Asmah Nasser, M.D.
PHARMACOKINETICS
Pharmacokinetics
 Pharmacokinetics is the quantitative study of
drug movement in, through and out of the
body
What Happens After Drug
Administration?
 Absorption
 Distribution
 Metabolism
 Elimination /Excretion
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
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
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
Transport
A. Passive diffusion: Concentration gradient across
membrane is the driving force for movement of drug
molecule across the membrane
1.
Small size, water soluble drug molecule penetrate
through aqueous channels or paracellular spaces
…Filtration …few drugs does this
2.
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
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 drug…acidic or basic
•
Ionized or non ionized
•
The pH levels on either side of cell membrane
•
pKa of the drug
Lipid/Water solubility
Once in solution, drugs exist as a mixture of two
interchangeable forms
1. Water-soluble is the ionized or electrically
charged form…Cannot cross membrane
2. Lipid-soluble is the non ionized, or
uncharged form….Can cross membrane
Concept of ionization…continued
• 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
BH+
H+ + AB + H+
10
Concept of ionization…continued
 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.
11
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.
12
% of Unionized form
Role of pH in ionization of a Weak base
100%
75%
50%
25%
0%
1
pH of the medium
14
13
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 .
14
% of Unionized form
Role of pH in ionization of a Weak acid
100%
75%
50%
25%
0%
1
pH of the medium
14
15
Question
 Aspirin is an acidic drug.
 In the stomach, is it mostly in the ionized or
unionized form?
Moral of the story...
Acidic drugs are Absorbed best in Acidic
environments
Basic drugs are Best absorbed in
Basic environments
17
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
18
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
19
% of Unionized form
100%
75%
50%
25%
0%
1
14
pH of the medium
pKa
20
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:
21
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
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. 0.1%
B. 1%
C. 10%
D. 90%
E. 99
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)
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
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