Principles of

Pharmacology:

Pharmacodynamics

Dennis Rosete, M.D.

Philippine Society of
Experimental and Clinical
Pharmacology
Learning Objectives:
 Understand the theoretical basis of drug-
receptor interactions.
 Understand the determinants and types of
responses to drug-receptor interactions
including the graded dose-response curve.
 Define potency and efficacy.
 Understand how to compare drug potency
and efficacy.
 Understand measures of drug safety.
 Understand the consequences of receptor
regulation
 DRUG MAN
Two
INTERACTION Way
Relationship

PHARMACODYNAMICS:
Action
Effect
PHARMACOKINETICS
Absorption
Distribution
Metabolism
Elimination
Excretion
A. Pharmacodynamics

 Study of the biochemical and

physiological effects of drugs and
their mechanism of action.
 Refers to the actions of a drug on
the body.
“ What a drug does to the body”
Pharmacodynamics

 drug-receptor interactions
 dose-response phenomena

 mechanisms of therapeutic and

toxic action
A drug receptor is a . . .

. . . macromolecular
component of the cell
with stereospecificity
and with which a drug
interacts in a lock-and-
key fashion initiating a
chain of events that lead
to a pharmacological
response.
 The Cell Membrane
Cell Membrane has protruding receptors waiting for a drug
Ligand-gated Ion
Channels
G-protein coupled
receptors

β γ
G-protein coupled
receptors

Membran
e

β γ
G-protein coupled
receptors

α β γ
Receptor-enzyme

Binding site

Catalytic
site
Cytosolic-Nuclear
receptors
Terminologies
Receptor affinity - tendency of a
drug to combine with a receptor
Receptor specificity - tendency of
a drug to combine with a specific
type of receptor and none other.
Receptors
Receptors are responsible for
selectivity of drug action
 Beta receptors (B1 vs B2)
 Histamine receptors (H1 vs others)
 Angiotensin receptors (AT1, AT2)
 Cycloxygenase enzyme receptors
(COX1, COX2)
Active vs Inactive
states
 Active states initiate cell
signaling.
 For any cell, there is an
equilibrium between active an
inactive states. The inactive
state usually predominates.
 Each state has its own affinity.
Pharmacodynamics

– Onset of action-time it takes to reach

minimum effective concentration (MEC)

– Peak action –occurs when drug reaches its

highest blood/plasma concentration

– Duration of action-length of time drug has a

pharmacologic effect
AGONIST /
ANTAGONIST

AGONIST – a drug that

binds to receptors and
produce an effect.

ANTAGONIST – a drug
that binds to receptors
and prevent an agonist
from producing an
effect.
Receptors
Receptors mediate the actions of
pharmacologic antagonists

 Mimics the chemical configuration

of the natural chemical in the body
 May displace the “usual partners”
when in excessive quantities or with
increased affinity
Pharmacodynamics
 Refersto the actions of a
drug on the body
 drug-receptor interactions

 dose-response phenomena

 mechanisms of therapeutic
and toxic action
Definitions and Concepts
 Selectivity: differential
responsiveness among the drug’s
multiple effects
 Dose: amount administered
 Posology: concerned with the
dosage or amount of a drug
given in the treatment of
disease.
 Efficacy: the property of a drug to
achieve the desired response
Efficacy
Graded dose-response
curves
 Individual responses to varying doses
 Concepts to remember:
– Threshold: Dose that produces a just-
noticeable effect.
– ED50 : Dose that produces a 50% of
maximum response.
– Ceiling: Lowest dose that produces a
maximal effect.
 Dose-response curve
100

80

60

40

20
s nops e R
e

0
0 200 400 600 800 1000

Dose
 Dose-response curve
100

80

60

40
s nops e R
e

20

0
0.1 1 10 100 1000 10000
Dose
 100

80

60

40

20

0
0.1 1 10 100 1000 10

= Agonist
 100

80

60

40

20

0
0.1 1 10 100 1000 10

= Agonist
 100

80

60

40

20

0
0.1 1 10 100 1000 100

= Agonist
 100

80

60

40

20

0
0.1 1 10 100 1000 100

= Agonist
 100

80

60

40

20

0
0.1 1 10 100 1000 100

= Agonist
 100

80

60

40

20

0
0.1 1 10 100 1000 100

= Agonist
 100

80

60

40

20

0
0.1 1 10 100 1000 100

= Agonist
 Dose-response curve
100 Ceiling
80

60
ED50
40

20
Threshold
s nops e R
e

0
0.1 1 10 100 1000 10000

Dose
Determinants of
Response
 Intrinsic Efficacy
(ε): Power of a drug
to induce a response.
 Number of receptors
in the target tissue.
Full vs Partial agonists
 These terms are tissue dependent
– Receptor density
– Cell signaling apparatus
– Other receptors that are present
– Drug history
Full vs Partial agonists
100
Full Agonist
80
% Effect

60

40

20
Partial Agonist
0
0.1 1 10 100 1000 10000

Dos
 Two types of
antagonism
competitive (reversible) antagonist
 drug molecule that will compete with an
agonist for binding to the receptor
 response is abolished or diminished as long
as the antagonist can successfully compete
with the agonist for the receptor site
 competition can be overcome by flooding
the receptor site with a very large
concentration of agonist and full response
can be restored
 
 Two types of
antagonism
noncompetitive (irreversible)
 a drug molecule which binds to the
receptor and does not dissociate
and cannot be displaced by
increasing agonist concentration
 Effectively, some of the receptors
become inactivated and the full
response cannot occur, although
some pharmacologic activity of the
agonist is usually still present.
 12 0

10 0

80

60

40

20

0
- 10 .5 - 10 - 9 .5 -9 - 8 .5 -8 - 7 .5 -7 - 6 .5

= Agonist =
 120
100
80
60
40
20
0
-11 -10 -9 -8 -7

= Agonist =
 120
100
80
60
40
20
0
-11 -10 -9 -8 -7

= Agonist =
 120

100
80

60
40

20
0
-11 -10 -9 -8 -7

= Agonist =
 120
100
80
60
40
20
0
-11 -10 -9 -8 -7

= Agonist =
 120

100

80

60

40

20

0
-11 -10 -9 -8 -7

= Agonist =
 120

100

80

60

40

20

0
-11 -10 -9 -8 -7

= Agonist =
 Competitive
1200

1000

800

600 IC50
t c eff E

400

200

0
-11
log
-10
[antagonist]
-9 -8 -7
= Agonist =
= Agonist =
= Agonist =
= Agonist =
= Agonist =
= Agonist =
= Agonist =
Competitive
antagonists
100
A B C
80
Response

60

40

20

0
0.1 1 10 100 1000 10000

Dos
Noncompetitive
antagonists
100
A
80
Response

60
B
40
C
20

0
0.1 1 10 100 1000 10000

Dos
Chemical and
Physiologic
antagonists
 Physiologic: Two drugs have
opposite effects through differing
mechanisms
 Response can be irregular
 Chemical: No receptors are
involved
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric antagonists
1
100
A
80
Response

60

40

20

0
0.1 1 10 100 1000 10000

Dos
Allosteric antagonists
2
100
A
80
Response

60
B
40
C
20

0
0.1 1 10 100 1000 10000

Dos
Receptor regulation
 Reduced responsivity: Chronic
use of an agonist can result in the
receptor-effector system
becoming less responsive
 Increased responsivity: Chronic
disuse of a receptor-effector
system can result in an increased
responsiveness upon re-exposure
to an agonist.
THREE MOST IMPORTANT
PROPERTIES OF A DRUG:

EFFICACY
SAFETY
QUALITY
Properties of a
biological system
 Potency: Dose of drug
necessary to produce a specified
effect.
– Dependent upon receptor density,
efficiency of the stimulus-response
mechanism, affinity and efficacy.
 Magnitude of effect: Efficacy
Relative Potency
100
A B
80

60
Effec

40
t

20

0
0.1 1 10 100 1000 10000

Dos
Relative Potency
100
A B
80

60
Effec

40
t

20

0
0.1 1 10 100 1000 10000

Dos
Relative Efficacy
100

80 Relative
Efficacy
60

40

20

0
0.1 1 10 100 1000 10000
Potency
- biological activity of a drug per unit of weight

Example 1:
drug A drug B drug C
1 ng 100 mg 1g

These 3 drugs differ in potency but

have identical or similar effects.
 Definitions and
Concepts
 Dose intensity relationship:
manner in which the intensity of
the effect in the individual
recipient relates to dose
 Dose frequency relationship:
manner in which the number of
responders among a population
of recipients relates to dose.
FIGURE A.
DOSE-FREQUENCY CURVE
THREE MOST IMPORTANT
PROPERTIES OF A DRUG:

EFFICACY
SAFETY
QUALITY
Therapeutic Index
 TI = LD50 / ED50
– LD – Lethal Dose
(lethal in 50% of animals)
– ED – Effective Dose
(therapeutic effect in 50%)
 Closer Ratio is to 1 = Greater
Danger Toxicity
 Safety index: LD1/ED99
ED99
100

80
Sleep Death
60

40

20
LD1
0 0

K
01
01

1
10

0K
-20 1K
10
0.
00

10
0.
00

10
0.
0.
 Therapeutic index:
LD50 /ED50
100

80
Sleep Death
60

40

20

0 0

K
01
01

1
10

0K
-20 1K
10
0.
00

10
0.
00

10
0.
0.
 Adverse effects
PHARMACOLOGY is
defined as:

– from the Greek word

pharmakon “poison”
Terminologies
Toxicology: deals with the toxic or
poisonous effects produced by drugs
Side Effects - other effects of drugs
(may be positive or negative)
According to the WHO definition,
an adverse reaction is any
untoward medical occurrence in a
patient:
1. that is harmful or noxious to
the body
2. unintended
3. may arise even from the
administration of the usual
recommended dose range of the
drug.
Excluding…
Serious adverse event

 Death

 Disability

 Prolonged hospitalization
 Congenital defect

 Life threatening condition

 Type A (augmented/predictable) reactions
 Expected extensions of an individual drug’s known
pharmacologic properties and are responsible for the
bulk of ADEs encountered.
 Even though their incidence and morbidity is high,
they are rarely life-threatening, although they can
produce significant disability.
Drug Allergy
Causes of Type A reactions
1. Pharmaceutical causes
- Drug quantity
- Drug release
2. Pharmacokinetic causes
- Drug absorption - Drug elimination
- Drug distribution - Drug metabolism
3. Pharmacodynamic causes
- Drug receptors
- Homeostatic mechanisms
- Disease
Type B (bizarre/unpredictable) reactions

• Type B reactions include idiosyncratic reactions,

immunologic or allergic reactions (e.g.anaphylaxis),
and carcinogenic/teratogenic events.
• While uncommon, are often among the most
serious and potentially life-threatening of all
ADEs, and are a major cause of important
drug-induced disease.
Adverse
reactions which
only occur with
long term use
Special Groups of
patients
 Pediatric patients
 Geriatric patients

 Patients with hepatic insufficiency

 Patients with renal insufficiency

 Pregnant patients

 Nursing mothers
FDA Classification of Drug
Safety
Teratogenic Effect -
adversely affect fetal
development.
 Probably the most
renowned is
Phocomelia, the
name given to the
flipper-like limbs
which appeared on
the children of
women who took
thalidomide
Teratogenic Effect -
adversely affect fetal
development.
Pediatric and Geriatric patients –
possible dose adjustments;
safety
Hepatic and renal insufficiency
– possible dose
adjustments; dialysability
Hepatic failure
Nursing mothers – some
drugs are excreted in
breastmilk
Overdose

 Beyond the
maximum dosage
 Could be
intentional
(suicidal) or
accidental
(medication error)
 Antidote?
Precautions

 Ability to operate
machinery

Are there sedating

effects?
Drug Abuse/ Misuse/
Addiction

 Misuse – indiscriminate use of drugs

(recreational purpose)
 Abuse – continual non-therapeutic use of
drug with resulting physical or
psychological dependence
 Addiction – presence of tolerance,
withdrawal, increasing dosage and
uncontrollable use
Drug Abuse/ Misuse/
Addiction
What is Tolerance?
 Tolerance is the
need to increase
the dose of
a drug over time
in order to
maintain a given
pharmacological
effect
Withdrawal
 Physiological
 Psychological
Habit forming drugs
Categories of Controlled
Substances
 Schedule I - not approved for medical use
and have high abuse potential
 Schedule II - used medically and have
high abuse potential
 Schedule III - less potential for abuse but
may lead to physical or psychological
dependence
 Schedule IV - some potential for abuse
 Schedule V - contain mod. amounts of
controlled substances, limited abuse
potential
DRUG INTERACTION
A pharmacologic phenomenon that occurs
when the action and/or effect of a given drug
is modified or altered significantly by another
drug when these are administered
concomitantly or sequentially.

A. Pharmacodynamic Drug-Drug
Interactions

B. Pharmacokinetic Drug-Drug Interactions

Pharmacodynamic Drug
Interaction
Additivity
 Administration of the dose of A
and B simultaneously gives an
effect equal to 20 units
 Synergism

 A certain dose of Drug A alone

produces an effect equal to 10
units. A certain dose of Drug B
alone produces an effect equal to
10 units. Administration of the
same doses of A and B
simultaneously produces an effect
equal to 50 units
Antagonistic
 Administration
of the dose of A
and B
simultaneously
negates the
effect of each
drug
P-K Drug
Interaction

- due to drug
interaction at any
point during their
absorption,
distribution,
metabolism, or
excretion resulting
either in increase
or decrease in the
drug
concentration at
the site of action.
Thank you.