Lecture 1 Part 2 Flashcards
how do drugs interact with their receptors
by chemical forces or bonds
3 types:
-covalent (strongest)
-electrostatic
-hydrophobic (weakest)
true or false
covalent bonds are very strong and in most cases are NOT REVERSIBLE under biologic conditions
true
give 2 examples of drugs that use covalent bonding in their mechanism
phenoxybenzamine forms a covalent bond to the alpha receptor for norepinephrine which blocks the receptor.
DNA alkylating agents used in cancer chemotherapy
explain the mechanism of phenoxybenzamine
when there is a tumor on the adrenal gland, too much epinephrine is secreted.
phenoxybenzamine is administered which covalently binds to the alpha receptor for norepinephrine which BLOCKS the receptor.
this bond is not readily broken and the blocking effect lasts LONG AFTER THE FREE DRUG HAS DISSAPPEARED FROM THE BLOODSTREAM
only reversed by the synthesis of new alpha receptors (takes ~48 hours)
how do DNA alkylating agents work?
they disrupt cell division in neoplastic (cancerous) tissue
when there is a tumor on the adrenal gland, what happens
too much epinephrine is secreted which causes vasoconstriction and HBP.
phenoxybenzamine can help to lower BP by blocking the alpha receptor for norepinephrine
which is more common in drug-receptor interactions:
covalent bonding or electrostatic bonding
electrostatic bonding
electrostatic bonds can be what 2 things
-relatively strong linkages between permanently charged ionic molecules to weaker H bonds
-weak H bonds to very weak dipole-induced interactions such as van der waals forces
true or false
electrostatic bonds are stronger than covalent bonds
false - weaker
what are van der waals forces
the relatively weak attractive forces that act on neutral atoms and molecules. arises bc of electric polarization in each of the particles
true or false
hydrophobic bonds are usually quite weak
true
hydrophobic bonds are probably important in what kind of interactions
interactions of highly lipid soluble drugs with the lipids of cell membranes
and perhaps in interaction of drugs with the internal walls of receptor “pockets”
drugs which bind through weak bonds to their receptors are generally more or less selective than drugs that bind to their receptor with strong bonds?
weak is generally MORE SELECTIVE
WHY are weak drug-receptor interactions more selective than strong ones?
bc a weak bond requires a very precise fit of the drug to its receptor for an interaction to occur.
only a few receptor types are likely to provide such a precise fit for a particular drug structure
what is the requirement for the shape of a drug molecule
must be able to permit binding to its receptor under optimal conditions.
shape should be complementary to the receptor site like a LOCK AND KEY model
the phenomenon of chirality (stereoisomerism) is common in ____
biology
how many useful drugs are chiral molecules that exist as enantiomeric pairs?
more than half of all useful drugs
drugs with 2 asymmetric centers have how many diastereomers?
give a specific example of a drug with these properties
4 diastereomers
labetolol (an alpha beta receptor blocking drug)
chiral refers to what kind of molecule?
with a center of 3D asymmetry
define stereoisomers
compounds that have the same molecular formula but different arrangement of the atoms in space
mirror images
enantiomers
4 different groups attached
chiral
true or false
enantiomers are associated with CHEMICAL IDENTITY
true
Define diastereomers
not mirror images and not super imposable
if a molecule has 1 asymmetric center - is it an enantiomer or diastereomer? what about 2 asymmetric centers
1 = enantiomer
2 = diasteromer
R,R
R,S
diasteromers
R,R
S,S
enantiomers
R,R
S,R
diasteromers
R,S
S,S
diasteromers
R,S
S,R
enantiomers
S,R
R,S
enantiomers
S,R
S,S
diasteromers
____ are usually stereospecific
enzymes
enzymes are usually stereospecific
therefore…
1 drug enantiomer is often more susceptible than the other to drug-metabolizing enzymes
THEREFORE, the duration of action of 1 enantiomer may be quite different from the other
most studies of clinical efficacy and drug elimination in humans has been carried out with what?
what does this mean?
racemic mixture
therefore, many patients are receiving drug doses of which 50% or more is either inactive or actively toxic
rational design of a drug implies the ability to predict what?
the appropriate molecular structure of a drug on the basis of information about its RECEPTOR
rational drug design implies the ability to predict the needed molecular structure of a drug on the basis of information about its biologic receptor.
until recently, no receptor was known in enough detail to permit such drug design,
what was used instead?
most drugs were developed through random screening of chemicals or modification of drugs that were already known to have some effect
however, during the last 3 decades many receptors have been isolated and characterized
Gleevec/STI571/Imatinib is used for what
a specific therapy used for CML
(chronic myelogenous leukemia)
how was Gleevec developed?
through a molecular design based on knowledge of the 3D structure of the receptor site
for the last several years, ________________ are new anticancer agents
EGFR-TK inhibitors
who discovered Gleevec/STI571/Imatinib mesylate? what is it?
Novartis
a small molecule compound approved by the FDA to treat CML (chronic myelogenous leukemia) and GIST (gastrointestinal stromal tumor) in 2001
efforts at establishing a clear naming system of receptors has been made by whom?
international union of pharmacology committee on receptor nomenclature and drug classification
the interactions between a drug and the body are conveniently divided into how many classes?
2 -
pharmacodynamic processes and pharmacokinetic processes
pharmacodynamic processes are the actions of the drug on the body.
these properties determine what about the drug?
-the group the drug is classified
-plays a major role in deciding whether that group is the appropriate therapy for a system or disease
pharmacokinetic processes are the actions of the body on the drug.
these properties determine what
the ADME of drugs
great importance in the choice and administration of a particular drug for a PARTICULAR PATIENT (ie: pt with impaired renal function)
when treating a patient with impaired organ function, which parameters would be most helpful - pharmacodynamics or pharmacokinetics
pharmacokinetics
explain agonists
do they have affinity, efficacy, or both?
agonists bind to and activate the receptor in some fashion which DIRECTLY or INDIRECTLY produces the effect
an agonist has both affinity and efficacy
explain how it is possible for an agonist to produce the effect of the receptor either directly or indirectly
direct – some receptors have effector machinery within their same molecule. therefore, when the drug binds the effect occurs.
indirect – some receptors are linked through 1 or more intervening coupling molecules to a separate effector molecule
give 2 examples of how an agonist brings about a DIRECT EFFECT
-opening of an ion channel
-activation of enzyme activity
explain antagonist drugs
bind to a receptor and PREVENT (BLOCK) binding by other molecules
do antagonists have affinity, efficacy, or both?
affinity but no efficacy
give an example and explain an antagonist
acetylcholine receptor blockers (ATROPINE)
prevent the access of acetylcholine (and similar agonist drugs) to the acetylcholine receptor.
thus, reduces the effects of acetylcholine and similar drugs in the body
drug —> ____ —>_____
drug –> receptor –> effects
the concept of an agonist, competitive inhibitor, allosteric activator, and alloseteric inhibitor are ________ principles
pharmacodynamic
define a competitive inhibitor
competes with the agonist for the same receptor site.
therefore this decreases the action of the agonist and a larger dose of agonist is needed to produce the desired effect
true or false
an allosteric activator could be another drug
true
what is the most/least efficacious?
which is the most/least potent?
-agonist
-agonist + allosteric activator
-agonist + competitive inhibitor
-agonist + allosteric inhibotir
most efficacious = allosteric activator + agonist
least efficacious = allosteric inhibitor + agonist
least potent = agonist + competitive inhibitor
most potent = allosteric activator + agonist (agonist is also pretty potent – very close)
which have the SAME EFFICACY, but different potency:
-agonist
-agonist + allosteric activator
-agonist + competitive inhibitor
-agonist + allosteric inhibitor
same efficacy but different potency= agonist & agonist + competitive inhibitor
agonist by itself is much more potent.
in the presence of competitive inhibitor, just needs a very high concentration to get the same effect
true or false
agonist + allosteric activator has a higher efficacy than the agonist by itself
true
true or false
agonist + agonist and competitive inhibitor have decreased efficacy
false
potency is decreased but efficacy remains the same
define a partial agonist
a drug that binds to and activates a receptor, but at PARTIAL EFFICACY (relative to a full agonist)
how can some drugs mimic agonist drugs?
by inhibiting the molecules responsible for terminating the action of the endogenous agonist
give an example of how some drugs mimic agonist drugs
acetylcholine esterase inhibitors
-they slow down the destruction of acetylcholine by inhibiting acetylcholine esterase
this causes cholinomimetic effects even though these ACHE inhibitors are not actually acting as true agonists and binding to the cholinoceptors
explain how some drugs bind to receptors and activate them but do NOT evoke as great of a response as a full agonist
pindolol - a “partial agonist”
can act as agonist or antagonist to the Beta-adrenoceptor.
if no full agonist is present, it will act as an agonist
HOWEVER, if there is an agonist present (like isoproterenol) it will act as an antagonist
name a true beta-adrenoceptor full agonist
isoproterenol
if in the presence of pindolol, pindolol will act as an antagonist
“even at maximal capacity, does not produce the full effects of an agonist”
partial agonist
true or false
if enough of partial agonist binds to the receptors, it can eventually act as a full agonist
FALSE
a partial agonist, even at MAXIMAL receptor occupancy, will never produce as great of a response as the full agonist
name 3 processes in which drug activity can be terminated at the receptor level
-drug effect only lasts as long as the drug occupies the receptor. once the drug dissociates = termination of effects
-the action of the drug may persist after the drug has dissociated
-if drugs COVALENTLY bind to the receptor, the effect may persist until the drug-receptor complex is destroyed and new receptors are synthesized
in many cases, the action of the drug may still persist even after the drug has dissociated from its receptor.
give an example of this
some coupling molecules may still be in their active form and signaling, even though the drug is no longer bound
give an example of a drug that covalently binds to its receptor and thus the effect does not stop until the receptor-drug complex is destroyed and new receptors are made
phenoxxybenzamine
explain what desensitization mechanisms are
they prevent excessive activation in a case of when the drug molecules continue to be present there for very long periods of time
this is responsible for drug addiction
-more drug is taken before all the receptors have been recycled and are ready to bind. thus, more and more dose keeps being taken because the person wants to achieve the effect, but there are not as many receptors available
don’t discontinue immediately - will lead to withdrawals
to function as a receptor, an endogenous molecule must FIRST do what
be SELECTIVE in choosing ligands (drugs) to bind
why is it that an endogenous molecule must have selective binding to be a receptor
to prevent the promiscuous binding of many different ligands
to function as a receptor, an endogenous molecule must 1st be selective.
what next
it must change its function when binding such that the function of the biological system is altered (required to produce a pharmacological effect)
true or false
the body contains MANY molecules that are capable of binding drugs, but not all of these molecules are “regulatory molecules”
(receptors)
TRUE
ie: plasma protein albumin is a nonregulatory molecule
what happens when a drug binds to a nonregulatory molecule such as plasma albumin?
thus, what can albumin be called?
there will be no detectable change in function of the biologic system
can be called an inert binding site
albumin is considered an inert binding site and therefore has no significance.
true or false
FALSE
has significance.
binding affects the distribution of the drug in the body. thus, this binding will determine the amount of free drug in circulation
true or false
only free drug can get metabolized
true
in practical therapeutics, a drug should be able to do what?
is this a pharmacokinetic or pharmacodynamic principle?
to reach its intended site of action after administration by some convenient route
pharmacokinetic principle
is it ever possible to directly apply a drug to its target tissue?
yes - in a few situations
topical application of an anti-inflammatory agent to inflamed skin/mucus membrane
IV and circulate in the blood directly to the target blood vessels or other parts of the body
which is more common - a drug being directly administered to its tissue target or the requirement for a drug being able to reach its intended site of action
more common for a drug to have to move from one compartment to another
ie: drug is given into the gut (oral) and it must move to its site of action in another compartment (brain)
usually, a drug is given into 1 body compartment and must move to its site of action in another compartment.
what does this require?
the drug must be absorbed into the blood from its site of administration and DISTRIBUTED to its site of action.
after effect, drug should be eliminated by metabolic inactivation, excretion, or combo of the 2
a basic drug will be excreted in what kind of urine?
(acidic or basic)
acidic
it will be ionized and thus easily leave the body
a drug is given orally to produce an effect in the CNS.
name some barriers this drug will face
-the tissues of the intestinal walls
-the walls of the capillaries that perfuse the gut
-BBB
-the walls of the capillaries that perfuse the brain
