Pharmacokinetics

Dr. Sheikh Nadeem Ahmed,

Assistant Professor,
Dept. of Pharmacology,
Dow Medical College,
DUHS, Karachi.
 Pharmacokinetics
 Abbreviated as PK, (from Ancient Greek
pharmakon "drug" and kinetikos "to do
with motion“

 Pharmacokinetics explores what the body

does to the drug
 PK
 Pharmacokinetics includes the study of:
 The mechanisms of absorption and
distribution of an administered drug,
 The rate at which a drug action begins and
the duration of the effect,
 The chemical changes of the substance in the
body (e.g. by enzymes) and the effects and
routes of excretion of the metabolites of the
drug
 PK
 Pharmacokinetics is divided into several areas
commonly referred as ADME scheme:
– Absorption,
– Distribution,
– Metabolism and
– Excretion.

 However recent understanding about the drug-body

interactions brought about the inclusion of new term
Liberation.

 Now Pharmacokinetics can be better described as
LADME
 PK
 Liberation is the process of release of drug from the
formulation.
 Absorption is the process of a substance entering the
body.
 Distribution is the dispersion or dissemination of
substances throughout the fluids and tissues of the
body.
 Metabolism is the irreversible transformation of parent
compounds into daughter metabolites.
 Excretion is the elimination of the substances from the
body. In rare cases, some drugs irreversibly accumulate
in a tissue in the body
 Drug Absorption
 The process by which a drug moves from the site of
administration to the site of measurement (usually
blood) or site of action requires passage across
biological membranes
 ABSORPTION
The basic processes by which a drug passes
through cell membrane are:
 Passive diffusion.
 Filtration.
 Facilitated diffusion.
 Active transport.
 Pinocytosis or endocytosis.
 PASSIVE DIFFUSION
In this process drug passes through cell
membrane from higher to lower
concentration. It follows the Fick’s Law &
is dependent upon:
Absorbing surface area
Lipid solubility
Concentration gradient
Molecular size
Thickness of cell membrane
Fick’s Equation:
dq/dt = (–D) (A) dc/dx
Thickness
Where dq / dt is the rate of drug flux
(absorption) or changes in concentration of
drug within given time.
 –D is the diffusion constant (It is directly
proportional to temperature and is inversely
proportional to molecular size ).
 A is the absorbing surface area.
 dc/dx is the concentration gradient.
 Cell membrane is about 100 Ǻ thick.
Fick’s Equation:
According to this law:
 Greater the concentration gradient greater will
be the drug absorption,
 Larger the surface area greater will be the drug
absorption,
 Higher the lipid solubility greater will be the
drug absorption.
 Thicker the membrane lesser will be the drug
absorption,
 Larger the molecular size lesser will be the drug
absorption.
 FILTRATION

Water, ions and some low

molecular weight substances pass
through the pores in cell
membrane this process is called
FILTRATION.
 FACILITATED DIFFUSION
In this specialized process drug pass
through cell membrane with the help of
carrier or transporter proteins.
o It works in concentration gradient.
o It does not require energy.
o It is selective for chemical structure of a
drug i.e. carrier transport only those
drugs having specific molecular
structure.
o It is saturable process.
 ACTIVE TRANSPORT
In this specialized process drug pass
through cell membrane with the help of
carrier or transporter proteins.
o It works against concentration
gradient.
o It requires energy.
o It is selective for chemical structure of
a drug i.e. carrier transport only those
drugs having specific structure.
o It is saturable process.
 PINOCYTOSIS
This is the minor method by which some
drugs are transported into the cell.
o Cell engulfs the drug by throwing
pseudopodia.
o Sucrose reaches the cell by this
process.
o It is the main process by which
unicellular microorganisms take the
nutrients.
 FACTORS MODIFYING THE DRUG
ABSORPTION
Majority of the factors affecting the drug
absorption discussed below, affect the drug
absorption through G.I.T. Factors are divided into:
FACTORS RELATED TO DRUG:
 Physical state of the drug.
 Disintegration of the drug.
 Molecular size of the drug.
 Concentration (dose) of the drug.
 Solubility of the drug.
 Ionization of the drug.
 FACTORS RELATED TO RECIPIENT:

 Area of the absorbing surface.

 Functional integrity of the absorbing surface.
 Vascularity of absorbing surface.
 Time of drug administration.
 Co-administration of the other drugs.
 pH of the medium.
 FACTORS RELATED TO DRUG
PHYSICAL STATE OF THE DRUG:
 Liquids are better and rapidly absorbed
than solids. Solutions are rapidly absorbed
than suspensions; crystalloids are better
absorbed than colloids.
DISINTEGRATION OF THE TABLETS:
 Rate of the drug absorption depends upon
disintegration (break down) of the tablets.
Normally large tablets break down rapidly
than small highly compressed tablets.
 MOLECULAR SIZE:
 Vast majority of drugs have molecular weights
between 100 and 1000. Drugs much larger than
MW 1000 will not diffuse easily through cell
membrane. In general larger the molecular size of
the drug particle; less will be the drug absorbed
and vice versa.
CONCENTRATION (DOSE) OF THE DRUG:
 As majority of the drugs is absorbed by passive
diffusion, that is concentration gradient
dependent, therefore larger the dose given, higher
will be the concentration achieved at the
absorption site and more drug will be absorbed.
 LIPID SOLUBILITY:
 Higher lipid solubility favors the drug
absorption; however, extremely lipid
soluble drugs can not cross the aqueous
phase outside the cell and are less
absorbed. For better absorption drug
should be lipid soluble and be sufficiently
water-soluble.
 FACTORS RELATED TO RECIPIENT
ABSORBING SURFACE AREA:
 Drugs are better absorbed from small
intestine and lungs due to large surface area.
Reduction in surface area due to disease or
surgery will reduce the drug absorption.
FUNCTIONAL INTEGRITY OF THE
ABSORBING SURFACE:
 Drug absorption decreases in presence of
G.I.T. diseases like diarrhea, and
malabsorption syndrome.

 VASCULARITY OF THE ABSORBING
SURFACE:
 Increased blood supply to the absorbing
surface increases drug absorption and vice
versa, thus drug absorption is low in
cardiac failure due to less blood supply.
CO-ADMINISTRATION OF OTHER DRUGS:
 Vitamin C increases the absorption of iron;
antacids decrease the absorption of
tetracyclines, liquid paraffin decreases
absorption of fat-soluble vitamins. Atropine
and opioids delay the gastric emptying and
decrease drug absorption.
 TIME OF DRUG ADMINISTRATION:
 Drug absorption through G.I.T. is slow if
the drug is taken orally after meals due to
alteration in gastric emptying time.
 Rate of gastric emptying greatly affects
drug absorption, particularly of alkaline
drugs, which are not absorbed at all from
stomach.
 A mixed meal of solids and liquids requires
about 4 hours and liquids alone require 1½
hours to completely leave the stomach.
 TIME OF DRUG ADMINISTRATION:
 Generally drugs are given after meals to
prevent G.I.T. irritation.
 Some drugs like insulin, sulfonylureas, and
penicillin should preferably be given before
meals.
 Fatty meals increase the absorption of
griseofulvin and some antihelmintic drugs.
 Dairy products reduce the absorption of
tetracyclines as Ca+2 present in dairy
products forms insoluble complexes with
tetracyclines.
 pH OF MEDIUM AND DRUG IONIZATION:
 Most of the drugs existing; are either weak
acids or weak bases. One of the important
factors for the transport of drug through cell
membrane is the ionization
Generally unionized or undissociated forms
of the drug are lipid soluble, less polar as
they have no charge, ionized forms are
polar, and water soluble and less absorbed.
pH of the medium plays important role in
ionization of the drug and affects the drug
absorption.
 Weak acids ionize less in acidic medium and
weak bases ionize less in alkaline medium,
therefore weak acids are better absorbed in
acidic medium and weak bases are better
absorbed in alkaline medium.
 Conversely Weak acids ionize more in alkaline
medium and weak bases ionize more in acidic
medium, hence poorly absorbed.
 pKa is the pH of the medium at which both
undissociated and dissociated forms are
equal (50% of the drug is ionized).
 Although the absorption of weak acidic drugs
begins in stomach they are also better
absorbed from intestine than stomach due to
extremely large surface area of intestine.
Ionization of the drugs at different pH values is
determined by HENDERSON HESSELBACK equation.

HA  (H+) + (A-)
(Unionized drug)
At certain stage dissociated and undissociated forms
become equal and their ratio is constant.
(H+) (A) = Ka
HA
OR
(H+) (A) = Ka  HA
OR
(H+) = Ka HA
(A)
Applying  log to both sides of equation
 log H+ =  log Ka HA
(A)
But  log = P
pH = P Ka HA
(A)
HA is unionized form of the drug and (A) is ionized
form of the drug.
Pka is the pH of the medium at which both
undissociated and dissociated forms are equal
(50% of the drug is ionized).
If pH and Pka are known, degree of ionization can be
calculated from following formula that is derived
from the above formula.
Antilog (HA) = Pka  pH
(A)
HA = contains proton  Pronated form.
A= lost proton  Unpronated.
Antilog (Pronated) = Pka  pH
(Unpronated)
For weak acids pronated form is unionized
and unpronated form is ionized, weak bases
accept the proton, therefore pronated form
is ionized and unpronated form is
unionized.
Calculate the ratio of dissociated to
undissociated forms of the drug with
Pka = 4.4 at pH = 2.4.
AT pH 2.4
Antilog (Pronated) = Pka  pH
(Unpronated)
= 4.4  2.4
=2
Antilog 2 = 102 = 100 ratio = 100:1
This indicates that at acidic pH undissociated
form of weak acid is 100 times higher than
dissociated form.
Calculate the ratio of dissociated to
undissociated forms of the drug with Pka = 4.4
at pH = 7.4.
AT pH 7.4
Antilog (Pronated) = Pka  pH
(Unpronated)
= 4.4  7.4
= 3
Antilog 3 = 103 = 1/1000 = 0.001 ratio =
0.001:1
This indicates that dissociated form is 1000
times higher than undissociated form.
Calculate the ratio of dissociated to undissociated forms
of the drug with Pka = 8.4 at pH = 7.4 & 6.4.
AT pH 7.4
Antilog (Pronated) = Pka  pH
(Unpronated)
= 8.4  7.4
=1
Antilog 1 = 101 = 10 ratio = 10:1
AT pH 6.4
Antilog (Pronated) = Pka  pH
(Unpronated)
= 8.4  6.4
=2
Antilog 2 = 102 = 100 ratio 100:1
This indicates that when pH becomes acidic dissociation of
weak base increases.
 Main mechanism of most drug
absorption in Gastro-intestinal tract is:

a. Active transport (Carrier mediated diffusion)

b. Filtration (Aquous diffusion)
c. Endocytosis & Exocytosis
d. Passive diffusion (Lipid diffusion)
Which kind of substances can not permeate
membranes by passive diffusion

a. Lipid soluble.
b. Non-ionized substances.
c. Hydrophobic substances.
d. Hydrophilic substances.