Drug Receptors - Pharmacodynamics Flashcards
The component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug’s observed effects.
Receptor
T/F: Receptors largely determine the qualitative relations between dose or concentration of drug and pharmacologic effects.
F; quantitative
T/F: Receptors are responsible for selectivity of drug action.
T
T/F: Receptors mediate the actions of pharmacologic agonists and antagonists.
T
Interferes with the ability of an agonist to activate the receptor
Antagonist
It used to identify or purify receptor proteins from tissue extracts; consequently, receptors were discovered after the drugs that bind to them.
Drug Binding
The best-characterized drug receptors are __________, which mediate the actions of endogenous chemical signals such as neurotransmitters, autacoids, and hormones
Regulatory Proteins
The receptor for the antineoplastic drug methotrexate
Dihydrofolate reductase
The receptor for statins; and various protein and lipid kinases.
3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase
_________ can be useful drug targets.
Transport Proteins
The membrane receptor for cardioactive digitalis glycosides
Na+/K+- ATPase
The receptor for colchicine, an anti-inflammatory drug
Tubulin (Structural Proteins)
Mediates the effects of the most useful therapeutic agents
Regulatory Proteins
Best characterized drug receptors
Regulatory Proteins
↑ Kd = _ Binding Affinity
↓
Smaller EC50 = ____ Potency of the Drug
Greater
Molecules that translate the drug-receptor interaction into a change in cellular activity
Effectora
T/F: All receptors are effectors.
F; Some
A single molecule may incorporate both the drug binding site and the effector mechanism
Effectors
The maximal response that can be produced by the drug
Emax
The concentration of drug that produces 50% of maximal effect.
EC50
Resembles the mass action law that describes the association between two molecules of a given affinity.
Hyperbolic Relation
_________________ have been used to confirm this occupancy assumption (Hyperbolic Relation) in many drug-receptor systems
Radioactive receptor ligands
The total concentration of receptor sites
Bmax
represents the concentration of free drug at which half-maximal binding is observed
Kd / Equilibrium Dissociatoon Constant
Response of a particular receptor-effector system is measured against increasing concentration of a drug
Graded Dose-Response Curve
↓ EC50 = _____ amount needed to produce 50% = _____ potent drug
Smaller; more
Graph of the response versus the drug dose
Graded-Dose Response Curve
Maximal response that can be produced by a drug
Emax
Emax & Bmax
Are all receptors occupied?
Yes
Emax
Is there a response even if the dose is increased?
No
Total number of receptor sites
Bmax
Measure of the affinity of a drug for its binding site on the receptor
Kd
Are often presented as a plot of the drug effect (ordinate) against the logarithm of the dose or concentration (abscissa), transforming the hyperbolic curve into a sigmoid curve with a linear midportion
Dose-response data
The overall transduction process that links drug occupancy of receptors and pharmacologic response
Coupling
The relative efficiency of occupancy-response coupling is determined by
- Receptor itself
- “Downstream” biochemical events
Maximal drug response is obtained at less than maximal occupation of the receptors
Not qualitatively different from nonspare receptors, not hidden or unavailable
Temporal in character, when occupied, they can be coupled to respond, there is still effect
Spare Receptors
Drugs with low binding affinity for receptors will be able to produce full response even at low concentration
Spare Receptors
Kd (>/<) EC50 with spare receptors
>
Spare Receptors
T/F: Effect lf the drug-receptor interaction may persist for a longer time than the interaction itself.
T
Spare receptors may exceed the number of effectors available
Yes, as long as they consume the effectors present, kahit dagdagan mo pa, di na tataas yung effect
nakadepend ang effect sa effectors
Non-regulatory molecules of the body
Inert Binding Sites
Binding with these molecules will result to no detectable change in the function of the biologic system
Inert Binding Sites
Buffers the concentration of the drug
Bound drugs do not contribute directly to the concentration gradient that drives diffusion
Inert Binding Sites
Binds to the receptor and directly or indirectly bring about an effect
Full activation of the effector system
Agonist
Produces less than the full effect, even when it has saturated the receptors
Acts as an inhibitor in the presence of a full agonist
Partial Agonist
Binds but do not activate the receptors
Blocks / competes with agonist
Antagonist
Classification of Antagonist
- Competitive Antagonist
- Irreversible Antagonist
- Chemical Antagonist
- Physiologic Antanogist
Competes with agonist receptor
Binds to the receptor reversibly without activating the effector system
Competitive Antagonist
T/F: Spare receptors may be demonstrated by using irreversible antagonists to prevent binding of agonist to a proportion of available receptors and showing that high concentrations of agonist can still produce an undiminished maximal response
T
Antagonist (increases/decreases) the agonist concentration needed for a given degree of response
increases
2 Therapeutic Implications of Competitive Antagonist
(1) Degree of inhibition produced by the competitive antagonist depends on the concentration of
antagonist (eg, propranolol)
(2) Clinical response to a competitive antagonist
depends on the concentration of agonist that is competing for binding to the receptor
Antagonist that will not achieve maximal effect
Irreversible Antagonist
Binds with the receptor via covalent bonds
Receptor is mot available to bind the agonist
Irreversible Antagonist
More dependent on the rate of turnover of receptors
Irreversible Antagonists
Concentration-effect curve moves downward
No shift of the curve in the dose axis
Emax is not reached
No increase in median effective dose (ED50) unless there are spare receptors
Irreversible Antagonist
Does not depend on interaction with the agonist’s receptor
Drug that interacts directly with the drug being antagonized to remove it or to prevent it from reaching its target
Chemical Antagonism
Makes use of the regulatory pathway
Effects that are less specific & less easy to control
Physiologic Antagonism
Binds to a different receptor producing an effect opposite to that produced by the drug it is antagonizing
Physiologic Antagonism
The total number of receptors present compared with the number actually needed to elicit a maximal biologic response.
Degree of Spareness
The concentration (C′) of an agonist required to produce a given effect in the presence of a fixed concentration ([I]) of competitive antagonist is greater than the agonist concentration (C) required to produce the same effect in the absence of the antagonist. The ratio of these two agonist concentrations (called the dose ratio) is related to the dissociation constant (Ki ) of the antagonist
Schild Equation
Occurs when a drug reduces the concentration of an agonist by forming a chemical complex
Chemical Antagonism
T/F: some types of antagonism do not involve a receptor at all
T
Binding to a different site “allosterically” on the receptor relative to the classical “orthosteric” site bound by the agonist.
Allosteric Modulators
Can also bind at targets lacking a known orthosteric
binding site
Allosteric Modulators
potentiate the receptor activity
Positive Allosteric Modulators
reduce the receptor activity
Megative Allosteric Modulators
Produce concentration-effect curves that resemble those observed with full agonists in the presence of an antagonist that irreversibly blocks some of the receptor sites.
Partial Agonists
T/F: Failure of partial agonists to produce a maximal response is not due to decreased affinity for binding to receptors.
T
competitively inhibit the responses produced by full agonists
Partial Agonists
Intracellular molecules that translate the drug-receptor interaction into a change in cellular activity (e.g. adenylyl cyclase)
Effectors
Bind to receptors but do not activate them
Receptor Antagonists
T/F: Most effectors are found inside the cell
F; surface of the cell
T/F: A single molecule may incorporate both the drug binding site and the effector mechanism
T
↑ PA Occupancy = _ FA Binding
↓
PA = _ Maximal Response
↓
Transmembrane Signaling Mechanisms
1: A lipid-soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor (which may be an enzyme or a regulator of gene transcription);
2: the signal binds to the extracellular domain of a transmembrane protein, thereby activating an enzymatic activity of its cytoplasmic domain;
3: the signal binds to the extracellular domain of a transmembrane receptor bound to a separate protein tyrosine kinase, which it activates;
4: the signal binds to and directly regulates the opening of an ion channel;
5: the signal binds to a cell-surface receptor linked to an effector enzyme by a G protein.
______ hormone, whose receptors stimulate the transcription of genes by binding to specific DNA sequences (often called ________) near the gene whose expression is to be regulated.
Thyroid; Response Elements
allows the DNA-binding and transcription-activating domains of the receptor to fold into their functionally active conformations, so that the activated receptor can initiate transcription of target genes.
hsp90
The mechanism used by hormones that act by regulating gene expression has two therapeutically important consequences:
- All of these hormones produce their effects after a characteristic lag period of 30 minutes to several hours.
- The effects lf these agents can persist for hours / days after the agonist concentration has been reduced to zero.
Mediates hormonal responses
cAMP (Cyclic adenosine monophosphate)
These receptors are polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain, which may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase
Ligand-Regulated Transmembrane Enzymes
The intensity and duration of action of EGF, PDGF, and other agents that act via receptor tyrosine kinases are often limited by a process called ___________.
Receptor down-regulation
respond to a heterogeneous group of peptide ligands, which include growth hormone, erythropoietin, several kinds of interferon, and other regulators of growth and differentiation.
Cytokine Receptors
A separate protein tyrosine kinase, from the _______ family, binds noncovalently to the cytokine receptor.
Janus-kinase (JAK)
Tyrosine kinase signaling function sequence
- Binding of Ligand
- Dimerization
- Activates the tyrosine kinase enzyme activity (phosphorylation)
- Phosphorykation of tyrosine residues
- Binding of EGF
- The receptor converts from its inactive monomeric state to an active dimeric state
7, The cytoplasmic domains become phosphorylated (P) on specific tyrosine residues (Y), then enzymatic activities are activated - Phosphorylation of substrate proteins (S).
bind to the extracellular domain of a particular receptor and interfere with binding of growth factor.
membrane permeant small molecule chemicals (eg,
gefitinib, erlotinib)
inhibit the receptor’s kinase activity in the cytoplasm
Inhinitors of tyrosine kinases / Monoclonal antibodies
