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)
