Pharmacology | Block 1.

3
Pharmacodynamics
Dr. Penecilla | August 17 and 22, 2023 | 7:30-9:30
Trans group: Delfin, Flores, Gadayan, Barranco

Notes:

• Allosteric Modulators: bind to a

Outline different site on the receptor than that
I. Pharmacodynamics bound by endogenous ligands; such
II. Receptors drugs can produce useful and quite
III. Macromolecular Nature of Drug Receptors different clinical effects.
IV. Drug-Concentration – Response Relationship
V. Receptor-Effector Coupling and Spare The Nicotinic Acetylcholine (ACh) Receptor
Receptors
VI. Signaling Mechanisms
VII. Basic Mechanisms of Transmembrane
Signaling
VIII. Family of Receptors
IX. Second Messengers
X. Interplay Among Signaling Mechanisms
XI. Receptor Classes and Drug Development

PHARMACODYNAMICS
• “Action of the drug on the body.”
• Receptors, Mechanism of action,
Therapeutic and Adverse effects.
• Importance: Drug development and
therapeutic decisions in clinical practice.
Effector
RECEPTORS
• Specific molecules in a biologic system • Molecules that translate the drug-receptor
with which drugs interact to produce interaction into a change in cellular activity
changes in the function of the system
• E.g., enzymes - adenylyl cyclase
• Selective
• Modifiable
MACROMOLECULAR NATURE OF DRUG
The Receptor Concept RECEPTORS
1. Receptors largely determine the
quantitative relations between dose or • Orphan Receptors - Natural ligands are
concentration of drug and presently unknown, and may be useful
pharmacologic effects.
2. Receptors are responsible for targets in the future for drug development.
selectivity of drug action. • Regulatory Proteins - best characterized
3. Receptors mediate the actions of drug receptors, mediate the actions of
pharmacologic agonists and endogenous chemicals such as
antagonists. neurotransmitters, autacoids, hormones
• Agonists: activate the receptor to e.g., GABA receptors (benzodiazepines).
signal as a direct result of binding to it.
• Enzymes - may be inhibited by binding a
• Antagonists: bind to receptors but do
not activate generation of a signal; drug e.g., dihydrofolate reductase
consequently, they interfere with the (methotrexate); HMG-CoA reductase
ability of an agonist to activate the (statins)
receptor.
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Dr. Penecilla slides
Past trans
Notes:

• Transport proteins – useful drug targets • Chemical antagonist - A drug that

e.g., Na+/K+ ATPase (Digitalis) counters the effects of another by binding
• Structural proteins – also important drug the agonist drug (not the receptor)
targets e.g., tubulin (colchicine) • Allosteric agonist, antagonist - A drug
that binds to a receptor molecule without
Other Key Terms: interfering with normal agonist binding but
• Inert binding molecule or site - A alters the response to the normal agonist.
molecule to which a drug may bind without • Partial agonist - A drug that binds to its
changing any function. receptor but produces a smaller effect
• Receptor site - Specific region of the (Emax) at full dosage than a full agonist.
receptor molecule to which the drug binds. • Constitutive activity - Activity of a
• Coupling - overall transduction process receptor-effector system in the absence of
that links drug occupancy of receptors and an agonist ligand.
pharmacologic response. • Inverse agonist - A drug that binds to the
• Spare receptor - Receptor that does not inactive state of a receptor molecule and
bind drug when the drug concentration is decreases constitutive activity.
sufficient to produce maximal effect;
present if ~ > EC50.
• Agonist - A drug that activates its receptor
upon binding.
• Biased agonist - An agonist that activates
the same receptor as other drugs in its
group but also causes additional
downstream effects that are not seen with
other agonists in the group.
• Pharmacologic antagonist - A drug that
binds to the receptor without activating it
and thereby prevents activation by an
agonist.
• Competitive antagonist - A
pharmacologic antagonist that can be
overcome by increasing the concentration
of agonist.
• Irreversible antagonist - A pharmacologic
antagonist that cannot be overcome by
increasing agonist concentration.
• Physiologic antagonist - A drug that
counters the effects of another by binding
to a different receptor and causing
opposing effects.

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Notes:

● Graded dose-response curve - A graph

of the increasing response to increasing
drug concentration or dose.
● Quantal dose-response curve - A graph
of the increasing fraction of a population
that shows a specified response at
progressively increasing doses.
● EC50 - in graded dose-response curves,
the concentration that causes 50% of the
maximal effect. In quantal dose-response
curves, the concentration that causes a
specified response in 50% of the
population under study.
● TD50 – in graded dose-response curves,
the dose that causes 50% of the toxicity. In
quantal dose-response curves, the dose
that causes a specified response in 50% of
the population under study.
● Kd - The concentration of drug that binds
50% of the receptors in the system.
● Efficacy, maximal efficacy - the largest
effect that can be achieved with a
particular drug, regardless of dose, Emax.
● Potency - the amount or concentration of
drug required to produce a specified effect,
usually EC50 or ED50.

DRUG-CONCENTRATION – RESPONSE
RELATIONSHIP

Concentration-Effect Curves and Receptor

Binding of Agonists

● E - effect observed at C.
● C – concentration.
● Emax -maximal response that can be
produced by the drug.
● EC50 - concentration of drug that produces
50% of maximal effect.

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Notes:

● A – agonist response in the absence of

antagonists.
● B - After treatment with a low concentration
of antagonist, the curve is shifted to the
right. Maximal responsiveness is
● B - drug bound to receptors. preserved, however, because the
● C - concentration of free (unbound) drug. remaining available receptors are still in
● Bmax - indicates the total concentration of
excess of the number required.
receptor sites (i.esites bound to the drug at
● C - produced after treatment with a larger
infinitely high concentrations of free drug).
concentration of antagonist, the available
● Kd (the equilibrium dissociation constant) receptors are no longer “spare”; instead,
represents the concentration of free drug at they are just sufficient to mediate an
which half-maximal binding.
undiminished maximal response.
● D & E - higher concentrations of
Receptor’s Affinity for Binding the Drug in a
antagonists reduce the number of available
Reciprocal Fashion receptors to the point that maximal
● If the Kd is low = binding affinity is high.
response is diminished. The apparent
● The EC50 and Kd may be identical but
EC50 of the agonist in curves D and E may
need not be.
approximate the Kd that characterizes the
binding affinity of the agonist for the
receptor.

RECEPTOR-EFFECTOR COUPLING AND

SPARE RECEPTORS

● Coupling - overall transduction process

Logarithmic transformation of the dose axis
and experimental demonstration of spare
receptors, using different concentrations of an
irreversible antagonist
that links drug occupancy of receptors and
pharmacologic response. The relative
efficiency of occupancy- response coupling
is determined, in part, at the receptor itself.
Determined by “downstream” biochemical
events that transduce receptor occupancy
into cellular response.

Spare Receptors (aka Receptor Reserve)

● Receptors are said to be “spare” for a
given pharmacologic response if it is
possible to elicit a maximal biologic
response at a concentration of agonist that
does not result in occupancy of all of the
available receptors.

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Notes:

Emax for the agonist remains the same for

any fixed concentration of antagonist.

Changes in agonist concentration-effect Agonist dose-response curves in the presence

curves produced by a competitive antagonist of competitive and irreversible antagonists
(A) or by an irreversible antagonist (B)
● In the presence of a competitive
antagonist, higher concentrations of
agonists are required to produce a given
effect; thus, the agonist concentration (C′)
required for a given effect in the presence
of concentration [I] of an antagonist is
shifted to the right, as shown. High agonist
concentrations can overcome inhibition by
a competitive antagonist. This is not the
case with an irreversible (or Effect of Partial Agonist
noncompetitive) antagonist, which reduces
the maximal effect the agonist can achieve, ● A: The percentage of receptor occupancy
although it may not change its EC50. resulting from full agonist (present at a
single concentration) binding to receptors
in the presence of increasing
Competitive and Irreversible Antagonists concentrations of a partial agonist.
● In the presence of a fixed concentration of Because the full agonist (blue line) and the
agonist, increasing concentrations of a partial agonist (green line) compete to bind
competitive antagonist progressively inhibit to the same receptor sites, when
the agonist response; high antagonist occupancy by the partial agonist increases,
concentrations prevent the response binding of the full agonist decreases.
almost completely. Conversely, sufficiently ● B: When each of the two drugs is used
high concentrations of agonist can alone and response is measured,
surmount the effect of a given occupancy of all the receptors by the
concentration of the antagonist; that is, the partial agonist produces a lower maximal

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Notes:
response than does similar occupancy by
the full agonist.
● C: Simultaneous treatment with a single
concentration of full agonist and increasing
concentrations of the partial agonist
produces the response patterns shown in
the bottom panel. The fractional response
caused by a single high concentration of
the full agonist decreases as increasing
concentrations of the partial agonist
compete to bind to the receptor with
increasing success; at the same time, the
portion of the response caused by the
partial agonist increases, while the total
response—i.e., the sum of responses to
the two drugs (red line)—gradually
decreases, eventually reaching the value
produced by partial agonist alone
(compare with B).
BASIC MECHANISMS OF TRANSMEMBRANE
Other Mechanisms of Antagonism
● Physiologic antagonist - A drug that
counters the effects of another by binding
to a different receptor and causing
opposing effects. E.g., glucocorticoid
(hyperglycemia) & insulin.
● Chemical antagonist - A drug that
counters the effects of another by binding
the agonist drug (not the receptor). E.g.,
Heparin (negatively charged) & Protamine
(positively)
SIGNALING MECHANISMS
● Why do some drugs produce effects that
persist for minutes, hours, or even days
after the drug is no longer present?
● Why do responses to other drugs diminish
rapidly with prolonged or repeated
administration?
● How do cellular mechanisms for amplifying
external chemical signals explain the
phenomenon of spare receptors?
● Why do chemically similar drugs often
exhibit extraordinary selectivity in their
actions?
● Do these mechanisms provide targets for
developing new drugs?
SIGNALING
1. Lipid-soluble ligand that crosses the
membrane and acts on an intracellular
receptor
2. Transmembrane receptor protein whose
intracellular enzymatic activity is
allosterically regulated by a ligand that binds
to a site on the protein’s extracellular
domain
3. Transmembrane receptor that binds and
stimulates an intracellular protein tyrosine
kinase
4. Ligand-gated transmembrane ion channel
that can be induced to open or close by the
binding of a ligand
5. Transmembrane receptor protein that
stimulates a GTP-binding signal transducer
protein (G protein), which in turn modulates
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Notes:

production of an intracellular second ▪ All of these hormones

messenger produce their effects after a
characteristic lag period of
30 minutes to several
hours—the time required for
the synthesis of new
proteins.
▪ The effects of these agents
can persist for hours or days
after the agonist
concentration has been
reduced to zero.
Fig. 1.1 Signaling Mechanisms for Drug Effects

FAMILY OF RECEPTORS

1. Intracellular Receptors for Lipid-Soluble

Agents
o Several biologic ligands are Fig. 1.2 Mechanism of Glucocorticoid Action
sufficiently lipid-soluble to cross the
plasma membrane and act on
intracellular receptors. 2. Enzyme-linked receptors
o Includes steroids (corticosteroids, o Ligand-Regulated
mineralocorticoids, sex steroids, Transmembrane Enzymes
vitamin D) and thyroid hormones Including Receptor Tyrosine
▪ Receptors stimulate the Kinases
transcription of genes by ▪ Mediates the first steps in
binding to specific DNA signaling by insulin,
sequences (often called epidermal growth factor
response elements) (EGF), platelet-derived
o The mechanism used by hormones growth factor (PDGF), atrial
that act by regulating gene natriuretic peptide (ANP),
expression has two therapeutically transforming growth factor-β
important consequences:

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Notes:

(TGF-β), and many other

trophic hormones.
▪ These receptors are
polypeptides consisting of an
extracellular hormone-binding
domain and a cytoplasmic
enzyme domain, which may be
a protein tyrosine kinase, a
serine kinase, or a guanylyl
cyclase

Fig. 1.4 Cytokine Receptors

3. Ion Channels
o Most useful drugs in clinical medicine
act on ion channels.
o For ligand-gated ion channels, drugs
often mimic or block the actions of
natural agonists.
o Natural ligands include acetylcholine,
serotonin, GABA, and glutamate; all are
Fig. 1.3 Mechanism of Activation of the Epidermal Growth Factor
synaptic transmitters
(EGF) receptor
o Each receptor transmits its signal
o Cytokine Receptors across the plasma membrane by
▪ Respond to a heterogeneous increasing transmembrane
group of peptide ligands, which conductance of the relevant ion, altering
include growth hormone, the electrical potential across the
erythropoietin, several kinds of membrane.
interferon, and other regulators o The nAChR is one of the best
of growth and differentiation. characterized of all cell-surface
▪ Use a mechanism closely receptors for hormones or
resembling that of receptor neurotransmitters
tyrosine kinases, except the
protein tyrosine kinase activity
is not intrinsic to the receptor
molecule.

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Notes:

Fig. 1.5 The Nicotinic Acetylcholine (ACh) Receptor

4. G Protein-coupled receptors
o Many extracellular ligands act by
increasing the intracellular
concentrations of second messengers
o They mostly use a transmembrane
signaling system with three separate
Fig. 1.6 G Protein-coupled Receptors
components.
▪ First, the extracellular ligand is
selectively detected by a cell-
surface receptor.
▪ The receptor in turn triggers the
activation of a GTP-binding
protein (G protein) located on
the cytoplasmic face of the
plasma membrane.
▪ The activated G protein then
changes the activity of an
effector element, usually an
enzyme or ion channel
changing the concentration of
the intracellular second
messenger

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Notes:

SECOND MESSENGERS o Conservation of water by the

kidney (mediated by
1. Cyclic Adenosine Monophosphate vasopressin)
(cAMP) o Ca2+ homeostasis
• Signaling Pathway (regulated by parathyroid
hormone)
o Increased rate and
contractile force of heart
muscle (β-adrenomimetic
catecholamines).
o Regulation of the production
of adrenal and sex steroids
(in response to corticotropin
or follicle-stimulating
hormone)
o Relaxation of smooth muscle

2. Phosphoinositides and Calcium

• Signaling Pathway
o Rec - hormone receptors
o Gs - stimulatory G protein
o AC - catalytic adenylyl
cyclase
o PDE - Phosphodiesterases
(PDE) – hydrolyze cAMP
o cAMP-dependent kinases
o R - regulatory subunit
o C – catalytic subunits
o S - protein substrates of the
kinases
o P’ase – phosphatases o R - hormone receptors
(remove phosphates from o G - protein (G)
substrate proteins) o PLC - phosphoinositide-
specific phospholipase C
o S - protein kinase C
• cAMP-mediated responses substrates of the kinase
o Mobilization of stored energy o CaM - calmodulin
(breakdown of o E – calmodulin-binding
carbohydrates in liver or enzymes (including kinases,
triglycerides in fat cells phosphodiesterases, etc.)
stimulated by β- o PIP2 - phosphatidylinositol-
adrenomimetic 4,5-bisphosphate
catecholamines) o DAG - diacylglycerol
o IP3 - inositol trisphosphate

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Notes:
3. Cyclic Guanosine Monophosphate
(cGMP)
INTERPLAY AMONG SIGNALING
MECHANISMS
• Isolation of signaling mechanisms – e.g.,
calcium signaling in the heart
• Reversible phosphorylation in almost all
second messenger signaling
o Amplification
o Flexible regulation – differing
substate specificities e.g.,
TKI
▪ Trastuzumab – Her2
(Breast ca)
▪ Imatinib – Abl (CML)
RECEPTOR CLASSES AND DRUG
DEVELOPMENT
• Existence of a specific drug receptor is
usually inferred from studying the
structure-activity relationship of a group
of structurally similar congeners of the drug
that mimic or antagonize its effects.
Receptor Regulation
1. Upregulation – long term increase in
receptor number, may occur when receptor
activation is blocked for prolonged periods
by pharmacologic antagonists or by
denervation.
2. Downregulation - Long-term reductions in
receptor number, may occur in response to
continuous exposure to agonists
Relation Between Drug Dose & Clinical
Response
1. Graded dose-response curve - A graph of
the increasing response to increasing drug
concentration or dose
• Maximal efficacy - the largest effect that can
be achieved with a particular drug,
regardless of dose, Emax
• Potency - the amount or concentration of
drug required to produce a specified effect,
usually EC50 or ED50
• EC50 - the concentration that causes 50%
of the maximal effect
• ED50 - the dose that causes 50% of the
maximal effect
• TD50 – in graded dose-response curves,
the dose that causes 50% of the toxicity
2. Quantal dose-response curve - A graph of
the increasing fraction of a population that
shows a specified response at progressively
increasing doses
• EC50 - the concentration that causes a
specified response in 50% of the population
under study
• ED50 - the dose that causes a specified
response in 50% of the population under
study
• TD50 – median toxic dose, the dose that
causes a specified response in 50% of the
population under study
• LD50 – medial lethal dose, the
concentration of drug that binds 50% of the
receptors in the system
• Therapeutic Index - relates the dose of a
drug required to produce a desired effect to
that which produces an undesired effect
“The dose that will heal over the
dose that will kill”
• Therapeutic Window - the range between
the minimum toxic dose and the minimum
therapeutic dose
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Notes:

Pharmacogenetics - study of genetic factors

determining drug response
Personalized or precision medicine - the use of
gene sequencing or expression profile data to
tailor therapies specific to an individual patient is
called
Clinical Selectivity: Beneficial versus Toxic
Effects of Drugs

• Beneficial or therapeutic effects

• Toxic or adverse effect
• Side effect – term used by pharmaceutical
Variations in Drug Responsiveness advertisements and prescribers implying
• Idiosyncratic response – unusual; one that the effect in question is insignificant or
that is infrequently observed in most occurs via a pathway that is to one side of
patients, usually caused by genetic the principal action of the drug; implications
differences in metabolism of the drug or by are frequently erroneous
immunologic mechanisms (e.g., allergic
reactions) A. Beneficial and toxic effects mediated by
• Hyporeactive/Hyperreactive response - the same receptor-effector mechanism
intensity of effect of a given dose of drug is (extension of pharmacologic effect – e.g.,
diminished or increased compared with the insulin & hypoglycemia)
effect seen in most individuals B. Beneficial and toxic effects mediated by
• Hypersensitivity - allergic or other identical receptors but in different tissues
immunologic responses to drugs or by different effector Pathways (e.g.,
glucocorticoids)
• Tolerance – responsiveness usually
C. Beneficial and toxic effects mediated by
decreases as a consequence of continued
different types of receptors (e.g., opioids)
drug administration
• Tachyphylaxis – responsiveness
diminishes rapidly after administration of a
drug
Mechanisms Contributing to Variation in Drug
Responsiveness
A. Alteration in concentration of drug that
reaches the receptor
B. Variation in concentration of an
endogenous receptor ligand
C. Alterations in number or function of
receptors
D. Changes in components of response distal
to the receptor

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