Drug

Pharmacodynamics

Dr.Datten Bangun MSc.SpFK

Dept.Farmakologi &
Therapeutik
Fak.Kedokteran UHN
MEDAN

Pharmacodynamics
(how drugs work on the
body)
The action of a drug on the
body, including:
=receptor interactions,
= dose-response phenomena,
= and mechanisms of
therapeutic and toxic action.
2004-2005

Pharmacodynamics
(how drugs work on the
body)
many drugs inhibit enzymes
Enzymes control a number of metabolic
processes
A very common mode of action of many
drugs
in the patient (ACE inhibitors)
in microbes (sulfas, penicillins)
in cancer cells (5-FU, 6-MP)
some drugs bind to:
proteins (in patient, or
2004-2005
microbes)

Pharmacodynamics
receptors have signal transduction

methods

most drugs act (bind) on receptors

in or on cells
form tight bonds with the ligand
exacting requirements (size, shape,
stereospecificity)
can be agonists (salbutamol), or
antagonists (propranolol)
2004-2005

Drug Receptor
A macromolecular component
of a cell with which a drug
interacts to produce a
response
Usually a protein

2004-2005

Types of Protein
Receptors
1. Regulatory change the
activity of cellular enzymes
2. Enzymes may be inhibited
or activated
3. Transport e.g. Na+ /K+
ATPase
4. Structural these form cell
parts
2004-2005

dose response curves

k

[D] + [R]
k

[DR]

-----------effect

-1

at equilibrium:
[D] x [R] x k1 = [DR] x k-1
so that: [DR] = k1
[D] [R]

k1/k-1 = affinity
const.
k-1/k1 = dissociation
const.(kd)

k-1
the lower the kd the
more potent the drug

2004-2005

Drug - Receptor
Binding
D+R

DR Complex
Affinity

Affinity measure of propensity of a

drug to bind receptor; the
attractiveness of drug and receptor
Covalent bonds are stable and
essentially irreversible
Electrostatic bonds may be strong
or weak, but are usually reversible
2004-2005

 The amount of drug bound at any

time is solely determined by:
the number of receptors
the concentration of ligand added
the affinity of the drug for its receptor.
Binding of drug to receptor is essentially the
same as drug to enzyme as defined by the
Michelis-Menten equation.

Drug Receptor
Interaction
DR Complex

Effect

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
2004-2005

What can we learn?

Ke (k1/k-1) is called the affinity constant
DR is the response; D is concentration
of drug
when DR = 50 percent (effect is half
maximal), D (or EC50) is equal to kd or
the reciprocal of the affinity constant
response is a measure of efficacy
drugs that have parallel dose-response
curves often have the same mechanism
of action
2004-2005

Arithmetic Dose Scale

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

2004-2005

Log Dose Scale

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
2004-2005

Potency
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
2004-2005

Relative Potency
hydromorphone
morphine

codeine

Analgesi
a

aspirin

Dose
2004-2005

Why are there 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

The receptor theory assumes that all receptors should be occupied to

produce a maximal response. In that case at half maximal effect EC50=kd.
Sometimes, full effect is seen at a fractional receptor occupation
2004-2005

Agonists and antagonists

agonist has affinity plus intrinsic activity
antagonist has affinity but no intrinsic activity
partial agonist has affinity and less intrinsic activity
competitive antagonists can be overcome

2004-2005

Agonist Drugs
drugs that interact with and
activate receptors; they possess
both affinity and efficacy
two types
Full an agonist with maximal
efficacy
Partial an agonist with less then
maximal efficacy
2004-2005

Agonist Dose Response Cu

Full agonist

Partial agonis

Response

Dose
2004-2005

Partial agonists
1.

2.
3.

4.

5.

Some agonists never elicit a

maximal response (compared to
the endogenous agonist) even
when nearly all of the receptors
are occupied.
However, the EC50 for these
are remarkably close to full
agonists:
Similar potency, but lower
efficacy: Intrinsic activity = 0~1
High efficacy drug: need to
occupy fewer receptors to
produce a response than one
with lower efficacy.
Why????
several conformation
changes can occur by
different agonists.
Similarly, partial agonists will
elicit a very low or no
measurable functional response
even when a significant number
of receptor are occupied.

Partial agonists can act as

functional antagonists when in
competition with higher efficacy
agonists.
Methadone for heroin abuse treatment.
Used to wean off abused drugs.
Basically competition between the full and partial
agonist.

Receptor antagonists.
Prevent agonist-mediated responses
by preventing a drug from binding and
eliciting its normal response.
Intrinsic activity = 0.
No sensitivity to Na+ or GTP.
Antagonists are measured by the
selectivity, affinity for their receptor,
and potency.

Antagonist Drug
Antagonists interact with the
receptor but do NOT change
the receptor
they have affinity but NO
efficacy
two types
Competitive
Noncompetitive
2004-2005

Competitive Antagonist
competes with agonist for
receptor
surmountable with increasing
agonist concentration
displaces agonist dose response
curve to the right (dextral shift)
reduces the apparent affinity of
the agonist i.e., increases 1/Ke
2004-2005

Receptor antagonists
Competitive antagonist.
Reversible or irreversible.
Bind to the same site as the
endogenous ligand or
agonist.
Can be over come!
Their presence produces a
right-ward shift in both the
binding and dose-response
curves.
No change in Emax or Bmax.
Similar dose-response curve
shapes indicates the
presence of a competitive
agonist (competing for the
same binding sites).

A = agonist alone
B = antagonist (one
concentration)
A+B = agonist + antagonist

Noncompetitive Antagonist
drug binds to receptor and stays bound
irreversible does not let go of receptor
produces slight dextral shift in the
agonist DR curve in the low
concentration range
this looks like competitive antagonist
but, as more and more receptors are
bound (and essentially destroyed), the
agonist drug becomes incapable of
eliciting a maximal effect

2004-2005

Non-competitive
antagonist
Does not prevent formation of
the DR complex, but impairs
the conformation change
which triggers a response.
Bind to a site different than
the agonist binding site at an
allosteric site (use a
hemoglobin example.).
Cannot be overcome by
adding more agonist
Emax and Bmax are reduced but
EC50 remains the same for the
unaffected receptors.
Dose-response curves will
have different shapes
indicating different
binding sites.

Irreversible
antagonists.
Binds in an irreversible manner, usually by
covalent modification of the receptor.

N-ethylmalemide (NEM) or other sulfhydryl

or alkylating agents (non-selective).
Antibodies
Molecular control (mutation) EXAMPLE
Prevents binding at the atomic level.
Effectively and practically lowers the
number of receptors capable of binding an
agonist.
Adding more agonist is useless
Only cure: Make New Receptors by
Protein Synthesis.

Desensitization
agonists tend to desensitize
receptors
homologous (decreased receptor
number)-----down-regulation
heterologous (decreased signal
transduction)
antagonists tend to up
regulate receptors
2004-2005

Receptor desensitization
A loss of agonist affinity, but not
receptor number after chronic agonist
stimulation.
Best example is 2-AR.
Phosphorylation
-arrestin
uncoupling of receptor and G-protein
results in a rightward shift of the binding
curve: DESENSITIZATION.

Receptor desensitization
KD of isoproterenol (1 100 nM) goes up
affinity goes down
number of receptors does not change (B max
does not change).
-arrestin binds with clathrin AP-2 binding site.
Complex internalizes into membrane-bound
endosomes.
Endosomes internalizes
transient decrease in surface receptor
number.

dose response curves-3

quantal dose response curves (used in populations,
response is yes/no)

2004-2005

Therapeutic index =Toxic Dose50/Effective Dose50

(TD50/ED50)

DR Curve: Whole Animal

Graded response measured on a
continuous scale
Quantal response is an either/or
event:
- death/alive;pregnant/not
relates dose and frequency of response
in a population of individuals
often derived from frequency distribution
of doses required to produce a specified
effect
2004-2005

Effectiveness, toxicity,
lethality
ED50 - Median Effective Dose 50; the
dose at which 50 percent of the
population or sample manifests a
given effect; used with quantal dr
curves
TD50 - Median Toxic Dose 50 - dose
at which 50 percent of the population
manifests a given toxic effect
LD50 - Median Toxic Dose 50 - dose
which kills 50 percent of the subjects
2004-2005

Quantification of drug
safety

TD50 or LD50

Therapeutic Index =

2004-2005

ED50

Drug A
100

sleep

death

Percent 50
Responding

ED50 LD50

dose
2004-2005

Drug B
100

sleep

death

Percent
50
Responding

ED50

dose
2004-2005

LD50

The therapeutic index

The higher the TI the better the drug.

TIs vary from:

drugs)

1.0 (some cancer

to: >1000 (penicillin)

Drugs acting on the same receptor or

enzyme system often have the same
TI: (eg 50 mg of hydrochlorothiazide
about the same as 2.5 mg of
2004-2005

Therapeutic Window
Useful range of concentration over which a
drug is therapeutically beneficial.
Therapeutic window may vary from patient
to patient
Drugs w/ narrow therapeutic windows
require smaller & more frequent doses or a
different method of administration
Drugs w/ slow elimination rates may rapidly
accumulate to toxic levels.can choose to
give one large initial dose, following only
with small doses

Therapeutic Window
Therapeutic failure results when
either:
= the concentration is too low,
= ineffective therapy, or
= is too high, producing
unacceptable toxicity.
Between these limits of
concentration lies a region
associated with therapeutic success

Wide therapeutic window

A

Toxicity

Response

Efficacy

Drug concentration (log scale)

Narrow therapeutic
window
Toxicity

Response

Efficacy

Drug concentration (log Scale)

Major sources of Variability:

Age- neonates, children, elderly
Physiology- gender, pregnancy
Disease- Hepatic, renal, cardiovascular,
respiratory
Drug interactions
Environmental influences on drug
metabolism
Genetic polymorphisms

Therapeutic Index
Therapeutic index = toxic dose/effective
dose
This is a measure of a drugs safety
A large number = a wide margin of safety
A small number = a small margin of safety

Therapeutic Index ******

TI = LD50 / ED50
Measure of the ratio of undesirable to
desirable drug effects.

For in vivo systems thee therapeutics

index could be the ratio of the LD50
( the lethal dose for 50 % of the test
animals) to the ED50 ( the effective
dose that produces the maximum
therapeutic effect in 50 % of the test

Drug variability and toxicity

assessment
ED50: Effective dose for 50% of
subjects
LD50: Lethal dose for 50% of subjects
The therapeutic index

TI = LD50 / ED50
No drug is 100% safe

LD50: Median lethal dose

LD50 (median lethal dose):
The dose of a drug that
produces death in 50% of
the animal population
tested

THANK

HAVE

YOU

FOR

THE

ATTENT

A BEAUTIFUL CHRISTMAS HOL