Drug Receptors and Pharmacodynamics Flashcards
Receptor:
component of the biological system to which a drug binds to bring about a change in the function of the system, specificity of the fit of drug to receptor (recognition) induces conformational change in receptor protein
Transduction:
conformational change in the receptor leads to the transduction that alters cellular function via effector molecules. Effectors accomplish the biologic effect after being activated by the receptor (they translate the drug-receptor interaction into a change in cellular activity). Examples: ligand-gated ion channels (fast response that changes membrane potential), G-protein-coupled receptors (fast response that produces 2ndary messengers, IP3, cAMP, cGMP), kinase linked or hormone (nuclear) receptors (slow response that changes gene expression/protein synthesis
Types of Receptor Molecules:
- Specialized: membrane proteins or ion channels designed to detect chemical signals and initiate a response via signal transduction pathways
- General: biological molecules with any function including enzymes, lipids or nucleic acids.
- Proteins: binding site for majority of drugs, great specificity (due to secondary and tertiary structure), example: hormone and neurotransmitter receptors, receptor or voltage gated ion channels, enzymes, transport proteins, structural proteins
- Nucleic acids and membrane lipids: lower specificity
Consequences of Drug Receptor Therapy
- Receptor mediate the actions of pharmacologic agonists and antagonists
- Receptors are responsible for selectivity of drug action
- Theory allows determination of quantitative relation between dose or concentration of drug and its pharmacologic effects via use of dose-response curve (know: potency and therapeutic efficacy)
Antagonist:
binding to receptors, but unable to generate characteristic response, effect results from preventing the binding of endogenous agonist and blocking their action, will have NO EFFECT in absence of the agonist for that receptor (extent of effect depends on normal “tone”)
Agonists:
bind to and regulate function or receptor macromolecules in the same manner as endogenous ligand promoting that receptor function
_______ determine binding affinity of drug to particular receptor relative to many other binding sites on patient
Size, shape, electrical charge, etc.
Explain the theoretical aspects of the hyperbolic shape of the dose-response curve.
a. Drug receptor theory assumes that interaction follows simple mass action relationships, binding is reversible and that response is proportional to receptors [R] occupied by drug [D]
b. R+ D ↔ R-D R-D is proportional to response
c. Dose response curves generated by giving increasing doses of drug and measuring the specified response to each dose
d. Hyperbolic shape of curve confirms the mathematical relationship between dose and response as show by this equation:
i. e/Emax = [D]/ EC50 + [D] = [D]/ED50 + [D]
Explain the therapeutic consequences of the hyperbolic shape of the dose-response curve.
i. Curve is relatively linear (straight) at low doses meaning that at low doses the response increases in direct proportion to the dose, this is consistent with receptor theory that states that the great the number of receptors occupied by drug, the greater the response provided.
ii. Curve levels off at high drug doses meaning that there is a limit to the increase in response that can be achieved by increasing the drug dose, consistent with theory that says the response by administration of drug is proportional to amount of receptors occupied by drug (HIGH dose=all receptors occupied, no further increase can be achieved and Emax achieved)
Describe the advantages of the log dose-response curve versus the dose-response curve
i. Allows for wide range of doses to be plotted allowing easy comparison of different drugs
ii. Dose-response relationship is nearly a straight line over large range of doses (corresponds to therapeutic range)
a. Potency = (equation)
affinity / Kd / EC50
Potency:
concentration (EC50) or dose (ED50) required to produce 50% of that drug’s individual maximal effect, depends on affinity (Kd) of receptors for binding the drug and in part of the efficiency of this drug-receptor complex to generate a response and is designated by EC50. Provides information on how much drug (dose) will be required to produce a given effect (more potent, less drug needed). EC50 values used to compare potencies of different drugs.
Efficacy = (equation)
power / Emax
Maximal effect or maximal efficacy (Emax):
limit of the dose-response relationship on the response axis (y-axis), indicates the relationship between binding to the receptor and the ability to initiate a response. Most important determinant of drugs clinical utility. Power is often used interchangeably with efficacy to describe the ability to initiate a response.
