Principles of Drug Therapy

Chapter 2
Drug-receptor interactions
and Pharmacodynamics
Main contents
 Overview

 Signal transduction

 Dose-response relationships

 Agonists

 Antagonists

 Quantal dose-response relationships

Ⅰ. Overview
 Pharmacodynamics

 Pharmacodynamics describes the action of a

drug on the body and the influence of drug
concentrations on the magnitude of the
response

What
Whatthe
thedrug
drug
does
doeswhen
whenititgets
getsthere
there
 Mechanisms of drug action

 (1) Physical and chemical reaction

 (2) Joining or interfering with cell metabolism
 (3) Affecting transportation of physical substances
 (4) Affecting enzyme activity
 (5) Affecting ion channels on the cell membrane
 (6) Affecting immunology function
 (7) Affecting nucleotide
 (8) Drugs and receptors
 Drugs and receptors
 A (specific) receptor can be defined as many
biologic target macromolecule in cells that
interacts specifically with extracellular signal,
e.g., a drug, the drug-receptor complex
initiates alterations in biochemical and / or
molecular activity of a cell by a process called
signal transduction, finally converts it into
intracellular effects.
 Receptor determine the maximum effect of a
drug, i.e., the response extent is proportional
to the number of drug-receptor interaction.
Ⅱ. Signal transduction
 The drug-receptor complex

 Each type of receptor is specific for a particular

ligand and produces a unique response
 The magnitude of the response is proportional
to the number of drug-receptor complex
 Drug + receptor→ drug-receptor complex
→ biologic effect
 The drug-receptor complex
 Features of drug-receptor interaction:
specificity of the receptor for a given ligand
 Receptor recognizes the ligand

 Receptor binds the ligand

 Receptor can transduce the binding into a

response by causing a conformational changes
or a biochemical effect
 Receptor states

Classically: the induced-fit model

• Inactivate state (R)→ activated state (R*)

• The activated R then interact with

intermediary effector molecules to produce a
biologic effect
 Receptor states
Recently
• inactivate (R) activate (R*)
• In reversible equilibrium
• In the absence of an agonist, the equilibrium
favors the inactive state
• Drugs occupying the R can stabilize the R in a
given conformational state
• Some drugs shift the equilibrium from R to R*
• Other drugs shift the equilibrium from R* to R
 Major receptor families

The type of receptor a ligand will interact with

depends on the chemical nature of the ligand
Transmembrane ligand-gated
ion channels
• Be responsible for regulation of
the flow of ions across cell
membranes
• Response to the receptors is very
rapid, only a few milliseconds
• Mediate diverse functions, e.g.
neurotransmission, cardiac
conduction, muscle contraction
• Nicotinic receptor, GABA receptor
Transmembrane G protein-
coupled receptors
• The most abundant type of
receptors
• Account for the actions of most
therapeutic agents
• Response to the receptors last
several seconds to minutes
• Mediate functions such as
neurotransmission, olfaction,
vision
Enzyme-linked receptors
• Response to the receptors last
minutes to hours
• Mediate functions such as
metabolism, growth,
differentiation
• EGF-R, PDGF-R, Insulin-R
 Intracellular receptors
• The receptor is entirely
intracellular
• Ligand must have sufficient lipid
solubility
• Response to the receptors is hours
to days
• Targets of these receptors include
transcription factors, structural
proteins, enzymes, RNA, etc.
• Receptors of steroid hormones
 Some characteristics of signal
transduction

Two important features of signal transduction

• The ability to amplify small signals
• Mechanisms to protect the cell from
excessive stimulation
 Signal amplification
• To amplify signal duration and intensity
• Amplification can be mediated by:
1. A single ligand-receptor complex can
interact with many G proteins
2. The activated G proteins persist for a longer
duration than the original ligand-receptor
complex
3. The interaction of G proteins and their
respective intracellular targets
 Signal amplification

Spare receptors
• Only a fraction of the total R for a specific
ligand may need to be occupied to elicit a
maximal response
• 99% of the insulin R are spare → an
immense functional reserve
• 5-10% of the β-R in the healthy heart are
spare, but little functional reserve exists in
the failing heart
 Desensitization and down-
regulation of receptors

• Repeated of continuous administration of an

agonist or an antagonist may lead to changes
in the responsiveness of the receptor
 Desensitization and down-
regulation of receptors
Continuous stimulation of receptor may
lead to:
① Receptors unresponsive to the ligand
② Receptors down-regulated (R may be
endocytosed and sequestered within
the cells)
• Then repeated administration of a
drug results in a diminished effect,
that is tachyphylax
• Can be recovered
Ⅲ. Dose-responsive
relationships
 Agonist
• An agonist is defined as an agent that can
bind to a receptor and elicit a biologic
response
• Mimics the action of the original
endogenous ligand on the receptor
• The magnitude of the drug effect depends
on the drug concentration at the receptor
site
 Graded dose-response relations

The response is a graded effect, meaning that the

response is continuous and gradual
 Potency
• Potency is a measure of the
amount of drug necessary to
produce an effect of a given
magnitude
• EC50 is the concentration of
drug producing an effect that is
50 percent of the maximum,
and is used to determine the
potency
• Therapeutic preparations of
drugs will reflect the potency
• Candesartan and Irbesartan
Efficacy (Emax)

• Efficacy is the ability of a drug

to elicit a response when it
interacts with a receptor
• Dependent on the number of
drug-receptor complexes
formed and the efficiency of
the coupling of receptor
activation to cellular responses
• A drug with greater efficacy is
more therapeutically beneficial
than one that is more potent
Ⅳ. agonists
 Agonist
• An agonist is defined as an agent that can bind
to a receptor and elicit a biologic response
• Mimics the action of the original endogenous
ligand on the receptor
• May elicit a different response from the
receptor and its transduction mechanism
• Full agonists
• Partial agonists
• Inverse agonists
 Full agonist
• Binds to the receptor and
produces a maximal biologic
response that mimics the
response to the endogenous
ligand
• Binds to a R and stabilizes the R in
its active conformational state
• Have actions on intracellular
molecules, cells, tissues, intact
organisms
• Strong affinity for the receptor and
good efficacy
 Partial agonist
• Efficacy greater than 0 but less
than that of full agonist
• Affinity > < = that of the full
agonist
• Act both as an agonist and an
antagonist
 Inverse agonist
• Stabilize the inactive R form
• Force all the constitutively
active R into the inactive state
• Decrease the number of
activated R to below that
observed in the absence of drug
• Reverse the constitutive activity
of R and exert opposite
pharmacological effects of
agonists
Ⅴ. antagonists
 Antagonist
• Drugs that decrease or oppose the actions of
another drug or endogenous ligand
• With strong affinity to receptors, while no
intrinsic activity
• Act on the same R as the agonist
• Have no effect if an agonist is not present
• Competitive antagonists
• Irreversible antagonists
• Functional and chemical antagonism
Competitive antagonists
• Bind to the same site of R
with agonist
• Prevent agonist from binding
to its R and maintain the R in
inactive conformational state
• Cause a shift of the agonist
dose-response curve to the
right, maximum response can
be obtained by increasing
amount of agonists
• Reduce agonist potency
Irreversible antagonists
• Cause a downward shift of
the maximum, with no shift
of the curve on the dose axis
• Maximal response of is not
observed even with
increasing dose of agonist
• The effects can not be
overcome by more agonists
 Irreversible antagonists
• Two mechanisms of irreversible antagonist:
① Irreversibly bind to the active site of R, reduce
the amount of R available to the agonist
② Bind to an allosteric site other than the agonist
binding site, then prevent the R from being
activated
 Irreversible antagonists
• A maximum response is not
observed even with increasing
dose of agonist
• Reduce agonist efficicy

reversible antagonists
• A maximum response can be
obtained by increasing dose of
agonist
• Result in an increase in EC50
value, but maintenance of
agonist efficacy
 Functional and chemical antagonism
Functional antagonism
(physiologic antagonism):
• Act at a completely separate R, initiating
functionally opposite effects of agonist
• E.g. epinephrine—histamine on bronchial SM
 Functional and chemical antagonism
Chemical antagonism
• Chemical antagonists modify or sequester
agonist so that it can not bind and active its R
• E.g. protamine sulfate—heparin

Pharmacokinetic antagonism
• Antagonism reduce active drug concentration
 Receptor Interactions

Lock and key mechanism

Agonist Receptor

Agonist-Receptor
Interaction
Receptor Interactions

Induced Fit

Receptor

Perfect Fit!
 Receptor Interactions

Competitive
Inhibition

Antagonist Receptor

Antagonist-Receptor
DENIED!
Complex
 Receptor Interactions

Non-competitive Antagonist
Inhibition

Agonist Receptor

DENIED!
‘Inhibited’-Receptor
Ⅵ. Quantal dose-response
relationship
 Drug responses
• Graded response: can be expressed by
continuous increase of decrease
• E.g. the decrease of BP or BG

• Quantal response: for any individual, the

effect either occurs or not

• Graded response can be defined as quantal if

a predetermined level of the graded response
is designated as the point at which a
response occurs or not
 Drug responses
• Graded response: can be expressed by
continuous increase of decrease
• E.g. the decrease of BP or BG

• Quantal response: for any individual, the

effect either occurs or not

• Graded response can be defined as quantal if

a predetermined level of the graded response
is designated as the point at which a
response occurs or not
 LD50
TI  Therapeutic Index (TI)
ED50
 A measure of a drug’s safety
 The larger value indicates a wide margin between
doses that are effective and doses that are toxic
 Digitalis has a TI of 2
 Penicillin has TI of >100

 LD50=the drug dose that produces a lethal effect

in half the population
 ED50=the drug dose that produces a therapeutic
or desired response in half the population
 Determination of
Therapeutic Index
 Be determined using drug trials and
accumulating clinical experience
 To calculate the doses that produce the
therapeutic effect (ED50) and the toxic
effect (TD50) in 50% of the population
 Usually reveal a range of effective doses and
a different range of toxic doses
 Determination of
Therapeutic Index
Drugs with narrow TIs
 are routinely used to treat certain diseases
like some lethal diseases
 The effective and toxic concentrations are
close
 Variations in patient response are most
likely to occur
 Dose is critically important

Drugs with large TIs

 are safe and common to give doses in excess
Time Response Relationships

Maximal (Peak) Effect

Effect/
Response

Latency Duration of Response

Time
 Time Response Relationships

IV IM
SC
Effect/
Response

Time
 Dose Response Relationships
B

A
Therapeutic
Effect
Effect

Dose
Which drug has the lower threshold dose? AA

Which has the greater maximum effect? BB

Dose Response Relationships

 Potency
 Absolute amount of drug required to produce an effect
 More potent drug is the one that requires lower dose to cause same
effect
 Potency

A B
Therapeutic
Effect
Effect
A!
Why?
A!
Why?

Dose
Which drug is more potent?
Dose Response Relationships

 Threshold (minimal) dose

 Least amount needed to produce desired effects
 Maximum effect
 Greatest response produced regardless of dose used
Dose Response Relationships

 Loading dose
 Bolus of drug given initially to rapidly reach therapeutic levels
 Maintenance dose
 Lower dose of drug given continuously or at regular intervals to
maintain therapeutic levels
 Factors Altering Drug Responses

 Age
 Pediatric or geriatric
 Immature or decreased hepatic, renal function
 Weight
 Big patients “spread” drug over larger volume
 Gender
 Difference in sizes
 Difference in fat/water distribution
Factors Altering Drug Responses

 Environment
 Heat or cold
 Presence or real or perceived threats
 Fever
 Shock
Factors Altering Drug Responses

 Pathology
 Drug may aggravate underlying pathology
 Hepatic disease may slow drug metabolism
 Renal disease may slow drug elimination
 Acid/base abnormalities may change drug absorption or elimination
Influencing factors

 Genetic effects
 Lack of specific enzymes
 Lower metabolic rate
 Psychological factors
 Placebo effect
Pediatric Patients

 Higher proportion of water

 Lower plasma protein levels
 More available drug
 Immature liver/kidneys
 Liver often metabolizes more slowly
 Kidneys may excrete more slowly
Geriatric Patients

 Chronic disease  Dietary

states deficiencies
 Decreased plasma  Use of multiple
protein binding medications
 Slower  Lack of
metabolism compliance
 Slower excretion
Pharmacodynamics

Drug actions:
 The cellular processes involved in the drug and
cell interaction

Drug effect:
 The physiologic reaction of the body to the drug
 Pharmacodynamics
Onset
 The time it takes for the drug to elicit a
therapeutic response

Peak
 The time it takes for a drug to reach its maximum
therapeutic response
Duration
 The time a drug concentration is sufficient to elicit
a therapeutic response
Pharmacodynamics:
Mechanisms of Action
The ways by which drugs can produce therapeutic effects:
 Once the drug is at the site of action, it can
modify the rate (increase or decrease) at which
the cells or tissues function.
 A drug cannot make a cell or tissue perform a
function it was not designed to perform.
Pharmacodynamics:
Mechanisms of Action
 Receptor interaction
 Enzyme interaction
 Nonspecific interactions
Pharmacotherapeutics:
Types of Therapies
 Acute therapy
 Maintenance therapy
 Supplemental therapy
 Palliative therapy
 Supportive therapy
 Prophylactic therapy
Pharmacotherapeutics:
Monitoring
 The effectiveness of the drug therapy must be evaluated.
 One must be familiar with the drug’s
 intended therapeutic action (beneficial)
 and the drug’s unintended but potential side effects (predictable,
adverse drug reactions).
Pharmacotherapeutics:
Monitoring
 Therapeutic index
 Drug concentration
 Patient’s condition
 Tolerance and dependence
 Interactions
 Side effects/adverse drug effects
Pharmacotherapeutics:
Monitoring
Therapeutic Index
 The ratio between a drug’s therapeutic benefits
and its toxic effects
Pharmacotherapeutics:
Monitoring
Tolerance
 A decreasing response to repetitive drug doses
Pharmacotherapeutics:
Monitoring
Dependence
 A physiologic or psychological need for a drug
Pharmacotherapeutics:
Monitoring
Interactions may occur with other drugs or food
 Drug interactions: the alteration of action of
a drug by:
 Other prescribed drugs
 Over-the-counter medications
 Herbal therapies
Pharmacotherapeutics:
Monitoring
Interactions
 Additive effect
 Synergistic effect
 Antagonistic effect
 Incompatibility
 Pharmacotherapeutics:
Monitoring
Medication Misadventures

Adverse drug events

 ALL are preventable
 Medication errors that result in patient harm

Adverse drug reactions

 Inherent, not preventable event occurring in the normal
therapeutic use of a drug
 Any reaction that is unexpected, undesirable, and occurs
at doses normally used
Pharmacotherapeutics:
Monitoring
Some adverse drug reactions are classified as side effects.
 Expected, well-known reactions that result in
little
or no change in patient management
 Predictable frequency
 The effect’s intensity and occurrence is related to

the size of the dose

Pharmacotherapeutics:
Monitoring
Adverse Drug Reaction

An undesirable response to drug therapy

 Idiosyncratic
 Hypersensitivity reactions
 Drug interactions
Pharmacotherapeutics:
Monitoring
Iatrogenic Responses

Unintentional adverse effects that are treatment-induced

 Dermatologic
 Renal damage
 Blood dyscrasias
 Hepatic toxicity
Pharmacotherapeutics: Monitoring

Other Drug-Related Effects

 Teratogenic
 Mutagenic
 Carcinogenic