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.Pharmacology > Lecture 3: Pharmacodynamics > Flashcards

Lecture 3: Pharmacodynamics Flashcards

1
Q

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

A

true

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2
Q

there are __ primary classes of receptors

A

4

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3
Q

what are the 4 primary classes of receptors?

A
  1. intracellular receptors
  2. enzyme-linked receptors
  3. ligand gated ion channels
  4. GPCRs
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4
Q

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

A

nucleus; intranuclear receptors

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5
Q

what is unique about intracellular class receptors?

A

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

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6
Q

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

A
  1. receptors that have enzymatic site as part of the receptor itself
  2. receptors that are associated with intracellular enzymes
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7
Q

in enzyme-linked receptors, activation of receptor causes __

A

increased activity of an enzyme

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8
Q

what are ligand gated ion channels?

A

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

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9
Q

what are G protein coupled receptors?

A

large proteins characterized by 7 transmembrane spanning domains

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10
Q

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

A

G protein complex; cellular events

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11
Q

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

A

fat. to cross the lipid membrane

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12
Q

when activated, intracellular receptors do what 3 things?

A

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

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13
Q

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

A

several hours to days

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14
Q

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

A

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

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15
Q

explain the structure of enzyme linked receptors

A

2 transmembrane spanning units with ligand binding sites the extracellular domains

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16
Q

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

A

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

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17
Q

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

A

interleukin 2 (iL 2)

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18
Q

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

A

tyrosine kinase; enzymatic domains

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19
Q

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

A

intracellular signalling cascade

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20
Q

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

A

closer; phosphorylate each other; autophosphorylation

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21
Q

what is the role of autophosphorylation of 2 receptor subunits?

A

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

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22
Q

what is it called when two receptor subunits associate?

A

dimerization

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23
Q

give an example of ligand gated ion channels

A

nicotinic acetylcholine receptors

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24
Q

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

A

transmembrane pore

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25
Q

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

A

in neurons and muscle cells

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26
Q

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

A

changes conformation, resulting in the opening of the channels

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27
Q

opening of ligand gated ion channel results in ___

A

action potential

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28
Q

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 __

A

fast

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29
Q

give an example of GPCR

A

beta adrenergic receptors

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30
Q

___ is the largest class of drug-targeted receptors

A

GPCR

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31
Q

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

A

50

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32
Q

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

A

7; agonist binding site

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33
Q

the intracellular domain of a GPCR interacts with the __

A

G protein complex

34
Q

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

A

G; GDP for ATP

35
Q

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

A

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

36
Q

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

A

G alpha s (stimulatory_

37
Q

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

A

alpha; enzymatic; adenyl cyclase

38
Q

adenyl cyclase catalyses the reaction that converts __ to __

A

ATP to cAMP

39
Q

what is cAMP and its role?

A

second messenger within cells that activates other proteins

40
Q

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

A

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

41
Q

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

A

protein kinase A

42
Q

another common G alpha protein is ___

A

G alpha I / Gi (inhibitory protein)

43
Q

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

A

adenyl cyclase; cAMP

44
Q

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

A

second messengers and mediators

45
Q

provide an example of G alpha I receptors

A

M2 and M4 muscarinic receptors in the PNS

46
Q

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

A

adenyl cyclase; cAMP

47
Q

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

A

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

48
Q

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

A

the net integration of all the inputs

49
Q

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

A

true

50
Q

what is a third type od G-alpha protein?

A

Gq

51
Q

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

A

phospholipase c (PLC)

52
Q

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

A

IP3 and DAG; PIP 2

53
Q

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

A

Ca2+; smooth muscle, proteins; second messanger

54
Q

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

A

enzymes and kinase; protein kinase C

55
Q

give 2 examples of Gq coupled receptors

A

alpha 1 and the odd numbered muscarinic receptor

56
Q

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

A

true

57
Q

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

A

yes

58
Q

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

A

described

59
Q

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

A

ion channels in neurons; excitability

60
Q

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

A

regulatory cascade to terminate the signalling response

61
Q

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

A

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

62
Q

receptor desensitization typically occurs within __ of exposure

A

minutes

63
Q

what is receptor desensitization?

A

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

64
Q

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

A

baseline

65
Q

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

A

beta-arrestin; internalized

66
Q

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

A

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

67
Q

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

A

agonist and phosphate groups

68
Q

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

A

recycling and desensitization

69
Q

what is desensitization of receptors?

A

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

70
Q

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

A

break them down in lysosome

71
Q

process of moving receptors to the cell surface is called __

A

receptor traficking

72
Q

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 __

A

smaller; receptor downregulation

73
Q

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

A

new receptors are made

74
Q

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

A

the first, agents binding to receptor and initiation of response

75
Q

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

A

brief

76
Q

___ exposure to agonist promotes ___ of receptor to prevent overstimulation

A

long; down regulation

77
Q

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

A

true

78
Q

cellular enzymes are important drug __

A

targets

79
Q

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

A

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

80
Q

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

A

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

81
Q

Drug Agonist

A

Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signalling compound

PRIMARY AGONIST - same recognition site with SAME result with the endogenous ligand

ALLOSTERIC AGONIST - same effect, different binding site with the original ligand

82
Q

Dissociation Constant

A

The strength of the reversible interaction between a drug and its receptor

IncreaseD Dissociation constant will indicate a MORE reversible interactiion

.Pharmacology (55 decks)

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