Pharmacodynamics

Question 1

explain dose potency

Answer 1

Question 2

agonists vs antagonists & conformation changes

Answer 2

recepeptors have 2 conformations: active and inactive

Agonists DO change the probability of active conformation change, while antagonists do NOT

Question 3

growth factors are transmitted by which receptor?

Answer 3

RTKs

growth factors actvate Ras GTPas protein

Question 4

compare the types of antagonists

Answer 4

Question 5

Answer 5

Look on the x-axis to find ED50

Pr

Question 6

ED50 vs Emax

Answer 6

Emax = maximum effect produced by the drub

ED50= effective dose 50 = dose of drug that produces 50% of it’s maximal effect

Question 7

Answer 7

estrogen

estrogen is a lipophilic molecule that YES can cross the cell membrane and bind to a nuclear receptor

Question 8

Answer 8

inhibiting PDE will elevate concentration of cAMP and increase activity of PKA

Answer 9

Efficacy

What: Max pharmacological effect a drug can produce

Represented by: Emax

Interpret: Big Emax = more efficacious drug

Determines: magnitude of clinical effect

Question 10

Answer 10

potency is inversely proportional

Question 11

if a disease is due to excessive activation of a receptor, which drug type is ideal to use for treatment

Answer 11

give an antagonist to block the excessive influence of the endogenous agonist

Partial & Inverse Agonists & Antagonists block the actions of endogenous ligands.

Clinical example: Prazosin

Question 12

Answer 12

Question 13

compare competitive vs non-competitive antagonists

Answer 13

Question 14

covalent vs. non-covalent bonds

Answer 14

Question 15

what is used to determine how many receptors a drug can bind to?

explain it’s role in drug safety

Answer 15

Selectivity

• compare drugs to the receptors they can bind to (comparision of affinities)
• determined by Kd ratio

Question 16

What type of receptor is ideal for mimicking the actions of endogenous chemicals at receptors?

Answer 16

full agonists

Question 17

non-cumulative vs cumulative dose response curves

Answer 17

non cumulative:

of % of pts that respond to the DOSE

shape: bell curve

cumulative:

or % pts that respond to dose AND all lower doses

shape: sigmoidal

Question 18

What endogenous ligands activate JAK-STAT pathway?

Answer 18

JAK-STAT Ligands:

• growth hormome: somatostatin
• erythropoietin
• leptin
• interferions
• IL2 —–> IL-10 + IL-15

Question 19

compare drug-receptor binding curve vs drug dose-response curve

Answer 19

Drug-receptor binding curve

• x-axis = drug concentration
• y-axis = B = fraction of receptor-bound drug
• Bmax = maximal binding = total # of receptor sites
• Bmax = acheived at infinitly high concentrations of drug
• shape = hyperbolic curve
• compare curves using Kd (Binding affinity)

Dose-response curve

• x-axis = drug concentration
• y-axis = E = drug effect (response)
• Emax = maximal effect
• shape = hyperbolic curve
• compare curves using EC50 (Potency)

Question 20

Answer 20

Question 21

receptor vs ligand

Answer 21

Question 22

3 types of agonists and features of each

Answer 22

Question 23

explain the role of affinity & equilibrium dissociation constant in drug interactions

Answer 23

Question 24

compare pharmocokinetics vs pharmacodynamics

Answer 24

pharmacokinetics: studies effects of drugs (ADME)
pharmacodynamcs: studies effects of drugs on the body

Question 25

which type of receptor is shown

Answer 25

Pharmacologic receptor--\> non-competetive allosteric allosteric receptors bind to sites other than the agonist site and are NOT surmountable fxn: reduce agonist or inactivate receptors

Question 26

agonist affect on GPCR affinity

Answer 26

false

Question 27

If you want to develop the safest drug, what are the ideal parameters for the following? * Kd ratio * K_D * Therapeutic window * ED50 * EC50 * Emax * TI

Answer 27

* Kd ratio = HIGH * more selective drug = less adverse side affects * K_D = LOW * low K_D = higher affinity so less drug is needed for clinical response * Therapeutic window = WIDE * space btwn ED50 and TD50 = more drug needed to become toxic * ED50 = LOW * median effective dose (therapeutic effect) * Emax = HIGH * higher pharmalogical effect = more efficacious * EC50 = HIGH * as potency curve moves right, potency is lower * lower potency = safer drug * TI = HIGH * TI = therapeutic index = drug safety index * TI = TD50 - ED50 * bigger # = wider therapeutic window = safer drug

Question 28

which kind of curve is more appropriate in clinical situations?

Answer 28

quantal dose-response curves

Question 29

do agonists have intrinsic activity?

Answer 29

Yes, Agonists have IA but it varies by the type of agonist

Question 30

explain the therapeutic window? compare wide vs narrow windows?

Answer 30

space btwn ED50 and TD50 on cumulative Quantal Dose-response curve (DRC) def'n: range of doses in body system that provides safe & effective therapy WIDE window = Narrow window =

Question 31

which type of receptor is shown?

Answer 31

Pharmacologic Non-competitive irreversible antagonist

Question 32

what is therapeutic index? how is it calculated? how is it interpreted?

Answer 32

TI = TD50/ED50 TD 50 = toxic effect; ED50 = therapeutic effect HIGH TI = safer drug low TI = more dangerous drug

Question 33

Answer 33

Question 34

Answer 34

Intrinsic activity (IA) describes what drugs do after binding to the receptor full agonists have max pharm effect and max IA, while partial agonists have sub-maximal IA

Question 35

4 key parameters for describing drug interactions w/the receptor

Answer 35

1. binding 2. affinity 3. selectivity 4. intrinsic activity

Question 36

what are the 5 major categories of drug targets

Question 37

Answer 37

glucocorticoids b

Question 38

What are the G-protein families and their ultimate functions?

Answer 38

Question 39

GTP hydrolysis

Answer 39

FALSE GTP binds to alpha subunit. only the alpha subunit has GTPase activity

Question 40

fxn of graded dose response curves

Answer 40

shows continuous gradation of an effect produced by different doses of a drug does NOT tell how individual patients in a pop respond to a drug only shows a SINGLE subject's response

Question 41

arithmetically plotted vs logarithmically plotted dose response curve

Answer 41

Question 42

what is the clinical significance of cumulative DRCs to population health?

Answer 42

Question 43

explain desensitization & endocytosis of receptors

Answer 43

``` Rapid desensitization, resensitization, and down-regulation of β adrenoceptors. A: Response to a β-adrenoceptor agonist (ordinate) versus time (abscissa). (Numbers refer to the phases of receptor function in B.) Exposure of cells to agonist (indicated by the light- colored bar) produces a cyclic AMP (cAMP) response. A reduced cAMP response is observed in the continued presence of agonist; this “desensi- tization” typically occurs within a few minutes. If agonist is removed after a short time (typically several to tens of minutes, indicated by broken line on abscissa), cells recover full responsiveness to a subsequent addition of agonist (second light-colored bar). This “resensitization” fails to occur, or occurs incompletely, if cells are exposed to agonist repeatedly or over a more prolonged time period. B: Agonist binding to receptors initiates signaling by promoting receptor interaction with G proteins (Gs) located in the cytoplasm (step 1 in the diagram). Agonist-activated receptors are phosphorylated by a G protein-coupled receptor kinase (GRK), preventing receptor interaction with Gs and promoting binding of a different protein, β-arrestin (β-Arr), to the receptor (step 2). The receptor-arrestin complex binds to coated pits, promoting receptor internal- ization (step 3). Dissociation of agonist from internalized receptors reduces β-Arr binding affinity, allowing dephosphorylation of receptors by a phosphatase (P’ase, step 4) and return of receptors to the plasma membrane (step 5); together, these events result in the efficient resensitiza- tion of cellular responsiveness. Repeated or prolonged exposure of cells to agonist favors the delivery of internalized receptors to lysosomes (step 6), promoting receptor down-regulation rather than resensitization. ```