Study Guide
Drug Receptor Interactions and Pharmacodynamics
-
University:
Michigan State University -
Course:
PHM 430 | Human Pharmacology Academic year:
2024
-
Views:
38
Pages:
61
Author:
behend6abs
Drug receptor interactions and
pharmacodynamics Overview
• The effects of most drugs result from their interaction with macromolecular
components of the organism that influence important biochemical or
physiologic processes (receptors or drug targets)
• Both therapeutic and toxic effects of drugs result from their interactions
with with macromolecular components of the organism (receptors or drug
targets) Receptors
▪ Regulatory proteins (physiological receptors)
▪ Enzymes (e.g. dihydrofolate reductase ,the receptor for the antineoplastic
drug methotrexate)
▪ Transport proteins (E.g. Na+/K+ ATPase, membrane receptor for digoxin)
▪ Structural proteins (E.g. tubulin, the receptor for colchicine)
▪ Not all drugs exert their effects by interacting with a receptor (e.g. antacids
neutralizes excess gastric acid, reducing the symptoms of heartburn) Relationship between drug concentration, response &
receptor binding: quantitative aspects of drug-receptor
interaction Drug receptor interaction
▪ Drugs bind receptors (Drug-receptor complex) and initiate events leading to alterations
in biochemical and/or biophysical activity of a cell, and consequently, the function of
an organ (biological response)
▪ In general, the drug-receptor interaction is characterized by (1) binding of drug to
receptor (receptor occupancy) and (2) generation of a response in a biological system
Drug + Receptor
Drug-receptor complex
Biological effect Drug-receptor binding
▪ The first step in drug action on specific receptors is the formation of a reversible
drug-receptor complex, the reactions being governed by the Law of Mass Action
k1
D+R
D-R
k2
[DR]
[RT]
=
[D]
Kd + [D]
Where [D] = concentration of free drug; [DR] = the concentration of bound drug; [RT] = the total concentration of receptors; kd = the equilibrium dissociation
constant and represents the concentration of free drug at which half-maximal binding is observed Relationship of binding to effect
▪ The binding of a drug to its receptor initiates events that ultimately lead to a
measurable biologic response
▪ The magnitude of response is proportional to the amount of receptors
bound/occupied according to the following equation:
E
=
Emax × [D]
[D] + EC50
Where [E] = is the effect observed at concentration [D], Emax is the maximal response that can be produced by the drug; and EC50 is the concentration of drug that produces
50% of maximal effect Drug receptor interaction
• The tendency of the a drug to bind to its receptor is governed by its affinity
• The equilibrium dissociation constant (kd) [k-1/k+1] characterizes the receptor
affinity for binding the drug in a reciprocal fashion i.e. a high affinity means a small
kd
• The ability of a drug , once bound, to activate a receptor and generate response is
denoted by its efficacy: a drug with high efficacy eliciting, at some concentration, a
full response Drug receptor interaction
% of receptor bound
100
+
ACTIVATION
Governed by affinity
Governed by efficacy
K+1
R
A
50
K-1
B
C
Kd
Dose (log scale)
RESPONSE
DR
% of Maximal effect/response
D
OCCUPATION
100
A
50
B
C
EC50
Dose (log scale) Drugs Have Different Affinities for the Same Receptor
1.00
Kd=0.5
Kd=1
kd=5
[DR]/RT
0.75
0.50
0.25
0.00
0.01
0.10
1.00
[D]
10.00
100.00 Classification of a drug based on drug-receptor interactions
• Drugs generally functions as either an agonist or an antagonist
• Agonist: Drug that bind to a receptor and produces a biologic response
that mimic the response to the endogenous ligand. In general, an
agonist has a strong affinity for its receptor and good/high efficacy
• Antagonist: drug decrease/ prevent the actions of another drug/ agonist
or endogenous ligand by binding to a receptor, compete with and
prevent binding by other molecules Classification of a drug based on drug-receptor interactions
▪ Partial Agonists: it demonstrates both agonist and antagonist action,
The submaximal effects represent intermediate to low efficacy.
▪ Inverse agonist: drug with negative efficacy (i.e. opposite
pharmacological effect) Receptor activation & confirmation
Agonist like to bind to receptor in R’
state and shifts the equilibrium
toward more LR’ and makes effect
Antagonist like to bind to receptor in R
and R” state without any preference
and makes no shifts in net equilibrium
R
R*
L
L
Effect
No effect
LR
Inverse agonist has more affinity
to receptor in R state and shifts
the equilibrium toward more LR
and make negative response
than resting state.
LR*
Partial agonist has a little more affinity for
receptor in R’ states than R state and
makes partial effect
Possible mechanism for the partial agonist phenomenon. Full agonist
Response
Partial agonist
Constitutive
activity
Dose (log scale)
Inverse agonist Antagonism
▪ Antagonists are drugs that decrease or oppose the actions of another
drug or endogenous ligand
▪ An antagonist has no effect if an agonist is not present
▪ Types of antagonism:
▪ Competitive antagonism
▪ Non-competitive antagonism
▪ Chemical antagonism
▪ Physiological/ functional Competitive antagonism
▪ Both the agonist and the antagonist bind to the same site on the
receptor
▪ Competitive antagonists can fall into either of two subtypes:
▪ Reversible competitive antagonism
▪ Irreversible competitive antagonism
▪ The degree of inhibition produced by a competitive antagonist
depends on the concentration of antagonist Reversible competitive antagonist
+ antagonist
Response
100
Agonist alone
50
0
Dose (log scale)
+ more
antagonist Irreversible competitive antagonist
100
Agonist alone
Response
+ antagonist
50
+ more
antagonist
0
Dose (log scale) Non-competitive (allosteric) antagonism
▪ The antagonist binds to a site other than where the agonist binds
▪ The antagonist block at some point the chain of events that leads to the
production of a response by the agonist
▪ The effect of a non-competitive antagonist on the dose–response curve for an
agonist would be the same as the effect of an irreversible competitive antagonist
▪ Example of non-competitive antagonists: calcium channel blockers (CCBs) Spare Receptors
▪ The maximal response can be elicited by an agonist at a concentration
that does not result in occupancy of the full complement of available
receptors
▪ If EC50 is lower than the Kd, spare receptors are said to exist % of maximum
Spare receptors
Drug Effect
Drug Binding
EC50
Dose(log scale)
Kd Spare receptors
A
B
C
D
reduced maximal
effect
E Signalling mechanisms: the molecular mechanisms by which a
drug acts Overview
▪ Receptors act as a signal detectors
▪ When a receptor is occupied by an agonist, the resulting conformational change is
only the first of many steps usually required to produce a pharmacologic response
▪ Receptors signals their recognition of a bound ligand by initiating a series of
reactions that ultimately result in specific intracellular response
▪ Receptors elicit many different types of cellular effect. Some of them are of very
rapid , intermediate, or long timescales Major receptor families
▪ Intracellular receptors
▪ Enzyme-linked receptors
▪ Transmembrane ligand-gated ion channels
▪ Transmembrane G-protein coupled receptors Ligand gated ion channel
ions
R
Hyper polarization
or
depolarization
Cellular effects Nuclear receptors
Nucleus
R
Gene
transcription
Protein synthesis
Cellular effects Enzyme linked receptors
ligand
R
R
R
R
ATP
ATP
ADP
ADP
P
E
P
P
P Ions
G protein coupled receptors
R
+
Change in
excitability
Ca2+ release
G
-
+
G
E
-
Second messengers
Protein
phosphorylation
Cell effects
other G-Proteins coupled receptors (GPCRs)
G-protein
Effector
Effector
substrate
Second messenger response
Response
Gs
Adenylyl cyclase
ATP
Increase cAMP
Increase Ca+2 & enzyme activity
Gi
Adenylyl cyclase
ATP
Decrease cAMP
Decrease Ca+2 & enzyme activity,
increase K+ efflux
Gq
Phosphlipase C
Membrane
lipids
Increase IP3 and DAG
Increase Ca+2 & protein kinase
activity Receptor Regulation
• Responses to agonists often attenuate with time (receptor de-sensitization)
• After reaching an initial high level, the response (eg, cellular cAMP accumulation,
Na+ influx, contractility, etc) diminishes over seconds or minutes, even in the
continued presence of the agonist
• It is often rapidly reversible; a second exposure to agonist results in a response
similar to the initial response (re-sensitization)
• Multiple mechanisms contribute to desensitization of receptors Mechanisms of Desensitization
• Change in receptors
• Loss of receptors (receptor downregulation)
• Exhaustion of mediators
• Increased metabolic degradation
• Physiological adaptation
• Active extrusion of drug from cells (mainly relevant in chemotherapy) G Protein-Coupled Receptor Signaling and Desensitization
agonist
agonist
-P arrestin
GRK
Desensitization
Decreased Response
G
Activation
Biological Response Relation between drug dose & clinical response Overview
▪ The magnitude of drug effect depends on the drug concentration at the
receptor site, which in turn determined by the dose of drug administered
and by factors of the drug pharmacokinetic profile
▪ There is a graded dose-response relationship in individuals and a quantal
dose-response relationship in a population Graded dose-response relationship
▪ The response to a drug is a graded effect, meaning that the response is continuous
and graded
▪ Graded dose response curves are constructed by plotting the magnitude of the
response against increasing doses of a drug (or log dose)
▪ It is characerized by:
▪ Potency (EC50 or ED50): a measure of the amount of drug necessary to produce
an effect of a given magnitude
▪ Efficacy (Emax): greatest effect (Emax) an agonist can produce if the dose is
taken to very high levels Effect
100
Potency
Efficacy
50
0
ED50
Dose (log scale) Quantal Dose-Effect Curves
▪ Are population-based dose-response curves
▪ It determines the dose of a drug required to produce a specific magnitude of
effect in a large number of patients
▪ The specified quantal effect may be chosen on the basis of clinical relevance or for
preservation of safety of experimental subjects, or it may be an inherently quantal
event (eg, death)
▪ Quantal effects can be determined by plotting the cumulative percentage of the
population that show the response at each dose versus the log of the dose
administered
▪ May also be used to generate information regarding the margin of safety to be
expected from a particular drug used to produce a specified effect Number of subjects
Frequency distribution
Dose Cumulative % of Subjects
Cumulative Dose-Effect Curve
Dose Quantal ‘all-or-none’ dose-response relation
▪ The quantal dose-effect curve is often characterized by:
▪ Median effective dose (ED50): the dose at which 50% of the
individuals/population exhibit the specified desirable/therapeutic effect
▪ Median toxic dose(TD50): the dose at which 50% of individuals/population
exhibit a particular toxic effect Therapeutic index And Therapeutic window
• It is the ratio of the dose that produces undesirable effect to the dose that
produces a clinically desired effect
TD50
Therapeutic Index =
ED50
• Therapeutic window is the range between the minimum toxic dose and the
minimum therapeutic dose
• The clinically acceptable risk of toxicity depends critically on the severity of the
disease being treated
• Examples of drugs with wide therapeutic index: aspirin, paracetamol, penicillins Total number responding
Therapeutic effect
Toxic effect
100
50
ED50
TD50
Dose Variation in drug responsiveness
Recorded lecture will be provided on the eLearning platform Variation in drug responsiveness
▪ Therapeutics would be a great deal easier if responses to the same dose of drug
were always the same
▪ Individuals may vary considerably in their response to a drug or within an
individual patient at different times during the course of treatment
▪ Inter-individual differences in drug delivery to its site(s) of action can profoundly
influence therapeutic effectiveness and adverse effects
▪ Variation in drug response may be explained by variation in environmental and
genetic factors, alone or in combination Factors that determine the relationship between prescribed drug dosage and drug
effect
Prescribed dose
Administered dose
Concentration at site of
action
Intensity of effect
• Patient compliance
• Medication error
• Rate & extend of absorption
• Body size & composition
• Distribution in body fluids
• Binding in plasma & tissues
• Rate of elimination
• Physiological variables
• Pathological factors
• Genetic factors
• Interaction with other drugs
• Development of tolerance
• Drug receptor interaction
• Functional state
• Placebo effect Variation in drug responsiveness
▪ Variation can be caused by different concentrations at sites of drug action
(pharmacokinetic variation) or by different responses to the same drug
concentration (pharmacodynamic variation)
▪ Pharmacokinetic variation can occur because of differences in absorption,
distribution, metabolism or excretion parmacodynamic variation Variation in drug responsiveness
▪ Variation in drug responsiveness can be broadly categorized as:
▪ Dose-independent (qualitative/idiosyncratic): infrequently observed in most
patients and usually caused by genetic differences in metabolism of the drug or by
immunologic mechanisms
▪ Dose-dependent: quantitative variation in drug response. An individual patient is
hyporeactive or hyperreactive to a drug in that the intensity of effect of a given
dose of drug is diminished or increased compared with the effect seen in most
individuals Desensitisation and tachyphylaxis
▪ Often, the effect of a drug gradually diminishes when it is given continuously or
repeatedly
▪ Desensitisation and tachyphylaxis are synonymous terms used to describe this
phenomenon, which often develops in the course of a few minutes
▪ Tolerance is conventionally used to describe a more gradual decrease in
responsiveness to a drug, taking days or weeks to develop Desensitisation and tachyphylaxis
▪ Four general mechanism may contribute to variation in drug
responsiveness:
▪ Alteration in concentration of drug that reaches the receptor (i.e.
Pharmacokinetic factors)
▪ Variation in concentration of an endogenous receptor ligand
▪ Alteration in or function of receptors
▪ Changes in components of response distal to the receptor Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
▪ Any drug, no matter how trivial its therapeutic actions, has the potential to
do harm
▪ No drug causes only a single, specific effect
▪ Drugs are only selective—rather than specific—in their actions
▪ Selectivity can be measured by comparing binding affinities of a different
receptors or by comparing ED50s for different effects of a drug in vivo Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
▪ Beneficial & toxic effects mediated by the same receptor-effector mechanism (i.e.
extension of the therapeutic effect)
▪ Beneficial & toxic effects mediated by identical receptors but in different tissues
▪ Beneficial and toxic effects mediated by different types of Receptors Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
toxicity
Drug
Receptor
Effector
Receptor 1
Effector 1
toxicity
Receptor 2
Effector 2
benefit
Effector 1
toxicity
Effector 2
benefit
benefit
Drug
Drug
Receptor The time course of drug effect
▪ Following administration of a dose of drug, its effects usually show a characteristic temporal
pattern: Onset of the effect is preceded by a lag period, after which the magnitude of the effect increases to a
maximum and then declines; if a further dose is not administered, the effect eventually disappears as the drug is
eliminated
▪ Pharmacokinetics refers to the process controlling drug concentration at any time, while
pharmacodynamics describe the relationship between drug concentration and effect (time
independent)
▪ PKs and PDs share a common feature, concentration, and they can be combined to describe
the overall drug effect vs. Time relationship. This is called the time course of effect Dose
Dose
PK
C
C
PD
Effect
PK
C
PD
Effect The intensity of a drug's effect is related to its concentration above a minimum effective
concentration, whereas the duration of effect reflects the length of time the drug level is above this
value
Drug effect (Cp)
MEC for toxic/ adverse
effect
Therapeutic
window
Onset of effect
Offset of effect
MEC for desirable
effect
Duration of action
Time (hours) The time course of drug effect
I. Immediate effect
▪ The drug effect are directly related to the plasma concentration (assuming
that the changes in the drug concentration in blood do mirror the changes
in concentration at the effect site)
▪ This does not necessarily mean that effect simply parallel the time course of
concentration
▪ There is a direct correlation between the effect site concentration of the
drug and the observed effect with time lag Time course of Enalapril (ACE inhibitor) concentrations and effect
E =91%
100
80
E =54.6%
C =50%
60
40
C =6.25%
20
0
0
4
8
1
12
Time (h)
2
3
Half-life (h)
16
4
20
5
24
6 The time course of drug effect
II. Delayed effect
▪ Changes in drug effects are often delayed in relation to changes in
plasma concentration. This delay may reflect:
▪ The time required for the drug to distribute from plasma to the site of action
(e.g. Thiopental)
▪ Slow turnover of a physiologic substance that is involved in the expression of
the drug effect (e.g. Warfarin) Mean (SD) of plasma warfarin concentration (mg/L) versus time (blue line) and Prothrombin Complex Activity percentage (PCA %) relative to 100% baseline
level (red line) in 32 healthy volunteers following single oral administration of 1.5mg/kg of body weight. %PCA = percentage prothrombin complex activity.
Adapted from O'Reilly and Aggeler (1968) The time course of drug effect
III. Cumulative effect
▪ Some drug effects are more obviously related to a cumulative action
(after it has given for some time) than to a rapidly reversible
/immediate one
▪ Too long continued administration of a drug (e.g. Gentamicin nephrotoxicity is greater
when administered as a constant infusion than with intermittent dosing)
▪ The therapeutic/desirable effect is a consequence of cumulative exposure to the drug
(e.g. Anticancers)
Drug Receptor Interactions and Pharmacodynamics
of 61
Report
Tell us what’s wrong with it:
Thanks, got it!
We will moderate it soon!
Free up your schedule!
Our EduBirdie Experts Are Here for You 24/7! Just fill out a form and let us know how we can assist you.
Take 5 seconds to unlock
Enter your email below and get instant access to your document