in intracellular
vesicles in the nerve terminal and released by exocytosis
Factors influencing absorption
Effect of pH
- 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 proton-
ated 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
(Figure 1.7). Thus, for a weak acid, the uncharged, proton-
ated 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
(Figure 1.8). [Note: The pKa
is a mea-
sure 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.
- Blood flow to the absorption site
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.]
Total surface area available for absorption
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
Contact time at the absorption surface
- Contact time at the absorption surface: If a drug moves
through the GI tract very quickly, as can happen with severe diar-
rhea, 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.]
Expression of p-glycoprotein
- Expression of P-glycoprotein: P-glycoprotein is a transmem-
brane 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 transport-
ing many drugs out of cells, it is also associated with multidrug
resistance.
Bioavailability
Bioavailability is the rate and extent to which an administered drug
reaches the systemic circulation. For example, if 100 mg of a drug
is administered orally and 70 mg is absorbed unchanged, the bio-
availability is 0.7 or 70%. Determining bioavailability is important for
calculating drug dosages for nonintravenous routes of administration.
- Determination of bioavailability: Bioavailability is determined
by comparing plasma levels of a drug after a particular route
of administration (for example, oral administration) with levels
achieved by IV administration. After IV administration, 100% of the
drug rapidly enters the circulation. When the drug is given orally,
only part of the administered dose appears in the plasma. By
plotting plasma concentrations of the drug versus time, the area
under the curve (AUC) can be measured. The total AUC reflects
the extent of absorption of the drug. Bioavailability of a drug given
orally is the ratio of the AUC following oral administration to the
AUC following IV administration (assuming IV and oral doses are
equivalent; Figure 1.10).
Factors that influence bioavailability:
In contrast to IV admin-
istration, which confers 100% bioavailability, orally administered
drugs often undergo first-pass metabolism. This biotransformation,
in addition to the chemical and physical characteristics of the drug,
determines the rate and extent to which the agent reaches the
systemic circulation.
a. First-pass hepatic metabolism: When a drug is absorbed
from the GI tract, it enters the portal circulation before enter-
ing the systemic circulation (Figure 1.11). If the drug is rap-
idly metabolized in the liver or gut wall during this initial
passage, the amount of unchanged drug entering the sys-
temic circulation is decreased. This is referred to as first-pass metabolism. [Note: First-pass metabolism by the intestine
or liver limits the efficacy of many oral medications. For
example, more than 90% of nitroglycerin is cleared during
first-pass metabolism. Hence, it is primarily administered
via the sublingual or transdermal route.] Drugs with high
first-pass metabolism should be given in doses sufficient to
ensure that enough active drug reaches the desired site of
action.
Solubility of the drug
Solubility of the drug: Very hydrophilic drugs are poorly
absorbed because of their inability to cross lipid-rich cell mem-
branes. Paradoxically, drugs that are extremely lipophilic are
also poorly absorbed, because they are totally insoluble in
aqueous body fluids and, therefore, cannot gain access to the
surface of cells. For a drug to be readily absorbed, it must be
largely lipophilic, yet have some solubility in aqueous solutions.
This is one reason why many drugs are either weak acids or
weak bases.
Chemical instability
Chemical instability: Some drugs, such as penicillin G, are
unstable in the pH of the gastric contents. Others, such as
insulin, are destroyed in the GI tract by degradative enzymes.
Nature of drug formulation
Nature of the drug formulation: Drug absorption may be
altered by factors unrelated to the chemistry of the drug. For
example, particle size, salt form, crystal polymorphism, enteric
coatings, and the presence of excipients (such as binders and
dispersing agents) can influence the ease of dissolution and,
therefore, alter the rate of absorption.
Bioequivalence
Bioequivalence
Two drug formulations are bioequivalent if they show comparable bio-
availability and similar times to achieve peak blood concentrations
Therapeutic equivalent
Therapeutic equivalence
Two drug formulations are therapeutically equivalent if they are
pharmaceutically equivalent (that is, they have the same dosage
form, contain the same active ingredient, and use the same route of
administration) with similar clinical and safety profiles. [Note: Clinical
effectiveness often depends on both the maximum serum drug con-
centration and the time required (after administration) to reach peak
concentration. Therefore, two drugs that are bioequivalent may not
be therapeutically equivalent.]
DRUG DISTRIBUTION
Blood flow
A. Blood flow
The rate of blood flow to the tissue capillaries varies widely. For
instance, blood flow to the “vessel-rich organs” (brain, liver, and kid-
ney) is greater than that to the skeletal muscles. Adipose tissue, skin,
and viscera have still lower rates of blood flow. Variation in blood
flow partly explains the short duration of hypnosis produced by an
IV bolus of propofol (see Chapter 13). High blood flow, together with
high lipophilicity of propofol, permits rapid distribution into the CNS
and produces anesthesia. A subsequent slower distribution to skel-
etal muscle and adipose tissue lowers the plasma concentration so
that the drug diffuses out of the CNS, down the concentration gradi-
ent, and consciousness is regained.
Capillary permeability
Capillary permeability
Capillary permeability is determined by capillary structure and by
the chemical nature of the drug. Capillary structure varies in terms
of the fraction of the basement membrane exposed by slit junc-
tions between endothelial cells. In the liver and spleen, a signifi-
cant portion of the basement membrane is exposed due to large,
discontinuous capillaries through which large plasma proteins can
pass (Figure 1.13A). In the brain, the capillary structure is con-
tinuous, and there are no slit junctions (Figure 1.13B). To enter
the brain, drugs must pass through the endothelial cells of the
CNS capillaries or be actively transported. For example, a specific
transporter carries levodopa into the brain. By contrast, lipid-solu-
ble drugs readily penetrate the CNS because they dissolve in the
endothelial cell membrane. Ionized or polar drugs generally fail to
enter the CNS because they cannot pass through the endothelial
cells that have no slit junctions (Figure 1.13C). These closely jux-
taposed cells form tight junctions that constitute the blood–brain
barrier.
Binding of drugs to plasma proteins and tissues
Binding to plasma proteins: Reversible binding to plasma
proteins sequesters drugs in a nondiffusible form and slows
their transfer out of the vascular compartment. Albumin is the
major drug-binding protein and may act as a drug reservoir (as
the concentration of free drug decreases due to elimination, the
bound drug dissociates from the protein). This maintains the free-
drug concentration as a constant fraction of the total drug in the
plasma
Binding to tissue protein
Binding to tissue proteins: Many drugs accumulate in tissues,
leading to higher concentrations in tissues than in the extracel-
lular fluid and blood. Drugs may accumulate as a result of binding to lipids, proteins, or nucleic acids. Drugs may also be actively
transported into tissues. Tissue reservoirs may serve as a major
source of the drug and prolong its actions or cause local drug
toxicity. (For example, acrolein, the metabolite of cyclophospha-
mide, can cause hemorrhagic cystitis because it accumulates in
the bladder.)
Lipophilicity
The chemical nature of a drug strongly influences its ability to cross
cell membranes. Lipophilic drugs readily move across most biologic
membranes. These drugs dissolve in the lipid membranes and pen-
etrate the entire cell surface. The major factor influencing the distribu-
tion of lipophilic drugs is blood flow to the area. In contrast, hydrophilic
drugs do not readily penetrate cell membranes and must pass through
slit junctions.
Volume of distribution
Volume of distribution
The apparent volume of distribution, Vd
, is defined as the fluid volume
that is required to contain the entire drug in the body at the same
concentration measured in the plasma. It is calculated by dividing the
dose that ultimately gets into the systemic circulation by the plasma
concentration at time zero (C0
).
V
C d = Amount of drug in the body
0
Although Vd
has no physiologic or physical basis, it can be useful to
compare the distribution of a drug with the volumes of the water com-
partments in the body.
1. Distribution into the water compartments in the body: Once a
drug enters the body, it has the potential to distribute into any one
of the three functionally distinct compartments of body water or to
become sequestered in a cellular site.
a. Plasma compartment: If a drug has a high molecular weight
or is extensively protein bound, it is too large to pass through the
slit junctions of the capillaries and, thus, is effectively trapped
within the plasma (vascular) compartment. As a result, it has a
low Vd
that approximates the plasma volume or about 4 L in a
70-kg individual. Heparin (see Chapter 22) shows this type of
distribution.
b. Extracellular fluid: If a drug has a low molecular weight but
is hydrophilic, it can pass through the endothelial slit junctions
of the capillaries into the interstitial fluid. However, hydrophilic
drugs cannot move across the lipid membranes of cells to
enter the intracellular fluid. Therefore, these drugs distribute
into a volume that is the sum of the plasma volume and the
interstitial fluid, which together constitute the extracellular
fluid (about 20% of body weight or 14 L in a 70-kg individual).
Aminoglycoside antibiotics (see Chapter 39) show this type of
distribution.
c. Total body water: If a drug has a low molecular weight and
is lipophilic, it can move into the interstitium through the slit
junctions and also pass through the cell membranes into the
intracellular fluid. These drugs distribute into a volume of about
60% of body weight or about 42 L in a 70-kg individual. Ethanol
exhibits this apparent Vd
.
2. Apparent volume of distribution: A drug rarely associates
exclusively with only one of the water compartments of the body.
Instead, the vast majority of drugs distribute into several compart-
ments, often avidly binding cellular components, such as lipids
(abundant in adipocytes and cell membranes), proteins (abundant
in plasma and cells), and nucleic acids (abundant in cell nuclei).
Therefore, the volume into which drugs distribute is called the
apparent volume of distribution (Vd
). Vd
is a useful pharmacokinetic
parameter for calculating the loading dose of a drug.
3. Determination of Vd: The fact that drug clearance is usually a
first-order process allows calculation of Vd
. First order means that
a constant fraction of the drug is eliminated per unit of time. This
process can be most easily analyzed by plotting the log of the
plasma drug concentration (Cp
) versus time (Figure 1.14). The
concentration of drug in the plasma can be extrapolated back to
time zero (the time of IV bolus) on the Y axis to determine C0
,
which is the concentration of drug that would have been achieved
if the distribution phase had occurred instantly. This allows calcu-
lation of Vd
as
V Dose
C d =
0
For example, if 10 mg of drug is injected into a patient and the plasma
concentration is extrapolated back to time zero, and C0 = 1 mg/L
(from the graph in Figure 1.14B), then Vd = 10 mg/1 mg/L = 10 L.
4. Effect of Vd on drug half-life: Vd
has an important influence on
the half-life of a drug, because drug elimination depends on the
amount of drug delivered to the liver or kidney (or other organs
where metabolism occurs) per unit of time. Delivery of drug to the
organs of elimination depends not only on blood flow but also on
the fraction of the drug in the plasma. If a drug has a large Vd
,
most of the drug is in the extraplasmic space and is unavailable to
the excretory organs. Therefore, any factor that increases Vd
can
increase the half-life and extend the duration of action of the drug.
[Note: An exceptionally large Vd
indicates considerable sequestra-
tion of the drug in some tissues or compartments.]
