Lecture 2: Pharmacokinetics Flashcards
in general, what is a drug?
any substance that causes a change in biological effect
epinephrine is an ___ in the heart
agonist
administration of epinephrine causes and increase in __ and __
heart rate and contractile force
t/f an increase in concentration of epinephrine caused an increase in response
true
what is represented by Emax?
the max physiologic effect achieved by a drug
Emax is a measure of __
efficacy
what is represented by Ed50?
the dose needed to reach 50% maximal response
ED50 is a measure of __
potency
two drugs can be equally effective, but Ifone drug requires a smaller dose to reach the same response, it is said to be more __
potent
a lower ED50 means __
the drug is more potent
comparisons of drugs should be made between drugs that produce the same ___ and ideally at the same __
response; receptor
graded response curves are useful for comparing parameters in ____
controlled experimental system
when comparing two drugs in a cell based assay, what type of dose curve would you use?
graded response curve
quantal dose is important to determining ___ and ___
range of therapeutic doses and doses where toxicity arises
therapeutic window
range of doses with therapeutic effect and minimal toxicity
the therapeutic index is measured as the ration of ___ over __
Td50/Ed50
as the therapeutic index (TI) increases, what will happen to the Effective and Toxic curves?
they will be further apart
as a therapeutic index increases, what happened to the safety of the drug?
increases
t/f the E and T curves can sometimes overlap
true
what does it mean when the E and T curves overlap?
that in order for the drug to be effective, some patients required a dose that was found to be toxic in some other patients
if a drug has a small therapeutic window, a small increase in dose could be expected to result in
more risk of adverse reactions
patients should be closely monitored if the drug has a __ therapeutic window
small
give an example of a drug with a small therapeutic window
warfarin
drugs with a __ therapeutic index and window can be given in large doses to reach effective dose with little risk of adverse effects
large
give an example of a drug with a large therapeutic window
penicillin
what is a receptor?
protein within a cell that is capable of modulating cellular effects based on the binding of drug or endogenous molecules
activation of a receptor results in __
cellular response
agonist binds preferentially to ___ receptors and stabilizes this conformation, resulting in a shift towards more __ and therefore more __
active; active conformation and physiologic effect
t/f binding of drug to receptor determines the level of effect
true
what is represented by Bmax/
max receptor binding
Kd is the __ constant
dissociation
what is represented by the Kd?
drug concentration required to produce 50% receptor occupancy
the Kd value is a measure of the drug __ for the __
Affinity; receptor
if you increase the __ of a drug, you better the chances of receptor binding, even if the affinity is low
dose
is there a 1:1 ratio between receptor binding and graded response?
not usually
explain the concept of spare receptors
not all receptors may need to be bound to agonist in order for the full response to be achieved
drug’s affinity can be used as a measure of __
selectivity
t/f it is very rare for a drug to be 100% selective for a specific receptor @ any given dose
treu
in most cases, a drug is more selective because it has a higher ___ for one receptor than another
affinity
how can knowledge about affinity be used to better drug therapy? Refer to example of prazosin and tamsulosin
prazosin and tamsulosin are drugs used to treat urine retention. praz has a higher affinity for A receptors in the blood vessels, but can cause orthostatic hypertension. Tamsulosin is designed to have higher affinity for B receptors in urinary tract (no dizziness)
t/f Kd can provide indication of response, efficacy, and/or potency
false
what causes off-target drug effect?
binding of drug to an unintended receptor
what is one of the most common causes of adverse dug effects?
unintended and off-target drug effects
what are three questions to ask when predicting off-target drug effects?
- is the target receptor expressed in other tissues?
- does the drug easily distribute to other tissues?
- does the drug have affinity for other tissue receptors?
t/F off-target drug effects are always adverse
false
explain the example of histamine as an on-target but in wrong tissue
blocking histamine receptors in the periphery manages the symptoms of allergies, but blocking the receptors in the CNS results in sedation
what are idiosyncratic effects?
effects that have origin/cause that is unrelated to known interactions of drug / receptors
allergic effects can sometimes be predicted, but are unrelated to the ___ of the drugs and are rather caused by __
pharmacological properties; immune system
propanolol is an example of a __ blocker
beta
if propranolol (a beta blocker) is administered before a dose of epinephrine, what is the result on heart rate?
no change
antagonists are classes by __
method used to reach blocking / inhibitory effect
non-receptor class antagonists do not __
bind to receptor
what are chemical non-receptor antagonists?
drugs that bind to another to prevent action of agonist
provide an example of chemical non-receptor antagonist
protamine sulfate to heprin
what are physiological non-receptor antagonists?
counteract agonist effect by modulating a different target
give an example of physiological non-receptor antagosnt
diazepam against epinephrine
explain the concept of receptor antagonists
interact with the receptor in the same way the agonist would
what are the 2 types of receptor class antagonists?
- orthostatic (“active”)
2. allosteric
what is the role of orthostatic receptor antagonists?
binds to same site as agonist and can be reversible or irreversible
reversible orthstatic receptor antagonists are called
competitive antagonists
irreversible orthostatic antagonists are called
non-competitive antagonists
allosteric receptor antagonists bind to ___
non-active site of receptor
t/f allosteric receptor antagonist binding can be either reversible or irreversible
true
both reversible and irreversible allosteric receptor antagonists are called
allosteric antagonist
most antagonist binding is __
reversible
ASA binding is ___ and inhibits ___ (the key enzyme in platelet aggregation
irreversible; COX-1
why is ASA binding irreversible?
platelets cannot make new receptors because they do not have a nucleus and will just die away anyway
competitive antagonists can be __ by the agonist
bumped out of place
you can totally negate the antagosnt by __. However, the agonist will still experience a significant loss in __
increasing the concentration of agonist; potency
non-competitive antagonists interact __ with the agonist site or bind the ___ site
strongly; allosteric
why does increasing the concentration of agonist not affect response when in the presence of a non-competitive antagonist?
the antagonist binds to a site different than active site the agonist binds to
when an allosteric antagonist binds, it makes a ___ to the receptor, which prevents __
conformational change; binding of agonist to active site
non-ciometive antagonists cause a decrease in __- and possibly ___
efficacy and potency
if an antagonist binds irreversibly, what must happen to restore full response?
new receptor must be made
if an antagonist binds reversibly, what must happen to restore full response?
wait it out, time course is amount of time taken for antagonist to release from the allosteric site
allosteric antagonists may also be called __
negative allosteric modulators
what is the effect of allosteric antagonists?
can decrease or increase the ability of the agonist to bind
positive allosteric modulators bind to what site on receptor?
non-active site
positive allosteric modulators may increase both __ and __
efficacy and potency
benzodiazepines are PAMs of the __ receptors
GABA
t/f antagonists are capable of producing a response on their own
false
t/f antagosnts have no defined Emax for efficacy
true
role of inverse agonists
cause reduction of effect below baseline levels by stabilizing the inactive receptor conformation
inverse agonists cause the equilibrium to shift towards __
Ri
it is very difficult to measure the effect of inverse agonists if the constitutive activity is very __ and in this case, it may be classed as a __ agonist
low ; neutral
t/f it is not clinically clear if there is a difference between antagonists and inverse agonists
true
