Pharm - #8 Flashcards
most, but not all, drugs produce their effects by interacting with what?
Biological response to drugs are graded. EXPLAIN
Receptors
- increasing dose increases the response (up to some maximal point).
– biologic effects of drugs can be therapeutic or toxic,
depends on: the drug, the dose and its receptor “selectivity”
Drug Nomenclature: Drugs are referred to by a name that reflects what?
their most prominent site of action or clinical effect
– Most drugs will likely interact with many other receptors within a given clinical dose range used therapeutically. (not just at target site, but other sites as well)
**Drug interactions with one or more receptor subtypes are determined by the drug’s chemical and structural properties, not by the name given to it by humans.
(ex: beta blocker also has high affinity for seratonin receptors)
What are the following:
- Electrostatic (+ and -)
- Hydrogen Bonding (dipolar interactions)
- Van de Waal’s Forces (at closer distances) overlapping electron clouds
- Hydrophobic Forces (between lipophilic components)
The Chemical Forces that Contribute to Drug Binding
MOST DRUG BINDING INTERACTIONS ARE ____.
Most Drug Binding Interactions DO NOT Form a____Bond.
IMPORTANT:all drugs interact only with unoccupied free receptors
- REVERSIBLE
- Covalent
- Drug “displacement” generally does NOT occur in drug receptor interactions
- Reversible interaction between drug & receptor should be viewed as a dynamic equilibrium process. Thus the drug is either on or off the receptor at any point in time.
______ - can bind a substance (e.g. drug) but are not themselves capable of initiating a subsequent response, whereas
______ – can bind a substance and are capable of initiating a subsequent response.
Binding Sites
Receptors
-Receptors represent only the first step in the transfer of drug information to the system ( D + R Response
What happens after receptor amplification?
Signal Amplification
- single drug interaction leads to amplification
Gives rise to concepts of efficacy, potency, and spare receptors (reserve capacity)
II. What is the Relationship between Drug Concentration and Receptor Occupation ?
For any receptor population, the percent occupied (“fractional occupancy”) is dependent only on the drug’s what? (2)
To initiate a response, drugs need to occupy receptors
- Affinity and
- Concentration (or dose)
- Drug Binding to Receptors is a Dynamic Equilibrium Process
- the term k2/k1 (or koff/kon ) is the equilibrium dissociation constant (aka, the drug affinity constant) which is denoted by the term KD .
What does the KD value represent?
- *Drug Affinity and KD values are ______ related
What ELSE does the Kd constant represent?
- The KD value (i.e. affinity constant) of a drug represents a measure of the propensity of a drug to bind to a given receptor (a.k.a.,… its affinity
- Inversely
- The Affinity Constant (i.e., the KD) of a drug also represents the concentration of that drug required to occupy 50% of a receptor population.
The Binding of Drugs to Receptors is Dictated by the what equation?
Simple Fractional Occupancy Equation
Fractional Occ = 1/ [ 1+ Kd/[D]}
receptor fractional occupancy is dependent only on what 2 things?
- Drug affinity
2. Drug concentration
total number of receptors occupied by a drug will depend on what 2 factors?
What type of plot will result from the plotting of concentration vs. receptor occupation (where drug conc. is in units Kd)
- The fraction of the receptor population occupied
- the number of receptors in a given tissue (Bmax)
- LINEAR PLOT
- For example: If the KD of a drug is 1nM, then a conc. of 1nM would be a conc. of 1 KD unit, 2nM would be 2 KD units, etc. If another drug’s KD were 1uM, then it would take a conc. of 1uM to be at a 1KD conc for that drug, 2uM to be at 2 KD units of conc., etc.
At its KD concentration, a drug will occupy ____of its receptor population
What happens once we approach Kd? Once we exceed?
- 50%
-First we see a linear increase, then at the drug’s Kd a drug will occupy 50% of
receptor
-as we approach Kd and exceed we tail off and get a SMALL increase
**Increasing dose will increase receptor occupation in a NON-LINEAR fashion over most of the dose range.
-As the concentration of drug increases, the fraction of receptors occupied by the drug will increase from 1-91% over approximately 3 orders of magnitude (3 log units of drug conc.) about its Kd value, as shown in the figure
The magnitude of a drug response will be some function of what?
Total number of receptors occupied
( fractional occupancy * receptor density)
-RESPONSE = ƒ [(Fractional Occupancy) (Receptor Density)]
= ƒ [ Total # Receptors Occupied]
Drug Selectivity – will be dependent on the relative _____ of a drug
for various receptors.
- selectivity will ____ as drug dose is increased
affinities
-(i.e. comparative KD values for various receptors).
- decrease
- - as conc. increases, likely to interact with sites that interact with SIDE EFFECTS
DRUG SELECTIVITY:
Remember- all drugs can interact with any receptor at_____
&
it takes at least____ log units of concentration to occupy 1-91% of receptors
The “selectivity window” of a drug is dependent on the what?
- high enough doses
- 3 log units to occupy 1-91% of receptors
- drug dose or concentration range employed.
- It can be difficult to obtain this range in vivo where numerous factors are operative (drug distribution, metabolism, tissue receptor heterogeneity)
_____;this is the correspondence between the amount of drug and the magnitude of the effect;
Dose Response Relationship
-increasing the dose, increases the effect in a graded manner.
What is the simple occupancy theory?
1:1 relationship between occupation & response
-It’s simple……..
but doesn’t represent the dose-response relationship in most biologic systems
- The magnitude of the pharmacological effect is linearly proportional to the NUMBER of receptors occupied by the drug
- the maximum response Is obtained when all receptors are occupied
What did the modified occupancy theory give rise to? What was it an expansion of?
gave rise to:
- Potency
- maximal efficacy
An expansion of the original theory to account for experimental findigns
The response of a drug was some positive function of receptor occupancy (i.e. not necessarily linearly proportional to the percent of receptors occupied
Maximum effects could be produced by an agonist occupying only a small proportion of receptors
Different drugs may have varying capacities to initiate a response
Potency refers to what?
What does it depend on (2)?
- refers to the concentration or dose of drug needed to produce 50% of that drugs maximal response (EC50 or ED50 value)
- Affinity for the receptor
- Efficiency with which the receptor activation is coupled to response
______: the maximal response produced by the drug.Used synonymously with?
What is the intrinsic activity of the following:
- Full agonists
- Partial Agonists
- Antagonists(neutral)
- Inverse agonists (negative antagonists)
Why are antagonists considered “neutral”?
Maximal efficacy
Intrinsic Activity
-This can be determined directly from the graded dose –response curve and is the limit of the dose response curve on the response axis
- Full agonists I = 0
- Partial Agonists IA
A negative antagonist (or inverse agonist) can do what?
Reduce the constitutive activity of receptors
Remember: Biological Activity CANNOT Be Determined From what?
Fractional Occupancy
example of 3 graphs:
Shown below, 3 drugs have equal affinity for a receptor, yielding equivalent fractional occupancy with dose, despite having different biological activities
= different response
could be antagonist, full agonist,
partial agonist
Dose response curves demonstrate the concepts of _____ and ____
Describe the example of Morphine & Petazocine
Efficacy & Potency
-Efficacy and Potency are Independent Properties of a Drug
- different POTENCY
- same degree of pain relief efficacy (but different MAXIMUM efficacy)
ex:Morphine is more potent so need a lower dose
but both achieve the same pain relief efficacy
Increase dose = increase degree of pain relief up to some max response
Pentazocine also has some response, but will never achieve the same degree of pain relief
as with Meparidine both drugs equipotent, but DIFFERENT MAXIMAL EFFICACY
True or false:The Clinical Effectiveness of a Drug Depends on it’s Maximal Efficacy (Emax) not Potency (ED50)
TRUE!
reference the example fo the graph
- max efficacy is the limit of the graph
- ED50 is the same for morphine & petnamazocine for example
