1-intro Flashcards
What kind of drugs are antihistamines??
Inverse agonists
Suppress activity / make it worse, unlike antagonist that stops it (not Necessarily making it worse)
Why gen 2 antihistamines non sedating
P-glycoprotein pumps remove it from the brain while gen 1 cant
Less in brain, less sedation
Pharmacodynamics
What drug does to body
Pharmacokinetics
what body does to the drug
Prodrug
not intrinsically active, activated by a metabolic step
off-target effect
influence on other receptors than the one target, they are often related receptors
G-protein coupled receptor
ligand bind to extracellular surface, conformational change, activates signalling cascade activated by G proteins
Gs
activates adenylate cyclase
what does adenylate cyclase do
catalyses ATP to cAMP
Gi
inhibits adenylate cyclase
Gq
activates phospholipase C
what does phospholipase C do
breakdown PIP2 to IP3 and DAG
what does IP3 and DAG do
triggers ER to release Ca2+
tyrosine kinase receptors
ligand binding causes auto-phosphorylation
dimerization of receptors (ligand binding)
Ion channel
fastest
makes electrical signals
ions flowing through proteins
LIGAND BINDING, VOLTAGE GATED
voltage gated ion channel
quick, milliseconds, movement of charged a.a. in transmembrane electric field charge position in response to changes in voltage
ligand gated
open or close in response to binding of a small molecule
agonism
binding of substrate to receptor that generates an effect
EC50
conc. of drug that yields 50% of its max effect, same as efficacy
Emax
max biological effect observed with the drug
efficacy
same as emax
Max biological effect observed with the drug
potency
concentration dependence, how much is needed for a certain effect.
what is potency related to
EC50
potency EC50 relationship
high potency, low EC50
low potency, high EC50
partial agonist
can generate a fractional effect
full agonist
can generate a max effect
antagonist
cannot generate a biological effect, influences receptors response to agonist
inverse agonist
suppresses basal activity, opposite effect of agonist
competitive antagonism
more agonist required to generate given response
what does competitive antagonism shift
potency/EC50
What does non competitive antagoism shift (efficacy and potency
reduce efficacy, no change in potency
steroid hormone receptors
what type and mechanism of action
intracellular, slow, requires DNA binding
cell surface receptor mechanism of action
fast, intracellular signalling cascades
dose ratio
EC50(w/antagonist) / EC50(w/o antagonist)
irreversible competitive antagonism
cannot be displaced by increased agonist concentration, binds to same site as the agonist
allosteric potentiation
increase efficacy and/or potency of the agonist
mixed antagonist
combo of weakened efficacy and potency
orthosteric site
agonist binding site
does COX-1 or 2 have a bigger active site
COX-2
what do NSAIDS inhibit
COX1 and 2
what drug is tylenol
acetaminophen
extraction ratio/factor
clearance/blood flow
what does low extraction ratio mean
organ doesn’t filter much so the drug stays in blood
what is high extraction ratio
organ clears out most of the blood, like the liver!
bioavailability
% of unprocessed drug that reaches systemic circulation after being administrated by a particular route
receptor reserve
when there are more receptors present than are required for a full biological effect
Effect formula
(Emax)/(1+ EC50/[drug])
first pass metabolism
drugs pass through hepatic circulation the liver (major metabolism) before entering heptic circulation
what is Kd
dissociation constant, when 50% receptors are bound
why can there be a mismatch between binding and effect?
receptor reserve (more receptors needed than required to make effect)
what is distribution
how drugs are partitioned into different body compartments
factors that effect distribution
- binding to plasma proteins, these are “bound” (not free or pharmacologically active)
- drug accumulation in tissues –> favored for lipophilic drugs and purfuse organs
are drugs bound to plasma proteins pharmacologically active?
NO ! they are not free
what does perfuse mean
more blood is supplied to the area
what kind of drugs collect more in tissues
lipophilic
volume of distribution formula
total amount of drug in body/[drug]
high volume of distribution means
and why
well distributed
often highly lipophilic
low volume of distributed means
poorly distributed
often lipophobic and bound to plasma proteins
what is biotransformation
metabolism in liver
phase 1 biotransformation
OXIDATION by CYP enzymes
mixed function oxidase system
phase 2 biotransformatin
add POLAR parts to make it more prone to excretion
does phase 1 or 2 biotransformation happen first
EITHER OR
capacity limited elimination
when [drug] is higher than their affinity of the enzyme that breaks it down
pharmacogenomics/genetics
how drugs affect people because of their genes
ex: CYP enzymes vary a lot
therapeutic index
TD50/ED50
toxic dose/effective dose
is big or small therapeutic index better
BIG
relative risk reduction
1-(event rate in treatment group)/(event rate in control group)
is relative risk reduction good?
misleading because it does not convey baseline risk and doesn’t capture the diff. b/w large reduction of something frequent vs. infrequent
absolute risk reduction formula
event rate in control group-event rate in treatment group
is absolute risk reduction good?
yes, describes # of cases prevented by drug instead of % relative to baseline (RRR)
numbers needed to treat formula
1/ARR
1/(event rate in control group-event rate in treatment group)
is numbers needed to treat good?
yes, it shows the population level drug benefit
what if you get a negative numbers needed to treat ???
it means event is higher in experimental than control group… BAD DRUG–> numbers needed to harm
numbers needed to harm
when you have a negative numbers needed to treat
meta-analysis
systematic review, data from multiple trials combined into a forest plot
Schild Plot
dose ratio vs. log[antagonist]
what is IIP3 role
bind to ER so calcium is released
what is DAG role
remains in membrane and activates PKC
