Asmah Nasser, M.D.

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 drugacidic 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 formCannot cross membrane
2. Lipid-soluble is the non ionized, or
uncharged form.Can cross membrane

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+

10

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.
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
ofpH
pH
on ionization
of will
a Weak
As
increases,
a weak acid
becomeAcid
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
B
Basic
asic drugs
drugs are
are B
Best
est absorbed
absorbed in
in
B
Basic
asic environments
environments

17

So...
To
To absorption
absorption of
of an
an basic
basic drug
drug
acidify
acidify the
the environment
environment
To
To absorption
absorption of
of an
an acidic
acidic drug
drug
alkalanize
alkalanize the
the environment...
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 HendersonHasselbalch 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

-2

-1

+1

+2

Weak acid:
%nonionized

99

90

50

10

01

Weak base:
%nonionized

01

10

50

90

99

23

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