Pharmacodynamics II, lect 3

Question 1

when spare receptors exist, the concentration-response curve (EC50) is shifted to the right or left?

Answer 1

Left; smaller dose concentrations

Question 2

what is the relationship between EC50 and Kd when there are spare receptors

Answer 2

EC50 is lower than Kd

Question 3

identify 1 and 2

Answer 3

1. agonist alone
2. agonist + allosteric activator

Question 4

identify 3 and 4

Answer 4

3. agonist + competitive antagonist
4. agonist + non-competitive antagonist

Question 5

what effect does a non-competitive antagonist have on an agonist

Answer 5

reduces the magnitude of the maximal response that can be attained by any amount of agonist

Question 6

what effect does a competitive antagonist have on a agonist

Answer 6

affect the amount of agonist necessary to achieve a maximal response (does not affect the magnitude of the maximal response)

Question 7

competitive antagonist bind to the same receptor as agonist. What effect does this have on the agonist’s Kd? Does the curve shift to the right or left?

Answer 7

• competitive antagonist decreases affinity (increases Kd) of an agonist for its receptor
• curves of agonist shift to the right

Question 8

As the concentration of antagonist increases, what happens to the potency of agonist

Answer 8

• potency of agonist decreases (increases EC50)

Question 9

non-competitive antagonist act either allosterically or covalently. Describe both

Answer 9

• allosteric: inhibit agonist binding at active site by binding to a secondary site on the receptor
• covalent: irreversibly bind to the same site as agonist

Question 10

What effect does adding non-competitive antagonist have on the affinity (Kd) and potency (EC50) of agonist?

Answer 10

affinity (Kd) and potency (EC50) do not change

* E max decreases

Question 11

what is functional (physiological) antagonism

Answer 11

• counteracts effects of agonist
• generally not as specific or as easy to control
• ex: reversing a fall in BP produced by histamine with epinephrine

Question 12

what is chemical antagonism

Answer 12

• directly interacts with agonist and inactivates it
• ex: inactivation heparin with protamine sulfate; neutralizing stomach acid with antacids

Question 13

partial agonist have what level of efficacy (alpha) compared to full agonist

Answer 13

• lower efficacy
• cannot produce the same maximal response as full agonist

Question 14

what is Bmax

Answer 14

the maximum amount of drug that can bind speficially to the receptors; used to measure density of receptor site

Question 15

efficacy

Answer 15

describes the way that agonists vary in the response they produce when they occupy the same number of receptors. High efficacy agonists produce maximal response while occupying a relatively low proportion of total receptor population

Question 16

dose response curve for a partial agonist will have what Emax and Bmax compared to agonist

Answer 16

• LOWER Bmax and Emax

Question 17

if you have a single concentration of full agonist and increasingly add concentrations of a partial agonist,

1. what happens to the response cause by the full agonist?
2. What happens to the response caused by partial agonist?
3. What happens to the total response?

Answer 17

1. response caused by full agonist decreases
2. response caused by partial agonist increases
3. total response gradually decreases

Question 18

when partial agonist is added to a full agonist, why does the response caused by full agonist decrease ? Why does the total response gradually decrease?

Answer 18

• partial agonist can act as competitive antagonist
• bind to receptor, displacing the agonist and the overall effect is lower

Question 19

what is the primary function of intracellular receptors

Answer 19

• modifies gene transcription and protein synthesis in the nucleus
• effect in not immediate
• effects are long lasting

Question 20

what type of ligans are able to stimulate intracellular receptors

Answer 20

lipid soluble ligands (hormones; steroid) : cross plasma membrane

Question 21

receptor tyrosine receptors are what type of receptors? How do they activate substrates when a ligand binds to them?

Answer 21

• transmembrane proteins
• ligand binding to receptor causes 2 receptors to dimerize and activate the kinase causing phosphorylation of the receptor and several down-stream substrates

Question 22

What is the mechanism of Imatinib (Gleevec)

Answer 22

anti-cancer agent: signal transduction inhibitor (STI)

Question 23

In cytokine receptors, where is the kinase activity?

Answer 23

in a seperate protein JAKs

Question 24

how do cytokine receptors work

Answer 24

1. ligand binding causes receptors to dimerize
2. JAKs phosphorylate tyrosine residues on recptor and activate STATs via phosphorylation
3. STATs dissociate from receptor and regulate gene expression

Question 25

ions channels come into 2 forms: name them

Answer 25

* ligand:ex: acetylcholine binds to nicotinic receptors which open Na+ channels and excites the cell * Voltage: ex: local anesthetics and anticonvulsants

Question 26

What is the effect of GABA on GABA receptors

Answer 26

* the binding of GABA to GABA receptors open Cl- channels * hyperpolarizes (inhibits) the cell

Question 27

benzodiazepines, barbituates, and ethanol all act on what receptor to increase Cl- flow in the cell

Answer 27

GABA

Question 28

G protein coupled receptors come as Gs and Gi: what are the action of these

Answer 28

* Gs: stimulatory; activate cAMP * Gi: inhibitory; inhibit cAMP

Question 29

List the steps associated with activation of G-protein receptor

Answer 29

1. GTP binds and GDP is releases 2. alpha unit of G-protein binds to adenylate cyclase to generate intracellular signal 3. the signal is terminated by hydrolysis of GTP

Question 30

B₁ and B₂ are stimulate Gs or Gi

Answer 30

stimulate Gs and activate cAMP

Question 31

alpha₂ stimulate Gs or Gi

Answer 31

stimulate Gi and inhibit cAMP

Question 32

what affect does G-protein receptor kinases (GRK) have on G-protein couples receptors

Answer 32

* increases binding of B-arrestin and decreases the ability of the receptor to interact with G-protein * reduces response and "desensitizes" the receptor

Question 33

binding of B-arrestin has what effect on G-protein coupled receptors

Answer 33

increases endocytosis of the receptor

Question 34

In receptor-effector coupling, what is the function of coupling

Answer 34

the transduction process that links the drug-induced change in receptor conformation to the biological effect

Question 35

In receptor-effector coupling, what are the effectors

Answer 35

the mechanisms coupled to the receptor (Adenylate cyclase; phospholipase C (PLC), etc)

Question 36

in receptor-effector coupling, the biological effect is either what?

Answer 36

* linear: (signal is 1-1) * amplified: biological response is greater than the degree of receptor occupancy

Question 37

adenylate cyclase has what effect on cAMP production

Answer 37

* Gs proteins activate AC which results in the conversion of ATP to cAMP

Question 38

What are the major intracellular targets for cAMP? What function does cAMP have on the targets?

Answer 38

* protein kinases (PKA; PKC) * kinases are composed of 2 regulatory (R) and 2 catalytic (C) subunits; binding of cAMP releases C unites that phosphorylate substrates

Question 39

Gq proteins activate what?

Answer 39

PLC

Question 40

After Gq activates PLC; what is the action of PLC

Answer 40

PLC hydolyzes PIP2 to form IP3 and DAG

Question 41

what is the function of IP3 and DAG

Answer 41

* IP3 diffuses through the cytoplasm and releases Ca2+ from intracellular stores * DAG activates protein kinase C (PKC)

Question 42

how does nitric oxide elicit relaxation of vascular smooth muscle

Answer 42

1. NO is a diffusable ligand that activates guanyl cyclase 2. activated guanyl cyclase converts GTP to cGMP 3. cGMP activates protein kinase G (PKG) 4. PKG -\> vasodilation