l. VanValkenburg, RVT, BAS

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Pharmacokinetics

• CHAPTER 4
• l. VanValkenburg, RVT, BAS

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DRUG MOVEMENT

• PHARMACOKINETICS is the physiological movement of
  drugs.
• 4 Steps
• Absorption
• Distribution
• Biotransformation
• (metabolism)
• Excretion

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DRUG MOVEMENT

• Pharmacokinetics includes the movement of
  substances across cell membranes.
• Basic mechanisms
• Passive diffusion
• Facilitated diffusion
• Active transport
• Pinocytosis/
• phagocytosis

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How do drug molecules know where to go?
They dont! Drugs molecules go wherever
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Movement of Drug Molecules
This process is called passive diffusion No
cellular effort is needed to transport the
molecules (hence the process is passive)
Drug molecules move randomly from one point to
another
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Passive Diffusion
Movement is random from areas of higher to areas
of lower concentration Eventually the drug
molecules are equally distributed (equilibrium)
High concentration in this area
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Passive Diffusion
Cell Membrane
But drug molecules will only cross by passive
diffusion if they can dissolve in the membrane
Drug molecules may move from one side of a cell
membrane to another by passive diffusion
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Facilitated Diffusion
Cell Membrane
Cell Membrane
These drug molecules need a carrier to get across
the membrane
These molecules cant pass through the membrane
without help
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Facilitated Diffusion
Cell
When the drug molecule encounters the carrier
protein, it carries it across
Membrane
Here is the carrier protein molecule in the
membrane
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Facilitated Diffusion
Cell
When the drug molecule encounters the carrier
protein, it carries it across
Membrane
Here is the carrier protein molecule in the
membrane
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Facilitated Diffusion
Cell
The carrier molecule then resets itself No
cellular energy is used to transport the molecule
across Only the concentration gradient moves the
molecules
Membrane
Here is the carrier protein molecule in the
membrane
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Active Transport
Cell
The drug molecule encounters the carrier molecule
Membrane
The cell expends energy to PUMP the molecule
across the membrane to the other side
Involves a carrier molecule again
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Active Transport
Cell
The drug molecule encounters the carrier molecule
The cell expends energy to PUMP the molecule
across the membrane to the other side
Membrane
Involves a carrier molecule again
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Active Transport
Cell
Unlike diffusion, active transport is not
dependent upon concentration gradient
Membrane
Involves a carrier molecule again
All of the molecules can end up on this side
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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
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In summary.
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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

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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

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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

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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

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Getting In DRUG ABSORPTION

• 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 animals age, health,
  metabolic rate, genetics, gender, and species
  (see Table 4-3)

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Getting in DRUG ABSORPTION
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Getting In DRUG ABSORPTION

• 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.

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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

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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.

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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).
• May initially have high levels of drug
• Drugs travel slowly to poorly perfused tissues
  (fat).
• 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 thats delivered to the tissues.

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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.

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Drugs highly protein bound have much of their
molecules stuck in the blood
Only the free form of the drug molecules can
distribute to tissues
Drug Molecules
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Normal blood and normal protein binding of
protein-bound drugs
Free Drug Molecules
Protein Bound Drug
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Normal blood and normal protein binding of
protein-bound drugs
Protein Bound Drug
Hypoproteinemic Blood and Binding
Protein Bound Drug
Free Drug Molecules
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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.

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Volume of Distribution
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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.

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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

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Drug InteractionsAffecting 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

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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.

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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.

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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

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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.

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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.

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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 animals
  body

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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

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RECEPTORS
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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

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AGONISTS VS ANTAGONISTS