farmakodinamik obat
DESCRIPTION
menjelaskan secara rini farmakodinamik obat , injeksi secara intravena,intramuscular,subkutanTRANSCRIPT
Pharmacodynamics FARMAKODINAMIK
Setyo Purwono
Bag. Farmakologi & Terapi FK - UGM
Pharmacology
• Study of the changes produced in living animals
by chemical substances, especially the actions of
drugs, used to treat disease
- or -
• A branch of medicine that deals with the
interaction of drugs with the systems and
processes of living animals, in particular, the
mechanisms of drug action as well as the
therapeutic and other uses of the drug
Two major subdivisions of pharmacology
Pharmacokinetics
Pharmacodynamics
Dose of Drug Resulting Drug
Concentration in
the Body over
Time
Mechanism &
Magnitude of Drug
Effect •Absorption
•Distribution
•Biotransformation
•Excretion
•Receptor Binding
•Signal Transduction
•Biological Effect
Pharmacodynamics
What a drug does to the body…..
The results may not be exactly as shown in the pictures,
but a drug should heal, cure or help the body in someway!
Bound Free Free Bound
LOCUS OF ACTION
“RECEPTORS”
TISSUE
RESERVOIRS
SYSTEMIC
CIRCULATION
Free Drug
Bound Drug
ABSORPTION EXCRETION
BIOTRANSFORMATION
Drugs, receptors and pharmacological response
• A receptor is a macromolecule whose biological
function changes when a drug binds to it
• Most drugs produce their pharmacological effects by
binding to specific receptors in target tissues
• Drug-Receptor binding triggers a cascade of events
known as signal transduction, through which the
target tissue responds
• Affinity is the measure of propensity of a drug
to bind receptor; the force of attraction
between drug and receptor
• Types of bonds between drug and receptor
(hydrophobic, electrolytic or covalent
interactions)
A macromolecular component of the organism that
binds the drug and initiates its effect.
Definition of RECEPTOR:
Most receptors are proteins that have undergone various
post-translational modifications such as covalent
attachments of carbohydrate, lipid and phosphate.
nicotinic
acetylcholine
receptor
Most drug receptors are membrane proteins
Outside the cell
Inside the cell = cytosol
(view in ~1995)
nicotine,
another agonist
Membrane = lipid bilayer
Natural ligand
(agonist)
Overall topology of the nicotinic acetylcholine receptor
(view in ~2000)
outside the cell:
5 subunits each subunit has 4 a-helices
in the membrane
(20 membrane helices total)
Little Alberts figure 12-42
© Garland publishing
Binding Region
The acetylcholine binding protein (AChBP) from a snail,
discovered in 2001, strongly resembles the binding region
(Swiss-prot viewer must be
installed on your computer)
Color by chain
Show 2 subunits,
Chains,
Ribbons
5 subunits
Little Alberts figure 12-42
© Garland publishing
http://www.its.caltech.edu/~lester/Bi-
1/AChBP+Carb-5mer.pdb
Binding
region
Membrane
region
Cytosolic
region
Colored by
secondary
structure
Colored by
subunit
(chain)
Nearly Complete Nicotinic Acetylcholine Receptor (February, 2005)
http://pdbbeta.rcsb.org/pdb/downloadFile.do?fileFormat=PDB&compression=NO&structureId=2BG9
~ 2200
amino acids
in 5 chains
(“subunits”),
MW
~ 2.5 x 106
Equation for drug-receptor interaction
[D] + [R] [DR] effect
k 1
k 2
at equilibrium:
[D] x [R] x k1 = [DR] x k2
k1/k2 = affinity constant (ka)
k2/k1 = dissociation constant (kd)
kd = k2/k1 the lower the kd the more affintiy the drug has for the
receptor
a
D is concentration of drug ; DR is the response, response is a
measure of efficacy, maximal effect or efficacy is denoted as Emax
=
k2 [D] [R]
k1 [DR]
= - or - so that: [DR] k1
[D] [R] k2
Correction
How do we measure or quantify a drug-receptor interaction
Dose-response curve
Dose
(mg)
% contraction
0.1 10
0.3 20
1 50
3 70
10 100
30 100
Contraction of muscle produced by adrug
1 3 10 300
25
50
75
100
Dose of drug (mg)
% c
ontra
ctio
n
Emax
EC50
Arithmetic vs. log scale of dose - which one is better?
Contraction of muscle produced by adrug
1 3 10 300
25
50
75
100
Dose of drug (mg)
% c
ontra
ctio
n
• Rate of change is rapid at first and
becomes progressively smaller as
the dose is increased
• Eventually, increments in dose
produce no further change in effect
i.e., maximal effect for that drug is
obtained
• Difficult to analyze mathematically
• Transforms hyperbolic curve to a
sigmoid (almost a straight line)
• Compresses dose scale
• Proportionate doses occur at equal
intervals
• Straightens line
• Easier to analyze mathematically
Arithmetic scale
Contraction of muscle produced by adrug
0.1 0.3 1 3 10 300
25
50
75
100
Dose of drug (mg)
% c
ontra
ctio
n
Log scale
Dose-response curves
Arithmetic vs log-dose scale
• EC50 – dose or concentration of a drug that produces
50% of maximal (half maximal) response
• Emax – maximal effect produced by a drug. It is a
measure of efficacy of a drug
• Efficacy (or Intrinsic Activity) – ability of a
bound drug to change the receptor in a way that
produces an effect; some drugs possess affinity but
NOT efficacy
• Kd – concentration of a drug that occupies 50% of
the total number of receptors at equilibrium
Potency of a drug
• Relative position of the dose-effect curve along the dose axis
• Has little clinical significance for a given therapeutic effect
• A more potent of two drugs is not clinically superior
• Low potency is a disadvantage only if the dose is so large that it is awkward to administer
• Potency is determined by the affinity plus intrinsic activity of the drug
Analgesia
Dose
hydromorphone
morphine
codeine
aspirin
Relative Potency
EC50 = 5 - concentration that produces half-maximal response
Kd = 5 - concentration that occupies 50% of receptors
In this case EC50 = Kd ; there are no spare receptors
Half-maximal
response
10 receptors produce
maximal response
5 receptors produce
half-maximal
response
Here there are a total of 10 receptors
EC50, Kd and spare receptors
Kd = 5 - concentration that occupies 50% of receptors
EC50 = 5 - concentration that produces half-maximal response
Kd = 10 - concentration that occupies 50% of receptors
When EC50 < Kd ; it suggests existence of spare receptors
Half-maximal
response
10 receptors produce
maximal response
5 receptors produce
half-maximal
response
Here there are a total of 20 receptors – only 10 are required to
produce a maximal response
When all receptors need to be occupied for a full
response: then EC50 = Kd i.e. the concentration of a
drug which produces half-maximal response (EC50) will
equal the concentration that occupies half the number
of total receptors (Kd)
Spare receptors
• allow maximal response without total receptor occupancy –
increase sensitivity of the system
• spare receptors can bind (and internalize) extra ligand
preventing an exaggerated response if too much ligand is
present
Drug-receptor interaction
Receptor
A
A
A
Drug molecule – in most cases the binding is transient, i.e. the
drug molecule binds and dissociates, binds again and so on.
Each binding triggers a signal
Equilibrium
between drug
molecule and its
receptor –
association and
dissociation
If we put two drugs (A
& B) acting at the same
receptor, they will
compete for the
receptor due to the
transient binding.
The drug with a higher
concentration will have
a greater chance of
binding
B
Drug molecule A
Agonists, partial agonists and antagonists
An agonist is a drug which binds to the receptor and produces an effect.
Thus it has affinity + intrinsic activity
A partial agonist has affinity for a receptor but less intrinsic activity (lower efficacy compared to an agonist acting at the same receptor)
An antagonist is a drug which binds (thus competes for binding against other ligands), but does not activate the receptor
It has affinity but no intrinsic activity
An antagonist can be Competitive (reversible)
Noncompetitive (irreversible)
Agonist and partial agonist
Dose
(mg)
Agonist Partial
agonist
0.1 10 10
0.3 25 15
1 50 25
3 75 30
10 100 40
30 100 50
100 50
e.g. morphine – agonist
buprenorphine – partial agonist
at µ opioid receptors
A partial agonist has less efficacy and a
lower Emax compared to an agonist
acting at the same receptor
Agonist -
higher Emax
0.1 1 10 10030
25
50
75
100
Dose (mg)
% c
on
tra
cti
on
EC50
Partial agonists - usefulness
• A partial agonist produces less than full effect when given alone
• A partial agonist acts as an antagonist in the presence of a full
agonist (blocks the full effect of an agonist)
• Therapeutic use of a partial agonist – e.g. buprenorphine, an
opioid analgesic, has a lower abuse potential, lower level of
physical dependence, and greater safety in overdose compared
with a full agonist such as morphine.
• Sometimes the antagonist properties of a partial agonist are
desirable (providing some agonist activity and at the same time
blocking the endogenous full agonists). Clinical example: pindolol
for high blood pressure and abnormal heart rhythms (It will
reduce the excessive stimulation due to norepinephrine)
Receptor
A
A B
Agonist
molecule A
Receptor
B A
A
Agonist
molecule Competitive
antagonist
molecule
When the agonist is
alone, a lower dose can
produce maximal effect
In the presence of a competitive
antagonist a higher dose of agonist is
required to produce the same effect
Competitive antagonism
e.g. acetylcholine – agonist
atropine – competitive antagonist
at muscarinic receptors
A
Competitive antagonism
Dose
(mg)
Agonist
alone
Agonist +
low dose
antagonist
Agonist +
high dose
antagonist
0.1 10
0.3 25 10
1 50 25 10
3 75 50 25
10 100 75 50
30 100 75
100 100
An agonist can still produce maximal effect but higher
doses are required in the presence of a competitive
antagonist
EC50 increases
Rightward shift of curve in thepresence of a competitive antagonist
0.1 0.3 1 3 10 30 1000
10
25
50
75
100
Dose of drug (mg)
% c
on
tra
cti
on
Same Emax
Receptor
A
A B
Agonist
molecule A
Receptor
A
A
Agonist
molecule Non-competitive
antagonist
molecule
When the agonist is
alone, a lower dose can
produce maximal effect
In the presence of a non-competitive
antagonist even a higher dose of
agonist cannot produce maximal effect
Non-competitive antagonism
e.g. noradrenaline- agonist
phenoxybenzamine – non-competitive antagonist
at α receptors
A
Non-competitive antagonism
Dose
(mg)
Agonist
alone
Agonist +
non-competitive
antagonist
0.1 10
0.3 25 5
1 50 10
3 75 25
10 100 40
30 100 50
100 50
Less maximal effect (Emax)
Agonist + non-competitive
antagonist
An agonist cannot produce maximal effect – Emax is
depressed, in the presence of a non-competitive antagonist
EC50
0.1 0.3 1 3 10 30 1000
25
50
75
100
Dose (mg)
% c
on
tra
cti
on
Agonist alone
Frequency distribution
Each bar shows the number of
people responding to that dose
– at 100 mg 21 people respond,
excludes people responding to
lower doses
Cumulative frequency –
each bar shows the number
of people responding to that
dose and to lower doses – at
200 mg all 100 people
respond
Quantal dose response curve – different doses of a drug are given to a
group of people and a given response is noted – e.g. induction of sleep
50 100 200
0
20
40
60
80
100
Dose of drug
Nu
mb
er
resp
on
din
g
2 7
16
29
44
65
80 88
94 98 100
50 100 200
0
20
40
60
80
100
Dose of drug
Nu
mb
er
resp
on
din
g
2 5 13 15
21 15
6 4 2 9 8
Quantal (Cumulative) Dose-Response curves
Quantification of drug safety
Here two effects have been
recorded – hypnosis and death
ED50 – effective dose in 50% of people
TD50 – toxic dose in 50% of people
LD50 – lethal dose in 50% of people
Therapeutic Index = TD50/ED50 (higher the ratio, safer the drug) Therapeutic Window = TD1 - ED>80 (the wider the safer)
Signal transduction Pathways
• Drug – receptor interaction
• produces a response
• The events involved in this response are known as
signal transduction
• Common responses in the body
• Transient increase in intracellular free calcium levels -
Muscle contraction
• Activation of enzymes for various biochemical reactions
• Neurotransmission
• Secretion of neurotransmitters and hormones
Signal transduction mechanisms
4 fundamental mechanisms or types
1. G-protein coupled receptor systems
(GPCRs, metabotropic receptors)
Half of all known drugs work through GPCRs
2. Ion-channel receptors
(Ionotropic receptors)
3. Enzymes as receptors – tyrosine kinase, serine/threonine kinase
4. Nuclear receptors
α γ β
GDP
Inactive G-protein –
bound to GDP
Inactive receptor
(GPCR)
Inactive enzyme -
adenylyl cyclase
α β
GTP
Activated G-protein –
bound to GTP
Activated
receptor
(GPCR) Activated enzyme -
adenylyl cyclase
Agonist binding
GTP
GDP
α γ β
GDP
GTP
GPCR – G protein coupled receptor, GTP – guanosine triphosphate, GDP – guanosine
diphosphate, α, β, γ – three subunits of G protein
Resting (inactive state)
Activated system
γ
Pathways are activated by G protein coupled receptors
K+ Channel
Phospholipase C-b
(IP3) (DAG)
↑ Ca2+ Protein
kinase C
Activated G protein
Adenylyl
cyclase
ATP cAMP
Protein kinase A
• Three major second messengers activated by GPCRs:
• cAMP (cyclic adenosine monophosphate)
• IP3 (inositol trisphosphate)
• DAG (diacyl glycerol)
Ion channel receptors
The receptor is a protein with a
channel in the centre. An agonist
causes the channel to open and
allows specific ions to cross the
cell membrane to the other side.
e.g. Nicotinic acetylcholine
receptor – conducts Na+ ions –
causes muscle depolarization and
contraction
Gamma aminobutyric acid
(GABA) receptor – conducts Cl-
ions – inhibits neurotransmission
Enzyme receptors The receptor consists of a pair of
protein molecules (monomers) that
are separate when inactive.
An agonist causes them to interact
and form a dimer.
The interaction phosphorylates
tyrosines in the intracellular region of
the receptor and the receptor
becomes an active enzyme.
The active receptor enzyme then
activates a number of other enzymes
that interact with the active tyrosine
of the receptor.
e.g. insulin receptor, growth factor
receptors
Nuclear receptors
Cytosolic receptor
Agonist
Nucleus
These receptors are in the cell cytosol.
An agonist enters the cell and binds to
the receptor.
The drug-receptor complex then enters
the nucleus and stimulates gene
transcription.
This leads to synthesis of new proteins
and enzymes.
This kind of signal transduction extends
over hours to days.
e.g. receptors for steroids, retinoids and
thyroid hormones
Gene
transcription
Cell cytosol
Up-regulation & Down-regulation of Receptors
• Agonists tend to desensitize receptors – e.g. treatment of
bronchial asthma with β-receptor agonists (such as salbutamol)
causes desensitization of receptors
• homologous (decreased receptor number)
• heterologous (decreased signal transduction)
• Antagonists tend to up regulate receptors – treatment with a β-
receptor antagonist causes a withdrawal rebound effect when the
antagonist treatment is stopped suddenly
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 (a)
• antagonists have affinity only
• antagonists can be competitive (change kd) or
• non-competitive (change a) when mixed with agonists
• agonists desensitize receptors.
• antagonists sensitize receptors.
Pharmacodynamics Objectives:
Upon completing this lesson the student will be able to:
1. Define receptor, dissociation constant, affinity, intrinsic activity
2. Describe 4 signal transduction pathways
3. Draw a dose response curve and a log dose response curve.
4. From these curves, point out potency and intrinsic activity.
5. Distinguish between potency and affinity.
6. Define spare receptors.
7. Define agonist, antagonist (competitive and non-competitive), partial agonist and understand the concepts of their interactions
8. Define desensitization, upregulation and understand their clinical significance
9. Draw a quantal log dose response curve
10. Define therapeutic index