Transcript Pharmacokinetics

Pharmacokinetics
CHAPTER 4
L . Va n Va l k e n b u r g , R V T, B A S
DRUG MOVEMENT
 PHARMACOKINETICS is the physiological
movement of drugs.
 4 Steps:
 Absorption
 Distribution
 Biotransformation
(metabolism)
 Excretion
DRUG MOVEMENT
 Pharmacokinetics includes the movement of
substances across cell membranes.
 Basic mechanisms:
 Passive diffusion
 Facilitated diffusion
 Active transport
 Pinocytosis/phagocytosis
They don’t!
Drugs molecules go “wherever”
Movement of Drug Molecules
Drug
molecules
move
randomly
from one
point to
another
This process is
called passive
diffusion
No cellular effort
is needed to
transport the
molecules
(hence the
process is
passive)
Passive Diffusion
High
concentration
in this area
Movement is
random from areas
of higher to areas
of lower
concentration
Eventually the drug
molecules are
equally
distributed
(equilibrium)
Passive Diffusion
C
e
l
l
Drug molecules
may move from
one side of a
cell membrane
to another by
passive
diffusion
M
e
m
b
r
a
n
e
But drug
molecules will
only cross by
passive
diffusion if they
can dissolve in
the membrane
Facilitated Diffusion
These
molecules can’t
pass through
the membrane
without help
C
C
e
e
l
ll
l
M
M
e
e
m
m
b
b
r
r
a
a
n
n
e
e
These drug
molecules need
a carrier to get
across the
membrane
Facilitated Diffusion
C
e
l
l
Here is the
carrier
protein
molecule in the
membrane
M
e
m
b
r
a
n
e
When the drug
molecule
encounters the
carrier protein,
it “carries” it
across
Facilitated Diffusion
C
e
l
l
Here is the
carrier
protein
molecule in the
membrane
M
e
m
b
r
a
n
e
When the drug
molecule
encounters the
carrier protein,
it “carries” it
across
Facilitated Diffusion
C
e
l
l
Here is the
carrier
protein
molecule in the
membrane
M
e
m
b
r
a
n
The carrier
molecule then
resets itself
No cellular
energy is used
to transport the
molecule across
Only the
concentration
gradient moves
the molecules
Active Transport
Involves a
carrier
molecule again
C
e
l
l
The drug molecule
encounters the
carrier molecule
M
e
m
b
r
a
n
e
The cell
expends energy
to PUMP the
molecule across
the membrane
to the other
side
Active Transport
Involves a
carrier
molecule
again
C
e
l
l
The drug
molecule
encounters the
carrier molecule
M
e
m
b
r
a
n
The cell
expends energy
to PUMP the
molecule across
the membrane
to the other
side
Active Transport
C
e
l
l
Involves a
carrier
molecule
again
M
e
m
b
r
a
n
e
Unlike
diffusion, active
transport is not
dependent
upon
concentration
gradient
All of the
molecules
can end up
on this side
Phagocytosis and Pinocytosis
Foreign
particle
Cell
Phagocytosis – the cell flows around
large particles and engulfs it
Pinocytosis – cell takes in molecules
through invaginations in the membrane
In summary….
Passive Diffusion
 Movement of
particles from an
area of high
concentration to an
area of low
concentration


Good for small,
lipophilic, nonionic
particles
The drug must
dissolve and pass
through in the cell
membrane
Facilitated Diffusion
 Passive diffusion
that uses a
special carrier
molecule
Good for bigger
molecules that are
not lipid soluble
 No energy is
needed for a
facilitated
diffusion

Active Transport
 Molecules move against
the concentration
gradient from areas of
low concentration of
molecules to areas of
high concentration of
molecules
 Involves a carrier
molecule
and energy

Good for accumulation of
drugs within a part of
the body
Phagocytosis and Pinocytosis
 Molecules are physically taken in or
engulfed. Pinocytosis is engulfing liquid;
phagocytosis is engulfing solid particles

Good for bigger molecules or liquids
Getting In: DRUG ABSORPTION
is the movement of a
drug from the site of administration into the
fluids of the body that will carry it to its
site(s) of action.
Drug factors: drug solubility, pH and molecular
size (see Table 4-2)
 Patient factors include the animal’s age, health,
metabolic rate, genetics, gender, and species (see
Table 4-3)
 Bioavailability is the percent of drug administered
that actually enters the systemic circulation
 IV and IA are 100% bioavailable and have a
bioavailability of 1.
 Drugs that are only partially absorbed have a
bioavailability of less than 1.

Getting in: DRUG ABSORPTION
Moving Around: DRUG DISTRIBUTION
 Drug distribution is the physiological movement
of drugs from systemic circulation into the tissues.
 Goal is for the drug to reach the target tissue or
intended site of action
 Factors affecting drug distribution:
 Membrane Permeability
 Tissue Perfusion
 Protein Binding
 Volume of Distribution
Membrane Permeability
 Capillary fenestrations allow movement of small
molecules in and out of them.
 Large molecules usually cannot pass through
them
Exception: Only lipophilic drugs can pass through the
blood-brain barrier because it has no fenestrations
and it has an extra layer of cells surrounding them
(glial cells). However, fever/inflammation can make
the membrane more permeable to some drugs.
Exception: The placenta has the ability to block SOME
drugs from affecting the fetus with its barrier.
TISSUE PERFUSION
 Definition – the relative amount of blood supply to
an area or body system. It affects how rapidly
drugs will be distributed.

Drugs travel rapidly to well perfused tissues (brain,
heart, liver, kidneys).


Drugs travel slowly to poorly perfused tissues (fat).


May initially have high levels of drug
May inititially have low levels of drug
Can also be affected by blood flow rates that are altered
via vasoconstriction or vasodilation.

Decreased rates decrease the amount and rate of the drug
that’s delivered to the tissues.
Protein Binding
 Protein bound drugs in the blood become trapped in
circulation because they cannot leave capillaries.
 Free or unbound drugs are able to leave the capillaries.


INCREASED PROTEIN BINDING = less free drug available to
the tissues
DECREASED PROTEIN BINDING = more free drug available
to the tissues.
 Equilibrium is typically established between
bound and unbound drugs.
 When given concurrently, protein bound drugs
compete for binding sites.
Hypoalbuminemia
 Albumin is the #1 transport protein in
circulation and is made in the LIVER.
 Animals with liver disease will have less
protein in their body, thus more drug will be
UNBOUND and available to the tissues.
 DECREASED dosages or different
medications should be chosen for patients
with liver disease.

Also important because most drugs will be
metabolized by the liver.
Volume of Distribution
Volume of Distribution
 Volume of distribution is how well a drug is
distributed throughout the body based on
concentration of drug in the blood.

Assumes that the drug concentration in the blood is equal to the drug
concentration throughout the rest of the body
NOTE: THE LARGER THE Volume of Distribution,
THE LOWER THE DRUG CONCENTRATION IN
THE BLOOD AND OTHER TISSUES AFTER
DISTRIBUTION.
 Lower concentrations may keep a drug out of therapeutic
range and decrease its effectiveness.
 Dose may need to be increased in cases of larger volumes of
distribution.
Changing: PHARMACOKINETICS
 Biotransformation is also called drug
metabolism, drug inactivation, and drug
detoxification
 Biotransformation is the chemical alteration
of drug molecules by the body cells into a
metabolite that is in an activated form, an
inactivated form, and/or a toxic form.
 Primary site of biotransformation is the
liver.

Inhibition or induction of Cytochrome P450
Drug Interactions
Affecting Drug Metabolism:
 Altered absorption: one drug may alter the
absorption of other drugs

Antacids alter pH of stomach.
 Competition for plasma proteins: drug A and
drug B may both bind to plasma proteins; one
may have a higher affinity than the other
 Altered excretion: some drugs may act directly
on the kidney and decrease the excretion of other
drugs

Diuretics increase production of urine and may affect drugs
excreted via the kidneys.
 Altered metabolism: the same enzymes may be
needed for biotransformation of two drugs that
are prescribed at the same time for an animal

Enzyme = saturated; rate of metabolism decreased for both drugs
Other ways in which drug interactions
affect drug metabolism:
 Some drugs induce the enzyme system,
altering metabolism by causing liver enzymes
to become more efficient.

Ex: Phenobarbital (may need to increase dose to
maintain adequate therapeutic levels)
 Liver damage or immaturity decreases
enzyme production and ability to metabolize
drugs

Doses may need to be decreased to avoid toxicity.
 Tolerance is decreased response to a drug
resulting from repeated use.



Metabolic – drug metabolized more rapidly
Cellular – “down regulation” = decreased receptor response
Doses need to be increased.
Getting out: PHARMACOKINETICS
 Drug elimination (drug excretion) is removal of a
drug from the body.
 Most important routes = kidneys and liver
 Renal elimination of drugs involves




Glomerular filtration
Tubular secretion
Tubular reabsorption
Urine pH can also affect rate of drug excretion.


Weak acids better excreted in basic urine
Weak bases better excreted in acidic urine
 Other elimination routes include the intestine and
through milk.
 Minor routes of elimination: sweat, saliva, and
pulmonary route.
Drug Elimination Terminology
 Drug residue: amount of drug that can be
detected in tissues after administration ceases.
 Withdrawal time: period of time after drug
administration during which the animal cannot be
sent to market for slaughter and the eggs or milk
must be discarded because of the potential for drug
residues
 Half-life: time required for the amount of drug in
the body to be reduced by half of its original level
 Steady state: point at which drug accumulation
and elimination are balanced
MEASURING DRUG ACTION
 Graphic depiction of the plasma concentration of
the drug vs. time


X axis represents time
Y axis represents drug concentration in plasma
 Onset of action occurs when the drug enters the
plasma
 The peak plasma level of the drug is when the
elimination rate of the drug is equivalent to its rate
of absorption
MEASURING DRUG ACTION
 The time elapsed from the time of administration to
the time that the peak plasma level is reached is
known as the time to peak

Important in making clinical judgments about the use of a
drug
 From the peak plasma level the concentration
declines since the amount of drug being eliminated
exceeds the amount being absorbed
HOW DO DRUGS WORK?
 Drugs work in a variety of ways:
 Drugs alter existing cellular functions
 Drugs alter the chemical composition of body
fluids
 Drugs can form a chemical bond with specific cell
components on target cells within the animal’s
body
RECEPTORS
 Receptors are three-dimensional proteins
or glycoproteins

Located on the surface, in the cytoplasm, or
within the nucleus of cells
 Affinity is the strength of binding between
a drug and its receptor

High-affinity drugs bind more tightly to a receptor
than do low-affinity drugs
RECEPTORS
AGONISTS VS ANTAGONISTS
 Agonist: drug that binds to a cell receptor
and causes action
 Antagonist: drug that inhibits or blocks the
response of a cell when the drug is bound to
the receptors
AGONISTS VS ANTAGONISTS