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Branch of pharmacology
Study of harmful effects of chemicals on living systems
Any substance/chemical that is foreign to the human body
- gr. "xenos"-stranger
Drug that requires bioactivation to release the active form of a drug
Most are proteins
Site of action of the drug
Binding site cannot be manipulated
actions of the drug on the body
concentration vs. effect
MOA determines drug class
actions of the body on a drug
concentration vs. time
ADME properties of a drug
Study of genetic variations among humans that cause differences in PD and PK
Ideal drug will shift to the right
Lousy drug will shift to the left
number of receptors the drug selects to bind to
measured by binding affinity
- Drug selectivity
- aka selective binding
number of specific effects (toxic/therapeutic) that the drug produces on the body
Drugs are only _______ in their actions they are not _______.
No drug causes a single effect because of what 2 things?
1) the drug will bind to more than one type of receptor
2) the postreceptor processes are linked to many other functions
List 4 things that affect selective binding
- 1) the MW (100-1000)
- 2) type of bond
- 3) chirality (stereochemistry)
- 4) effect of the receptor site
Drug molecules that form _____ bonds with receptors are likely to be highly _______ and _____-acting.
List the 3 types of bonds in order from strongest to weakest
- 1) covalent (irreversible)
- 2) electrostatic (ionic, hydrogen, van der waals)
- 3) hydrophobic (requires a precise fit)
How do you terminate covalent binding?
The body must degrade the drug-receptor complex and synthesize a new receptor molecule
What do these drugs have in common?
Asprin, Plavix (clopidrogel), Beta-lactam antibiotics
They all form covalent bonds with the receptor molecule
The more chiral a drug is the more ______ the binding.
"Dextro" signifies the ____-enatiomer
"Levo" signifies the ___-enatiomer
With some racemic mistures the patient is receiving doses where 50% is either _________ or _________.
Racemic mixtures are sometimes used because of the _________ of the molecule in the body
bind to and activate the receptor
What is an effector?
Binds to and indirectly activates the receptor via signal transduction that produces the effect
Some drugs mimic the effect of the receptor agonist by ________ the molecules responsible for terminating the action of the __________ agonist, and do NOT bind to the receptor but ______ the pharamcological effect
activates the receptor
has maximum pharmacological effect
has high intrinsic efficacy
stabilizes receptor into the active conformation
activates the receptor
has a low pharmacological effect
has low intrinisc efficacy
can act as an agonist or antagonist
does not activate the receptor
stabilizes the receptor in its inactive conformation
opposite effects of conventional agonists
enhances the efficacy/binding affinity of the agonists
bind to an allosteric site other than the binding site of the agonist
- Allosteric agonists
- aka allosteric activators
bind to but do not activate the receptor
block the binding of agonists
can be competetive/noncompetitive
- Pharmacologic antagonists
- aka blockers
- aka receptor-specific antagonists
inhibit/reduce the binding affinity of the agonist
binds to allosteric sites on the receptor
non-competitive & receptor specific
not overcome by increasing concentration of the agonist
- Allosteric antagonists
- aka allosteric inhibitors
- aka receptor-specific allosteric antagonists
- aka noncompetitive allosteric antagonists
What does ADME stand for?
True or false, the Ri conformation is favored in equilibrium?
True-the inactive conformation is more stable
In the ___ confirmation the receptor can produce an effect in the _______ of a ligand.
What is consitutive activity?
The effect produced in the absence of a ligand in Ra confirmation
What factors determine the degree of constitutive activity? (4 total)
1- The equilibrium between Ri and Ra
2- receptor density
3- concentration of coupling molecules
4- number of effector molecules
Humans exist in a _____ level of constitutive activity in the absence of an agonist
_____ agoinsts have a high affinty for binding to the _R__ confirmation and fully stabilize it.
A partial agonist has an affinity for which form(s)?
Both the active and inactive
Partial agonists have what type of intrinsic efficacy?
In the presence of a full agonist a partial agonist acts as ___________
an antagonist (blocker)
Binding to a pharmacologic antagonist does what to the equilibrium?
It does NOT shift it
No effect will be observed
__________ has equal affinity for binding to both the Ra and Ri forms.
Inverse agonists have a higher affinity for binding to the _______ form of the receptor molecule
What two mechanisms terminate drug action at the receptor?
1- dissociation of the drug from the receptor
2- biosynthesis of a new receptor molecule
What is an inert binding site?
Binding of a drug to a nonregulatory inert molecule that will NOT alter the biologic function of response
Name 4 types of drug receptors:
- 1- regulatory proteins
- 2- enzymes
- 3- transport proteins
- 4- structural proteins
In what 3 ways does the receptor influence clinical use of drugs:
- 1- responsible for establishing the relationsihps between dose/concentration vs. pharmacologic effects
- 2- responsible for selectivity of drug action
- 3- mediate actions of agonists and antagonists
What is the name of this equation?
What does it tell us?
Graded dose-response curve
Concentration vs. effect
What is Emax?
Maxium response produced by the drug
Highest value on y-axis
Measures drug efficacy
What is EC50? (ED50)?
that produces 50% of the maximum effect
EC50 and potency have a(n) ________ relationship
(When EC 50 is ____ potency is _____)
What is the name for this equation?
What does it tell us?
Graded dose-binding curve
Bound drug vs. Unbound drug
What is Bmax?
Total concentration of receptor sites that are bound to the drug
Maximum number of drug-receptor complexes you can form at the receptor site
What is KD?
What does it tell us?
- Equilibrium dissociation constant
- Characterizes affinity for binding
KD and binding affinity have a(n) ________ relationship
(When KD is ____ affinity is ______)
Emax and drug potency have a(n) _______ relationship
(When Emax is ____ drug efficacy is _____)
Efficency in coupling is determined by what 2 things?
1- Initial conformational change in the receptor
2- Biochemical events (and how complicated they are)
Spare receptors are said to exist if.....
....the Emax(max pharmacologic effect) is obtained at less than max occupation of receptor molecules (Bmax)
If EC50 is ______ than the KD spare receptors are said to exist
What does it mean when EC50 and KD are equal?
Spare receptors do not exist
Spare receptors are caused by what 2 mechanisims?
1- duration of activation may be much greater than the duration of the drug-receptor interaction
2- The number of receptor molecules may exceed the number of effector molecules
Sensitivity of a cell or tissue depends on what 2 things?
1- affinity of the receptor for binding of the agonist
2- degree of spareness of the receptor
Spareness and sensitivity have a _______ relationship
(____ spareness leads to ______ sensitivity in the tissue)
reversibly bind to the same binding site of the agonist on the receptor molecule without activating the receptor
- competitive antagonists
- aka reversible
The success of competetive agonists depends on what 2 things?
1- its own concentration
2- concentration of the endogenous agonist
**you would have to adjust the dose frequently
irreversibly bind to the same binding site of the agonist without activating the receptor
- noncompetitive antagonists
- aka irreversible
Irreversible binding can be caused by what 2 things?
1- extremely high affinity for that antagonist to bind
2- they form covalent bonds
Irreversible antagonists cause a ________ shift of the max in dose-response curve
(tell you the receptors are being sealed up which is why you cannot see full max effect)
The duration of action of an irreverible antagonist depends on what?
The rate of turnover of receptor molecules
What is a disadvantage of irreversible antagonists?
there is no way to cure an overdose
Partial agonists produce a ______ response than do full agonists
Partial agonists are also used as ________
What do these 3 drugs have in common?
protaminm dimercaprol, pralidoxime
They are all chemical antagonists
What is chemical antagonism?
Occurs when 1 drug prevents the second drug from binding to its receptor site
True or false, a chemical antagonist does not depend on interaction with the agonist's receptor
true, it is NOT receptor-specific
What do these 3 hormones have in common?
insulin, epinephrine, glucagon
They are all physiologic antagonists
What is physiologic antagonism?
The physiologic antagonist binds to a different receptor molecule producing an opposite effect than the drug it antagonizes