Lecture 2 - Pharmacodynamics (Receptors)

Question 1

what is the Law of Mass Action?

Answer 1

the rate of a reaction is dependent on the concentration of the reagents and how well they mix together

Question 2

how fast a drug and receptor bind

Answer 2

rate of association

Question 3

how fast the drug and receptor unbind

Answer 3

rate of dissociation

Question 4

in pharmacology, the “reagents” of a reaction are:

Answer 4

the drug and the receptor

Question 5

at equilibrium, the rates of association and dissociation are equal so:

Answer 5

the amount of drug bound to the receptor is stable

Question 6

what is the equilibrium dissociation constant (Kd)?

Answer 6

the ratio of the dissociation constant (Koff) and association constant (Kon) at equilibrium

Question 7

what does it mean for a drug to have low Kd?

Answer 7

the drug binds to the receptor very well (very little dissociation)

Question 8

what is the Hill-Langmuir equation?

Answer 8

[AR] = ([A][Rt]) / ([A]+[Kd])
*A = drug
*R = receptor

Question 9

the law of mass action equation forms what type of curve?

Answer 9

a sigmoidal curve

Question 10

when [A]=Kd, the concentration of the drug is just enough to:

Answer 10

occupy half the receptors (Kd = [Rt]/2)

Question 11

what two characteristics the law of mass action can be determined using the Hill-Langmuir equation (but more specifically the graph)?

Answer 11

the maximum system capability (Rt) and the system sensitivity (Kd)

Question 12

most drugs interact with receptors in a _____ manner to produce change in the state of the receptor

Answer 12

reversible

Question 13

the binding of a drug and receptor determines the quantitative relationship between:

Answer 13

dose and effect

Question 14

most drugs influence a cellular process, either by interacting with a ____, ____, ____, or _____

Answer 14

receptor, channel, transporter, or enzyme

Question 15

proteins that respond to an external stimulus, and induces a change inside the cell

Answer 15

receptors

Question 16

proteins which form pores in the cell membrane that allow passive movement of ions into or out of the cell

Answer 16

channels

Question 17

movement of ions across the cell membrane through channels is driven by:

Answer 17

passive diffusion, and do not require energy

Question 18

proteins which actively transport molecules across the membrane using ATP or other high energy molecules

Answer 18

transporters

Question 19

types of receptors which are located inside the cell

Answer 19

intracellular receptors

Question 20

in order for drugs to act on an intracellular receptor, they must:

Answer 20

cross the plasma membrane

Question 21

in order for drugs to cross the plasma membrane, they must be:

Answer 21

lipid soluble

Question 22

what is an example of drugs which act on intracellular receptors?

Answer 22

steroid hormones

Question 23

a steroid binds to the _____ of a steroid hormone receptor, leading to displacement of _____ or other chaperones, which exposes a DNA recognition domain and leads to _____

Answer 23

ligand binding domain (LBD), heat shock protein (HSP), transcription of target genes (receptor enters nucleus and binds DNA)

Question 24

how quickly do steroid hormones act?

Answer 24

effects typically have a slow-onset and are long-lasting

Question 25

the largest group of membrane receptors in eukaryotes

Answer 25

G-protein-coupled-receptors (GPCRs)

Question 26

how many marketed drugs act at GPCRs?

Answer 26

1/3 to 1/2

Question 27

in GPCRs, ligands bind to the extracellular side, and trigger a conformational change that:

Answer 27

activates a signalling cascade mediated by intracellular G-proteins

Question 28

GPCRs are made of a single polypeptide that is folded into a globular shape embedded in the plasma membrane called a:

Answer 28

7 transmembrane receptor

Question 29

what is the purpose of the extracellular loops of GPCRs?

Answer 29

form a pocket where signalling molecules can bind

Question 30

specialized proteins that bind nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP)

Answer 30

G-proteins

Question 31

GPCR G-proteins are _____, meaning they have three different subunits (alpha, beta, gamma)

Answer 31

heterotrimeric

Question 32

what does the alpha subunit do when the GPCR is activated?

Answer 32

the alpha subunit swaps a GDP nucleotide (resting form) for a GTP nucleotide (active form)

Question 33

when GDP is swapped for a GTP on a GPCR, this causes the protein to:

Answer 33

dissociate into two parts (alpha and beta-gamma)

Question 34

true or false: when the G-protein dissociates, both subunits remain tethered to the membrane and can interact with other signalling molecules

Answer 34

true

Question 35

has GTPase activity that acts like a molecular 'timer' to terminate the signal

Answer 35

the alpha subunit

Question 36

what happens to the G-protein after GTP is hydrolyzed back to GDP?

Answer 36

the inactive G-protein complex reassembles and the system can reset

Question 37

GPCRs can be categorized based on:

Answer 37

the type of alpha subunit that is associated

Question 38

what are the three types of alpha subunits?

Answer 38

Gs, Gi, and Gq

Question 39

different alpha subunits influence different signalling cascades via effects on _____ or _____

Answer 39

adenylate cyclase (AC), phospholipase C (PLC)

Question 40

can influence the activity of a variety of protein types including ion channels

Answer 40

beta-gamma subunits

Question 41

one of the most common G-protein mediated signalling cascades is via:

Answer 41

adenylate cyclase (AC)

Question 42

list the mechanism of action when a drug binds to a receptor coupled to the Gs signalling cascade

Answer 42

1) increased activity of AC 2) production of cAMP 3) activation of cAMP dependent protein kinases (ex: PKA) 4) phosphorylation of targets

Question 43

list the mechanism of action when a drug binds to a receptor coupled to the Gi signalling cascade

Answer 43

1) suppressed activity of AC 2) decreased production of cAMP 3) inactivation of cAMP dependent protein kinases 4) no phosphorylation of targets

Question 44

list the mechanism of action when a drug binds to a receptor coupled to the Gq signalling cascade

Answer 44

1) increased activity of PLC 2) production of inositol triphosphate (IP3) and diacyl glycerol (DAG) from the breakdown of PIP2 3) IP3 triggers the release of intracellular Ca++ (influences a variety of signalling pathways) 4) DAG activates protein kinase C (PKC) and target substrates

Question 45

activation of tyrosine kinase receptors is driven by _____ in the presence of a ligand, causing the receptors to _____ and become activated

Answer 45

dimerization of receptors, autophosphorylate

Question 46

drugs that inhibit or stimulate the activation of tyrosine kinase receptors will influence:

Answer 46

downstream signalling molecules

Question 47

the fastest mechanism of signalling in the body depends on:

Answer 47

electrical signals generated by ion channel proteins

Question 48

allow ions to cross the membrane rapidly, leading to changes in membrane voltage

Answer 48

ion channels

Question 49

different ion channels are controlled by distinct stimuli, such as _____ or changes in _____

Answer 49

ligand binding, membrane voltage

Question 50

proteins which open or close in response to the binding of a small signalling molecule (like amino acids or neurotransmitters)

Answer 50

ligand-gated channels

Question 51

proteins which response very rapidly to changes in membrane voltage

Answer 51

voltage-gated ion channels

Question 52

specialized proteins that assist in the movement of ions, peptides, small molecules, lipids, and macromolecules across a biological membrane, moving the substrate against their concentration gradient (uses energy)

Answer 52

active transporters

Question 53

what is an example of an active transporter?

Answer 53

the dopamine transporter: which clears dopamine from the synapse cocaine blocks the dopamine transporter, leading to an accumulation of dopamine in the synapse