02: Dose Response Relationship 2 Flashcards
What does a kinase do?
It phosphorylates something
What does IP3 do once it is activated
Helps release Calcium Ion from the lumen of the ER
What is the membranous enzyme that is activated under the Gq transduction mechanism
PIP2
What two messengers does PIP2 activate in the transduction pathway?
DAG and IP3
Tyrosine Kinase Receptor are individual transmembranous proteins, but what happens when ligands bind to their extracellular receptors?
Two individual receptors dimerize and activate Tyrosine Kinase activity
What is the structure that spans the membrane in a tyrosine kinase receptor?
Single alpha helix
What makes up the intracellular tail of the tyrosine kinase receptor?
Several tyrosine molecules
What is a common ligand for tyrosine kinase receptors
Insulin
What is the structure of intracellular receptors?
They have a DNA binding domain attached to a ligand binding and transcriptional control domains
What is an Agonist
Molecules that activate receptors. A drug with affinity and efficacy
What is an Antagonist
Molecules that bind to receptor sites bind prevents any response. They have affinity and no efficacy
What is the formula for a drug-receptor interaction
Drug (D) + Receptor (R) = DR —> Effect
What is the drug affinity formula (Kd)
Kd = k2/k1
What is a spare receptor?
Spare receptor are drug receptors that will bind the drug ligand but they will not transduce a response.
What ion channels are typically being affected when the beta/gamma complex of a GPCR is the effector molecule instead of the alpha unit?
Potassium (K+)
After DAG is activated, what molecule does it effect?
PK-C
What types of cellular receptors are most relevant to diabetes?
Tyrosine Kinase Receptors
What are Intracellular Receptors typically mediated by?
Hormones
What are the two basic domains of the Intracellular Receptors?
A DNA binding domain attached to a ligand-binding and transcription controlling domain
Are the effects of an intracellular receptor experienced quickly or slowly?
Slowly, the effect takes a long time because the effector proteins have to be synthesized after the DNA has been stimulated by the transduction pathway.
What does Kd mean?
It is the concentration of a drug we 50% of the binding sites are bound
What is Emax
The enzyme is maximally bound by the ligand
What is affinity?
How “tightly” the drug binds to the receptor
What is an example of a common drug whose break down product binds irreversibly to liver cells increasing the chances for overdose
Acetominophen/Tylenol
Is irreversible binding a problem that many drugs have (like Tylenol does)?
No, its actually rare. Some drugs have slow dissociation rates however.
Using Simple Occupancy Theory: If a receptor has 4 binding sites for drug molecules and 3 of the 4 are successfully bound by the drug, what would its efficacy be? What if only 1 binding site were bound?
3 bound sites = 75%
1 bound site = 25%
What does the existence of spare receptors allow for in terms of a drug’s response vs. a cell’s receptor capacity?
It means that a maximal response is possible without total receptor occupancy
How does the presence of spare receptors increase the sensitivity of the system?
Because of the spare receptors you can up the dose of the drug (ie Morphine) to increase the effect after a tolerance has built up.
Tolerance represents a shift in which direction on the Dose Response/Occupancy Curve?
A Shift to the Right
What does the term Pharmacokinetics describe?
The study of the concentration of a drug needed to reach the receptor and elicit a response
What does the term Pharmacodynamics describe?
It is the study of how a drug transduces a response once it has succesfully docked with its target receptor
What are we trying to describe with a Dose-Response curve?
the EC50 which describes the dose at which a response is observed in 50% of the experimental population
When reviewing Dose-Response curves, what is the difference between EC50 and ED50?
EC50 implies that the test was done on cells in a dish; and that a concentration was tested, not a dosage
What do you need on the Dose-Response curve in order to determine the ED50??
You need a plateau
Why do you need a plateau on the D-R curve to calculate ED50?
Because the Plateae represents the Emax, and the ED50 is 50% of the Emax
