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by Lee Eun Jin
UNIT I:Introduction to Pharmacology
Chapter 2Drug-ReceptorInteractions andPharmacodynamics
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics2
DoseDose EffectEffectEffect site Effect site ConcentrationConcentration
Pharmacokinetics Pharmacodynamics
AbsorptionAbsorption
DistributionDistribution
MetabolismMetabolism
Elimination Elimination
Drug interactionsDrug interactions
Tissue/organ sensitivity Tissue/organ sensitivity (target status)(target status)
What is pharmacodynamics?I. OVERVIEW
Lecture Objectives
To understand the basic concepts regarding pharmacodynamics To define agonist and antagonists and other terms in relation to pharmacodynamics To explain the mechanism of drug receptor interaction Define spare receptors To differentitate between different tyes of antagonism
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics3
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics4
Action of a drug on the body receptor interactions, mechanisms of therapeutic dose-response phenomena, toxic action.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics5
A drug will not work unless it is bound
PARTICULAR CONSTITUENTS OFCELLS & TISSUES IN ORDER TO
PRODUCE AN EFFECT
PROTEINS LIPIDS DNA
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics6
DRUGS THAT ACT WITHOUT BEING BOUND TO ANY OF THE TISSUE CONSTITUENTS
OSMOTIC DIURETICSOSMOTIC PURGATIVESANTACIDSHEAVY METALS CHELATING
AGENTS
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics7
Drug Receptor
A macromolecular component of a cell with which a drug interacts to produce a response
Usually a protein
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics8
Receptors
Receptors must be biologically important molecules
Receptors must have structural features that permit drug specificity
Receptors must have a drug-binding site and a biologically active site
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics9
Characteristics of Characteristics of ReceptorsReceptors
a. specificity a. specificity
b. selectivity of response b. selectivity of response
c. sensitivity c. sensitivity
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics10
Molecules capable of serving as Molecules capable of serving as ReceptorsReceptors
Enzymes
Membrane proteins
(glycoproteins, lipoproteins)
Nucleic acids
Complex polysaccharides
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics11
Many drugs inhibit enzymes
in the patient (ACE inhibitors)
in microbes (sulfas, Penicillins)
in cancer cells (5-FU, 6-MP)
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics12
Types of Protein ReceptorsRegulatory – mediate the action of endogenous
chemicals e.g. hormones, NT , autocoids
Enzymes – may be inhibited or activated e.g. dihydrofolate reductase, receptor for methotrexate
Transport – e.g. Na+ /K+ ATP’ase for digitalis glycosides
Structural – e.g. tubulin,receptor for colchicin
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics13
some drugs bind to:
the genome (cyclophosphamide)
microtubules (vincristine)
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics14
Non-receptor Mediated EffectsNon-receptor Mediated Effects Interaction with small molecules
(e.g. binding of heavy metals)
Interaction with enzymes
(e.g. sulfonamides, digitalis)
Incorporation into a macromolecule
(e.g. some anticancer agents - purine and pyrimidine analogues)
Nonspecific effects (e.g. membrane perturbation by general anesthetics)
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics15
Receptor regulationReceptor regulation
1.1. HomeostasisHomeostasis
2. Up and down regulation 2. Up and down regulation
3. Desensitization 3. Desensitization
4. Tolerance o4. Tolerance or regulationr regulation
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics16
agonists desensitize receptors
homologous
(decreased receptor number)
heterologous
(decreased signal transduction
a. Occupation theorya. Occupation theory
D + R D + R DR DR RESPONSE RESPONSE:response is proportional to the fraction of occupied :response is proportional to the fraction of occupied receptors receptors :maximal response occurs when all the receptors are occupied :maximal response occurs when all the receptors are occupied
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics17
AriensAriens
response is proportional to the fraction of response is proportional to the fraction of
occupied receptors occupied receptors ANDAND the the intrinsic activity intrinsic activity
Stephenson Stephenson response is aresponse is a FUNCTION FUNCTION of occupancy of occupancy maximum response can be produced maximum response can be produced
WITHOUT 100% occupation, WITHOUT 100% occupation,
i.e. tissues have i.e. tissues have spare receptorsspare receptors
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics18
Schematic representation of the relationship Schematic representation of the relationship between threshold, receptor between threshold, receptor reserve, reserve, receptorreceptor occupancy, biological stimulus occupancy, biological stimulus and biological responseand biological response
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics19
BIOLOGICAL STIMULUSBIOLOGICAL STIMULUS
0%0%TRETHOLDTRETHOLD BIOLOGICAL RESPONSEBIOLOGICAL RESPONSE
100%100%RECEPTOR RESERVERECEPTOR RESERVE
Threshold EffectThreshold EffectMax Max EffectEffect
PERCENT RECEPTOR OCCUPANCYPERCENT RECEPTOR OCCUPANCY
Receptors are said to be sparespare
for a given pharmacological response
when 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
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics20
Spare receptors More receptors available than
needed
to elicit maximum response allow maximal response without total
receptor occupancy – increase sensitivity of the system
Agonist has to bind only a portion of receptors for full effect
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics21
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics22
Some terminologies regarding drug receptor interaction
Affinity
Efficacy
Potency
Ligand
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics23
Affinity: measure of propensity of a drug to bind receptor; the attractiveness of drug
and receptor
Efficacy: Potential maximum therapeutic response that a drug can produce.
Potency: Amount of drug needed to produce an effect.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics24
Ligand:
Molecules that binds to a receptor
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics25
Classification of Ligands Classification of Ligands a.a. agonist agonist
b. partial agonistb. partial agonist
c. antagonist c. antagonist
pharmacological vs. physiological vs. chemical pharmacological vs. physiological vs. chemical
pharmacological antagonistspharmacological antagonists
- - competitive competitive
surmountable surmountable
- - noncompetitive noncompetitive
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics26
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics27
kk11
kk22
DrugDrug
ReceptorReceptorEffectEffect
Drug-Receptor Drug-Receptor ComplexComplex
Ligand-binding Ligand-binding domain domain
Effector domain Effector domain
Drug(Ligand) Receptor interactionLangley (1878)
EffectD+R DRk1
k2
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics28
- Primary way for drug to produce an action
non-specific receptors
neurotransmitters
hormones enzymes transport systems
• ion channels • active transporters, e.g. uptake blockers
Drug Receptor interaction
Targets of drug action
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics29
III. MAJOR RECEPTOR FAMILIES
Figure 2.2Transmembrane signaling mechanisms. A. Lignad binds to the extracellular domain of a
ligand-gated channel. B. Ligand binds to a domain of the serpentine receptor, which is coupled to G protein. C. Ligand binds to the extracellular domain of a receptor that activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact with its intracellular receptor.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics30
III. MAJOR RECEPTOR FAMILIESG-protein coupled receptors triggers an increase (or, less
often, a decrease) in the activity of adenylyl cyclase.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics31
III. MAJOR RECEPTOR FAMILIESMechanism of intracellular receptors (e.g. nuclear receptors).
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics32
III. DESENSITIZATION OF RECEPTORS
- Receptor structure change
- Receptor inactivation (protein inhibitors, modifications)
- Down regulation of receptor byendocytosis or degradation
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics33
What is a receptor “agonist”?
Any drug that binds to a receptor and stimulates the functional activities
e.g.: adrenaline (epinephrine)
Receptor
Epinephrine
Cell
Effect
agonist
Drugs that cause a responseDrugs that interact with and activate receptors;
They possess both affinity and efficacyTypes Full agonists An agonist with maximal efficacy (response)
has affinity plus intrinsic activityPartial agonists
An agonist with less then maximal efficacy
has affinity and less intrinsic activity
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics34
Agonists differing in potency and maximum efficacy
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics35
PARTIAL AGONISTS - EFFICACYEven though drugs may occupy the same # of receptors, the magnitude of their effects may differ.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics36
[D] (concentration units)
% M
axim
al E
ffec
t
0.01 0.10 1.00 10.00 100.00 1000.000.0
0.2
0.4
0.6
0.8
1.0
Partial agonist
Full Agonist
Partial agonist
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics37
What is a receptor “antagonist”?
Any drug which can influence a receptor and produce no response
e.g.: propranolol (a beta blocker)
epinephrine
propranololHey, you’rein my way!
Competitive Antagonist: both the drug and its antagonist compete for the same site of the receptor Non-competitive Antagonist: the drug and its antagonist do not compete for the same site
NOT change the receptor Interact with the receptor but do
Have affinity but NO efficacy
Block the action of other drugs
Effect only observed in presence of agonist
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics38
Types of Antagonists
Competitive(Surmountable)decrease apparentPotency
Noncompetitivedecrease apparent maximum efficacy
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics39
Competitive Antagonist
competes with ________for receptor
surmountable with increasing agonist concentration
displaces agonist dose response curve to
the ___________(dextral shift)
reduces the apparent affinity of the __________.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics40
Noncompetitive Antagonist
drug binds to receptor and stays boundirreversible – does not let go of receptor
produces slight dextral shift in the agonist DR curve in the low concentration range
but, as more and more receptors are bound (and essentially destroyed),
the agonist drug becomes incapable of eliciting a maximal effect
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics41
AGONIST VS ANTAGONIST
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics42
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics43
What happen when you increase agonist concentration even higher
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics44
How do non competitive antagonist affect receptor function
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics45
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics46
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics47
Monitoring drug responsesMonitoring drug responses
LevelLevel Molecular (e.g., enzyme inhibition, receptor Molecular (e.g., enzyme inhibition, receptor
binding assay)binding assay) Cellular (Cellular (in vitroin vitro tissue culture, blood cells) tissue culture, blood cells) Tissue or organ (Tissue or organ (in vitroin vitro or or in vivoin vivo)) Animal disease modelAnimal disease model
Endpoint used to measure the effect may be different Endpoint used to measure the effect may be different at each levelat each level
Overall effect = Sum of multiple drug effects and Overall effect = Sum of multiple drug effects and physiological responses to drug effectsphysiological responses to drug effects
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics48
Endpoints to monitor drug effectsEndpoints to monitor drug effects
LEVEL ENDPOINT
Molecular Farnesyltransferase inhibition
Cellular Proliferation rate, Apoptosis
Tumor Response (Change in tumor size)
Organism Survival, Quality of life
Farnesyltransferase inhibitors for cancerFarnesyltransferase inhibitors for cancer
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics49
IV. DOSE-RESPONSE RELATIONSHIPS
Figure 2.6The effect of dose on the
magnitude of pharmacologic response.
Panel A is a linear graph.
*Effect =*Effect =EffectEffectMaxMax • [Drug] • [Drug]
KKDD + [Drug] + [Drug]
*EC50=drug dose that shows fifty percent of maximal response.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics50
IV. DOSE-RESPONSE RELATIONSHIPS
Figure 2.6The effect of dose on the
magnitude of pharmacologic response.
Panel B is a semi-logarithmic plot of the
same data.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics51
Determinants of Drug Activity
1. Potency: the amount of drug to produce an effect of a given magnitude
2. Efficacy: the maximal response (effect) produced by drug
Bio
logi
c ef
fect
Log dose
potency
efficacy
0
50
100
Bio
logi
c ef
fect
(%)
Log dose (mg)
1 10 100
MorphineCodeine
Aspirin
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics52
IV. DOSE-RESPONSE RELATIONSHIPS
Figure 2.7Typical dose-response
curve for drugs showing differences in potency and efficacy.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics53
IV. DOSE-RESPONSE RELATIONSHIPS
Figure 2.9Effects of drug antagonists.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics54
IV. DOSE-RESPONSE RELATIONSHIPS
Figure 2.10Effects of partial agonists.
-1 0 1 2
RE
SPO
NS
E
Full Agonist
Partial Agonist
Antagonist
Log([A]/KA)
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics55
Therapeutic Index
Therapeutic index =
toxic dose(LD50)/effective dose(EC50)
This is a measure of a drug’s safety• A large number = a wide margin of safety• A small number = a small margin of safety
V. QUANTAL DOSE-RESPONSE RELATIONSHIPS
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics56
V. QUANTAL DOSE-RESPONSE RELATIONSHIPS
Figure 2.11Effects of partial agonists.
(Continued overleaf)
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics57
V. QUANTAL DOSE-RESPONSE RELATIONSHIPS
Figure 2.11Effects of partial agonists.
Walter Straub (1874-1944)“There is only a quantitative difference between a drug
and a poison”
Summary (T or F)
Pharmacodynamics is the study of absorption, distribution,
metabolism and elimination of drug. Some drugs can act without binding to a receptor spare receptors allow maximum response without full receptor occupancy Efficacy is the amount of drug needed to produce an effect. Affinity is the attractiveness between 2 drug molecules. Agonist are the drugs that block the response. Partial agonist has affinity and maximum efficacy. Antagonist has efficacy but no affinity. Competitive antagonist decreases potency Non competitive antagonist decreases efficacy
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics58
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics59
Quiz on Monday (Chap 1 & 2)