Lecture 3: Pharmacodynamics Flashcards by AFD Alvarez

t/f all receptors exhibit similar basic principles wrt their interactions with drugs

true

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there are __ primary classes of receptors

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what are the 4 primary classes of receptors?

intracellular receptors
enzyme-linked receptors
ligand gated ion channels
GPCRs

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the intracellular class of receptors is sometimes further subdivided for receptors that remain in the __. These are called __

nucleus; intranuclear receptors

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what is unique about intracellular class receptors?

the ligands acting on them must enter the cell in order to have their effect

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enzyme-linked receptors can be divided into what 2 categories?

receptors that have enzymatic site as part of the receptor itself
receptors that are associated with intracellular enzymes

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in enzyme-linked receptors, activation of receptor causes __

increased activity of an enzyme

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what are ligand gated ion channels?

membrane channels that allow passage of ions based on binding ion ligand

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what are G protein coupled receptors?

large proteins characterized by 7 transmembrane spanning domains

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in a GPCR, the intracellular domain associates with a __, which when activated will initiate a series of __ to cases a cellular response

G protein complex; cellular events

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most drugs that bind to intracellular receptors are __ soluble. why is this?

fat. to cross the lipid membrane

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when activated, intracellular receptors do what 3 things?

. Interact with gene response elements on DNA and modulate gene transcription, resulting in changes in protein synthesis

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what is the time frame of intracellular receptor drugs to have aparent effects?

several hours to days

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why does it take so long for intarcellaulr receptor drugs to take effect?

processes of receptor stimulation to protein synthesis takes a significant amount of time

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explain the structure of enzyme linked receptors

2 transmembrane spanning units with ligand binding sites the extracellular domains

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what happens to the 2 subunits of an enzyme linked receptor when a ligand binds?

the 2 subunits associate together to initiate enzymatic activity within the cell

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give an example of an enzyme linked receptor that associates with intracellular tyrosine kinase enzymes

interleukin 2 (iL 2)

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the epidermal growth factor is an example of a ___ type receptor, which contains ___ as part of the intracellular parts of the receptor itself

tyrosine kinase; enzymatic domains

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the associated / “built in” tyrosine kinase domains initiate ___ when receptor is activated

intracellular signalling cascade

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when 2 receptor subunits associate, they become __ in relation to each other and this allows them to _____, which is called ___

closer; phosphorylate each other; autophosphorylation

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what is the role of autophosphorylation of 2 receptor subunits?

activates enzymatic activity and initiates the downstream signalling response in the cell

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what is it called when two receptor subunits associate?

dimerization

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give an example of ligand gated ion channels

nicotinic acetylcholine receptors

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ligand gated ion channels contain a ___ that when opened allows the flow of ions across the membrane

transmembrane pore

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where can ligand gated ion channels be found in the body?

in neurons and muscle cells

binding of a ligand to a ligand gated ion channel causes what to happen to the receptor?

changes conformation, resulting in the opening of the channels

opening of ligand gated ion channel results in ___

action potential

the time from the ligand binding to the gated ion channel receptor to when there is a physiologic response (such as muscle contraction) is very __

fast

give an example of GPCR

beta adrenergic receptors

___ is the largest class of drug-targeted receptors

GPCR

it is estimated that approximately ___% of drugs interact with GPCR

A GPCR has __ transmembrane domains with an ___ formed within them

7; agonist binding site

the intracellular domain of a GPCR interacts with the __

G protein complex

when an agonist binds to the GPCR pocket, there is a conformational change in the large ___ protein, which facilitates now the exchange of ___ for ___

G; GDP for ATP

what happens to the high-energy G protein complex and the G protein subunits after exchanging GDP for GTP?

the high energy G protein complex dissociates from the receptor and the subunits (alpha and beta) separate and initiate intracellular signalling cascades

when epinephrine activates the beta-adrenergic receptors in the heart, what g-protein is activated?

G alpha s (stimulatory_

when a GPCR is coupled to a Gs protein, the activated __ subunit dissociates and increases the __ activity of ___

alpha; enzymatic; adenyl cyclase

adenyl cyclase catalyses the reaction that converts __ to __

ATP to cAMP

what is cAMP and its role?

second messenger within cells that activates other proteins

one of the primary effector molecules activated by the Gs signalling pathway is the ___. what are 4 cellular roles of this effector molecule?

protein kinase A; increase heart rate and calcium, increase metabolism, increase hormone production

___ is the mediator responsible for initiating the cellular changes that increase heart rate and contractility when epinephrine activates the beta-adrengeric receptors

protein kinase A

another common G alpha protein is ___

G alpha I / Gi (inhibitory protein)

G alpha I inhibits ____ and reduces the cellular production of __

adenyl cyclase; cAMP

G alpha I has an inhibitory effect in cells that regulates activities of __ and __

second messengers and mediators

provide an example of G alpha I receptors

M2 and M4 muscarinic receptors in the PNS

activation of Gs and Gi receptors converge on __ , the enzyme that produces __

adenyl cyclase; cAMP

when Gs and Gi are activated simultaneously, there will be ___ input into adenyl cyclase enzymes within a cell. why is this?

competing; because most cells in the body express many receptor types and it is possible that several are being modulated by endogenous molecules and drugs at the same time

the overall cellular response when there are many competing inputs will be ___

the net integration of all the inputs

t/f the observed physiologic response may be the result of many signalling pathways converging

true

what is a third type od G-alpha protein?

activated G alpha q enhances the activity of the cellular enzyme __

phospholipase c (PLC)

Gq enhancing the activity of PLC increases the production of ___ an d__ by splitting the membrane phospholipid __

IP3 and DAG; PIP 2

increased cellular levels of IP3 causes release of __ which promotes contraction of ___ and is also able to modulate other ___ and act as a ___

Ca2+; smooth muscle, proteins; second messanger

DAG can activate other ___ and ___ such as __ to cause further intracellular changes

enzymes and kinase; protein kinase C

give 2 examples of Gq coupled receptors

alpha 1 and the odd numbered muscarinic receptor

t/f there are many more subtypes of Gbeta and Ggamma than G alpha, which results in a lot of combinations of G. beta gamma

true

do the beta and gamma subunits remain together when the G protein dissociates from the receptor?

yes

the extent of G beta gamma downstream effects are not as well __as for G alpha

described

some key cellular effects of G beta gamma are the interactions and modulations of __ in __, which alters the __ of these cells

ion channels in neurons; excitability

in order to regulate cellular response and prevent over stimulation, the activation of G-protein receptors also initiates a __

regulatory cascade to terminate the signalling response

after the G protein dissociates, the receptor remains on the ____. Kinases called ____ phosphorylate the __ of the receptor, which prevents the association of another ___

cell surface, G-protein coupled receptor kinase (GRK); G-Protein

receptor desensitization typically occurs within __ of exposure

minutes

what is receptor desensitization?

cellular response to agonist declines (due to phosphorylation of receptors) even though the agonist is still present

in receptor desensitization, the response will not go completely to __ when the agonist is still present, but will be significantly reduced

baseline

___ binds to the phosphorylated tail of the inactivated complex, causing the receptor to be ___

beta-arrestin; internalized

once internalized, what are the two options for the fate of a receptor?

can be recycled and brought back to the surface of cell or can be broken down by lysosomes

if the cell decides to recycle a receptor, what 2 things have to be removed?

agonist and phosphate groups

the brief periods of agonist exposure with periods of none present promotes receptor ___ and ____ of the cell

recycling and desensitization

what is desensitization of receptors?

the receptors that have been recycled are moved back to the surface when no agonist is present, and will be ready to accept more if it comes

if the cell is being overstimulated, what is it likely to do with the internalized receptors?

break them down in lysosome

process of moving receptors to the cell surface is called __

receptor traficking

if the cell has fewer receptors available, even after a period of no agonist, when the agonist comes back, the response may be ___ this is a hallmark of __

smaller; receptor downregulation

when a cell chooses to break down its receptors, the full response cannot be achieved agin until___

new receptors are made

the majority of our considerations of the actions of drugs will be based on which step of the G-protein life cycle ?

the first, agents binding to receptor and initiation of response

___ exposure to agonist promotes quick turn around times between desensitization and resensitization, which promotes repeated physiologic responses

brief

___ exposure to agonist promotes ___ of receptor to prevent overstimulation

long; down regulation

t/f there are any druggable targets which are not receptors

true

cellular enzymes are important drug __

targets

give 2 examples of drugs that target enzymes and how they work

ACE inhibitors that reduce blood pressure by decrease enzyme production of angiotensin. 2) cyclooxyrgenase inhibitors have anti-inflammatory effects by reducing the synthesis of inflammatory mediators

give 2 examples of drugs that do not have a specific target but rather change the physiologic environment

antacids that act by simple acid-base chemistry to neutralize stomach and 2) osmotic laxatives attract water to be absorbed into the intestine to relive constipation

Drug Agonist

Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signalling compound ## Footnote **PRIMARY AGONIST** - same recognition site with SAME result with the endogenous ligand **ALLOSTERIC AGONIST** - same effect, different binding site with the original ligand

Dissociation Constant

The strength of the reversible interaction between a drug and its receptor ## Footnote IncreaseD Dissociation constant will indicate a MORE reversible interactiion