Podgorski - Dose Response Curves

Question 1

Pharmacokinetics

Answer 1

How factors affect the conc. of drug at active site as a function of time

Question 2

Pharmacokinetic processes

Answer 2

ADME - absorption, distribution, metabolism, excretion

Question 3

Pharmacodynamics

Answer 3

How target cells respond to delivered conc. of drug

Question 4

Majority of drug receptors:

Drugs:

Answer 4

Cell-surface signaling protein. Bind NT/hormones

Proteins

Question 5

Basic mechs of transmembrane signalling

Answer 5

1. Lipid-soluble ligand
2. Transmembrane receptor protein
3. Transmembrane receptor
4. Ligand-gated ion channel
5. G-protein coupled receptor – production of intracellular second messengers

Question 6

Transmembrane receptor protein

Answer 6

Its activity regulated allosterically by a

ligand binding to extracellular domain

Question 7

Lipid-soluble ligand

Answer 7

Acts on intracellular receptor

Question 8

Transmembrane receptor

Answer 8

Binds and stimulates protein tyrosine kinase

Question 9

Ligand-gated ion channel

Answer 9

Opening and closing regulated by ligand binding

Question 10

G-protein coupled receptor

Answer 10

Production of intracellular second messengers

Question 11

Receptor Properties (3)

Answer 11

1. Determine the quantitative relations between dose or
   concentration of drug and pharmacologic effects
2. Determine drug selectivity of action (depending on
   molecular size, shape, and electrical charge of a drug)
3. Mediate the actions of pharmacologic agonists and
   antagonists.

Question 12

Drug receptor vs. target

Answer 12

Phospholipids, gangliosides, channel proteins, intracellular enzymes, DNA = Targets

Question 13

Lipid Soluble Drugs:

Enzymes
Transcription factors
Structural proteins

Answer 13

Enzymes: alter production of metabolic molecule (vit k and coagulase cascade)

TFs: steroids and thyroid hormone

SPs: antimitotic vinca alkaloids

Question 14

Glucocorticoid receptor action

Act by:
Lag period:
Persists:

Answer 14

Act by regulating gene expression

Lag period of 30 min to several hours

persisting effects – hours or days

Question 15

Transmembrane enzyme receptors:

Extracellular vs intracellular

Answer 15

extracellular hormone-binding domain

intracellular enzyme domain

Question 16

Transmembrane enzyme receptors:

Mediate first steps in:

Answer 16

insulin, EGF, PDGF, ANP, and TGFb signaling

Question 17

Transmembrane enzyme receptors intensity and duration regulated by:

Answer 17

receptor downregulation

Question 18

Transmembrane enzyme receptors:

examples:

Answer 18

monoclonal antibodies (trastuzumab,
cetuximab); small molecule inhibitors (gefitinib, erlotinib)

Question 19

Source of protein kinase activity in cytokine receptors:

Answer 19

Jak kinases (not intrinsic)

Question 20

Cytokine receptors examples:

Answer 20

Ligands include growth hormone, erythropoietin, several kinds of interferon; mechanism closely related to RTKs

Question 21

LIGAND-GATED CHANNELS Mimic action of:

Answer 21

endogenous ligands (acetylcholine,
serotonin, GABA, glutamate)

Question 22

LIGAND-GATED CHANNELS Transmit signal across plasma membrane by:

Answer 22

Transmit signal across plasma membrane by increasing transmembrane conductance and changing membrane potential

Question 23

LIGAND-GATED CHANNELS regulated by:

Answer 23

multiple mechanisms (e.g. phosphorylation
and endocytosis)

Question 24

LIGAND-GATED CHANNELS response time:

Answer 24

rapid (milliseconds)

Question 25

Voltage gated channels are controlled by:

Answer 25

membrane potential

Question 26

Voltage gated channels ex:

Answer 26

verapamil (voltage-gated calcium channel). anti arrhytmic effects through actions on voltage-gated calcium channels. remember, both ligand and voltage-gated channels have very fast response times (millliseconds)

Question 27

Examples of ligand-gated receptor:

Answer 27

Nicotinic acetylcholine (ACh) R

Question 28

G-protein coupled receptors, | mech

Answer 28

second messengers

Question 29

G-protein coupled receptors, | examples

Answer 29

Biggest group | beta-adrenoreceptors, glucagon receptors, thyrotropin receptors, subtypes of DA and 5HT Rs

Question 30

2nd messenger activation: adenylyl cyclase type of response: acts via: response

Answer 30

Hormonal responses Acts via stimulation of cAMP-dependent neurotransmitters, growth factors protein kinases Response: increase or decrease in cAMP

Question 31

2nd messenger activation: Phospholipase C triggered by: acts via: response:

Answer 31

Triggered by hormones, neurotransmitters, growth factors * Acts via binding to GPCR (G Protein-Coupled Receptors) or RTKs (receptor tyrosine kinase) * Response: increase in IP3, DAG

Question 32

Mass action

Answer 32

increasing ligand conc. produces more binding controls binding of ligands to receptor

Question 33

Kd =

Answer 33

Equilibrium dissociation constant conc. at which 50% of receptors or occupied Kd = [D][R]/ [DR] = Koff/Kon ``` D= free drug R= free receptor DR= drug-receptor complex ```

Question 34

Kd at equilibrium =

Answer 34

[D][R] Kon = [DR] Koff

Question 35

Why do the binding and response curves look identical?

Answer 35

assume response is directly proportional to the amount of drug-receptor complex that is formed.

Question 36

How is drug-receptor binding like enzyme kinetics?

Answer 36

Response ~ velocity Kd ~ km

Question 37

Response/response max =

Answer 37

[DR]/[R]t = [D]/[D] + Kd

Question 38

Agonist definition

Answer 38

binds to a receptor and stabilizes | it in a particular conformation

Question 39

Efficacy def:

Answer 39

measure of max response (height on curve)

Question 40

EC50 def:

Answer 40

conc. req. for 50% of the max response

Question 41

Potency def:

Answer 41

comparison of EC50s. More potency = less conc. needed for response (The one closer to the left has higher potency)

Question 42

Antagonist def:

Answer 42

An agent that binds to a receptor but cannot produce the conformational change necessary to trigger the downstream events.

Question 43

Response when antagonist binds by itself:

Answer 43

None; binds but can't produce the conformational change necessary to trigger downstream events

Question 44

Competitive vs noncompetitive antagonists

Answer 44

competitive: reversible non: irreversible

Question 45

effects of competitive antagonists on chart:

Answer 45

Apparent Kd for the agonist increases Shifts to the right (higher conc. needed for same response) No effect on efficacy

Question 46

NC antagonist binds: effect on efficacy

Answer 46

binds to active or allosteric site of the receptor (downstream effects) This cannot be overcome by increasing agonist concentrations reduces efficacy

Question 47

Non competitive antagonist summary effect on affinity and potency

Answer 47

As the noncompetitive inhibitor conc.increases, the apparent efficacy decreases since the inhibitor inactivates receptors or downstream effectors. no effect on apparent affinity (Kd) for pure noncompetitive antagonists potency is not affected

Question 48

Physiological antagonism: Exs:

Answer 48

Caused by agonist and antagonist acting at two independent sites and inducing independent, but opposite effects Exs: glucocorticoid hormones and insulin)

Question 49

Chemical antagonism: Exs:

Answer 49

Caused by combination of agonist with antagonist, with resulting inactivation of the agonist (e.g., dimercaprol and mercuric ion; heparin and protamine)

Question 50

Inverse agonist

Answer 50

Inverse agonist produces effect opposite to the effect of agonist

Question 51

Which of the following terms best describes a drug that blocks the action of epi at its vascular alpha receptors by occupying the epi receptor binding sites without activating them?

Answer 51

Non-competitive antagonists

Question 52

What best describes an antagonist that interacts directly with the agonist and not at all, or only incidentally with the receptor?

Answer 52

Chemical antagonist

Question 53

"Spare receptors" What pathway? Effects? common for: linked to:

Answer 53

alpha 1 adrenergic pathway full response with less than 100% receptor occupancy common for hormone receptors and neurotransmiiters true for receptors linked to enzymatic signal transduction cascades

Question 54

Mechanism of spare receptor: Results:

Answer 54

receptor remains activated after the agonist departs, allowing one agonist molecule to activate several receptors cell signaling pathways allow for significant amplification of relatively small signal, and activation of only few receptors produces maximal response result: high sensitivity with fast turn-off

Question 55

Receptor regulation:

Answer 55

Rapid desensitization Resensitization Downregulation

Question 56

congeners of ACh Analog of ACh

Answer 56

congeners of ACh: propionylcholine and butyrylcholine Analog of ACh: acetylthiocholine