Pharmacodynamics Flashcards
explain dose potency
agonists vs antagonists & conformation changes
recepeptors have 2 conformations: active and inactive
Agonists DO change the probability of active conformation change, while antagonists do NOT
growth factors are transmitted by which receptor?
RTKs
growth factors actvate Ras GTPas protein
compare the types of antagonists
Look on the x-axis to find ED50
Pr
ED50 vs Emax
Emax = maximum effect produced by the drub
ED50= effective dose 50 = dose of drug that produces 50% of it’s maximal effect
estrogen
estrogen is a lipophilic molecule that YES can cross the cell membrane and bind to a nuclear receptor
inhibiting PDE will elevate concentration of cAMP and increase activity of PKA
Efficacy
What: Max pharmacological effect a drug can produce
Represented by: Emax
Interpret: Big Emax = more efficacious drug
Determines: magnitude of clinical effect
potency is inversely proportional
if a disease is due to excessive activation of a receptor, which drug type is ideal to use for treatment
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
compare competitive vs non-competitive antagonists
covalent vs. non-covalent bonds
what is used to determine how many receptors a drug can bind to?
explain it’s role in drug safety
Selectivity
- compare drugs to the receptors they can bind to (comparision of affinities)
- determined by Kd ratio
What type of receptor is ideal for mimicking the actions of endogenous chemicals at receptors?
full agonists
non-cumulative vs cumulative dose response curves
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
What endogenous ligands activate JAK-STAT pathway?
JAK-STAT Ligands:
- growth hormome: somatostatin
- erythropoietin
- leptin
- interferions
- IL2 —–> IL-10 + IL-15
compare drug-receptor binding curve vs drug dose-response curve
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)
receptor vs ligand
3 types of agonists and features of each
explain the role of affinity & equilibrium dissociation constant in drug interactions
compare pharmocokinetics vs pharmacodynamics
pharmacokinetics: studies effects of drugs (ADME)
pharmacodynamcs: studies effects of drugs on the body
which type of receptor is shown
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
agonist affect on GPCR affinity
false
If you want to develop the safest drug, what are the ideal parameters for the following?
- Kd ratio
- KD
- Therapeutic window
- ED50
- EC50
- Emax
- TI
- Kd ratio = HIGH
- more selective drug = less adverse side affects
- KD = LOW
- low KD = 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
which kind of curve is more appropriate in clinical situations?
quantal dose-response curves
do agonists have intrinsic activity?
Yes, Agonists have IA but it varies by the type of agonist
explain the therapeutic window?
compare wide vs narrow windows?
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 =
which type of receptor is shown?
Pharmacologic Non-competitive irreversible antagonist
what is therapeutic index?
how is it calculated?
how is it interpreted?
TI = TD50/ED50
TD 50 = toxic effect; ED50 = therapeutic effect
HIGH TI = safer drug
low TI = more dangerous drug
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
4 key parameters for describing drug interactions w/the receptor
- binding
- affinity
- selectivity
- intrinsic activity
what are the 5 major categories of drug targets
glucocorticoids b
What are the G-protein families and their ultimate functions?
GTP hydrolysis
FALSE
GTP binds to alpha subunit. only the alpha subunit has GTPase activity
fxn of graded dose response curves
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
arithmetically plotted vs logarithmically plotted dose response curve
what is the clinical significance of cumulative DRCs to population health?
explain desensitization & endocytosis of receptors
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.
