Pharmacology and Therapeutics Lecture #2

PHARMACODYNAMICS
Dr. Esquivel | September 28, 2020

OUTLINE: the response)

I. PHARMACODYANMICS
 MODIFIABLE when they bind a drug
II. RECEPTORS
III. EFFECTORS
molecule
IV. GRADED DOSE-RESPONSE RELATIONSHIPS
A. Maximal efficacy
B. Potency
V. GRADED DOSE-BINDING RELATIONS &
BINDING AFFINITY
VI. QUANTAL DOSE-RESPONSE RELATIONSHIPS
VII. POTENCY
VIII. SPARE RECEPTORS
IX. INERT BINDING SITES
X. AGONISTS & PARTIAL AGONISTS
XI. ANTAGONISTS
XII. THERAPEUTIC INDEX
XIII. THERAPEUTIC WINDOW
XIV. SIGNALING MECHANISMS
XV. RECEPTOR REGULATION
XVI. References

*RED - recording
PHARMACODYNAMICS
 What the DRUG does TO the BODY whereas
pharmacokinetics refers to what the body does to
the drug
 Refers to the biochemical, physiological, molecular
effects of drug thru their actions on receptors
providing that the receptor is complementary to the
shape of the drug
 deals with the effects of drugs on biologic systems
especially on its action on receptors
RECEPTORS
 specific molecules in a biologic system with
which drugs interact to produce changes in
the function of the system
 selective, ligand-binding macromolecules
mediating effects of endogenous substances
 characteristic:
 SATURABLE (meaning if the
receptors are saturated, no matter
how much you increase the dose of
the drug, its effect would no longer be
increased)
 SELECTIVE in their ligand-binding
characteristics (in order to maximize
 most are proteins but those enzymes that are
affected by drugs are considered receptors
 The RECEPTOR SITE (also known as the
RECOGNITION SITE) for a drug is the
specific binding region of the receptor
macromolecule and has a relatively high and
selective affinity for the drug
 The interaction of a drug with its receptor is
the fundamental event that initiates the action
of the drug.
EFFECTORS
 molecules that translate the drug-receptor
interaction into a change in cellular activity
 examples:
1. Adenylyl cyclase: cAMP Pathway
- cAMP serves as secondary
messenger
- actions of cAMP:
a. mobilization of stored energy
b. conservation of water by the
kidney
c. calcium homeostasis
d. increased rate & contractile rate of
the heart
e. regulates the production of
adrenal & sex steroids
f. relaxation of smooth muscle
2. Tyrosine kinase effector enzyme
- kinases are responsible for
phosphorylation of proteins
- it incorporates both drug-binding site
& effector mechanism
3. Sodium-potassium channel

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Modified by: DAGAMI, RPh & PAMI, RPh. soon MD
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 Pharmacology and Therapeutics Lecture #2
PHARMACODYNAMICS
Dr. Esquivel | September 28, 2020

 Efficacy reflects the limits of the dose-response

relation on the response axis
 the maximal efficacy of a drug is crucial in making
clinical decisions when a large response is
GRADED DOSE-RESPONSE RELATIONSHIPS needed
 Graded dose-response curve  Factors affecting Efficacy:
- the graph of the response versus  nature of the drug (if lipid soluble ang
the drug concentration or dose drug it will be absorbed faster compared
when the response of a particular to water soluble drugs)
receptor-effector system is  receptor characteristics (drug must fit with
receptor)
measured against increasing
 associated effector systems (availability
concentrations of a drug (Figure of the different effectors)
2–1A)(increasing the dose,  in Figure 2-15, Drugs A,C & D have an equal
increases also the response; maximal efficacy and all have greater maximal
however plateau is observed efficacy than Drug B
when the receptors are already
saturated)

 usually produces a sigmoid curve (Figure 2-

1B)

 Partial agonists have lower maximal efficacy

than full agonists

 parameters are EFFICACY (EMAX) &

POTENCY (EC50 or ED50)

EFFICACY (EMAX)  Drug A is more efficacious as compared to

 aka MAXIMAL EFFICACY drug D even though they have the EC50
 It is the greatest effect an agonist can produce of
the dose is taken to the highest tolerated level (or
simply, the maximum achievable response a drug
can have)

NASINOPA, RPh (Dravergonz 2022)

Modified by: DAGAMI, RPh & PAMI, RPh. soon MD
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 Pharmacology and Therapeutics Lecture #2
PHARMACODYNAMICS
Dr. Esquivel | September 28, 2020
POTENCY
 Refers to the concentration (EC50) or dose (ED50)
of a drug required to produce 50% of that drug’s
maximal effect.
 The smaller the EC50 or ED50, the more potent
the drug is
Figure 2-15, Drugs A and B are said to be more
potent than drugs C and D because of the relative
positions of their dose response curves along the
dose axis.
 Thus, the pharmacologic potency of drug A in Figure
2–15 is less than that of drug B, a partial agonist
because the EC50 of A is greater than the EC50 of
B of receptors in the system from the
 Note that some doses of drug A can produce larger
effects than any dose of drug B, despite the fact that
we describe drug B as pharmacologically more
potent. The reason for this is that drug A has a
larger maximal efficacy as compared with drug B.
 Factors affecting potency:
 affinity of receptors for the drug
 number of receptors available
NOTE:
The clinical effectiveness of a drug does not
depend on its potency, but on its maximal efficacy and
its ability to reach the relevant receptors. This ability
can depend on route of administration, absorption,
distribution through the body and clearance from the
blood or site of action. In deciding which of the two is to
administer, the prescriber usually consider their relative
effectiveness rather than their relative potency.
Pharmacologic potency can largely determine the
administered dose of the chosen drug
GRADED DOSE-RESPONSE RELATIONS &
BINDING
 Dose-Binding Graph
- a plot of the percentage of
receptors bound by a drug against
the log of the concentration of the
NASINOPA, RPh (Dravergonz 2022)
Modified by: DAGAMI, RPh & PAMI, RPh. soon MD
drug (Figure 2–1C)
 Dissociation constant (Kd) is the
concentration of drug required to bind
50% of the receptor sites and is a useful
measure of the affinity of a drug
molecule for its binding site on the
receptor molecule.
 The smaller the Kd, the greater the
affinity of the drug for its receptor.
 If the number of binding sites on each
receptor molecule is known, it is
possible to determine the total number
Bmax.
QUANTAL DOSE-RESPONSE RELATIONSHIPS
 Quantal dose-response relationship
- the minimum dose required to
produce a specified response in each
member of a population (Figure 2–
16).
- records the individuals response to
the drug
 For example, a blood pressure-lowering
drug might be studied by measuring the
dose required to lower the mean arterial
pressure by 20 mm Hg in 100
hypertensive patients.
 A cumulative quantal dose-response
curve is obtained and usually it is
sigmoid
 The median effective dose (ED50), median
toxic dose (TD50), and (in animals) median
lethal dose (LD50) are derived from
experiments carried out in this manner
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 Pharmacology and Therapeutics Lecture #2
PHARMACODYNAMICS
Dr. Esquivel | September 28, 2020

POTENCY
 Potency - the amount of drug needed to
produce a given effect.
 Factors affecting potency:
 Affinity for the drug
- In a solution with natural agonist
and antagonist drug. There will be
competition for available binding
site. So we should increase the
concentration of natural agonist to
overcome the antagonistic effect
of the drug.
- Affinity = Potency

 Number or receptors available

- # of receptors available = 0
Potency

 Median Effective Dose (ED50) – efficacy dose;

it means 50% of the population has
experienced the therapeutic effect of the drug
- The dose at which 50% of the population
exhibit the specified quantal effect. (Note
that the abbreviation ED50 has a different
meaning in this context from its meaning in
relation to graded dose-effect curves,
described in previous text)
 Median toxic dose (TD50) - the dose required
to produce a particular toxic effect in 50% of In the graph we can observe the different potencies and
animals different doses of drugs: A (red), B (blue), C (black),
- means 50% of the population has D(green)
experienced the toxic effect of the drug
 If the toxic effect is death of the animal, a Drug A – even at lower dose of the drug, there is
median lethal dose (LD50) may be already a maximal effect or response of the drug.
experimentally defined. Whereas…
 Note that the quantal dose-effect curve and the
graded dose-response curve summarize Drug D – needs increased dose to in order to reach the
somewhat different sets of information, maximal effect of the drug.
although both appear sigmoid in shape
 both curves provide information  In graded dose-response measurements, the
regarding the potency & selectivity of effect usually chosen for potency variable are
drugs 50% of the maximal effect and the
 the graded dose-response curve concentration or dose causing this effect is
indicates the maximal efficacy of a
drug called the EC50 or ED50 .
 the quantal dose-response curve  In quantal dose- response measurements,
indicates the potential variability/ ED50, TD50, and LD50 are also potency
differences of responsiveness variables.
among individuals  Thus, a measure of potency can be determined
from either graded or quantal dose-response

NASINOPA, RPh (Dravergonz 2022)

Modified by: DAGAMI, RPh & PAMI, RPh. soon MD
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 Pharmacology and Therapeutics Lecture #2
PHARMACODYNAMICS
Dr. Esquivel | September 28, 2020

curves, but the numbers obtained are not

identical and they have different meanings.
REFER
SPARE RECEPTORS
 Receptor occupancy vs. Physiological
response
 With spare receptors:
- 50% response = 10% occupancy
- Biological effect is proportional to [DR]
only at low drug conc.
- We expect that, even at lower
concentration of occupancy, we have
already reached maximum effect of the
drug
 Without spare receptors:
- 50% response = 50% occupancy
- Biological effect is proportional to [DR]
at all drug conc.
 So tinawag siyang spare receptor kasi nga may
spare pa na mga receptor na hindi na occupy
ng drug dahil nga naabot niya na yung
maximum effect 

 When Drug A agonist and Drug C allosteric

INERT BINDING SITE
 Different binding sites in the receptor, in which
some bounded substances may enhance or
inhibit the effect of the drug.
o Agonist – normal effect
o Antagonist/Competitive inhibitor –
inhibits agonist
o Allosteric activator- increases effect
o Allosteric inhibitor- decreases effect
activator bind to their binding sites, we expect
enhanced effect or maximum effect of the
drug
 When only Drug A agonist natural
substance binds to its binding site, we expect
the normal effect of the drug
 When Drug A natural substrate and drug B
competitive inhibitor binds to their binding
sites, we expect competitive inhibitory
effect. Wherein we must increase the conc. of
the agonist to achieve the normal effect of the
drug.
 When Drug A agonist and Drug D allosteric
inhibitor binds to their binding sites, we
expect decreased effect of the drug.
 Transport Receptor: Albumin

NASINOPA, RPh (Dravergonz 2022)

Modified by: DAGAMI, RPh & PAMI, RPh. soon MD
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 Pharmacology and Therapeutics Lecture #2
PHARMACODYNAMICS
Dr. Esquivel | September 28, 2020
 The free drug which is the active drug, will
bind to the albumin. Bounded drug is inactive,
thus decreasing the effect of the drug.
 Because of the huge size of albumin, drugs
that are bounded will not be able to go out of
the blood vessel wall and can’t enter the organ
to which it will produce its effect.
 Albumin may also act as a buffer wherein
when all the free drug is consumed, bounded
drug can be used for additional effect since
their binding is reversible.
AGONIST & PARTIAL AGONIST
 The natural substrate interacts with the
receptor completely and produces effect.
NASINOPA, RPh (Dravergonz 2022)
Modified by: DAGAMI, RPh & PAMI, RPh. soon MD
 Agonist drug which has similar shape to the
natural substrate, when bounded to the same
receptor produces the same effect
FULL AGONIST
 Interacts with natural receptor. Fully
complementary to the receptor.
 Maximum activity of the drug.
PARTIAL AGONIST
 May also interact win natural receptor but
produces less effect because the drug is not
fully complementary to the receptor.
FULL AGONIST + PARTIAL AGONIST
 Competition of the available receptors
 Antagonistic effect
 Decreased activity of the drug
NIST
ANTAGONIST
 Antagonist drug also interacts with the same
receptor, but the shape of the antagonist does
not complement that of the receptor, thus
producing no effect. It also blocks the agonist
from binding to the receptor.
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 Pharmacology and Therapeutics Lecture #2
PHARMACODYNAMICS
Dr. Esquivel | September 28, 2020

TYPES OF ANTAGONISM  Pharmacological Antagonism

 Physical Antagonism
o Based on physical properties of drugs
o Ex: Activated charcoal (adsorb
alkaloid) in alkaloidal poisoning.
-Represents the
 To minimize or prevent abs. of normal reaction of
the poison the natural substrate
 Chemical Antagonism and its receptor
which produces
o A type of antagonism where a drug
100% response
counters the effect of another by
simple chemical reaction /
neutralization
o Not necessarily binds to the receptor
o Ex:
 Ca Na edate form insoluble
complexes with arsenic/lead
 NaHCO3 with HCl
(neutralization)
 Physiological/Functional Antagonism
o Two drugs act on two diff types of
receptors & antagonize action of each
other
COMPETITIVE
o Ex: Glucagon and Insulin on blood
ANTAGONIST
sugar level
 Hyperglycemia- use insulin to - The natural
dec. blood sugar substrate competes
 Hypoglycemia- use glucagon with the competitive
to inc.blood sugar antagonist for the
same receptor
- 2 types:
Equilibrium
(reversible)
Non-equilibrium
(irreversible)

Competitive
Equilibrium
-binds to receptor
reversibly

-effects can be
overcome by adding
more agonist
1 ACH acts on the Muscarinic receptor
produces Inhibitor effect in the neuron -increase the ED50
2 Norepinephrine interacts with Beta-
adrenergic receptor produces Excitatory
effect in neuron

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Modified by: DAGAMI, RPh & PAMI, RPh. soon MD
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 Pharmacology and Therapeutics Lecture #2
PHARMACODYNAMICS
Dr. Esquivel | September 28, 2020

 In the figure take note that TI is in between

therapeutic effect and toxic effect
Competitive
Non-equilibrium
-binds to receptor
irreversibly

-effects not
overcome by
adding more
agonist

- cause a downward shift of the Emax w/ no shift of

the curve on the dose axis unless spare receptors
are present
- do not increase ED50 (unless spare receptors are
present)
THERAPEUTIC WINDOW
 Dosage range between the minimum
therapeutic dose, and the minimum toxic dose.

NON-COMPETITIVE
ANTAGONIST
-the non-competitive
antagonist and natural
substrate does not
compete for the same
receptor  In the figure the minimum therapeutic dose is
6mg and the minimum toxic dose is 19mg. So
that means the therapeutic window of the drug
is bet. 6mg-18mg.

SIGNALING MECHANISMS
 Once an agonist drug has bound to its
receptor, some effector mechanism is
THERAPEUTIC INDEX (TI) activated or produces the pharmacological
 Measure of the safety and usefulness of the effect
drug.
 TI = LD50/ED50
 The larger the therapeutic index, the safer the
drugs, so it needs larger doses to produce
toxic effects.
 For example, in Figure 2–16, the ED50 is
approximately 3 mg, and the LD50 is
approximately 150 mg. The therapeutic
index is therefore approximately 150/3, or END OF TRANSCRIPTION
50, in mice. Factors such as the varying
slopes of dose- response curves make Figure 2-6 Signaling mechanisms for drug effect. Five major cross
membrane signaling mechanisms are recognized: (1)
this estimate a poor safety index even in
transmembrane diffusion of the drug to bind to an intracellular
animals. receptor; (2) transmembrane enzyme receptors, whose outer
domain provides the receptor function and the inner domain

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Modified by: DAGAMI, RPh & PAMI, RPh. soon MD
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 Pharmacology and Therapeutics Lecture #2
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provides Dr. Esquivel | September 28, 2020

the effector mechanism converting A to B; (3) transmembrane Utiization of membrane bound receptors that are
receptors that, after activation by an appropriate ligand, activate attached to an enzyme
separate cytoplasmic tyrosine kinase molecules (JAKs), which
phosphorylates STAT molecules that regulate transcription (Y,
tyrosine; P, phosphate); (4) transmembrane channels that are
gated open or closed by the binding of a drug to the receptor site;
and (5) G protein coupled receptors, which use a coupling protein
to activate a separate effector molecule.

 5 major signaling mechanisms

Diffusion across the Plasma Membrane

 Ex: The binding of ligand to receptor

 Lipophilic subs. can easily pass through the
plasma membrane due to its lipophilic
solubility
 Hydrophilic subs. use Channel protein to
transport the drug into the cell.
Enzyme-effector enzymes
Receptors associated with ion channels
bounded enzyme, will activate the tyrosine
residues through the kinases enzyme, thus
causing the phosphorylation of protein which
are responsible in creating cellular response.
 It does not require the subs to enter into the
cell
 NOTE! The difference to the 2nd mechanism is
that yung 2nd ang receptor ay enzyme talaga.
Dito ang receptor is associated with an
enzyme lang.

 When the ligand binds to the receptor which

also act as an enzyme system, it will activate
the active catalytic domain of the which
causes cascading of signals for other
processes inside the cell.

 The binding of the drug to the receptor will

cause a conformational change in the ion
channel that will facilitate the opening of the
ion channel that will then allow the transfer of

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Modified by: DAGAMI, RPh & PAMI, RPh. soon MD
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 Pharmacology and Therapeutics Lecture #2
PHARMACODYNAMICS
Dr. Esquivel | September 28, 2020

RECEPTOR REGULATION
ions inside the cell and change the electrical  Frequent or continuous exposure to agonist
potential of the cell. results in the reduction of the receptor
 Ex: Is the action of oral antidiabetic drug response, sometimes called tachyphylaxis.
Gliclazide (belongs to Sulfonylurea group). It Several mechanisms are responsible for this
will interact with sulfonylurea receptor 1 phenomenon:
(SUR1), located at the beta cells in the
pancreas thus resulting to the opening of Ca A. Intracellular molecules may block access of a G
channels allowing the entry and increase the protein to the activated receptor molecule
conc. of Ca inside the cell and cause the
release of insulin inside the beta cells of
pancreas.
- The activation
is blocked and
the receptor is
desensitized and
it will no longer
be able to
produce its
effects

B. Agonist-bound receptors may be internalized by

Receptors linked with effector/second messenger endocytosis, removing them from further
protein exposure to extracellular molecules.
- Once the agonist is bounded to the
receptor, it will cause invagination in
the cell membrane, forming the
vesicle. Once inside the vesicle, it is
enclosed in an endosome and
undergoes digestion. Proteins are
then utilized for other processes in
cell.

 Ex: When a Nonsteroid hormone interacts with

the receptor it will cause the activation of GDP
protein will in turn activate adenine cyclase
enzyme which is responsible in cleaving your
ATP to produce cAMP. cAMP acta as a 2nd
messenger system resp in creating celluar
resp.

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Modified by: DAGAMI, RPh & PAMI, RPh. soon MD
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 Pharmacology and Therapeutics Lecture #2
PHARMACODYNAMICS
Dr. Esquivel | September 28, 2020

C. Continuous activation of the receptor-effector

system may lead to depletion of some essential
Tolerance = response to
substrate required for downstream effects. drug is changed than they
- For example, depletion of thiol cofactors may did at the beginning
be responsible for tolerance to nitroglycerin.
- In some cases, repletion of the missing Patient is no longer
substrate (e.g. by administration of
glutathione) can reverse the tolerance.
responding well to
nitroglycerin because of
D. Long-term reductions in receptor number depletion of thiol
(downregulation) may occur in response to
continuous exposure to agonists. The opposite
change (upregulation) occurs when receptor
activation is blocked for prolonged periods
(usually several days) by pharmacologic
antagonists or by denervation.

 So plateau of drug is not only caused by

saturation of the agonist but also the change
in receptor when bombarded with agonist
drug.

***END OF TRANSCRIPTION***

REFERENCES
 Katzung & Trevor’s Pharmacology
Examination & Board Review, 11th edition
 Katzung Basic & Clinical Pharmacology 12th
edition
 Doc Esquivel’s Lecture

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Modified by: DAGAMI, RPh & PAMI, RPh. soon MD
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