Pharmacodynamics &
Drug-Receptor Interactions
Dr. Ma. Fidelis Espiritu-Quiza, MD, FPCP
Two branches of Pharmacology:
 Pharmacokinetics
- “What the body does to the drug”
 Pharmacodynamics:
- “What the drug does to the body”
Mechanisms of Drug Action
 Primarily mediated by binding or coupling with drug
receptor (active or antagonize)
 Bind small molecules or ions that are found normally or
abnormally in the body
 Non-pharmacological colligative properties w/o a
requirement for highly specific chemical structure
 Counterfeit incorporation mechanism: certain drugs that
are structural analogs of normal biological chemicals
may be incorporated into cellular components and alter
their function
Concept of specific drug receptors
 Most drugs combine with specific sites on
macromolecules (e.g. cell membrane components,
enzymes, proteins) by precise physiochemical and
steric interactions between specific chemical groups of
the drug
 These sites are termed receptors
Drug Receptors
 Proteins – form the most important class of drug
receptors
- Receptors for hormones, growth factors,
transcription factors and neurotransmitters
- Enzymes of crucial metabolic or regulatory pathways
- Proteins involved in transport processes
- Secreted glycoproteins
- Structural proteins
 Nucleic acids
Types of Bonding of Drug to Receptors
 Ionic bonding (electrostatic)
 Hydrogen bonding
 Hydrophobic
 Van der Waals
 Covalent bonding – duration of action is frequently
prolonged (often irreversible)
 Multiple combination
Mechanism of Drug-Receptor Interaction
 Receptors that affect concentration of endogenous
ligands
 Drug receptors associated with extracellular processes
 Receptors utilized by anti-infective agents
 Receptors that regulate the ionic milieu
 Intracellular pathways activated by physiological
receptors
Receptors for Physiological Regulatory Molecules
 Physiological receptors bind to endogenous regulatory
ligands (hormones, neurotransmitters, growth factors)
and propagate its regulatory signal the target cell
 Two functions of a receptor:
- Ligand binding – ligand domain
- Message propagation (signaling) – effector domain
Receptors for Physiological Regulatory Molecules
 Regulatory actions of a receptor may be exerted directly
on its cellular target(s), effector protein(s) or may be
conveyed by intermediary cellular signaling molecules
called transducers
 Receptor-effector system or signal-transduction
pathway: receptor, cellular target and any intermediary
molecules
 Receptors and effector and transducer proteins also act
as integrators of information as they coordinate signals
from multiple ligands with each other and with metabolic
activities of the cell
 Receptors act as catalysts and hence are biochemical
signal amplifiers (especially if the receptor itself is the
enzyme)
 Proximal cellular effector protein is not always the
ultimate physiological target but may be an enzyme or
transport protein that creates, moves or degrades a
small metabolite or ion known as second messengers
 Second messengers diffuse in the proximity of their
binding sites and convey information to a variety of
targets
Structural and Functional Families of Physiological
Receptors
1. Ion channels
2. G Protein-coupled receptors (GPCR)
3. Transmembrane enzymes (enyme-linked receptors:
protein kinases and guanylyl cyclases)
4. Nuclear receptors
5. Transmembrane non-enzymes: protease-activated
receptor signaling
1. Ion Channels
a. Voltage-gated
- Activated by alterations in membrane voltage
- Ex. Voltage-gated Na channels open when
membrane is depolarized to a threshold potential
and contribute to further membrane depolarization
by allowing Na influx into the cell
b. Ligand-gated
- Activated after binding to specific ligands or drugs
- Many neurotransmitters and drugs activate
membrane-bound ligand ion-gated channels,
including several types of glutamate receptors
c. Store-activated
d. Stretch-activated
e. Temperature-activated channels

2. G-Protein Coupled Receptors (GCRP)

 Multiple GPCR subtypes differ from each other both in
ligand selectivity and in coupling to G proteins
 Compose a large class of membrane-bound receptors
 The structure of these receptors includes a common
seven-membered transmembrane domain
 Receptors linked to G proteins greatly amplify the
biologic signal – receptors activate the G proteins,
which in turn activate ion channels or, more
commonly, other enzymes (e.g., adenylate cyclase),
leading to stimulation of still other enzymes (e.g.,
protein kinase A)
 This amplification system, which generally involves an
extended duration of activation of the G protein
relative to the binding of drug to the receptor, may
explain why maximal pharmacologic effects are often
observed when only a small proportion of receptors
are activated
 Concept of “spare receptors”
3. Transmembrane Receptors Linked to Intracellular
Enzymes
 Receptor tyrosine kinases
 Jak-STAT receptor pathway
 Receptor-serine-threonine kinases
 Toll-like receptors
 TNF-a receptors

Enzyme-linked receptors
 Enzyme-linked receptors have only one
transmembrane domain per protein subunit
 The enzymatic catalytic site is on the cytoplasmic side
of the receptor
 Dimerization of activated receptors provides the
conformational change required for expression of
enzymatic activity
Receptors that stimulate synthesis of cGMP
 Hormonal regulation of transmembrane guanylyl cyclases
and activation of sGC by NO
- Natriuretic peptide receptors: ligand-activated
guanylyl cyclases
- NO synthase and soluble guanylyl cyclase
Cytoplasmic Second Messengers
 Binding of a drug to a receptor may just simply provide
the first message in receptor signal transduction to
effector pathways
 The first messenger promotes the cellular production or
mobilization of a second messenger which initiates
cellular signaling through a specific biochemical pathway
 Cyclic AMP
- Activates cyclic AMP-dependent protein kinase
- Directly regulates the activity of plasma membrane
cation (CNG) channels
 Cyclic GMP
 Calcium
 Intracellular receptors
 Lipophilic substances capable of crossing the plasma
membrane may activate intracellular receptors: sex
steroids, mineralocorticoids, glucocorticoids, and thyroid
hormones

4. Nuclear Hormone Receptors

 Transcription factors
 Regulate the expression of genes controlling
numerous physiological processes
 Include receptors for circulating steroid hormones
(androgens, estrogens, thyroid hormone,
glucocorticoids and Vit D)
 Include receptors for a diverse group of fatty acids,
bile acid, lipids and lipid metabolites
 Important property: must bind their ligand, the
appropriate HRE (repetitive DNA sequences) and a
coregulatory to regulate their target genes
 Co-regulator: corepressor/ coactivator
Structure-Activity Relationship and Drug Design
 Affinity: strength of the reversible interaction between a
drug and its receptor
 Affinity and intrinsic activity of the drug are determined
by its chemical structure
 Stringent relationship: minor modifications in the drug
molecule may result in major changes in the
pharmacological properties based on altered affinity
 Exploitation of the structure-activity relationship leads to
development of new agents
- Develop a more favorable therapeutic index
- Enhanced selectivity among different cells or tissues
- More acceptable secondary characteristics than those
of the parent drug
- Chemical modification of the agonist may result in
development of an antagonist
- Modification of pharmacokinetic profiles
Theory and assumptions of drug-receptor interaction
 Combination or binding to receptor causes some event
which leads to the response
 Response to a drug is graded or dose-dependent
 Drug receptor interaction follows simple mass-action
relationship. i.e., only one drug molecule occupies each
receptor site and binding is reversible
 For a given drug, the magnitude of response is directly
proportional to the fraction of total receptor sites
occupied by drug molecules (i.e., the occupancy
assumption)
 The number of drug molecules is assumed to be much
greater than the number of receptor sites
 Combination of drug with a receptor produces a specific
response “Lock-and-key”.
 Drug-receptor interactions are analogous to enzyme-
substrate interactions. Most of the same principles
apple.
 Endogenous ligands (e.g., encephalin versus morphine)
 Drugs without specific receptors (e.g., gaseous
anesthetics)
 Drug-receptor interactions with characteristics outlined
above can treated with an equation analogous to the
Michaelis Menten equation utilized for enzyme-
substrate interactions
Quantification of Drug-receptor Interactions and
Effects
 Defined by the dose-response curve
 EC50: concentration that produces half maximal effect
 Hormesis:
- Low-dose stimulation, high-dose inhibition
- U-shaped dose response curve
 Potency: potent drugs are those which elicit a
response by binding to a critical number of a particular
receptor type at low concentration compared with other
drugs acting on the same system and having lower
affinity
 More drug is required to bind to the same member of
receptors
Terminology
 Terms which indicate ability of drug to bind to receptor
- Potency
- Affinity
- KD or ED50: corresponds to Km in Michaelis-Menten
analogy
 Terms which indicate ability of drug to produce a
response
- Efficacy
- Power
- Intrinsic activity: corresponds to Vmax in Michaelis-
Menten analogy
Agonists (or Full Agonists)
 Drugs that occupy receptors and bring about a full or
maximal response
 The maximal response is usually defined as that
produced by the most powerful agonists, or that
produced by a drug associated classically with the
response

Partial Agonists
 Drugs that occupy receptors but bring about less than
the maximum response
 These drugs are less powerful and 100% occupancy
produces a lesser response (corresponds to substrates
with a lower Vmax in enzyme analogy)
Antagonists
 Drugs that occupy or change the receptor but does not
cause any response
 Occupancy by an antagonist interferes with occupancy
by a drug capable of causing a response

General Types of Drug Interactions

1. Antagonism, Pharmacological Competitive or
Surmountable
2. Non-competitive or Non-surmountable
3. Additive
4. Synergism

1. Antagonism, Pharmacological Competitive or

Surmountable
 The antagonist reversibly competes for or displaces the
agonist from the preceptor
 Since occupancy by an antagonist produces no
response, the action of the agonist is blocked
 Higher concentrations of agonist, however, can
overcome this competition and restore the full response
 In the presence of a competitive antagonist, there is no
change in maximal response; but the log dose-
response curve is shifted towards higher concentrations
of the drug (shifted to the right)
Classification of Chemical Interactions  The apparent potency of the drug is reduced in the
 Additive presence of a competitive antagonist but maximal
 Synergistic efficacy is unchanged
 Potentiation  The effectiveness of a competitive antagonist depends
 Antagonism on its affinity for the receptor site relative to the affinity
- Functional (physiological) of the agonist
- Chemical (inactivation)
- Dispositional
- Receptor

2. Antagonism, Non-Competitive or Non-
Surmountable
 The antagonist changes the receptor to decrease
the efficacy of the agonist or irreversibly blocks the
agonist from combining with the receptor
 The potency of a noncompetitive antagonist
depends on its affinity to its binding site and is
independent of the dose of agonist and the relative
affinity of the agonist
 The effect is the same as eliminating a certain
fraction of total receptors from the response
 The maximum response (Emax) to the agonist
(power) is reduced, but potency remains the same
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 >20 units
Antagonism, Physiological
 Defined as the antagonism that results when two drugs
produce opposite effects by interacting with two
separate receptor systems
 E.g., the effect of acetylcholine on muscarinic receptors
causing bronchoconstriction and salbumatol on beta
receptors causing bronchodilation
Antagonism, Chemical
 The antagonism of the effect of a drug by another agent
as a result of chemical interaction
 E.g., EDTA (a chelating agent) and lead
Antagonism, Dispositional
 The antagonism results in the alteration of the
disposition of a substance so that less of the agent
reaches the target organ or its persistence there is
reduced
 E.g., concomitant antacid an acid milieu for GI
absorption
Antagonism, Receptor
 Blockade of the effect of an agonist with an appropriate
antagonist that compete for the same receptor size
 E.g., Flumazenil is used as antidote to benzodiazepine
(diazepam) toxicity
Potentiation
 Increased effect of a toxic agent acting simultaneously
with a nontoxic agent
 A certain dose of Drug A alone produces an effect
equal to 10 units. A certain dose of drug B alone
produces no effect
 Administration of the same doses of A and B
simultaneously produces the effect of drug A equal to
>10 units
Regulation of Receptors
 Modulating inputs may come from other receptors
 Receptors are subject to feedback regulation
 Regulation of synthesis of the receptor
 Regulation of the degradation of the receptor
- Covalent modification
- Association with either regulatory proteins
- Relocation within the cell
Receptor regulation
A. Sensitization or Up-regulation
- Prolonged/ continuous use of receptor clocked or
antagonist
- Inhibition of synthesis or release of
hormone/neurotransmitter – Denervation
B. Desensitization or Down’s syndrome
- Prolonged/ continuous use of agonist
- Inhibition of degradation or uptake of agonist
Diseases Resulting from Receptor Malfunction –
Aberrant receptors
 Transformation of normal cells to malignant cells
- Retinitis pigmentosa
- Precocious puberty
- Malignant hyperthyroidism
 Mutation of receptors – alter responsiveness – rate and
extent
Other Mechanisms of Drug Action
 Disrupting of structural enzymes
- Vinca alkaloids for cancer
- Colchicine for gout
 Functioning as enzymes
- Streptokinase for thrombolysis
 Covalently linking to macromolecules
- Cyclophospamide for cancer
 Reacting chemically with small molecule
- Antacids for dyspnea due to gastric acids
 Binding free molecules or atoms
- Chelators (drug for removal of systemically
absorbed heavy metals)
- Infximab (anti-TNF agent)
 Being nutrients
- Vitamins and minerals
 Exerting actions due to physical properties
- Mannitol (serving as osmotic agents, lavatives)

Regulation of receptors
 Tachyphylaxis: continued stimulation of cells with
agonists resulting in a state of desensitization
(adaptation, refractoriness, down-regulation) such that
the effect that follows continued or subsequent
exposure to the same concentration of drug is
diminished
 Desensitization: may be the result of
- Temporary inaccessibility of the receptor to agonist
(internalization of cell surface receptors)
- Results from synthesis of fewer receptors
- Fewer receptors available at the cell surface
 Homologous desensitization: feedback inhibition of
signaling limited to output only from the stimulated
receptor
 Heterologous desensitization: regulation extending to
the action of all receptors that share a common
signaling pathway

Diseases Resulting from Receptor Malfunction –

Deficiencies in Signaling
 Genetic deficiency of the androgen receptor in the
testicular fermininization syndrome
- Myasthenia gravis
- Insulin-resistant DM
- Pseudohypoparathyroidism