Lecture 2 Part 2 Flashcards
how can agonists be divided?
into 2 classes based on the maximum pharmacological response that occurs when ALL RECEPTORS ARE OCCUPIED-
-partial agonist
-full agonist
true or false
partial agonists produce a lower response at full receptor occupancy than full agonists
true
true or false
emax is lower for full agonists than partial
false
emax is lower for partial agonists than full
partial agonists produce concentration-effect curves that resemble what?
resembles the concentration-effect curve of full agonist in the presence of an irreversible antagonist
______ experiments have demonstrated that partial agonists may occupy all receptor sites
Radioligand-binding experiments
what happens when partial agonists saturate all receptor sites
they still fail to produce a maximal response (compared to that of a full agonist)
TRUE OR FALSE
increasing concentration of partial agonist cannot displace a fixed conc of agonist from the receptor
FALSE - it can
true or false
partial agonists may occupy all receptor sites
true
in the presence of partial agonist, can emax be reached?
NO
partial agonists are “not as good” at activating the receptor
the response caused by a single concentration of full agonist ______with increasing concentrations of partial agonist
why?
decreases
the partial agonists are competing with the agonists to bind to the receptor. The partial agonist with increasing concentration, increasingly occupies the receptors and is “not as good” at activating them
true or false
all methods of antagonism involve interaction of drugs/endogenous molecules at a single type of receptor
FALSE
there are chemical antagonists and physiologic antagonists
explain chemical antagonists and give an example
one drug may antagonize the actions of another drug by binding to and inactivating the drug.
ex: heparin is an anticoagulant that is negatively charged.
PROTAMINE is positvely charged and can be used to clinically counteract the effects of heparin.
protamine antagonizes the effect of heparin by binding to it and making it unavailable for interaction with proteins involved in blood clot formation
what is a major side effect of heparin
excessive bleeding
what is the antidote to heparin
protamine - a chemical antagonist
antacids could be considered what kind of antagonist
chemical
physiologic antagonism takes advantage of _______ regulatory pathways
endogenous
many physiologic functions are controlled by what?
give an example
opposing regulatory pathways
ex: glucocorticoids increase blood sugar and the pancreas produces insulin to lower blood glucose levels (clinician could also administer insulin)
to oppose the hyperglycemic effects of a glucocorticoid hormone, the clinician must sometimes administer what? what is this an example of?
insulin
physiologic antagonism
GRADED dose response curves show……….
the effects on a continuous scale and the intensity of the effect is proportional to the dose
when choosing among drugs and determining the appropriate dose for a drug, what must be considered?
the drug’s POTENCY and MAXIMAL EFFECT
define potency
the concentration/dose of drug required to produce 50% of the drug’s maximal effect
-EC50/ED50
potency depends on what 2 things
the affinity of drug binding (KD)
the maximal response for that drug (efficacy)
potency depends on __ and ___
affinity (KD) and efficacy
define efficacy
the measure of an effect produced by a drug
what terms are most important to use when COMPARING DRUGS
potency and efficacy
_____ is determined by the maximal response of the drug
efficacy
when comparing the potency of drugs, what exactly are you comparing?
the EC50/ED50
what is a Quantal dose effect curve
basically just tells whether the desired effect occurred or it didn;t
explain how quantal/graded dose response curves can be used in different scenarios
graded dose response curves are limited in their application to clinical decision making bc they can’t be used if the pharmacological response is QUANTAL EVENT (either-or)
ie: prevention of convulsions, death
ALSO clinical releavance of graded dose response curve in a single patient may be limited in its application to other patients (the severity of the disease/responsiveness to the drug)
name 2 limitations of graded dose response curves
how can these problems be avoided?
-does not work for a quantal event (either/or) ie: prevention of convulsions, death
-clinical application – graded dose response curve for a single patient may not apply to all patients in that the severity of the disease and responsiveness to the drug may be different
can be avoided by determining the dose of drug required to produce an effect of specific magnitude in a LARGE NUMBER OF PATIENTS (or animals) and lpotting the cumulative frequency distribution of responders vs the log dose (GAUSSIAN NORMAL CURVE – how pts tend to respond to drugs)
________- may be used to generate information regarding the margin of safety
quantal dose-effect cirves
besides quantal dose effect curves, toxic effects of a drug on humans/animals can also be assessed by….
plotting the cumulative frequency distribution of responders vs log dose
in order for a drug to have a HIGH MARGIN OF SAFETY, the therapeutic effects should be observed at _______ doses than toxic effects
lower
true or false
therapeutic effects and toxic effects should overlap
false - should not
however, this is not always possible.
true or false
graded dose response curves can be used to generate information regarding the margin of safety
FALSE - quantal dose-effect curves
the margin of safety of a drug depends on……
ratio between ED50 and TD50
TD50/ED50
ideal to have a LARGE VALUE (meaning TD50 is high and ED50 is low)
TRUE OR FALSE
BOTH graded and quantal dose effect curves provide information regarding the potency and selectivity of drugs
true
the ____ curve indicates the maximal efficacy of a drug
graded dose response curve
the ____ curve indicates the potential variability of responsiveness in patients
quantal dose-effect curve
NO DRUG CAUSES A SINGLE, SPECIFIC EFFECT.
give 4 reasons for this
diversity of:
-receptors
-biochemical processes
-cell types, tissue types, and organs
DRUGS ARE SELECTIVE BUT NOT SPECIFIC
drugs are ____ but not _____
selective but not specific
meaning that a drug is selective for a general type of receptor but not specific to one specific receptor
as mentioned, no drug causes a single, specific effect
how do you deal with this?
carefully manage the dose to avoid toxicity, along with careful monitoring of the patient
OR not administering the drug at all and using an alternate
in some instances, a drug may be clearly necessary and beneficial but produces unacceptable toxicity at the doses which bring this benefit.
what can be done?
the addition of another drug may be possible
give a specific example of a drug that is clearly necessary and beneficial but produces a certain toxicity/side effect at normal doses
prazosin - an antihypertensive.
a1-adrenergic receptor antagonist acts on receptors in vascular smooth muscle to reduce BP.
as a consequence, patients may suffer postural hypotension (drop in BP when you stand up - hardest for tall ppl)
true or false
when drugs act on their receptor, they can produce both a toxic and therapeutic effect mediated by the same receptor-effector mechanism
true - prazosin causes a drop in BP which is good, but also causes postural hypotension
what are some therapeutic strategies to avoid drug toxicities
-drug should be administered at the lowest possible dose that produces an acceptable benefit
-adjunctive (another) drug that acts through a different receptor mechanism may allow the dose of the 1st drug to be lowered, which would decrease its toxicity
-the drug can be specifically placed in parts of the body where it will have reduced toxicity (infusing the drug directly into the tumor)
the drug should always be administered at what dose
the lowest possible dose that produces acceptable benefit
true or false
individuals may vary in their responsiveness to a drug
true
individuals may vary in responsiveness to a drug.
name 6 different responses
idiosyncratic
hypo reactive
hyper reactive
hypersensitivity
tolerance
tachyphylaxis
idiosyncratic response
an unusual response that is rarely observed in patients
hypo reactive response
a drug effect that is smaller than expected
hyper reactive response
a drug effect that is larger than expected
hyper sensitivity response
an allergic reaction to the drug
tolerance response
responsiveness decreases as a result of continued drug administration (desensitization)
tachyphylaxis response
responsiveness diminishes rapidly after administration of the drug
there were 6 different responses listed in which individuals can vary in their response to a drug.
when these effects occur, what should be done?
the dose should be modified or the drug itself should be changed
name 5 factors to be considered in variable drug responses
age
body size
sex
disease state
simultaneous administration of other drugs
explain how body size can cause varying drug responses
a high body weight may affect the distribution of the drug due to high fat content
beneficial and toxic effects can be mediated by the same receptor-effector mechanism to the SAME TISSUE or…..
-by identical receptors that affect 2 DIFFERENT TISSUES or by different effector pathways – toxic in 1 tissue and therapeutic in another
-by DIFFERENT TYPES OF RECEPTORS
give a specific example of when a beneficial or toxic effect is mediated by an identical receptor but in different tissues or effector pathways
digitalis (digoxin) is therapeutic in cardiac contractility but has toxic effects in the GI and eye
new drugs are emerging with improved_____
explain this
receptor selectivity
a drug can bind to 1 receptor to produce response 1 and bind to another receptor to produce response 2
ex: alpha and beta adrenergic agonists
almost all of the several thousand drugs currently available can e arranged in about ____ groups based on what?
70 groups
based on structure activity relationships
define structure activity relationships
understanding the relationship between drug structures and biological activities
-forms the basis of RATIONAL DRUG DESIGN
what forms the basis of rational drug design
structure activity relationships
many of the drugs within each group are very similar in what?
pharmacodynamic actions and often in pharmacokinetic properties as well
for most drug groups, what can be identified that typifies the most IMPORTANT CHARACTERISITICS of that group?
one or more prototype drugs
a patent expires how long after filing an NDA?
20 years after filing
how many types of FDA applications are there? name them
5 types:
-IND (investigational new drug)
-NDA (new drug application)
-ANDA (abbreviated NDA)
-OTC
-BLA (biologic license application)
how many phases of study are there? name them in order
in vitro studies
animal testing
clinical testing
marketing
how long are in vitro studies
0-2 years
how long is animal testing (in vivo)
2-4 years after discovering drug
how long is clinical testing
4-8 years after discovering drug
how long is NDA
8-9 years after discovering the drug (1 year)
how long is postmarketing surveillance
9-20 years after discovering drug
what leads to finding the “lead compound” which undergoes in vitro studies?
biologic products
chemical synthesis and optimization
what is discovered in animal testing (in vivo)
efficacy
selectivity
mechanism
how many phases of clinical testing are there?
name what is looked for in each
phases 1 -4
phase 1 - safety (pharmacokinetics)
phase 2 - effficacy (does it work)
phase 3 - efficacy - but DOUBLE BLIND
phase 4 - postmarketing surveillance
name the # of pts in each phase of clinical testing
phase 1: 20-100
phase 2: 100-200
phase 3: 1000-6000
phase 4: general public
throughout the entirety of clinical testing, what is assessed
metabolism and safety assessment
biological products include a wide range of products such as…….
what FDA application is required?
BLA - biologic license application
vaccines
blood/blood components
somatic cells
allergenics
gene therapy
tissues
recombinant therapeutic proteins
what are orphan drugs
for the treatment of rare disease – those that affect less than 200k in the US
explain the pathway that the FDA has created for the approval of orphan drugs
orphan drug destination program – provides ORPHAN STATUS to drugs and biologics which are those intended for the safe and effective treatment, diagnosis, or prevention of rare diseases/disorders that affect FEWER THAN 200,000 ppl in the US or affect more than 200k but are not expected
