FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

Pharmacology A – 1.2
LECTURER: JESSICA OÑA-CRUZ, MD, MHPED, FPOGS
PHARMACODYNAMICS MEDISINA 2019

OUTLINE  Note that drug-receptor binding is usually a mixture of several

I. DRUG-RECEPTOR INTERACTION types of bonds
II. PHARMACODYNAMICS  Generally, the weaker bond types make up most of the drug-
receptor binding (i.e., van der Waals + hydrogen bonds)
 Example 1: Observed in platelet aggregation-blocking effect of
OBJECTIVES aspirin that lasts even after free acetylsalicylic acid has
o Describe the four major types of receptors disappeared from the bloodstream (about 15 minutes) 
o Describe the different types of receptor intrinsic activities Reversed only by the synthesis of new enzymes that takes
o Explain potency & efficacy several days
o Explain signal amplification ◌ Aspirin has the ability to inhibit cyclooxygenase resulting to
o Discuss the phenomenon of tachyphylaxis the inhibition of prostaglandin (for inflammation) &
thromboxane (for clotting) synthesis
 Example 2: the S enantiomer of warfarin is several times more
PHARMACODYNAMICS potent than the R enantiomer because of a better fit between
 Describes the actions of a drug on the body & includes the the S form & the binding site of the receptor: vitamin K epoxide
principles of receptor interactions, mechanisms of therapeutic & reductase
toxic action & dose-response relationship  Some binding sites are very specific that the strongest bond is
only formed with one stereoisomeric form of a drug
CONFORMATION & CHEMISTRY OF DRUGS & RECEPTORS  Interaction of a drug with its receptor is the fundamental event
RECEPTOR that initiates the actions of the drug
 Macromolecule typically made of proteins that interacts with
either an endogenous ligand or a drug to mediate a IMPACT OF DRUG BINDING ON THE RECEPTOR
pharmacologic or physiologic effect
 Two main functions of receptor:
◌ Ligand binding
◌ Activation of effector system (message propagation)
 Component of a cell or organism that interacts with a drug &
initiates the chain of events leading to the drug’s observed
effects
 Must be selective in their ligand-bind characteristics (so as to
respond to the proper chemical signal & not to meaningless
ones)  In many cases, when a drug binds to its receptor, conformation
 Must also be modifiable when they bind a drug molecule (so as changes occur in the binding site 
to bring about the functional change)  Some drugs however prevent binding of endogenous ligands to
 Receptor site (also known as the recognition site or binding site) their receptors without producing such changes
for a drug is the specific binding region of the receptor  When a drug interacts with a receptor, conformation changes
macromolecule & has a relatively high & selective affinity for the occur in the binding site which sometimes alters the receptor’s
drug molecule affinity to the drug
 Receptor Site – specific region of the receptor molecule to which  When receptor changes increases drug affinity, this is called an
the drug binds “induced fit” because the conformation changes in the receptor
◌ Made up of amino acids arranged in 3D orientation (so- enhanced drug-receptor binding quality & changes receptor
called conformation) action as well
 Receptors exist in at least two states or conformation:
◌ Open (Active) DRUG-RECEPTOR INTERACTION & THE CELL MEMBRANE
◌ Closed (Inactive) Receptor Structure
◌ Refractory State (3rd state for other cells such as neurons)  Binding affinity of Receptors is determined by:
□ State wherein receptors do not respond to a ◌ Receptor structure
ligand/drug  Similar to the refractory phase of AP ◌ Location of receptor
 The chemical interaction that occurs between the drug molecule  Structure varies in different locations:
& the binding site governs how tight the drug & receptor ◌ Proteins receptors with large lipophilic areas are seen in the
interaction plasma membrane
RELATIVE STRENGTH OF BONDS BETWEEN RECEPTORS & DRUGS ◌ Receptors that transverse the entire cell membrane have:
BOND TYPE BOND STRENGTH □ Lipophilic areas penetrating the cell membrane
Van der Waals + □ Hydrophilic areas which are exposed at bond ends in
Hydrogen ++ contact with the intracellular & extracellular spaces
Ionic +++ ◌ Receptors with hydrophilic areas only are typically seen in
Covalent ++++ the cytoplasm or nucleus
 If chemical interaction results to covalent binding between a
drug & a receptor, this is often irreversible

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 1 of 11
 PHARMACODYNAMICS Pharmacology A

Drug Structure  D+R = opening of channel to let ions enter cell & stimulate effects
 Determines how it reaches the receptor  Ligand (molecule or drug) binding to the channel controls the
 Hydrophilic ligands interact with receptors that are found on the conductance of ions across the channel
cell surface
 Hydrophobic ligands enter cells through the lipid bilayers of the Voltage-Gated Channels
cell membrane or utilize the transmembrane channels to
interact with receptors found inside the cell (i.e., cytoplasm or
nucleus)

MEMBRANE EFFECTS ON DRUG-RECEPTOR INTERACTIONS

 Upon binding to receptors, drugs or ligands can change or
modify the shape of receptors on the cell surface & affect
intracellular functions
 Receptor changes after drug binding:
◌ When change occurs in the extracellular domain of a
receptor, there are resulting changes in conformation or  D + R = change in voltage gradient causing opening of ion
shape of the transmembrane portion as well as the channels which enable it to elicit effect
intracellular domain on the cytoplasm which causes  Voltage gradient across membrane controls the ion conductance
changes in the function of that receptor
◌ Formation of a dimer which in turn activates intracellular Second-Messenger Regulated
molecules  D + R = Activation of 2nd messenger which in turn activates
opening of a channel letting ions pass through
MAJOR TYPES OF DRUG RECEPTORS
 Movement of ions across the channel is determined by ligands
binding to plasma membrane receptor linked to the channel
 cAMP is usually the 2nd messenger

State Dependent Ion Channel Blockade

 Channels are selective for the ions they conduct (Na channels are
only for Na)
 Nevertheless, most of them have similarities in structure, size of
conductance & mechanism of activation or inactivation
 There are several conformation states that these ion channels
undergo:
◌ Open – active
Transmembrane Ion Channels
◌ Closed – inactive
 Site of Drug-Receptor Interactions: Extracellular, Intracellular or ◌ Refractory – during this state, the channel cannot be
Intrachannel reactivated for a short time (milliseconds) even if the
 Site of Consequent Action: Cytoplasm membrane accumulates a voltage that usually is able to
 These regulate processes which necessitate passage of ions or trigger opening
molecules across the plasma membrane  Drugs have different binding affinities depending on their
 These channels have several roles including neurotransmission, conformational state
cardiac conduction & muscle contraction  Exemplified by class III anti-arrhythmic drugs who have greater
 Drugs that act on such receptors have great effect on important affinity to active conformation receptors which are only present
body functions in arrhythmic cardiac cells (receptors in normal cells are usually
 There are three main types of these ion channels depending on closed or refractory so they will not be targeted)
the mechanisms by which they are regulated:
◌ Ligand-gated channels SUMMARY OF MAJOR TYPES OF TRANSMEMBRANE ION CHANNELS
◌ Voltage-gated channels CHANNEL
MECHANISM OF ACTIVATION FUNCTION
◌ Second messenger-regulated TYPE
 Examples: Benzodiazepines & Local Anesthesia Altered Ion
Ligand-gated Binding of ligand to channel
Conductance
Ligand-Gated Channels Change in transmembrane Altered Ion
Voltage-gated
voltage gradient Conductance
Binding of ligand to Second
Second transmembrane receptor messenger
messenger- with G protein-coupled regulates ion
regulated cytosolic domain, leading to conductance of
second messenger generation channel

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 2 of 11
 PHARMACODYNAMICS Pharmacology A

Transmembrane G protein-coupled receptors Enzyme-Linked Receptors

 Span the thickness of cell membrane with:
◌Extracellular domain containing the ligand (drug) binding
area
◌ Intracellular domain (when activated) interacts with a G
protein or effector molecule
 Most abundant of all body receptors & are involved in important
processes such as neurotransmission, olfaction & vision
Steps
1. Drug binds to the extracellular region of the receptor
2. Binding causes conformation changes on the receptor that
exposes G protein binding site
3. GDP, which is originally bound to the  subunit (inactive) will
dissociate & be replaced by GTP forming -GTP (active)
4. GTP binding to  subunit will cause it to dissociate from 
subunits & they subsequently diffuse along the inner surface of
the cell membrane to interact with several receptors:
 AKA Transmembrane receptors with enzymatic cytosolic
domains
 These are transmembrane receptors that convert (transduce)
extracellular ligand-binding interaction into intracellular events
via stimulation of associated enzymes
 When activated, these receptors undergo conformational
changes resulting in increased cytosolic enzyme activity
depending on their structure & function
 These receptors have roles in cellular metabolism, growth &
tissue differentiation
 Span the cell membrane only once VS. transmembrane G
protein-coupled receptors who span the membrane seven times
 Many of these receptors form dimers or many subunits
complexes for signal transduction
 Most are involved I phosphorylation type of signaling – changing
proteins by reversibly adding or removing phosphate groups to
the main moiety of an enzyme or protein causing changes in the
protein’s effect or action
 There are five subclasses of these receptors based on their
actions in the cytoplasm
◌ Receptor Tyrosine Kinase
◌ Receptor Tyrosine Phosphatases
◌ Tyrosine Kinase – Associated Receptors
◌ Receptors Serine Threonine
◌ Receptors Guanylyl Cyclase
Receptor Tyrosine Kinase

 Largest subgroup under this class

 D + R (extracellular end) = initiates phosphorylation of tyrosine
residues on the cytoplasmic area of the receptor causing the
start of a cascade of signaling events within the cell
 If effector is adenylyl cyclase  conversion of ATP to cAMP  Example: Insulin
occurs
Receptor Tyrosine Phosphatases

 If effector is phospholipase C  cleavage of phosphatidyl

 Take away phosphate groups from particular tyrosine residues
inositol to DAG & IP3 occurs
to trigger intracellular biochemical mechanisms
5. Dissociation of drug from receptor returns it to original
 Regulators of immune cell activation
conformation

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 3 of 11

Tyrosine Kinase-Associated Receptors/Cytokine Receptors
 AKA nonreceptor tyrosine kinases or cytokine kinases
 Do not have an inherent catalytic activity
 Often located in the surface of the cell membrane
 (+) initiation of events in the cell similar to those that occur with
tyrosine kinases  only difference between this receptor &
receptor tyrosine kinase is that it is nonreceptor tyrosine kinases
that get activated
 Also involved in immune cells
Receptor Serine/Threonine Kinases
 Exemplified by members of the transforming growth factor 
receptor family (TGF ) which are involved in cell growth
regulation & differentiation
 Associated with progression & spread of cancer
 Phosphorylate serine & threonine residues on target proteins in
the cytoplasm
 No clinical agents have been made yet for this receptor
Receptor Gunanylyl Cyclase
 Represent the smallest number of transmembrane receptors
 Exemplified by B-type natriuretic peptide which is secreted by
the ventricles in response to volume overload
 Unlike the other receptor types, they are activated directly by its
ligand without any intervening G protein
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed
PHARMACODYNAMICS Pharmacology A
Intracellular Receptors
 Differ considerably from the other three in that the receptors is
entirely intracellular, & therefore, the ligand must diffuse into
the cell towards the cytosol to interact with the receptor
 In order to move across the target cell membrane, the ligand
should be lipophilic so it can easily pass through the cell
membrane
 Play a role in regulation of transcription of DNA & translation of
RNA
 Time course of activation & response of these receptors take
hours to days  drugs from these particular ligands have a
longer onset & duration of effect than other agents
 For example, steroid hormones exert their action on target cells
via intracellular receptors
 Other intracytosolic structures (structural proteins, enzymes,
RNA & ribosomes) can also be considered as belonging to other
type of receptors
 Examples include:
◌ Structural proteins or tubulin is the target of antineoplastic
agent such as paclixactel
◌ RNA or ribosomes can also be the target for anticancer or
antimicrobial effects
◌ Vitamin K epoxide reductase which is an intracytosolic
target for warfarin
PROCESSING & INTEGRATION OF SIGNALS
FROM DRUG-RECEPTOR INTERACTIONS
 After drug-receptor binding & interaction, a series of events
occur within the cell that ultimately leads to the drug effects on
the cell
 Limited mechanisms by which these signals from ligand-receptor
interactions are processed within the cell to produce said effects
 Examples of such processes include:
◌ Second Messenger System
□ Provide a common avenue by which various external
stimuli are processed to produce coordinated cellular
effects
◌ Intracellular Ionic Concentration
□ Drug-receptor binding can lead to the opening of ionic
channels & consequent efflux or influx of specific ions
□ Changes in the level of ions within the cell leads to the
particular cellular effect
□ Example: Movement of Ca2+ into the cell that brings
about smooth muscle contraction
SIGNAL TRANSDUCTION
 Drugs act as signals & their receptors act as signal detectors
 Receptors transduce their recognition of a ligand that binds to a
site on a receptor protein & activates it by initiating a series of
reactions that ultimately result in a specific intracellular
response
 “Second messenger” or effector molecules are part of the
cascade of events that translate ligand binding into a cellular
response
 Has two important features:
◌ Ability to amplify small signals
◌ Mechanisms to protect the cell from excessive stimulation
SIGNAL AMPLIFICATION
 Appears to be an inherent ability of the cell
 Cellular responses to signals from drug-receptor binding is often
much greater than the quantity of the stimulus that initiates it
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◌ For example, a single ligand-receptor complex can interact
with many G proteins thereby multiplying the original signal
manifold
◌ Additionally, activated G proteins persist for a longer
duration than does the original agonist-receptor complex
 Characteristic of G protein-linked & enzyme-linked receptors is
their ability to amplify signal intensity & duration
◌ For example, when a ligand binds to a G protein-coupled
receptor, one G protein molecule is activated  (+) binding
& stimulation of many effector molecules (e.g., adenylyl
cyclase) which in turn activates even more second
messengers
◌ Similarly, a small influx of Ca2+ (so-called trigger Ca2+) via the
voltage-gated Ca2+ channels cause the release of large
quantities of stored Ca2+ into the cytoplasm
DESENSITIZATION & DOWN-REGULATION OF RECEPTORS
 Repeated or continuous administration of a ligand may lead to
changes in the responsiveness of receptor
 To prevent potential damage to the cell (e.g., high
concentrations of calcium  initiating cell death), several
mechanisms have evolved to protect a cell from excessive
stimulation such as tachyphylaxis
Tachyphylaxis & Desensitization
 Occurs when a receptor is exposed to repeated administration
of an agonist which then causes the receptor to become
desensitized resulting in a diminished effect
 This phenomenon is due to either phosphorylation or a similar
chemical event that renders receptors on the cell surface
unresponsive to ligand
 Refers to the diminishing response to repeated administration of
drug with the same dosage that occurs with time leading to
reduced clinical effects  Receptor can be said to be
desensitized to drug action at this point
 Two types of desensitization
◌ Homologous – diminished action of agonists at one class of
receptors
◌ Heterologous – diminished action of agonists on a number
of class of receptors
 Example of desensitization
◌ -receptor to repeated epinephrine stimulation comes
about from epinephrine-induced phosphorylation of
cytoplasmic end of the receptor  facilitates -arresting
binding to the receptor  inhibition of ability of receptor
to stimulate the G protein receptor (Gs)  lower levels of
Gs  lower production of cAMP by adenylyl cyclase  less
cellular effects over time
INACTIVATION
 Upon receptor phosphorylation, there is complete blockade of
its signaling activity
RECEPTOR REFRACTORINESS
 Some receptor, particularly ion channels, require a finite time
following stimulation before they can be activated again
 During this recovery phase, unresponsive receptors are said to
be “refractory”
 Exemplified by the voltage-gated channels mediating the firing
of nerve cell action potentials
◌ Here, the refractory period of the neuron is characterized
by spontaneous closure of the sodium channels following
channel opening or depolarization
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed
PHARMACODYNAMICS Pharmacology A
◌ At this point, the cell is refractory and does not reopen for
a while regulating the maximum rate of neuronal firing &
transmission
DOWN REGULATION
 Another effect of drug-receptor binding is a change in the
number of receptors on the cell
 Receptors may be down-regulated such that they are
internalized (endocytosed) & sequestered within the cell,
unavailable for further ligand interaction
 These receptors may be recycled to the cell surface, restoring
sensitivity or alternatively may be further processed & degraded,
decreasing the total number of receptors available
 Recycling of the receptors back into the surface ensues when
stimulation by the drug subsides
 Alternatively, the cell itself can change the level of synthesis of
receptors thereby regulating what is available for binding to a
particular drug or ligand
 Occur over a longer period of time than inactivation & therefore
may have longer cellular effects
SUMMARY OF MECHANISMS OF RECEPTOR REGULATION
Tachyphylaxis Repeated administration of the same dose of a
drug results in a diminishing effect of the drug
over time
Desensitization Decreased ability of a receptor to respond to
stimulation by a drug or ligand
Inactivation Loss of ability of a receptor to respond to
stimulation by a drug or ligand
Refractory After a receptor is stimulated, a period of time
is required before the next drug-receptor
interaction can produce an effect
Down-regulation Repeated or persistent drug-receptor
interaction results in removal of the receptor
from sites where subsequent drug-receptor
interactions could take place
DETERMINANTS OF DRUG SELECTIVITY
 Specificity: a drug will bind & interact only to a particular
receptors & not to others
 An ideal drug is one that will interact only with a specific
molecular target & produce only the desired clinical effect. It
does not affect other targets & will not produce unwanted side
effects or toxicities
 Still, drug selectivity is a goal that drug development continues
to aim for & there is a growing list of new medications that are
more specific in terms of molecular targets & clinical effects than
their predecessors
 Example: Haloperidol, a dopamine (DA) antagonist, is given for
schizophrenia to block D2-dopamine receptors, suggesting that
schizophrenia is associated with increased activity in the
dopaminergic mesolimbic and/or mesocortical pathway
◌ Since Haloperidol is nonselective, it also blocks dopamine
receptors in the basal ganglia which frequently results in
distressing & disabling extrapyramidal side-effects such as
akathisia (motor restlessness), tardive dyskinesia (orofacial
& trunk movements), bradykinesia, etc
Several mechanisms that confer drug selectivity
1. Cell-type specificity of receptor subtypes
2. Cell-type specificity of receptor-effector coupling
Page 5 of 11
 PHARMACODYNAMICS Pharmacology A

Cell-type specificity of receptor subtypes  Applying the law of mass action (which explains & predicts
 Some receptors are distributed less than others & drug behaviors of solutions in dynamic equilibrium, the relationship
interaction with these leads to more selective therapeutic between free & bound receptors can be described in the
effects & possibly less potential for certain toxicities equation below:
 Example: Imatinib, used in treatment of certain cancers. Unlike
chemotherapeutic agents with target DNA synthesis which is Equation 2 (Relationship between free & bound receptors)
common in almost all cells (normal & cancer cells alike), Imatinib
[𝐿][𝑅] [𝐿][𝑅]
is extremely selective because it targets the BCR-Abl protein 𝐾𝑑 = 𝑜𝑟 𝐿𝑅 =
expressed only in cancer cells [𝐿𝑅} 𝐾𝑑
 In general, the more restricted the cell-type distribution of the
receptor targeted by a particular drug, the more selective the  From the above equation, several deductions are made as Kd is
drug is likely to be constant:
◌ As the ligand concentration increases, the concentration of
Cell-type specificity of receptor-effector coupling bound receptor likewise increases
 Drugs may have same target molecule drug but have different ◌ As the free receptor concentration increases, the
effects because of differences in the receptor-effector coupling concentration of bound receptor also increases
mechanisms in the requirements for the targets in the different  Therefore, an increase in effect of the drug may result from an
cell type increase in the concentration of either the ligand or the receptor
 Example: Cardiac pacemaker cells (SA nodal cells) are more  However, it is usually assumed that the total receptor
sensitive to Ca2+ channel blockers than cardiac ventricular cells concentration is constant thus the equation below:
even if both have voltage-gated Ca2+ channels
◌ Such is due to the fact that Ca2+ channels play a greater role [𝐿𝑅] + [𝑅] = 𝑅𝑜
in impulse propagation in the pacemarker cells whereas this Ro = Total number of receptors bound & free
role is delegated to sodium channels in the ventricular cells  Which when rearranged & LR is substituted with the equation
 In general, the more the receptor-effector coupling mechanisms earlier will be:
differ among the various cell types that express a particular
Equation 3 (Computing for total number of receptors)
molecule target for a drug, the more selective the drug is likely to
be [𝐿][𝑅] [𝐿]
𝑅𝑜 = + 𝑅 [𝑅] (1 )
DRUGS ACTING BY NONRECEPTOR-MEDIATED MECHANISMS 𝐾𝑑 𝐾𝑑
 To solve for R & substituting & substituting Equation 3 to
 Some drugs exert effects not by interacting with the four basic
Equation 2 will result to:
receptor types above but by other means [𝑅𝑜][𝐿]
 Example: Osmotic diuretics & antacids [𝐿𝑅] =
[𝐿] + 𝐾𝑑
◌ Osmotic diuretics – influence the amount of water When rearranged will be:
reabsorbed from the filtrate in the descending limb of loop
of Henle by altering the osmolarity within Equation 4 (Computing fraction of bound receptors)
◌ Antacids – act by neutralizing hydrochloric acid secreted by
the stomach [𝐿𝑅] [𝐿]
=
[𝑅𝑜] [𝐿] + 𝐾𝑑
DRUG-RECEPTOR BINDING [𝑳𝑹]
= represents the fraction of all bound receptors in
 Consider a receptor (R) which is free (unoccupied) or reversibly [𝑹𝒐]
bound (occupied) to a drug or ligand (L) which can be expressed relation to the total amount of receptors (Fractional Occupancy)
by the equation below: ◌  in LR complex =  response

Equation 1 DRUG-RECEPTOR BINDING CURVES

𝐾𝑑 = 𝐿 + 𝑅 ↔ 𝐿𝑅

L = drug or ligand
R = Receptor
LR = Bound drug-receptor complex
Kd = Dissociation Constant
 Kd in the graph
Dissociation Constant (Kd) ◌
represents the concentration of drug that produces a
 Intrinsic property of any drug-receptor complex response equal to 50% of the maximal response
 Expression of the tendency of drug-receptor complex (LR) to ◌ corresponds to the drug concentration at which 50% of the
bind together or dissociate receptors are occupied by the drug
 At state of equilibrium, the fraction of receptors in free & in  Since Kd of drug A is lower, it has a greater affinity for the
bound forms is dependent upon the Kd receptor than drug B & therefore will bind to more receptors
◌  Kd =  affinity of ligand to receptor than drug B at any given concentration
□ Favors equation above to go to the right ◌ The smaller the Kd = the more potent the drug 
◌  Kd =  affinity = greater chance of dissociation ◌ Potency – ability of a drug to promote at least 50% response
□ Favors equation to go to left  Since the rang of drug concentrations (from 1% to 99% of the
maximal response) usually spans several orders of magnitude,

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 PHARMACODYNAMICS Pharmacology A

semi logarithmic plots (Plot B above) are used so that the dose range for candesartan is 4 to 32 mg, as compared to 75 to
complete range of doses can be graphed 300 mg for irbesartan.
 Therefore, candesartan is more potent than is irbesartan (it has
DOSE-RESPONSE RELATIONSHIPS a lower EC50 value similar to Drug A in the figure above)
 For most drugs, the drug or ligand-receptor binding relationship
& the dose-response relationship are closely related Efficacy
 The dose-response relationship is the quantitative  AKA maximal efficacy
representation of pharmacodynamics  Represented by Emax
 Relationship between the amount of a drug (concentration) &  Magnitude of response a drug causes when it interacts with a
the patient’s response to it receptor
 Often assumed that this said response is proportional to the  Largest effect that can be achieved with a particular drug
concentration of receptors occupied by the drug, as is shown in regardless of dose
the equation below:
 Dependent on the number of drug-receptor complexes formed
Equation 5 (Drug-Dose Relationship)
& the intrinsic activity of the drug (its ability to activate the
𝑹𝒆𝒔𝒑𝒐𝒏𝒔𝒆 [𝑫𝑹] [𝑫] receptor & cause a cellular response)
𝑴𝒂𝒙𝒊𝒎𝒖𝒎 𝑹𝒆𝒔𝒑𝒐𝒏𝒔𝒆
=
𝑹𝒐
=
[𝑫] + 𝑲𝒅  Assumes that all receptors are occupied by a drug & no increase
in response is observed if a higher concentration of drug is
[D] = Concentration of free drug administered
[DR] = Concentraiton of drug-reeptor complex  More clinically useful than drug potency since a drug with
[Ro] = concentration of total receptors greater efficacy is more therapeutically beneficial than is one
Kd = equilibrium dissociation constant for the drug- that is more potent
receptor complex

◌ The right side of the equation is equivalent to equation 4

with [D] substituted with [L]

 There are two main dose-response relationship:

◌ Graded dose-response relationship
□ Response of an individual to a drug
◌ Quantal dose-response relationship
□ Response of a population to a drug (more accurate)

GRADED DOSE-RESPONSE RELATIONSHIP

 Typical dose-response curve for drugs showing differences in

potency & efficacy
 Potency & efficacy are not intrinsically related: a drug can be
very potent but have little efficacy & vice versa (although what
Graded dose-response curve we want is a very potent & very effective drug
 Graph of the increasing response to increasing drug
concentration or dose
 Plotting the magnitude of response against increasing doses of a
drug produces a graded dose-response curve that can be
described as a rectangular hyberbola depicted in Figure A above
 Two important properties of drugs: potency & efficacy, can be
determined by graded dose-response curves

Potency
 Represented by EC50
 Measure of the amount of drug necessary to produce an effect
of a given magnitude
 Concentration of drug producing 50% of the maximum effect
(EC50)
 In the figure above, the EC50 for drug A & B indicate that Drug A
is more potent than Drug B. Why?
◌ Because a lesser amount of Drug A is needed when
compared to Drug B to obtain 50% effect
 Therapeutic preparations of drugs reflect their potency. For
example, candesartan & irbesartan are angiotensin receptor
blockers that are used to treat hypertension. The therapeutic
 Drug A & B are said to be more potent than C & D
 Drug A, C & D have equal maximum efficacy & all have a greater
maximal efficacy than drug B
 Although the responses depicted in curves A, B & C
approximated the shape of a simple Michaelis-Menten relation
(transformed to a logarithmic plot), some clinical responses do
not
 Extremely steep dose-response curves (e.g., curve D) may have
important clinical consequences if the upper portion of the curve
represents an undesirable extent of response (e.g., coma caused
by a sedative-hypnotic)

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 7 of 11

Ability of a drug to reach receptors depends on or is influenced by
several factors:
1. Route of administration
2. Absorption
3. Distribution
4. Clearance from the blood or site of action
Note:
 In choosing a drug to administer to a patient, the clinician
considers their relative effectiveness rather than their relative
potency
 Potency largely determines the administered dose of the chosen
drug which is usually stated in dosage units in relation to a
particular therapeutic goal (e.g., mild sedation)
QUANTAL DOSE-EFFECT CURVES
 Graph of the increasing fraction of a population that shows a
specified response at progressively increasing doses
 Describe the drug concentrations that elicit a particular effect in
a population
 Plots plot the fraction of the population that responds to a
certain dosage of the drug versus the drug dose
 These curves show the average drug effect elicited by particular
dosages in a population
 These curves show the percentage of individuals that respond to
each drug dose
 Useful in predicting the effects of a drug when it is given to a
population of individuals & for determining population-based
toxic & lethal doses
 Concerned with the following important drug doses:
◌ ED50 – drug dose that causes a therapeutic response in half
of the population (median effective dose)
□ Vs. EC50 – dose at which a drug elicits a half-maximal
effect in an individual subject
◌ TD50 – drug dose that causes a toxic response in half of the
population (median toxic dose)
◌ LD50 – drug dose at which 50% subjects die (median lethal
dose)
DRUG-RECEPTOR INTERACTIONS
 Generally speaking, drug receptors have two conformational
states:
◌ Active State
◌ Inactive States
 These 2 forms are in reversible equilibrium
 Pharmacologic properties of drugs reside in their ability to affect
this balance by favoring receptors to assume one configuration
over the other
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed
PHARMACODYNAMICS Pharmacology A
Agonists
 Drug that activates its receptor upon binding
 Drug or endogenous ligand that stabilizes their corresponding
receptors into their active conformation upon binding
 If an agonist binds to its receptor, it will become activated & an
effect will be elicited
Full Agonists
 Drug capable of fully activating the effector system when it binds
to the receptor
 If a drug binds to a receptor & produces a maximal biologic
response that mimics the response to the endogenous ligand, it
is a full agonist
 Binds to a receptor, stabilizing the receptor in its active state &
are said to have an intrinsic activity of one
Partial Agonists
 Have intrinsic activities greater than zero but less than one
 Produces less than the full effect even when it has saturated the
receptors
 Even if all the receptors are occupied, partial agonist cannot
produce the same Emax as a full agonist
 In the presence of a full agonist, a partia agonist acts as an
inhibitor
 As the number s of receptors occupied by the partial agonist
increases, the Emax would decrease until it reached the Emax of
the partial agonist  this potential of partial agonists to act as
both an agonist & antagonist may be therapeutically utilized
 For example, aripiprazole, an atypical antipsychotic, is a partial
agonist at selective dopamine receptors
◌ Dopaminergic pathways that are overactive tend to be
inhibited whereas pathways that are underactive are
stimulated
Inverse Agonists
 Typically, bound receptors are inactive & require interaction
with an agonist to assume an active conformation. However,
some receptors show a spontaneous conversion from the
inactive form to active form in the absence of an agonist
 Inverse agonists, unlike full agonists, stabilize the inactive form
 Causes active form of receptor to convert to inactive form 
decreasing the number of activated receptors to below that
observed in the absence of drug
 Thus, inverse agonists have an intrinsic activity less than zero,
reverse the activity of receptors & exert the opposite
pharmacologic effect of agonists
Page 8 of 11
 PHARMACODYNAMICS Pharmacology A

ANTAGONISTS
 Antagonists bind to a receptor with high affinity but possess zero
intrinsic activity
 Has no effect in the absence of an agonist BUT can decrease the
effect of an agonist when present
 Antagonism may occur either by blocking the drug’s ability to
bind to the receptor or by blocking its ability to activate the
receptor
◌
Although the potency of the agonist decreases as the
concentration of competitive antagonist increases, the
efficacy of the agonist is unaffected. WHY?
□ Because the agonist concentration can be increased to
fight off antagonistic effect – “outcompete” 
antagonist’s effect is said to be “reversed or washed
out”
 Example: Statins
◌ Competitive antagonists of HMG CoA on the active site of
HMGCoA reductase enzyme (rate-limiting step in
cholesterol biosynthesis)
◌ Statins & HMG CoA are similar in structure allowing statins
to bind to the active site of the reductase enzyme leading
to decreases endogenous cholesterol synthesis

Noncompetitive Receptor Antagonists

 Types of Antagonists
◌ Receptor antagonists
□ Competitive receptor antagonists
□ Noncompetitive receptor antagonists
◌ Non Receptor antagonists
□ Chemical antagonists
□ Physiologic antagonists

Receptor antagonists
 Can bind to the active site or allosteric site in the receptor
 Irreversible binding
◌Occurs when a drug is bound covalently or has a very high
affinity to a receptor
◌ Cannot be outcompeted by increasing the dose of the
agonist & is therefore noncompetitive
 Allosteric binding
 Binds either to the ◌ Drug that binds to a receptor molecule without interfering
◌ active site (where the agonist binds)  preventing binding with normal agonist binding but alters the response to the
of the agonists to the receptor (competitive binding) normal agonist
◌ allosteric site of the receptor  preventing the ◌ Occurs when antagonists binds to an allosteric site of the
conformational change required for receptor activation receptor preventing the receptor from being activated by
(noncompetitive binding) the agonist
 can be reversible or irreversible ◌ Also a form of noncompetitive antagonism whether the
binding is reversible or irreversible
Competitive Receptor Antagonists □ If reversible, effects wash out over time as it
dissociates
□ If irreversible, effects will not diminish
 Characteristically causes a downward shift of the Emax, with no
shift of EC50 values

Competitive Vs. Noncompetitive Antagonists

 If both the antagonist & the agonist bind to the same site on the
receptor in a reversible manner, they are said to be
“competitive”
 Prevents an agonist from binding to its receptor & maintains the
receptor in its inactive state
 Competitive agonists
 Can be overcome by increasing the concentration of agonist
◌ Reduces agonist potency (increase EC50)
relative to antagonist
◌ Shifts the agonist curve to the right
 Characteristically shift the agonist dose-response curve to the
 Noncompetitive antagonists
right (increased EC50) without affecting Emax
◌ Reduce agonist efficacy (decrease Emax)
 End Result:  potency but efficacy remains the same ◌ Shifts the agonist curve downward
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 9 of 11
 PHARMACODYNAMICS Pharmacology A

Non-Receptor Antagonists SPARE RECEPTORS

 Inhibits agonist action by several mechanisms:  Receptor that does not bind drug when the drug concentration
◌ Binds to a downstream molecule in the activation pathway is sufficient to produce maximal effect; present when Kd > EC50
(antibodies)  Said to exist if the maximal drug response (Emax) is obtained at
◌ Activates a pathway opposite to the action of the agonist less than 100% occupation of the receptors (Bmax)
◌ Physiologic antagonism causes a physiologic effect opposite  In practice, the determination is usually made by comparing the
to the agonist effect concentration for 50% of maximal effect (EC50) with the
 Can be either: concentration for 50% of maximal binding (Kd)
◌ Chemical antagonists  If the EC50 is less than the Kd, spare receptors are said to exist
◌ Physiologic antagonists  Mechanisms explaining the concept of spare receptors:
◌ First, the duration of the effector activation may be greater
Chemical Antagonists than the duration of the drug-receptor interaction
 Drug that counters the effect of another by binding the agonist ◌ Second, the actual number of receptors may exceed the
drug (not the receptor) number of effector molecules available
 Inactivates the agonist by modifying or sequestrating it such that
the said agonist is incapable of activating the receptor by not
being able to bind to it
 Example: Protamine
◌ Heparin can be neutralized by the IV injection of protamine,
a basic peptide that combines with the acidic heparin

Physiologic Antagonists
 Drug that counters the effect of another drug by binding to a
different receptor & causing opposing effects
 Binds to a different receptor molecule producing an effect
opposite to that produce by the drug it antagonizes
 Example: -blockers in tachycardia induced by hyperthyroidism
◌ -blockers can relieve the condition by blocking cardiac -
adrenergic stimulation to produce an opposite physiologic
effect to that produced by thyroid hormones (which bind
receptors found in the nuclear membrane)
◌ Note that the tachycardia produced by elevated thyroid
hormones is not mediated through stimulation of -
adrenergic receptors in the heart
 Example: Epinephrine in histamine-induced bronchoconstriction
◌ Histamine binds to H1 receptors on bronchial smooth
muscle causing bronchoconstriction of the bronchial tree
◌ Epinephrine is an agonist at 2-adrenoceptors on bronchial
smooth muscle which causes the muscles to relax
 In a system with spare receptors, the EC50 is less than the Kd,
indicating that to achieve 50% of maximal effect, less than 50%
of the receptors must be activated
 In some cases, it is not necessary to occupy every receptor with
drug to elicit a full response
◌ Presence of spare receptors increases sensitivity to the
agonist because the likelihood of a drug-receptor
interaction increases in proportion to the number of
receptors available
Effect of Noncompetitive Antagonist in the
absence & presence of spare receptors

Summary

Stabilizes active form (DR*) of drug-receptor

Full Agonists complex
Activates receptor with maximal efficacy
Stabilizes both inactive (DR) & inactive (DR*)
form of drug-receptor complex
Partial Agonists
Activates receptor but not with maximal
efficacy
Stabilizes inactive form (DR) of drug-receptor
Inverse
complex  Without spare receptors, a noncompetitive antagonist causes
Agonists efficacy to decrease
Inactivates constitutively active receptor
Stabilizes inactive form of receptor (R)  With spare receptors, potency is decreased but efficacy is
Competitive unaffected at low concentration of the noncompetitive
Antagonists Prevents binding of full, partial & inverse antagonist. Why?
agonists to the receptor ◌ Because a sufficient number of free receptors is available to
Noncompetitive Binds irreversibly to active site of receptor generate a maximum response
Active Site ◌ At low concentration the noncompetitive antagonist binds
Prevents agonist binding to this site
Antagonist receptors that are not required to produce a maximal
response
Noncompetitive Binds reversibly or irreversibly to site other than
□ Efficacy of the agonist is not affected
Allosteric Site active site of receptor
Antagonist Prevents conformational change required for
receptor activation by agonist

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 10 of 11
 PHARMACODYNAMICS Pharmacology A

□ Potency is decreased because potency is proportional Equation (Therapeutic Index)

to the fraction of available receptors that must be 𝑻𝑫𝟓𝟎
𝑻𝒉𝒆𝒓𝒂𝒑𝒆𝒖𝒕𝒊𝒄 𝑰𝒏𝒅𝒆𝒙 =
occupied to produce 50% response 𝑬𝑫𝟓𝟎
□ Recall that some noncompetitive antagonist are able TD50 = dose of the drug producing toxic response in 50% of
to bind to active sites covalently rendering them the population
permanently unavailable ED50 = dose of the drug therapeutically effective in 50% of
 As increasing concentrations of antagonist binds the population
noncompetitively to more & more receptors, the antagonist TITE: Therapeutic Index = TD50/ED50
eventually occupies all of the “spare” receptors  efficacy is  Single number that represents the safety margin of a drug in a
reduced given population
 Safer drugs have higher TI values 
THERAPEUTIC WINDOW & THERAPEUTIC INDEX  Large TI = large window so toxic dose is 1000x more than
Therapeutic index (TI) of a drug therapeutic dose
 Small TI = toxic dose is very close to the therapeutic dose
 Drugs with LOW TI = warfarin, lithium, phenobarbital, digoxin

 Ratio of the dose that produces toxicity in half the population
TD50 to the dose that produces a clinically desired or effective
response ED50 in half the population
 Measure of a drug’s safety because a larger value indicates a
wide margin between doses that are effective & doses that are
toxic
Therapeutic Window
 More clinically useful index of safety
 Describes the dosage range between the minimum effective
therapeutic concentration or dose & the minimum toxic
concentration or dose
 For example, if the average minimum therapeutic plasma
concentration of theophylline is 8 mg/L & toxic effects are
observed at 18 mg/L, the therapeutic window is 8-18 mg/L
 Both the therapeutic index & the therapeutic window depend on
the specific toxic effects used in the determination

Agonists with Effect

Shifts curve to the right ( potency)
Competitive Antagonist
Can be overcome by  the concentration of agonist substrate
Shifts curve down ( efficacy)
Noncompetitive Antagonist
Cannot be overcome by  agonist substrate concentration

Act at same site as full agonist, but with lower maximal effect ( efficacy)
Partial Agonist (alone)
Potency is an independent variable

Competitive Antagonist Noncompetitive Antagonist

Will higher doses of the overcome the inhibition? Yes No
Does the antagonist bind the receptor at the same site as the agonist? Yes No
What effect does the antagonist have on the efficacy of the agonist? No effect Reduced
What effect does the antagonist have on potency of the agonist? Reduced No effect

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 11 of 11