INTRODUCTION TO

PHARMACOLOGY

DR.DATTEN BANGUN,MSC,SPFK
DEPT.FARMAKOLOGI &TERAPEUTIK
FAKULTAS KEDOKTERAN
UHN

In general terms, pharmacology is the

science of drug action on biological
systems.
The term pharmacology comes from the Greek words:
pharmakon - drug or medicine
logos - the truth about or a rational discussion

Pharmacology embraces knowledge of the sources,

chemical properties, biological effects and therapeutic
uses of drugs.

What is drugs?
Humans have used drugs of one sort or
another for thousands of years

-wine was used at least from the time of

the early Egyptians
-narcotics from 4000 BC
-medicinal use of marijuana has been
dated to 2737BC in China

Drugs
Drugs can be defined as chemical agents that
uniquely interact with specific target molecules in
the body, thereby producing a biological effect.

Drug a substance that

causes a physical or
emotional change
in a person
Drugs can be stimulatory
or inhibitory

Drug
Chemical substance that affects the
functioning of living things
May treat, diagnose, and prevent disease
Dates to ancient times
Over 9900 drugs available in U.S.

A synthesis of several biomedical sciences.

Physiology

m
e
h
c
o
Bi

ry
t
is

Pharmacology

m
e
Ch

y
r
t
is

Me
dic
i

ne

but unique in its own right

Important Definitions
Pharmacodynamics:
The study of what a drug does in the body
Pharmacokinetics: The study of what
the body does to the body
Quantitative description of the time
course for the disposition of a drug in the
body in terms of its absorption,
distribution, metabolism and elimination.

Disposition: Where does the drug go?

Pharmacodynamics
Is what the drug does to the body.
Interaction of drugs with cellular proteins, such
as receptors or enzymes, to control changes in
physiological function of particular organs.
Drug-Receptor Interactions
Binding

Dose-Response
Effect

Signal Transduction
Mechanism of action, Pathways

How drug act ?

Paul Ehrlich :
Corpora non agunt nisi fixata

A drug will not work

Unless it is bound
Kecuali : -

osmotic diuretic
osmotic purgatives
antasida
heavy metal chelating agents

Dengan apa berikatan ?

- Protein Molecules

- DNA * antimikroba
* anti neoplasma
* karsinogen

PROTEIN TARGETS FOR

DRUG BINDING
ada 4 jenis
1.
2.
3.
4.

Enzymes
Carrier nolecules
Ion channels
Receptors

Receptors
Most drugs combine (bind) with specific receptors
to produce a particular response. This association or
binding takes place by precise physicochemical and
steric interactions between specific groups of the
drug and the receptor.
1. Proteins
a. Carriers
b. Receptors
i. G protein-linked
ii. Ligand gated channels
iii. Intracellular
c. Enzymes
2. DNA

PROPERTIES OF RECEPTORS
1.

Receptor binding
-Ionic bonding between ionisable
groups in the ligand (e.g. NH3+) and in
the receptor (e.g. COO- )
-Hydrogen bonding between amino,
hydroxyl-, keto-functions, etc.
-Hydrophobic interactions between lipidsoluble sites in the ligand and receptor.
-Van der Waals forces, which are very
weak interatomic attractions.

PROPERTIES OF RECEPTORS
2.

Receptor specificity
- Most drugs are specific act only
on one type of receptor.
- If not specific display a wide
variety of adverse effect (eg. TCA).

3.

Three dimensional aspects.

- receptors have a threedimensional organisation in space
so the ligand has to be
presented, to the receptor in the
correct configuration (hand-and
glove).

Stereoisomers.
Eg levodopa.

Theory of Drug Action

Fischers Lock and Key Hypothesis

Every lock has its own key

If the key is not precise, the lock does not open
The drug is the key that has to fit the target specifically and
productively

Theory of Drug Action

Corollary of Lock & Key Hypothesis
O
CH3

CH3 OH

HO

CH3 OH
C

HO

HO

OH

HO

O
H3C

CH2

CH3

H2C

CH3

CH3
HO

H3C

Does not explain why some keys open doors partially? e.g.,
partial agonists or antagonists

CH2

OH

CH

Theory of Drug Action

Koshlands Induced-Fit Hypothesis

At least two steps e.g., step 1 is initial binding and step 2

is a change in structure of the receptor (and/or drug)

Receptor is flexible! can wrap around the drug the

zipper model is extreme case of induced-fit

All intermediate cases do exist in nature

Endogenous compounds act on their

Receptors

Neurotransmitter
Neuropeptides
Hormones
Ions

Types of Receptors
MEMBRANE BOUND RECEPTORS
G-Protein-linked receptors
Serotonin, Muscarinic, Dopaminergic, Noradrenergic

Enzyme receptors
Tyrosine kinase

Ligand-gated ion channel receptors

Nicotinic, GABA, glutamate

INTRACELLULAR AND NUCLEAR RECEPTORS

Hormone receptors
Autocoid receptors
Growth factors receptors
Insulin receptors

G Proteinlinked Receptors

http://www.sp.uconn.edu/~bi107vc/images/anim/SigtranRA.gif

Enzyme-like Receptors

Ligand-gated Ion-Channel
Receptors

Nuclear Receptors

Drug-Receptor Interactions
Physicochemical and steric interactions
1)
2)
3)
4)
5)
6)
5)
6)
7)

Lipophilic
Hydrophilic
Ionic
Hydrogen bonds
Van der Waals bond
Covalent bond
Steric (stereospecificity) effects
Electronic effect
pK effects

Drug-Receptor Interactions
Chemical Bonds
Van der Waals Interactions

Hydrophobic Interactions

Drug-Receptor Interactions
Drug-receptor interactions serve as signals to trigger a cascade of events. This cascade or signaling pathway, is a
collection of many cellular responses which serve to amplify the signal and produce a final effect.
Effectors are thus the molecules that translate the drug-receptor interaction into changes in cellular activity.

+
DRUG

STIMULUS

DRUG + RECEPTOR
INTERACTION

BINDING

DRUG + RECEPTOR
COMPLEX

ACTIVATION

EFFECT
EFFECTOR

TRANSDUCTION

EFFECTOR
SYSTEM

AMPLIFICATION

RESPONSE

SIGNALLING PATHWAY

Receptor Signaling Pathways

Second Messengers:
1.
2.
3.
4.

Ions (Ca2+, Na+, K+, Cl-)

cAMP, cGMP, IP3, Diacylglycerol
DNA binding Transcriptional regulation.
Phosphorylated proteins and enzymes via
tyrosine kinase receptors.

Third Messengers:
1. Enzymes (PKC, PKA)
2. Ions (Ca2+, K+)

Receptor Signaling Pathways

Adenylate Cyclase (AC)

SECOND
MESSENGER
cAMP

Guadenylyl Cyclase (GC)

cGMP

Phospholipase C (PLC)

DAG and IP3

Phospholipase A (PLA2)

Arachidonic acid

Nitric oxide Synthase

NO and CO

Ions

Na+, Ca2+, K+, Cl-

EFFECTORS

Receptor Signaling Pathways

Receptor Conformation

-adrenergic
receptor
N

Extracellular space
TM3

TM2
TM1

2)5)
3)
6)The
Binding
After
hydrolysis
of i3
NE
tocauses
the
GTP
subunit
to
third
4)
1)
Activated
TheGTP-bound
-adrenergic
adenyl
of
subunit
receptor
is a
s the
scyclase
intracellular
7-transmembrane
produces
many
from
subunit
molecules
(i3)
spanning
of
theaoftoand
its
ofGDP,
dissociates
the Gthe
the
results
returns
subunit
in
sloop
s protein
receptor
protein.
cAMP
to
Achange
negatively
ATP.
conformation
Asp
original
conformation,
dissociates
from
thefrom
AR
receptor
and
binds
conformation
change
incharged

s,
rd
and
residue
bind
on
to
the
the
GDP-bound
3
transmembrane

to
from
adenyl
AC
cyclase
(which
(AC).
then becomes
s
causing
GDP
to dissociate
and
(Click
to see
animation;
click
region
(TM3),
along
with
other
subunit
(Meanwhile,
inactive),
of
the
and
norepinephrine
G
reforms
protein.
the
trimeric
may
s next step)
GTP to bind.
again for
charged,
residues,
allows
dissociate
Gs proteinpolar
from
complex.
the
receptor,
but a
(Click
to
see
animation;
click
positively
charged
norepinephrine
the
s subunit
can remain
active
(Click
to
see
animation;
click
again
for
next
step)
(NE)
molecule
bindthis
to the
for
many
secondstoafter
again
for
next
slide)
hydrophobic core of the receptor.
dissociation.)

TM4

Asp -

NE +
TM7

TM5
TM6

(Click
to see
animation;
click
(Click
to see
animation;
click
again
for
next
step)
again for next step)

GDP

Gs protein

C
A
s

GTP

i3 loop

ATP
GDP

G
TP

cAMP

Cytoplasm

cAMP
cAMP
cAMP

cAMP

cAMP

M
cA

R
R
cA
MP

Cytoplasm

3) The
1)
2)
Protein
CREB
active
binding
kinase
catalytic
Aprotein
(PKA)
subunit
(CBP)
is a of
tetramer
PKA
can
now
travels
consisting
bindinto
to the
theofnucleus
two and
regulatory (R) subunits
physphorylates
phosphorylated
CREB
CREB.dimers
and
Thistwo
catalyticon
located
activated
(C)
CREB/CBP
DNA
subunits.
promoter
complex
Binding
regions.
of
two cAMP
comes
in contact
molecules
with to
and
each R
subunit causes
activates
RNA polymerase
the C subunits
II to
(Click to see animation; click
dissociate andonbecome
downstream
the DNA
active.
strand,
again for next step)
enabling transcription of various
(Click to see animation; click
genes. (CREB can also activate
again for next step)
fos, regulating transcription of
slower-response genes.)

C
PKA

(Click to see animation. Click

again for next slide.)

C
Nucleus

C
C

PO

EB
4

CBP
CBP

PO4
CREB
CREB

PO4

EB

PO

CR

CR

CB
P

CB
P
RNA pol II

TBP
TATA

Transcription Begins

DNA

-adrenergic
receptor
N

Extracellular space
TM3

TM2
TM1

TM4

Asp -

NE +
TM7

TM5
TM6

3)2)
4)
1)The
Phosphorylation
Inactivation
After
This-arrestin/receptor
change
aboutof
5inminutes
the
conformation
ofGthese
of
5)
s protein
residues
complex
stimulation
allows
allows
binds
to
-arrestin
norepinephrine,
tomembranebindoftocAMP
to
thebind.
results
in-ARK
the by
lowering
The
bound
AR
receptor
AR
changes
AP2,
i3
and
which
loop
phosphorylate
conformation,
changes
is responsible
the
levels
and
the
subsequent
conformation
for
exposing
Ser
endocytosis
and
Thr
Ser
residues.
and
and
of
uncouples
the
Thr
receptor
residues
from
reduction of gene transcription
the
near
Gclathrin-coated
protein.
C-terminal
end of
the
into
pits.
After
through
the
CREB
pathway.
s the
(Click
to see animation;
click
about
receptor.
24 hours, some of the
again
for
next
step)
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to returned
see animation;
click
receptors
to the cell
(Click
tofor
seenext
animation;
click
again
step)
membrane.
again for next step)
(Click to see animation.)

hr
PO Ser Thr
ar
re C4 PO4 PO4
sti
-ARK
n
-arrestin

i3 loop

GTP

Se
PO r T

AP2

The End.

GDP
GDP

Gs protein

Cytoplasm

cAMP
cAMP
cAMP

Drug-Receptor Interactions
Theory and
interactions.

assumptions

of

drug-receptor

Drug Receptor interaction follows simple mass-action

relationships, i.e. only one drug molecule occupies each
receptor and binding is reversible (We know now there
are some exceptions).
For a given drug the magnitude of the response is
proportional to the fraction of total receptor sites
occupied by drug molecules.
Combination or binding to receptor causes some event
which leads to a response.
Response to a drug is graded or dose-dependent.

Law of Mass Action

When a drug (D) combines with a receptor (R), it
does so at a rate which is dependent on the
concentration of the drug and the concentration of
the receptor.
[D] + [R]

D = drug
R = receptor
DR = drug-receptor complex
k1 = rate for association
k2 = rate for dissociation
KD = Dissociation Constant
KA = Affinity Constant

k2

k1
[DR]
k2

KD =

k1
1
KD

[D][R]
[DR]

KA =

k1
k2

[DR]
[D] [R]

Read the Appendix at the back of lecture 1B

Signal transduction
1.

enzyme linked
(multiple actions)

2.

ion channel linked

(speedy)

3. G protein linked
(amplifier)

4. nuclear (gene) linked

(long lasting)

1.

Gproteinlinkedreceptors

Structure:
Single
polypeptide
chain
threadedback
andforth
resultingin7
transmembran
ehelices
TheresaG
protein
attachedtothe
cytoplasmic
sideofthe
membrane
(functionsasa

2.

Tyrosinekinasereceptors
Structure:
Receptorsexistasindividual
polypeptides
Eachhasanextracellularsignalbinding
site
Anintracellulartailwithanumberof
tyrosinesandasinglehelixspanning
themembrane

3.

Ionchannel
receptors
Structure:
Proteinpores
intheplasma
membrane

Intracellularreceptors

Notallsignalreceptorsarelocatedontheplasma
membrane.Someareproteinslocatedinthe
cytoplasmornucleusoftargetcells.
Thesignalmoleculemustbeabletopass
throughplasmamembrane.
Examples:
~Nitricoxide(NO)
~Steroid(e.g.,estradiol,progesterone,
testosterone)andthyroidhormonesofanimals).

B.

SecondMessengers
Small,nonprotein,watersolublemolecules
orions
Readilyspreadthroughoutthecellby
diffusion
Twomostwidelyusedsecondmessengers
are:
1. CycleAMP
2. CalciumionsCa2+

2. CalciumIons(Ca2+)andInositol
Trisphosphate
CalciummorewidelyusedthancAMP
usedinneurotransmitters,growthfactors,
somehormones
IncreasesinCa2+causesmanypossible
responses:
Musclecellcontraction
Secretionofcertainsubstance
Celldivision

Twobenefitsofasignaltransductionpathway

A.

1.

Signalamplification

2.

Signalspecificity

Signalamplification
Proteinspersistinactiveformlongenough
toprocessnumerousmoleculesofsubstrate
Eachcatalyticstepactivatesmoreproducts
thenintheproceedingsteps

Agonists and Antagonists

AGONIST
A drug is said to be an agonist when it binds to a
receptor and causes a response or effect.
It has intrinsic activity = 1

+++

++-

---

---

+--

+++

Depolarization

Agonists and Antagonists

ANTAGONIST
A drug is said to be an antagonist when it binds to a
receptor and prevents (blocks or inhibits) a natural
compound or a drug to have an effect on the
receptor. An antagonist has NO activity.
Its intrinsic activity is = 0

Agonists and Antagonists

PHARMACOLOGICAL ANTAGONISTS
1. Competitive
They compete for the binding site

Reversible
Irreversible

2. Non-competitve
Bind elsewhere in the receptor (Channel Blockers).

Agonists and Antagonists

FUNCTIONAL ANTAGONISTS
1. Physiologic Antagonists
2. Chemical Antagonist

Agonists and Antagonists

Physiologic ANTAGONIST
A drug that binds to a non-related receptor, producing
an effect opposite to that produced by the drug of
interest.
Its intrinsic activity is = 1, but on another receptor.

Glucocorticoid Hormones

Blood Sugar

Insulin

Blood Sugar

Histamin
Adrenalin

Blood Pressure
lood Pressure

Agonists and Antagonists

Chemical ANTAGONIST
A chelator (sequester) of similar agent that interacts
directly with the drug being antagonized to remove it
or prevent it from binding its receptor.
A chemical antagonist does not depend on interaction
with the agonists receptor (although such interaction
may occur).

Heparin, an anticoagulant, acidic

If there is too much bleeding and haemorrhaging
Protamine sulfate is a base. It forms a stable
inactive complex with heparin and inactivates it.

Agonists and Antagonists

PARTIAL AGONIST
A drug is said to be a partial agonist when it
binds to a receptor and causes a partial
response.
It has intrinsic activity < 1.

Agonists and Antagonists

1. COMPETITIVE ANTAGONIST
Reversible & Surmountable
The effect of a reversible antagonist can be overcome
by more drug (agonist). A small dose of the antagonist
(inhibitor) will compete with a

fraction of the
receptors thus,
the higher the
concentration of
antagonist used,
the more drug
you need to get
the same effect.

Agonists and Antagonists

1. COMPETITIVE ANTAGONIST
Irreversible & Non-surmountable
The effect of irreversible antagonists cannot be
overcome by more drug (agonist). The
antagonist inactivates the receptors.

Agonists and Antagonists

RECEPTOR RESERVE OR SPARE
RECEPTORS.
Maximal effect does not require occupation of
all receptors by agonist.
Low concentrations of competitive irreversible
antagonists may bind to receptors and a
maximal response can still be achieved.
The actual number of receptors may exceed
the number of effector molecules available.

Agonists and Antagonists

Synergism
The combined effect of two drugs is
higher than the sum of their
individual effects.
Additivity
The combined effect of two drugs is
equal to the sum of their individual
effects.

Classes of cell-surface
receptors

Intercellular Signaling

HOW DO CHEMICALS WORK BY

UNCONVENTIONAL MECHANISMS OF ACTION?
Disrupting of Structural Proteins
e.g. vinca alkaloids for cancer, colchicine for gout

Being Enzymes
e.g. streptokinase for thrombolysis

Covalently Linking to Macromolecules

e.g. cyclophosphamide for cancer

Reacting Chemically with Small Molecules

e.g. antacids for increased acidity

Binding Free Molecules or Atoms

e.g. drugs for heavy metal poisoning, infliximab (anti-TNF)

HOW DO DRUGS WORK BY UNCONVENTIONAL

MECHANISMS OF ACTION (Continued)?

Being Nutrients
e.g. vitamins, minerals

Exerting Actions Due to Physical Properties

e.g. mannitol (osmotic diuretic), laxatives

Working Via an Antisense Action

e.g. fomivirsen for CMV retininitis in AIDS

Being Antigens
e.g. vaccines

Having Unknown Mechanisms of Action

e.g. general anesthetics

So
Those drug do not act through receptor,

They do not fit the drug-receptor models

12

Summary

most drugs act through receptors

there are 4 common signal transduction methods
the interaction between drug and receptor can be described
mathematically and graphically
agonists have both affinity (kd) and intrinsic activity ()
antagonists have affinity only
antagonists can be competitive (change kd) or
non-competitive (change ) when mixed with agonists
agonists desensitize receptors.
antagonists sensitize receptors.
some drugs do not fit the drug-receptor model