Pharmacokinetics

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Pharmacokinetics

• Asmah Nasser, M.D.

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Pharmacokinetics

• Pharmacokinetics is the quantitative study of
  drug movement in, through and out of the body

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What Happens After Drug Administration?

• Absorption
• Distribution
• Metabolism
• Elimination /Excretion

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Important factors to know

• Factors affecting absorption
• Concept of ionization , pKa and pH
• Henderson Hassel Balch equation
• Bioavailability , Bioequivalence , AUC
• Distribution , volume of distribution (Vd),
  redistribution
• Plasma protein binding

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Important factors to know

• Metabolism (biotransformation) , CYP 450 etc
• Excretion
• First and zero order kinetics of elimination
• Plasma Half life
• Clearance
• Steady state ,loading and maintenance dose
• Therapeutic drug monitoring
• Pharmacokinetic calculations

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Absorption

• After a drug is administered, how does it reaches
  site of action?
• Absorption is the transfer of a drug from its
  site of administration to the blood stream. In
  order to reach their site of action, a drug has
  to pass through several membranes

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Transport

• A. Passive diffusion Concentration gradient
  across membrane is the driving force for movement
  of drug molecule across the membrane
• Small size, water soluble drug molecule
  penetrate through aqueous channels or
  paracellular spaces Filtration few drugs does
  this
• Lipid soluble drugs readily pass through membrane
  by dissolving in membrane .many drugs does this
• B. Active Transport
• Movement occurs against the concentration
  gradient and needs energy like ATP

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Factors that affects absorption

• The particle size Smaller is better
• concentration gradient
• Surface area and vascularity of that area
• Lipid solubility / Water solubility
• Nature of the drugacidic or basic
• Ionized or non ionized
• The pH levels on either side of cell membrane
• pKa of the drug

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Lipid/Water solubility

• Once in solution, drugs exist as a mixture of two
  interchangeable forms
• 1. Water-soluble is the ionized or electrically
  charged formCannot cross membrane
• 2. Lipid-soluble is the non ionized, or uncharged
  form.Can cross membrane

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Concept of ionizationcontinued

• We know most of the drugs are either weak acid
  or a weak base and when dissolved in body
  fluids, some or all of a drugs molecules become
  ionized/unionized

HA H A-
BH
B H
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Concept of ionizationcontinued

• What percentage is ionized /unionized determined
  by following factors
• 1.Whether the drug was an acid or a base.
• 2. Whether it is dissolved in an acid or base
  medium (Eg Stomach or intestine ?) i.e pH of the
  medium.
• 3. And also the pKa of the drug.

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Role of pH in ionization of a Weak base

• As pH increases, a weak base will become more and
  more unionized, lipid soluble and better absorbed
• As pH decreases, a weak base will become more
  and more ionized, lipid insoluble, and will not
  be absorbed. Also becomes more water soluble and
  better excreted.

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Role of pH in ionization of a Weak base
100
75
50
of Unionized form
25
0
1
14
pH of the medium
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Role of pH on ionization of a Weak Acid

• As pH increases, a weak acid will become more
  and more ionized , lipid insoluble and will not
  be absorbed. Also becomes more water soluble and
  better excreted .
• As pH decreases, a weak acid will become more and
  more unionized , lipid soluble and better
  absorbed .

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Role of pH in ionization of a Weak acid
100
75
50
of Unionized form
25
0
1
14
pH of the medium
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Question

• Aspirin is an acidic drug.
• In the stomach, is it mostly in the ionized or
  unionized form?

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Moral of the story...

• Acidic drugs are Absorbed best in Acidic
  environments

Basic drugs are Best absorbed in Basic
environments
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So...
To ? absorption of an basic drug acidify the
environment
To ? absorption of an acidic drug alkalanize the
environment...
This concept is very important in treatment of a
drug poisoning
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pKa

• pKa is equivalent to the pH at which 50 drug
  is ionized and 50 is unionized.Remember this
  point
• pKa Is the negative logarithm of acidic
  disassociation constant of the weak electrolyte
  not necessary to know

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100
75
of Unionized form
50
25
0
1
14
pH of the medium
pKa
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Henderson-Hasselbalch equation

• The ratio of lipid-soluble form to water-soluble
  form for a weak acid or weak base is expressed by
  the Henderson-Hasselbalch equation
• The Henderson-Hasselbalch equation relates the
  ratio of protonated to unprotonated weak acid or
  weak base to the molecule's pKa and the pH of the
  medium as follows

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Henderson-Hasselbalch equation

• pH pKa log (Unprotonated form)
• (Protonated form)
• For a weak acid, if pH pKa is low it will be
  more non-ionized and better absorbed
• For a weak base if pH pKa value is high it
  will be more non-ionized and better absorbed

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pH-pKa -2 -1 0 1 2
Weak acid nonionized 99 90 50 10 01
Weak base nonionized 01 10 50 90 99
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Question

• 1. The pKa of acetylsalicylic acid is 3.5. What
  percentage of the drug is in an absorbable form
  in the stomach at pH of 1.5?A. 0.1B. 1C.
  10D. 90E. 99

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Question

• The greater proportion of the dose of a drug
  administered orally will be absorbed in the small
  intestine. However, on the assumption that
  passive transport of the nonionized form of a
  drug determines its rate of absorption, which of
  the following compounds will be absorbed to the
  least extent in the stomach?
• a. Ampicillin (pKa 2.5)
• b. Aspirin (pKa 3.0)
• c. Warfarin (pKa 5.0)
• d. Phenobarbital (pKa 7.4)
• e. Propranolol (pKa 9.4)

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Summary

• A drug molecule carrying an electrical charge is
  said to be Ionized
• Lipid-soluble is the non ionized, or uncharged
  form.Can cross membrane
• Percentage of ionized drug depends on
• 1.Whether the drug was an acid or a base
• 2. Whether it is dissolved in an acid or base
  medium (Stomach or intestine ?) i.e pH
• 3. And also the pKa of the drug
• As pH increases, a weak base will become more and
  more unionized ,lipid soluble and better absorbed
• As pH decreases, a weak acid will become more and
  more unionized ,lipid soluble and better absorbed

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Summary

• pKa is equivalent to the pH at which 50 drug
  is ionized and 50 is unionized
• For a weak acid if pH pKa is low it will be
  more nonionized and better absorbed
• For a weak base if pH pKa value is high it will
  be more nonionized and better absorbed