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Chapter 2
PHARMACOKINETI
CS
“What the body does to the drug”
Lei Wang
Department of Pharmacology
Pharmacology
Drug - Body Interactions
Pharmacodynamics
Pharmacokinetics
What drug does to
the body
What body does to
the drug
Three Phases of Pharmacokinetics
ELIMINATION
Adapted from Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 26
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Part 1
Transmembrane
transport of drugs
Filtration
Simple
Diffusion
Facilitated
Diffusion
Active
Transport
Simple Diffusion (Passive Diffusion )
(down hill movement)


Most drugs move down their concentration
gradients until the concentration of the drug
reaches equilibrium.
Greater the difference in the concentration of the
drug on the two sides of the membrane, faster of
its diffusion (Fick’s law)
Simple Diffusion (Passive Diffusion )
Passive diffusion requires no energy expenditure
but does depend on the size of the drug and the
lipid solubility of the drug.
Most drugs cross biologic barriers
by passive diffusion

Simple Diffusion (Passive Diffusion)
Cell Membrane Structure
Biological membranes are
bilayer, phospholipids
matrices containing
cholesterol, protein, and
other constituent.
Due to the cell membrane's
hydrophobic nature and like
dissolves like, lipid soluble
drugs can diffuse by
dissolving in the lipoidal
matrix of the membrane
Simple Diffusion (Passive Diffusion)



For drugs that cross membrane by passive
diffusion, the lipid solubility of the drug is a
key determinant.
In order to directly penetrate cell
membranes by simple diffusion, a drug
must be lipid soluble
Polar molecules and ions are not lipid
soluble and so cannot penetrate membranes
by simple diffusion
Simple Diffusion (Passive Diffusion)
The drugs which are unionized, low
polarity and higher lipid solubility are easy
to permeate membrane.
The drugs which are ionized, high polarity
and lower lipid solubility are difficult to
permeate membrane.
Weak Electrolytes and Influence of pH

Many drugs are weak acids or weak bases
Weak acids and weak bases exist in both
non-ionized form and ionized form in solution
HA
H+ + A(unionized) (ionized)
Weak Acids and Weak Bases Cross
Membranes in Their Non-ionized State
12
Effect of the environment pH on
the degree of ionization



Most of drugs are weak acids or weak bases.
The ionization of drugs may markedly influence
their ability to penetrate membranes.
The ratio of ionized versus un-ionized fraction of
drug (the degree of ionization) depends on the
pKa (ionization constant) of the drug and the pH
of the surrounding tissues or fluids.
pKa: the pH at which 50% of the drug is ionized
and 50% is un-ionized.
Effect of the environment pH on the degree of ionization
When the pH of a
solution is below the pKa,
acids are preferentially
un-ionized.
When the pH of a
solution is higher than
the pKa, acids are mostly
ionized.
HA
H+ + A(unionized) (ionized)
Handerson-Hasselbalch Equation
For acids (A)：
For bases (B)：
Effect of the environment PH on the degree of ionization


A weak acid is most likely to be unionized
when in an acidic environment, and an
alkaline drug is preferentially unionized in
an alkaline environment.
A weak acid is most likely to be ionized
when in an alkaline environment, and an
alkaline drug is preferentially ionized in an
acidic environment.
Filtration
Filtration is passage of drugs through aqueous
pores in the membrane or through paracellular
spaces.
Aqueous
Diffusion
Filtration
Aqueous Diffusion


Water can cross cell membranes through
aqueous pores.
Bulk flow of water can carry with it drug
molecules.
Aqueous
Diffusion
Bulk Flow
Aqueous Diffusion




Cell membrane works like a sieve
Depends on the size of the membrane pores
Majority of cells have very small pores
Small and water soluble molecules move
through the pores of the membrane while drug
with molecular weights (MW) exceeds 100 to
200 daltons are not able to penetrate.
Paracellular Transport
Paracellular transport refers to passing through
the intercellular space between the cells.
Capillaries (except those in brain) have
large paracellular space and most drug
can filter through these.
Paracellular movement generally is limited to
unbound drug
Carrier-Mediated Membrane Transport
Active transport
Facilitated diffusion
Active Transport
Cells use ENERGY (ATP) to transport materials
that cannot diffuse across a membrane
Move a substance against its concentration gradient
Accumulates some molecules that the cell needs
Sodium-potassium pump
The excretion and secretion
of renal tract
Facilitated diffusion
 Requires
a carrier molecule
 No energy is needed
 Drugs move down their concentration gradients
Cephalexin undergo facilitated diffusion by an
oligopeptide transporter protein located in intestinal
Absorption
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Absorption
Drug absorption refers to the passage of
a drug from its site of administration into
the circulation
Intravascular administration does not involve
absorption

intravenous
oral
rectal
sublingual
transdermal
Absorption
inhalation
Absorption
circulation
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Which route is the fastest route of
absorption?
The rate of absorption：
Inhalation→Sublingual→Rectal→intramuscular
→subcutaneous→oral→transdermal
The rate of absorption determines how soon the
effects will begin.
The amount of absorption determines how
intense the effects will be.
Absorption
The absorption of a drug is influenced by the
physical and chemical properties of the drug itself
and by the physiologic and anatomical factors at
the site of absorption.
Absorption
Ionization
Drug
absorption requires that drugs cross one or
more layers of cells and cell membranes
Most
Only
drugs are absorbed by passive diffusion
the nonionized form of the drugs is
sufficiently soluble in membrane lipids to cross cell
membranes
Ionization
In the stomach (pH 2.0)，which will be better
absorbed, a weak acid (pK 6.8) or a weak base
(pK 7.1)?


A weak acid is most likely to be unionized
when in an acidic environment
An alkaline drug is preferentially ionized in an
acidic environment.
Weak acid
Ionization
Weak
acids can also be absorbed more readily
from the intestines than from the stomach,
despite their greater ionization in the intestines
Most
drugs are absorbed in the intestines
The greater surface area in the intestines
outweighs the influence of greater ionization in
the intestines.

Dosage Form
Absorption
The formulation of a drug affects the drug’s
absorption and onset of action.
Drugs that are available as liquid formulations
are absorbed faster than drugs that are
suspensions, suspensions are absorbed more
rapidly than capsules,
and capsules
are absorbed more
rapidly than tablets
Routes of Administration
Routes Of Drug
Administration
Enteral
Parenteral
Injection
Topical
Respiratory
Rectal
Subling
ual
Oral
Routes of Administration
Oral Administration
©2006 Twentieth Century Fox Film Corporation
Clinical sketch
A man with angina has not understood
instruction on the use of glyceryl trinitrate
tablets. He swallows them instead of
putting them under his tongue. There is no
therapeutic benefit.
Comment: this drug is subject to extensive
first-pass metabolism.
First-Pass Metabolism
Before the drug
reaches the systemic
circulation, the drug
can be metabolized in
the liver or intestine.
As a result, the
concentration of drug
in the systemic
circulation will be
reduced.
First-pass elimination
The result of first pass
metabolism means that
only a proportion of the
drug reaches the
circulation.
First-pass elimination
The
liver is usually assumed to be the major site
of first-pass metabolism of a drug administered
orally.
Broadly, first-pass
elimination takes place when
a drug is metabolized between its site of
administration and the site of sampling for
measurement of drug concentration.
Other
potential sites are the gastrointestinal tract,
blood, vascular endothelium, lungs, and the arm
from which venous samples are taken.
Bypassing First Pass
Metabolism
Injection
Sublingual route
Effects of Food on Oral Drug Absorption
Food tends to slow the rate of gastric emptying
and results in slower absorption of many drugs.
Drugs are often administered on an empty stomach.
Penicillin V should be administered
on an empty stomach.
Metoprolol and propranolol
should be taken with meals
Oral
Administration
Advantages:
It is convenient.
It is the cheapest
available route.
It is easy to use.
It is safe and
acceptable.
Routes of Administration
Sublingual
Administration
©2006 Twentieth Century Fox Film Corporation
Sublingual Administration
In sublingual administration the drug dissolves
in salivary secretions and diffuses through
mucous membrane beneath the tongue.
Advantages:
Rapid absorption takes place.
Drug is dissolved easily
Drug enters the blood directly
Less first pass effect.
Sublingual Administration
Disadvantages:
Irritation of the mucous membrane might occur
Person may swallow the drug
Might be unpleasant in taste
Routes of Administration
Rectal Route
©2006 Twentieth Century Fox Film Corporation
The rectal route of
administration (ROA) is a
way of administering drugs
into the rectum to be
absorbed by the rectum's
blood vessels and into the
body's circulatory system.
Approximately 50% of the
drug that is absorbed from the
rectum will bypass the firstpass metabolism.
The upper part is
connected with the portal
system, whereas the lower
part is directly connected
with the systemic
circulation.
Drugs inserted in the lower
part can bypass hepatic
portal circulation and firstpass elimination of the
drugs is partially avoided.
Rectal Route
Advantages:
This route is preferred in unconscious or
uncooperative patients.
This route avoids nausea or vomiting
Disadvantages:
It is not preferred by patients.
Rectal absorption often is
irregular and incomplete.
Many drugs can cause irritation
of the rectal mucosa.
Acetaminophen
Suppository
Routes of Administration
Parenteral Administration
©2006 Twentieth Century Fox Film Corporation
The parenteral routes of administration
include any routes that bypass the
gastrointestinal tract entirely.
Intravenous
Intravenous
Intramuscular or IM
Drugs administered intramuscularly enter the
blood through gaps in capillary walls.
The rate of absorption：
Intramuscular→subcutaneous
Slow releasing drugs can
be given by this route.
Oily preparations can be used.
Intramuscular
Disadvantages:



Uncomfortable and inconvenient
Irritating substances may cause muscle
necrosis
Irritating substances or improperly placed
injections may damage nerves
Intramuscular
The absorption rate of intramuscular
administration is directly affected by blood flow
at the site of injection.
Application of heat, exercise and activity at
the injection site increase blood flow, which
speeds drug absorption.
Absorption may be reduced by immobilizing
the limb, applying ice, administering a
vasoconstrictive agent (adrenaline +local
anaesthetic).
Clinical sketch
A patient with extensive burns is
given intramuscular opiate for the
pain. His blood pressure is very low.
Adequate pain relief is not achieved
for over half an hour.
Comment: muscle blood flow is
reduced by shock, and the rate of
drug absorption can be affected.
Subcutaneous Injection
Subcutaneous (SQ) Route

Used for solutions, emulsions and suspensions

Absorption is usually slower for SQ than IM

Highly irritating or corrosive substances should
not be given subcutaneously
Subcutaneous Insulins
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Topical Application
A topical effect, in the pharmacodynamic sense,
may refer to a local, rather than systemic, target
for a medication.
Routes of Administration
Inhalation
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Inhalation
Inhaled drugs are often given to directly affect
bronchial and alveolar targets, thus achieving
efficacy with minimal systemic effects.
Drugs used involve volatile
drugs, gases and dry-powder.
Anesthetic gases, inhaled
glucocorticoids and β-adrenergic
agonists
Inhalation
Inhalation can be thought of conceptually as a
topical administration
A proportion of inhaled drugs still reaches
the systemic circulation.
Inhaled drugs with systemic sites of action
include the anesthetic gases and some drugs of
abuse that are smoked.
Routes of Administration
Eye
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Eye Drops
Eye drops often mean a local medication. However,
because drug is absorbed via nasolacrimal canal,
undesirable systemic absorption occurs.
Such risk can be minimized by
occluding the lacrimal punctum,
for a short while after instilling
drops.
Routes of Administration
Skin
(Transdermal
absorption)
©2006 Twentieth Century Fox Film Corporation
Skin (Transdermal absorption)
Not all drugs readily penetrate the intact skin.
Drugs applied on the skin may be used either for
their local effects or for systemic effects.
Drugs for transdermal delivery must have
suitable skin penetration characteristics and
high potency.
Transdermal patches :
for birth control, hormone
replacement therapy, and
prevention of motion sickness.
Transdermal controlled-release
forms are designed to release
the drug for extended periods.