Pharmacodynamics

Sjarif Ismail
SETYAWATI S. KARYONO

How drugs act

 Pharmacokinetics

Pharmacodynamics

Pathways of drug distribution

Farmakodinamik

Cara kerja obat, efek obat terhadap

fungsi berbagai organ, dan
pengaruh obat terhadap reaksi
biokimia dan struktur organ
Langley (1905) Receptive substance
Nicotin Stimuli listrik
(-) CURARE
Skeletal muscl. Skeletal muscl.
contraction contraction

Ehrlich (1913) specificity of the chemical

structure

reseptor structure

corpora non agunt nisi fixata

(A drug will not work unless it is bound)
 KERJA OBAT TANPA
PERANTARAAN RESEPTOR
1. Efek non spesifik dan gangguan pada membran
Perubahan sifat osmotik (urea, manitol, MgSO4)
Perubahan sifat asam-basa (antasida, NH4Cl, NaHCO3)
Kerusakan non spesifik (antiseptik-desinfektan)
Gangguan fungsi membran (anestesi volatile)
1. Interaksi dengan molekul kecil atau ion
(CaNa2EDTA- Pb2+)
2. Masuk ke dalam komponen sel (obat kanker)
 Receptor

The
The macromolecular
macromolecular (protein)
(protein) complex
complex with
with which
which
drugs
drugs interact
interact to
to elicit
elicit their
their characteristic
characteristic biological
biological
effects.
effects.

Structure -Activity Relationship

Structure-Activity Relationship:: the
the relationship
relationship
between
between the
the chemical
chemical structure
structure of
of aa drug
drug and
and its
its
biological
biological effect.
effect.
Receptor

Drug
Drug binding
binding sites
sites are
are generally
generally on
on proteins
proteins,,
glycoproteins
glycoproteins,, and
and proteolipids
proteolipids..

Proteins
Proteins fold
fold to
to form
form unique
unique 33-D
-D structures.
structures.

Exposes
Exposes sites
sites on
on particular
particular residues
residues that
that
selectively
selectively accommodate
accommodate drugdrug molecule
molecule binding.
binding.
Types of Bonds and Attractive Forces
Pertinent to Drug-Receptor Binding

In order of decreasing bond

strength:
Covalent (irreversible; least common)
Ionic (+/-)
Hydrogen (H - O)
Hydrophobic Interactions
Van der Waals (dipole interactions)
Interaction of Acetylcholine with Its
Receptor
Goldstein, Aronow, Sumner, 1974.
Structure-Activity Relationship
Polar

Nonpolar

Polar
Drug-receptor interaction
Model of simple
occupancy theory
Characteristics of Drug-Receptor
Interactions
Chemical Bond: covalent, ionic,
hydrogen, hydrophobic, and Van der
Waals.
Competitive, agonist-antagonist
Specific and Selective
Structure-activity relationships
Transduction mechanisms
Definisi:

Ligan: molekul spesifik (obat) yg

dapat mengikat reseptor
Affinitas: Kemampuan ligan
untukmengkat reseptor.

Efikasi: perubahan/efek maksimal

yg dapat dihasilkan oleh suatu obat.
Agonis
Agonists: ligan/obat yg dapat berikatan dg
resptor dan menghasilkan efek.
Produce effects similar to those produced
by naturally occurring hormones,
neurotransmitters and other substances
Example: beta agonists stimulate beta cells
(B2) in the lungs causing relaxation of the
bronchial smooth muscles. (Albuterol/
Alupent)
 Antagonis
Antagonis: ligan yg dapat berikatan dg
reseptor tapi tidak menghasilkan efek
Inhibit cell functions by occupying receptor sites.
Prevent natural body substances or other drugs from
occupying receptor sites and activating cell functions
Example: beta antagonists (beta blockers) occupy
beta sites throughout the body causing slowing of the
pulse, decrease blood pressure and decreased
cardiac output. (Atenolol, Timolol)
Agonist & Antagonist
Agonist & Antagonist
Agonist & Antagonist
Agonist & Antagonist
Macam kurva dosis vs respon
 KONSENTRASI DAN RESPON OBAT
Dosis berbanding lurus dengan respon obat
Respon berhenti pada konsentrasi tertentu
 Efikasi
Potensi dinyatakan dengan ED50
Slope kurva dosis-respon
Syarat agonis dapat menimbulkan respon
Contoh slope kurva dosis-respon
 INDEKS TERAPI & OBAT IDEAL

Indeks Terapi
= LD50/ED50
Menentukan
tingkat
keamanan
obat
Obat Ideal =
LD1/ED99
1
The four main type receptor :
1. Ligand-gate ion channels /
Receptors operated channels / ROCs
2. G-protein coupled Receptors / GPCRs
3. Receptors As Enzyme /
Enzyme coupled receptors
3. Cytosolic Receptors / Intracellular
receptors / DNA-coupled receptor

1,2,3 Transmembrane receptors

These receptors span the membran
Schematic representation of general structure
of the four main type receptor :
Ligand-gate G-protein coupled Receptors Cytosolic
Ion channel Receptors As Enzyme Receptor

The four main type receptor

 The four main type receptor
Receptors Intracellular
ROCs GPCRs
as Enzyme receptors
Location Membrane Membrane Membrane intracellular
Effector Channel Enzyme or enzyme Gene
Channel Transcription
Coupling Direct G-Protein Direct or Via DNA
indirect
Examples NicAch, Musc Ach, GF, Cytokine, Steroid & Thyroid
GABAA , Adreno- ANF, insulin hormone,
glycine, receptor receptor retinoid receptor
glutamate,
5HT3 seroto
receptor
1: Ligand -gated Ion Channels / ROCs /
Ligand-gated
Receptors operated channels

The
The signal
signal activates
activates the
the flow
flow of
of ions
ions across
across
the
the membrane
membrane

Eg
Eg :: Neurotransmitters
Neurotransmitters GABA
GABAAA,, ACh
ACh ((nic),
nic),
-HT33 serotonin,
55-HT serotonin, Glutamate,
Glutamate, Glycine
Glycine bind
bind inin
part
part to
to ligand-gated ion
ligand-gated ion channels.
channels.
 The acethylcholine receptor is a ligand-gate
ion channels that allow cations to flow out of
the neuron to initiate an action potential
during neurotransmision.
When the receptor binds acethylcholine,
aconformational change of the receptor opens
a membrane channel that conducts ion.
2: G -Protein Coupled Receptors / GPCRs
G-Protein
They are called G-proteins because they are
intimately involved with the nucleotide, GTP.

These activate a G-protein that activate

downstream signal.
G-protein activation usually lead to an
increase cAMP, DAG, IP3, AA
Eicosanoid

Activated PKA Activated PKC, AA [Ca2+]i

Continue GPRs

G proteins are inactive when GDP is bound

and active when GTP is bound.

G proteins consist of an , a , and a

subunit. The subunit interacts with the
activated receptor, with GDP/GTP, and with
the effector enzyme (or channel).

Types of G proteins: Gs, Gi, Gq, Go, Gt, Gdf

Continue GPRs

Action of important G-proteins :

Gs stimulates adenylyl cyclases and
activates Ca2+ channels.
Gi inhibits adenylyl cyclases and
activates K+ channels.
Gq activates phospholipase C
Go inhibits Ca2+ currents
Gt stimulates adenylyl cyclases in the eye
Gdf stimulates adenylyl cyclases in the nose
Several type of transduction lead to
phosphorylation of protein target
Continue GPRs

The chemical message is transduced

across the cell membrane in four stages.
1)
1) Binding
Binding of
of drug
drug (i.e.,
(i.e., ligand)
ligand) to
to
receptor.
receptor.
2)
2) Receptor
Receptor activation
activation of
of aa G
G protein.
protein.
3)
3) G
G protein
protein regulation
regulation of
of an
an enzyme
enzyme or
or
ion
ion channel.
channel.
4)
4) Change
Change in
in the
the concentration
concentration of
of aa
second
second messenger.
messenger.
 Stage 1

Stage 2

6
 Stage 3

Stage 4
4: Receptors As Enzyme /
Enzyme coupled receptors

Activation of the receptor turn the

receptor itself into an active enzyme.
Eg:
Tyrosine kinases
Janus kinase (JAK)
Tyrosine phosphatase
Serin / threonin kinases
Guanylyl cylase
Continue Enzyme coupled receptors

Signal transduction generally

involves conformation change &
dimerization of receptors, followed by
autophosphorylation of tyrosine
residues.
The phosphotyrosine residues act as
acceptors for the SH2 domain of
variety of intracellular protein thereby
allowing control of many cell
functions controlling cell growth &
differentiation, regulating gene
transcription.
Continue Enzyme coupled receptors

Two important pathway after

conformation change & dimer formation:
Binding SH2 domain protein Grb2
activated Ras/Raf/MAP kinase pathway
important in cell division, growth and
differentiation.
Eg: receptor insulin, EGF, PDGF, ANF, TGF
Binding SH2 domain protein Stat
activated Jak/Stat pathway activated by
many cytokines control the synthesis &
release of many mediator.
Eg: receptor cytokine
Continue Enzyme coupled receptors
Continue Enzyme coupled receptors
 GTP

cGMP
4: Cytosolic Receptors /
Intracellular receptors
In this drug-receptor mechanism, the drug is
sufficiently lipid soluble to cross the lipid bilayer of
the cell membrane, diffuse into cytoplasm, & attach
to an intracellular polipeptida receptor.
The drug-receptor complex translocates to the cell
nucleus & bind to specific DNA sequences termed
hormon response elements stimulate or repress
the transcription of genes in the nucleus.
Eg: steroid (Glucocorticoid, mineralocorticoid,
estrogen, androgen), thyroid hormon, retinoic acid,
vitamin D
Continue intracellular receptor
Continue intracellular receptor
CONCLUTION