Pharmacodynamics And Drug Receptors Flashcards
What does the drug receptor complex do
The drug-receptor complex initiates alterations in biochemical
and/or molecular activity of a cell by a process called signal transduction
How do Receptors signal their recognition of a
bound ligand?
by initiating a series of reactions that
ultimately result in a specific intracellular
response
What are second messagers
are
part of the cascade of events that translates
agonist binding into a cellular response.
What are the different type of receptors do cardiac cells have
- p-adrenergic receptors that bind and respond to epinephrine or norepinephrine.
2.Cardiac cells also
contain muscarinic receptors that bind and respond to acetylcholine.
These two receptor populations dynamically interact to control the
heart’s vital functions.
What is the relationship between The magnitude of the response
to the number of drug–receptor complexes?
The magnitude of the cellular response is proportional to the number of drug-receptor complexes
How are Most receptors named
Depending on the compounds that connects to them
Do all drugs exert their effects by interacting with a receptor.
Examples?
No
Antacids, for
instance, chemically neutralize excess gastric acid, thereby reducing
stomach upset.
What are the receptors states
inactive (R) and active (R*),
that are in reversible equilibrium with one another, usually favoring the
inactive state
How do agonists affect the receptors
Fully shift the equilibrium to R*
How do partial agonists affect the equilibrium
shift the equilibrium
from R to R* , but the fraction of R* is less than that caused by an
agonist.
How do fully inverted agonists effect the equilibrium
Shift it all to R
How do antagonists affect the equilibrium
Antagonists are drugs that bind to
the receptor but do not increase the fraction of R*
What are the different definitions for a receptor
any biologic molecule to which a drug binds and produces a measurable response.
Protein molecules whose function is to recognize and
respond to chemical signals.
What is the richest source for pharmacologic receptors
proteins that transduce extracellular signals into
intracellular responses
What are the different receptors
1) ligand-gated ion channels, 2) G protein-coupled receptors, 3)
enzyme-linked receptors, and 4) intracellular receptors
What are lingard-gatee ion channels responsible for
Responsible for regulation of the flow of ions across cell
membranes.
The ligand gated channel is usually
closed until the receptor is activated by an agonist
True
What’s the duration of response of ligand gated channels
a few milliseconds
What do linfand gated channels meditate
these receptors mediate diverse
functions, including neurotransmission and muscle contraction.
For example, stimulation of the nicotinic receptor by acetylcholine opens a channel that allows sodium influx and potassium
outflux across the cell membranes of neurons or muscle cells
(GABA) receptor increases
chloride influx, resulting in hyperpolarization of neurons and less
chance of generating an action potentia
Give examples for drugs that bind on voltage gated channels
local anesthetics bind to
the voltage-gated sodium channel, inhibiting sodium influx and
decreasing neuronal conduction
What are the 3 subunits for proteins
The a subunit
binds guanosine triphosphate (GTP), and the B and y subunits
anchor the G protein in the cell membrane
What are the changes that happens to the G protein when an angonist binds to the receptor
Binding of
an agonist to the receptor increases GTP binding to the a subunit,
causing dissociation of the a-GTP complex from the Itt complex.
The a and Itt subunits are then free to interact with specific cellular
effectors, usually an enzyme or an ion channel, that cause further
actions within the cell
What’s the duration of response for g protein
last several seconds to minutes
•What is a common effector, activated by Gs, and the second messenger ?
is adenylyl cyclase (enzyme) , which produces the second messenger cyclic
adenosine monophosphate (cAMP).
(activated by Gs. and inhibited by Gi)
What’s enzyme does the Gq active
phospholipase C,
What does phospholipaseC, generate
two other second messengers ip3 and DAG
What are enzyme linked receptors
•These consists of a protein that may form dimers
or multi-subunit complexes.When activated, these receptors undergo
conformational changes, resulting in increased
cytosolic enzyme activity
What’s the duration for enzyme like receptors
minutes to hours
•What is the most common enzyme linked to the enzyme linked receptors?
growth factors and insulin
What happens after activating enzyme linked receptors
•The activated receptor autophosphorylates,
• and then phosphorylates tyrosine residues on
specific proteins.
•Phosphorylation can modify the structure of the
target protein, thereby acting as a molecular
switch.
How do intracellular receptors differ from other classes
the
receptor is entirely
intracellular, and, therefore,
the ligand
(for
example,
steroid
hormones) must have sufficient lipid solubility to diffuse into the cell
How long is the response
hours to days
•What is the primary targets of these ligand-
receptor complexes in intracellular receptors
ranscription factors in
the cell nucleus that regulate gene expression
How do intercellular receptors work
The activation
or inactivation of transcription factors alters the transcription of
DNA into RNA and subsequently translation of RNA into proteins.
What are the characteristics of signal transduction
Signal amplification and Desensitization and down-regulation of receptors
How does signal amplification works
A characteristic of G protein-linked and
enzyme-linked receptors is the ability to amplify signal intensity
and duration via the signal cascade effect,activated
G proteins persist for a longer duration than does the original agoist-receptor complex. The binding of albuterol, for example, may
only exist for a few milliseconds, but the subsequent activated G
proteins may last for hundreds of milliseconds.
What are spare receptors
n, only a fraction of the total
receptors for a specific ligand may need to be occupied to elicit a
maximal response
•Compare between the % of Spare receptors
exhibited :
•by insulin receptors,
•To the human heart β-adrenoceptors
About 99% of insulin receptors are “spare;•
providing an immense functional reserve that ensures that adequate amounts of glucose enter the cell.
about 5% to 1 0% of the total b-adrenoceptors in the heart are
spare. Therefore, little functional reserve exists in the failing heart,
because most receptors must be occupied to obtain maximum
contractility.
What is down regulation?
The
receptor may become desensitized due to too much agonist
stimulation
What is the fate of down regulated receptors
receptors may be internalized within the cell, making them
unavailable for further agonist interaction
The magnitude of the drug effect depends on the drug
concentration at the receptor site, which in turn is
determined by:
• 1) the dose of drug administered
• 2) and by the drug’s pharmacokinetic profile.
what is a graded response
the response is continuous and gradual.
what is a quantal response
describes an all-or-nothing response.
what is the potency
A measure of the amount of drug necessary to
produce an effect of a given magnitude.
what is EC50
The concentration of drug producing 50%
of the maximum effect
Therapeutic preparations of drugs reflect their
potency.
❑E.g., candesartan (4 to 32 mg) and irbesartan (75
to 300 mg )are used to treat hypertension.
true
what is the efficacy
The magnitude of response a drug
causes when it interacts with a
receptor.
what does efficacy depends on
1) the number of drug–receptor
complexes formed
2) and the intrinsic activity of the
drug.
what is the maximal efficacy of the drug [E max]
the max response that a drug gives after occuping all of the receptors [no change after increasing the conc]
whats the difference between the E max of the following
- full agonist
- partial agonsit
- antagonist
- full agonist — 100% effect
- partial agonist — 0<x<100%
- antagonist — 0% effect [no effect]
Efficacy is a more clinically useful characteristic than
drug potency.
true
what is the Effect of drug concentration on receptor bindin
quantitative relationship between drug concentration
and receptor occupancy
what is the Kd
the equilibrium dissociation constant for the drug
from the receptor. determines the affinity
what is the affinity
describes the strength of the interaction (binding) between a ligand and its receptor
whats the relationship between the affinity and the Kd
• The higher the Kd value, the weaker
the interaction and the lower the
affinity.
The affinity of an agonist for binding to receptors
should be related to the potency of that drug for
causing that physiological effect.
true
Many drugs and most neurotransmitters can bind to
more than one type of receptor, thereby causing both
desired therapeutic effects and undesirable side
effects.
norephedrine and alpha and beta receptors
what is inrinsic activity
The intrinsic activity of a drug determines its ability to
fully or partially activate the receptors.
what are full agonists
a drug binds to a receptor and produces a maximal biologic response that mimics the response to the endogenous ligand,
what is the intrinsic activity for full agonists
1
what are partial agonists
a drug that cant preduce the same E max as the full agonist even if it has a higher affinity
what is the intrinsic activity for partial agonits
0<x<1
When a receptor is exposed to a partial agonist
and a full agonist, how does the partial agonist
behave?
it behaves as an partial antagonist
What would happen to the Emax
of a receptor saturated with an agonist in the
presence of increasing concentrations of a
partial agonist.
As the number of receptors occupied by the
partial agonist increases, the Emax
would decrease until it reached the Emax of the
partial agonist
aripiprazole (for schizophrenia) is a
partial agonist at dopamine receptors.
true
what is an inverse agonist
it turns all R* to R in spontaneous receptors
what is the intrinsic activity of inverse agonists
less than zero
what is the effect of inverse agonists
reverse the activation state of receptors, and exert the
opposite pharmacological effect of agonists.
what are antagonists
Antagonists bind to a receptor with high affinity but possess zero
intrinsic activity. An antagonist has no effect on biological function in
the absence of an agonist,but can decrease the effect of an agonist
when present by blocking it from binding
what are competitive antagonists
If both the antagonist and the agonist
bind to the same site on the receptor
(reversible), they are “competitive.”
Competitive antagonists shift the
agonist dose–response curve to the
right (increased EC50) without affecting
Emax
true
what are irreversible antagonists
irreversible antagonist bind covalently to the active site of the
receptor, thereby reducing the number of receptors available to
the agonist.
what does irreversible antagonest
An irreversible antagonist causes a downward shift of the Emax,
with no shift of EC50 value.
whats the difference between competitive antagonists and irreversable ones
• Irreversible antagonists cannot be overcome by adding more
agonist.
whats is allosteric antagonists
binds to a site (allosteric site) other than the agonist-binding site and prevents receptor activation by the agonist.
whats the effect of allosteric antagonists
Similar to non-competitive effect on the Emax, and
EC50 value.
whats functional antagonism
An antagonist may act at a completely
separate receptor, initiating effects that are functionally opposite
those of the agonist. A classic example is the functional antago-
nism by epinephrine to histamine-induced bronchoconstriction
what is Quantal Dose–Response Relationships
The influence of the magnitude of the dose on
the proportion of a population that responds. [all or nothing]
what is the therapeutic index
TI = TD50/ED50.
TI is a measure of a drug’s safety, because a larger value
indicates a wide margin between doses that are effective
and doses that are toxic.
What is the Clinical usefulness of the therapeutic index?
These usually reveal a range of effective doses and a
different range of toxic doses.
