Flashcards in Lec 52: Pharmacology: Mechanisms of Drug Action Deck (21):
Summarize the basic principles underlying ligand-receptor interactions
Ligand-receptor interactions are similar to enzyme-substrate binding interactions studied previously.
•Drug, D, combines with receptor, R, to form drug receptor complex, RD which will cause events, E, to occur and subsequently the effect or response.
•KD is the dissociation constant of drug-receptor RD complex
•KD defines the concentration of drug needed to give 50% receptor occupancy
•Affinity = 1/KD
What assumptions are made in the relationship between binding and effect?
-1. Drugs interact reversibly with receptors (non-covalently) - mostly true.
2. One drug molecule interacts with one receptor site - often true (Other molecular ratios possible, i.e. two drug molecules per receptor)
3. Drug is present in great excess (concentration of bound drug is negligible relative to free drug) - not always true.
4. Response is proportional to receptor occupancy, and maximal response is achieved when all receptors are in the bound (RD) form - often wrong (spare receptors).
Describe spare receptors
Limiting factor in response size may be participating events (E) not number of RD* complexes. Max effect may be observed when number of receptors in active RD* form is less than total number of receptors, RT.
“Spare receptors” are present when the number of activated receptors is not the limiting factor for drug action
What happens when spare receptors are present?
•100% receptor occupancy not necessary to induce max effect
•Agonist concentration needed to produce 50% max effect is less than agonist concentration needed to give 50% receptor occupancy
•Concentration-response curve is shifted to the left relative to concentration-binding curve
Describe agonist function
Bind to or stabilize the active form of the receptor and thereby initiate a response
Describe antagonist function
Produce no effect on their own, but block effects of agonist
Describe competitive agonists
Bind reversibly to the same site on the receptor as the agonist, thereby preventing the agonist from gaining access to the receptor site. The potency of a competitive antagonist is usually determined by its rate of dissociation from the receptor (which is often slow compared with the rate of dissociation of an agonist
Describe irreversible antagonists
React covalently with the agonist binding site on the receptor, thus cannot be competed by high concentrations of agonist; antagonism is insurmountable
Describe reversible or irreversible non-competitive antagonists
Antagonists bind to a different allosteric site on the receptor that can regulate the affinity of the agonist for the agonist site
Describe chemical antagonism
One drug complexes with another in solution - no receptor interaction occurs. (Nonreceptor antagonist)
Describe physiologic antagonism
Two different drugs activating two mutually antagonistic regulatory pathways through different receptors reduce the effect of each agent given alone. (Nonreceptor antagonist)
Describe inverse agonists
Produce effects that are opposite to those of an agonist. Observed only in systems with constitutive activity (where receptor is active in the absence of any regulatory ligand)
Define efficacy (in theory)
The capacity of an agonist to induce a response by stabilizing the active forms of the receptor
Define efficacy (clinically)
Refers to the max therapeutic benefit of a drug, regardless of mechanism.
• For instance, morphine gives greater relief than aspirin against intense pain, hence more clinically efficacious, even though morphine is a partial agonist (they work through different mechanisms)
Explain affinity as applied to drug-receptor interactions
Affinity governs occupancy or the ability to form RD, whether by an agonist or antagonist
Explain efficacy as applied to drug-receptor interactions
Efficacy governs activation or the ability to form RD* (activated), which can only be done by agonist, not antagonist
What is desensitization?
Repeated or prolonged exposure to agonist that leads to a reduction of response to the agonist
What is homologous desensitization?
specific desensitization for agonist acting at a specific receptor type
What is heterozygous desensitization?
Loss of responsiveness to agonists acting at several receptor types
What is down-regulation?
Down-regulation occurs during prolonged agonist exposure. Reduced rate of receptor synthesis and/or degradation is observed with reduction in receptor number becoming apparent over period of hours or days