farmakodinamik obat

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