Pharmacokinetics Psych 223

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PharmacokineticsPsych 223

• February 4th 2005

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Lecture Outline

• Life of an Administered Drug
  Pharmacokinetics
• Routes of Administration
• Enteral
• Parenteral
• Drug Distribution
• Drug Inactivation and Elimination
• Tolerance
• Time Course
• Turnover

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Life of an Administered Drug

• Administered by some route
• Absorbed into the blood
• Distributed throughout the circulatory system
• Binds to some receptor
• Inactivated or broken down into inactive
  components
• Eliminated from the body

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Life of an Administered Drug
(4) Binds
(6) Excreted
(2) Absorbed
(3) Distributed
(1) Administered
(5) Inactivated
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Life of an Administered Drug

• Administered by some route
• Absorbed by the blood
• Distributed throughout the circulatory system
• Binds to some receptor
• Inactivated or broken down into inactive
  components
• Eliminated from the body

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Routes of Administration

• Enteral directly into the GI tract
• Oral
• Anal
• Parenteral
• Sublingual
• Intravenous
• Intramuscular
• Intraperitoneal
• Subcutaneous
• Inhalation

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Enteral AdministrationOral (PO)

• Advantages
• Safe
• Economical
• Convenient
• Disadvantages
• Absorption is slow
• Absorption is variable and depends on the
• Contents of the stomach
• Stomach acidity
• Dosage is difficult to control

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Enteral AdministrationEffect of tablet size and
solubility on blood concentration of a drug
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Routes of Administration

• Enteral directly into the GI tract
• Oral
• Anal
• Parenteral
• Sublingual
• Intravenous
• Intramuscular
• Intraperitoneal
• Subcutaneous
• Inhalation
• Topical

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Parenteral Administration

• Sublingual
• Advantages
• Safe
• Convenient
• Disadvantages
• Absorption is slow
• Drug must be dissolvable by saliva
• Dosage is difficult to control

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Parenteral Administration

• Sublingual
• Advantages
• Safe
• Convenient
• Disadvantages
• Absorption is slow
• Drug must be dissolvable by saliva
• Dosage is difficult to control
• Intravenous
• Advantages
• Rapid
• Reliable dosing
• Larger steady state doses can be given over time
• Disadvantages
• Inconvenient
• Rapid and can be dangerous
• Air may be injected too close to organs
  (embolisms)
• Drugs not soluble in blood cannot be given IV

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Parenteral Administration

• Intramuscular
• Advantages
• Faster than oral, slower than IV
• Reliable dosing
• Large volumes can be injected
• Disadvantages
• Inconvenient
• Absorption is variable depending on blood flow to
  the muscle
• Irritating substances cannot be injected

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Parenteral Administration

• Intramuscular
• Advantages
• Faster than oral, slower than IV
• Reliable dosing
• Large volumes can be injected
• Disadvantages
• Inconvenient
• Absorption is variable depending on blood flow to
  the muscle
• Irritating substances cannot be injected
• Intraperitoneal (IP)
• Advantages
• Rapid absorption
• Reliable dosing
• Disadvantages
• Inconvenient
• Potential for tissue damage
• Injections are painful
• Irritation and infection can easily develop

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Parenteral Administration

• Subcutaneous (SC)
• Advantages
• Absorbed rapidly, but more slowly than IV
• Reliable dosing
• Disadvantages
• Inconvenient
• Potential for tissue damage
• Injections are painful

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Paraenteral Administration

• Subcutaneous (SC)
• Advantages
• Absorbed rapidly
• Reliable dosing
• Disadvantages
• Inconvenient
• Potential for tissue damage
• Injections are painful
• Inhalation (pulmonary mucosal)
• Advantages
• Absorption is faster than oral, slower than IV
• Convenient
• Disadvantages
• Potential for tissue damage
• Dosing is difficult to control
• Expensive equipment is often necessary to control
  dosing
• Irritation and infection can easily develop

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Paraenteral Administration

• Topical
• Advantages
• Convenient
• Disadvantages
• Dosing is difficult to control
• Drugs must be able to pass through the skin

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Life of an Administered Drug

• Administered by some route
• Absorbed into the blood
• Distributed throughout the circulatory system
• Binds to some receptor
• Inactivated or broken down into inactive
  components
• Eliminated from the body

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Absorption Into the Blood

• Absorption into the blood is determined by the
  ability of the drug to diffuse into and out of
  the blood stream. Diffusion is governed by
• Drugs lipid solubility
• Drugs ionization factor

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Lipid solubility
Membrane oil-like
Membrane oil-like
Lipid Soluble
Water Soluble
Oil
Partition coefficient drug in oil drug in
water
Water
Lipophilic Hydrophobic
Hydrophilic Lipophobic
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Ionization
Membrane charged
non-ionized

• Most drugs are non-ionized
• However, when dissolved in the stomach a portion
  of the drug becomes ionized
• The degree of ionization depends on the relative
  acidity of the drug and the solution
• Acids are less ionized in acidic solutions (low
  ph), alkalines are less ionized in basic
  solutions (high ph)
• pKa ph of the solution at which 50 of the drug
  is ionized

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Life of an Administered Drug

• Administered by some route
• Absorbed into the blood
• Distributed throughout the circulatory system
• Binds to some receptor
• Inactivated or broken down into inactive
  components
• Eliminated from the body

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Distribution
After a drug finds its way into the blood, it
still has a long way to go before it affects the
brain.
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Two Models of Drug Distribution
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Factors Affecting Distribution

• Areas of the body well vascularized will get the
  highest concentration of drug.
• The amount of drug reaching these areas will
  depend on the rate through which blood is
  distributed and the rate through which the drug
  passes through blood vessel walls.
• Cardio-pulmonary system
• Capillaries
• The brain has a barrier that limits drug access,
  the blood-brain barrier.

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Cardio-pulmonary System
Left Atrium
Right Atrium
Left Ventricle
Right Ventricle
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Capillaries
Protein
Fenestration (outside the brain)

• Capillaries are so abundant that no neuron is
  less than 40 to 50 microns from a capillary
• Drugs must pass out of the capillary through
  openings called fenestrations
• Normally, a drug will pass through the capillary,
  however, the drug can become bound to large blood
  born proteins that are too large to pass through
  the fenestrations
• Unbound drug can then pass on to

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Blood-Brain Barrier

• Diffusion in the brain is affected by the brains
  three fluid compartments
• Capillaries
• Cerebrospinal fluid (CSF)
• Extracellular fluid (ECF)

Capillaries
CSF
ECF
CSF
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Brain Capillaries
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Brain Capillaries
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Blood-Brain BarrierSee httphttp//www.sfn.org/br
iefings/blood-brain.html
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Blood-Brain BarrierSee http//www.med.ucla.edu/di
visions/endo/TextOnly/Introduction.html
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Blood-Brain BarrierSee http//faculty.washington.
edu/chudler/bbb.html

• Functions of the BBB
• Protects the brain from "foreign substances" in
  the blood that may injure the brain.
• Protects the brain from hormones and
  neurotransmitters in the rest of the body.
• Maintains a constant environment for the brain.

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Blood-Brain BarrierSee http//faculty.washington.
edu/chudler/bbb.html
General Properties of the BBB 1.Large molecules
do not pass through the BBB easily. 2.Low lipid
(fat) soluble molecules do not penetrate into the
brain. However, lipid soluble molecules, such as
barbituate drugs, rapidly cross through into the
brain. 3.Molecules that have a high electrical
charge to them are slowed.
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Blood-Brain BarrierSee http//faculty.washington.
edu/chudler/bbb.html

• The BBB can be broken down by
• Hypertension (high blood pressure)
• Hyperosmolitity
• Microwaves
• Radiation
• Infection
• Trauma, Ischemia, Inflammation, Pressure

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By-passing the BBBCircumventricular Organs

• There are several areas of the brain where the
  BBB is weak. These areas are known as
  "circumventricular organs and include
• Pineal body Secretes melatonin and neuroactive
  peptides. Associated with circadian rhythms.
• Neurohypophysis (posterior pituitary) Releases
  neurohormones like oxytocin and vasopressin into
  the blood.
• Area postrema "Vomiting center" when a toxic
  substance enters the bloodstream it will get to
  the area postrema and may cause vomiting.
• Subfornical organ Important for the regulation
  of body fluids.
• Vascular organ of the lamina terminalis A
  chemosensory area that detects peptides and other
  molecules.
• Median eminence Regulates anterior pituitary
  through release of neurohormones.

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By-passing the BBB

• It is possible to by-pass the blood-brain barrier
  by directly infusing drugs into the brain. This
  can be accomplished by
• Intraventricular infusion
• Intrathecal infusion
• Intracerebral infusion

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Life of an Administered Drug

• Administered by some route
• Absorbed into the blood
• Distributed throughout the circulatory system
• Binds to some receptor
• Inactivated or broken down into inactive
  components
• Eliminated from the body

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Life of an Administered Drug

• Administered by some route
• Absorbed into the blood
• Distributed throughout the circulatory system
• Binds to some receptor
• Inactivated or broken down into inactive
  components
• Eliminated from the body

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Metabolism

• Metabolism is not synonymous with inactivation.
  Metabolites are often active themselves. For
  example, a metabolite of codeine is morphine and
  several metabolites of valium are themselves
  sedatives.
• Metabolism occurs in
• Intestines (with enteric administration)
• Blood
• Liver
• Brain
• Metabolism involves enzymes altering the drug to
  make it water soluble
• Metabolism occurs by
• Conjugation
• Degradation

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Metabolism of Aspirin
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Metabolism of Alcohol
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Metabolism - Issues

• Metabolic Competition - examples
• Enzyme Induction
• Effects of Metabolites
• Propranalol (adrenergic receptor antagonist
  antihypertensive) has 17 metabolites
• Antiarryhythmia
• Antianxiety
• Antimigrane
• Antitremor
• Anticonvulsant
• Antiacne
• Hypotensive
• Stage fright

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Life of an Administered Drug

• Administered by some route
• Absorbed into the blood
• Distributed throughout the circulatory system
• Binds to some receptor
• Inactivated or broken down into inactive
  components
• Eliminated from the body

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EliminationKidneys
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A word About Potency

• Potency is a product of
• Absorption
• Distribution
• Metabolism
• Elimination

• A drug that is less potent than another may be
  because it is
• slowly absorbed
• slowly distributed
• rapidly metabolized

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Recap

• Absorption into the blood
• Lipid solubility/ionization
• Capillaries
• Blood Brain Barrier
• Metabolism
• Conjugation
• Degradation
• Active Metabolites
• Elimination

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Tolerance

• A reduction in the effectiveness of a drug with
  repeated administration
• Drug Disposition (metabolic) Tolerance a
  decrease in the concentration of the drug at the
  target site due to changes in bioavailability.
• Reduced absorption
• Increased binding to inert substances
• Altered rate of passage across membranes
• Increased rate of elimination (e.g., enzyme
  induction)
• Pharmacodynamic Tolerance a decrease in the
  number of receptors for the drug or a decrease in
  affinity/intrinsic activity .
• Behavioral Tolerance compensatory mechanisms
  occurring elsewhere in the cellular network.
• Cross Tolerance Tolerance to one drug is
  evidenced in another drug when it is administered
  for the first time.

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ToleranceTypes of Tolerance Exhibited by Common
Drugs
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ToleranceBlood Levels of a Drug
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Time Course and Drug Clearance
Clearance refers to the rate by which drugs are
metabolized from the blood plasma and is a common
method for measuring the rate by which drugs are
eliminated from the body.
Figure 1.10
Plasma Concentration
0 15 30 45 60 75 90
Time since injection (min)
T1/2
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Time Course and Drug Clearance
Slow Distribution, rapid clearance
Rapid Distribution, slow clearance
Figure 1.10
Figure 1.10
Plasma Concentration
Plasma Concentration
0 15 30 45 60 75 90
0 15 30 45 60 75 90
Time since injection (min)
Time since injection (min)
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Time Course and Drug Clearance
Slow Distribution, slow clearance
Rapid Distribution, rapid clearance
Figure 1.10
Figure 1.10
Plasma Concentration
Plasma Concentration
0 15 30 45 60 75 90
0 15 30 45 60 75 90
Time since injection (min)
Time since injection (min)
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Neurotransmitter Turnover

• Neurotransmitters are made in neurons from
  various precursors
• The neurotransmitter is used and released from
  the neuron and binds to a receptor.
• The neurotransmitter is metabolized

synthesis
metabolism
A
B
C
precursor
neurotransmitter
metabolite
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Neurotransmitter TurnoverSerotonin
synthesis
metabolism
A
B
C
precursor
neurotransmitter
metabolite
Synthesis
Metabolism
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Neurotransmitter TurnoverSerotonin 5-HT
synthesis
metabolism
A
B
C
precursor
neurotransmitter
metabolite
L-tryptophan
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How fast is the neurotransmitter turning over?
synthesis
metabolism
A
B
C
precursor
neurotransmitter
metabolite
Measure the neurotransmitter?
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How fast is the neurotransmitter turning over?
synthesis
metabolism
A
B
C
precursor
neurotransmitter
metabolite
Measure the neurotransmitter?
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How fast is the neurotransmitter turning over?
synthesis
metabolism
A
B
C
precursor
neurotransmitter
metabolite
Measure the neurotransmitter?
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Drugs Can Affect Turnover
Block Metabolism
Block Synthesis
Drug A
Drug A
Drug B
Drug B
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Affecting 5-HT Turnover
L-tryptophan
MAOI
PCPA
5-HT MAOI
5-HT
5-HT
5-HT PCPA