Pharmacodynamics: Drug-Receptor Interactions and Dose-Response Relationships (Pilch) - 080816 Flashcards
What are drugs?
Any substance that brings about a change in biologic function (desired therapeutic outcome) through its chemical actions
May be synthesized in the body (e.g., hormones) or by nature or by man
Can vary in size from very small (MW10,000)
- Too small: nonspecific (will interact with everything)
- Too large: can’t get around body easily (difficulty getting to target)
Vast majority have MW values between 100 and 1000
Explain The Receptor Concept.
Most drug molecules interact with a specific molecule (receptor)
Receptors = macromolecular components of a cell (e.g., proteins, DNA, RNA, lipids, membranes, etc…)
Drug-receptor binding initiates a cascade of events ==> leading to drug’s observed effect or response
Describe the relationship between drug-receptor binding and pharmacologic response.
Drugs can show a differential capacity for initiating a pharmacologic response upon binding to a receptor.
Differential behavior provides basis for 3 models linking drug binding to pharmacologic response:
- Agonism (Induction)
Drugs (agonists) that mimic actions of endogenous compounds (e.g., neurotransmitters or hormones) and interact with a receptor to produce a pharmacologic response - Partial agonism
Lesser response than an agonist when the receptor is fully saturated (some drugs bind to a given receptor and produce a maximal response, while others bind to same receptor and produce only a partial response)
*Note: partial agonist can bind tighter to receptor than agonist but still induce only partial response - Antagonism
Interferes w/ action of an agonist - blocker (although antagonists bind to receptors, they do not produce pharmacologic responses)
Describe the relationship between drug dose and pharmacologic response.
Relationship determined by receptors
AFFINITY: determines # of drug-bound receptors (Kd)
TOTAL # OF TARGETS (RECEPTORS): determines maximal effect a drug may produce
Once agonist binds receptor, pharmacologic effect (E) determined by:
E = ([D] x Emax)/([D] + EC50)
where:
[D] = drug conc.
Emax = max effect (absolute highest effect a drug can have)
EC50 = effective drug concentration that elicits a 50% of max effect
A plot of E vs. [D] is:
hyperbolic
The more drug you have, the more the effect goes up - but it doesn’t go up forever (don’t have an infinite # of receptors –> saturation)
Emax = plateau level
Why are graded dose-response profiles often plotted in a semilog form of E vs. log[D]?
Allows for a greater range of drug concentrations to be examined (i.e. bc Drug A and B have differing dose-response profiles)
Also alters shape of curve from asymptotic to sigmoidal
EC50 corresponds to inflection point of sigmoidal curve
What is the difference between potency and potency ratio?
Potency = measure of how much drug is required to elicit a response (reflected in EC50 value); the lower the EC50, the more potent the drug
Less drug used –> less chance for toxicity
Potency ratio = difference in potency between two drugs
EC50 of Drug A / EC50 of Drug B
What is the efficacy of a drug?
Emax (the maximal response)
Two drugs can bind the same receptor but elicit differing maximal responses (i.e., the behavior of an agonist versus a partial agonist)
By definition, a partial agonist is less efficacious than an agonist
In the clinical setting, what is drug selection typically based on?
EFFICACY (Emax) and potential side effects
Once a drug is chosen, the AMOUNT OF DRUG to be administered is determined by the POTENCY of the selected drug
Summary:
Efficacy determines selection.
Potency determines amount.
Describe the activity of antagonists.
How would one plot the dose-response curve of antagonists?
Block the actions of endogenous agonists…
Therefore, in an environment devoid of agonists, they have no activity.
Observing the influence of antagonists therefore requires one to monitor and plot their impact on the actions of preexisting agonists
Dose-response curve: plot dose-response curve of an agonist and determine how curve is affected by differing antagonist concentrations
Describe the activity of a competitive antagonist.
Effects can be overcome by adding more agonist (i.e. the agonist and antagonist compete with one another)
Example: propranolol binds beta-adrenoreceptors and competitively inhibits action of endogenous norepi and epi.
How do increasing concentrations of a competitive antagonist shift the E vs. log[D] curve of the agonist?
Shifts R (x-axis is never antagonist)
Emax –> no change
EC50 –> increased (making agonist appear less potent)
What are the two important therapeutic implications of using competitive antagonists?
- Degree of inhibition produced by competitive antagonist depends on the [antagonist]
- Inter-individual variation in plasma level of antagonist may require dosage adjustment to achieve appropriate therapeutic response - Clinical response to competitive antagonist depends on [endogenous agonist competing for binding to receptors]
- If episodic inc. in endogenous agonist levels.. may reduce therapeutic response of administered antagonist
Describe the activity of a noncompetitive (irreversible) antagonist.
Prevents an agonist from producing a maximal effect
No amount of agonist can overcome the addition of a noncompetitive antagonist.
Therefore, Emax decreases in the presence of a noncompetitive antagonist (fewer receptors available to produce a response).
EC50 remains unchanged
