Receptor Theory Flashcards
That which does not bind does not act.
Most drugs physically bind to receptors in the body in order to have an effect. If no receptor is present it cannot have an effect.
Which drugs work without receptors?
Antacids
Metal chelators (defroxmine)
How do most drugs bind reversible with their receptors?
Reversibly:
Electrostatic Interactions
Hydrophobic Interactions
Van der waals
What is an example of a drug that binds covalent you to the receptor?
Aspirin
Acetylates serine 530 of cyclooxygenase enzyme destroying ability to synthesize prostaglandins
Which receptors do most drugs target
Membrane bound G-Protein coupled Receptors
What are some molecules involved in G protein coupled receptors?
Norepinephrine, epinephrine, dopamine, histamine, acetylcholine, glutamate, parathyroid
What are some senses handled by gprotein coupled receptors?
Vision olfaction taste pain cognition memory emotion muscle function digestion urination
What is the first step in a second messenger system that is used by GCPRs?
The molecule binds to the receptor and then the g-protein is activated.
Epinephrine activates b1 adrenergic receptors in the heart
What is the final step in 2nd messenger systems used by Gprotein coupled receptors?
The effector cell is excited or inhibited by the second messenger.
Example Ca2+ influx increases contraction and cardiac conduction.
What is Signal transduction:
Extra cellular signal is transmuted to intracellular events.
What is unique about Receptor Tyrosine Kinases?
They are both receptors and enzymes.
Kinase - substrate gains a phosphate group.
What are the main steps in Receptor Tyrosine Kinase?
- Insulin binds to the receptor and the receptor phosphorylates itself.
- Eventually GLUT4 glucose is translocated to membrane of skeletal myocytes and adipose tissue.
What is the meaning of gated ion channels?
This means that there are ion channels that are blocked in response to voltage or ligands where a change in membrane potential or binding of Logan’s can open or close it.
Voltage gates Ca2 channels blocked by:
Ca2 channel blockers ( hypertension)
Voltage gated Na channels blocked by
Lidocaine controlling axons transmission (anesthesia)
Nicotinic receptors controlling voluntary muscle blocked by
Succinylcholine choline ( paralytic)
Cardiac K+ channels blocked by
Class 3 antiarrythmics
What are membrane transporters?
Serotonin reuptake transproter ( inhibited by SSRI)
Na/ K ATPase ( inhibited by Digitalis)
What are receptors in the nucleus?
Nuclear receptors are transcription factors.
How do nuclear receptors work?
They are receptors for steroids that form dimers upon activation.
The activated complex binds DNA initiating or inhibiting transcription.
Effects of drugs that inhibit nuclear receptors is long lasting.
How does acetylation regulate transcription?
Histone acetylation relaxes DNA for easier reading (HATS)
Done by Histone Acetyl Transferase.
Removal of acetylcholine tightens DNA for storage.
Done by Histone deacetylase
Increase in HDAC causes gene repression.
What binds to the nuclear receptors to increase HDAC activity?
Corticosteroids bind to glucocorticoid and mineralcorticoid.
What is the law of mass action?
the principle that the rate of a chemical reaction is proportional to the masses of the reacting substances.
What assumptions does the law of mass action make? (5)
Binding is completely reversible.
Binding does not alter the ligand or the receptor.
All receptors are equally accessible to ligands
Receptor and ligand for 1:1 complex and no partial binding occurs.
The concentration of available ligand greatly exceeds the available receptor populations.
What is the fractional occupancy of receptors? (f)
Is equal to the total concentration of ligand [L]divided by the sum of the total ligand concentration [L] + Kd ( the dissociation constant where half the receptor population is occupied by ligand) affinity
[L]
f= \_\_\_\_\_\_\_\_\_\_
[L]+Kd
When [L] = Kd half the receptors are occupied by ligands
Slide 18 be able to explain the graph.
Slide 18
Potency slide 19
Potency refers to the amount of drug concentration it takes to reach the maximum intensity of effect.
If a drug is more potent in an organism then it’s probably has a higher affinity in vitro.
What is Intrinsic activity?
The ability of a drug to produce maximal operation of a receptor.
Define efficacy:
Efficacy refers to the ability of a drug to produce a maximum therapeutic response.
How is efficacy affected
Pharmacokinetics properties ADME.
See slide 21 to look at graded dose curve.
Slide 21
How does Efficacy relate to concentration of drugs?
It has nothing to do with the concentration of drug only the magnitude of therapeutic benefit.
Potency
The amount of drug needed to produce an effect.
How much drug you need to get an effect.
Efficacy
How big the effect of the drug will be. Does it reach maximum intensity of effect.
What is an agonist?
Possesses intrinsic activity at a receptor
Partial agonist:
Agonist that achieves only partial efficacy even at full receptor occupancy.
Antagonist:
Binds to receptor lacks intrinsic activity, blocked the agonist
Competitive Agonist:
Binds reversibly at the active site
Noncompetitive agonist:
Binds to a site that is distinct from the active site and forces changes that inhibit the activity of the agonist.
What effect does agonist have on the concentration response curve?
At a given concentration the agonist alone reached the maximum intensity of effect.
What effect does a non competitive agonist have on the concentration response curve?
A non competitive agonist lowers the maximum intensity of effect at a given concentration.
What effect does a competitive agonist have on the concentration- response curve?
A competitive agonist shifts the curve to the right requiring a higher agonist concentration to reach the maximum intensity of effect.
What is an Allosteric co-agonist
Increases the effect of the agonist by binding to a site distinct from the active site.
Mixed Agonist /antagonist
Had activating properties at one site on the receptor and blocking on others.
How do we get a quantal does response?
We consider a population of subjects.
What is the median effective dose?
The dose of drug that produces a particular effect on 50% of the population.
How can you use quantal dose to compare to drugs and what can it tell you?
Look at a graph of the dose compared to the % of animals effected.
The one that reaches the ED50 at the lowest dose is is more potent.
If the both eventually have the same maximum % of effect , then their efficacy’s are the same.
Slide 27
What is the therapeutic index?
Based in the quantal dose graph.
The ratio of the lethal dose compared to the Effective dose.
Therapeutic Index = Lethal Dose / Effective dose.
TI = LD50:ED50
Smallest therapeutic index is preferred
Large Lethal dose and small therapeutic does is preferred.
What is an example of a drug with a low therapeutic index?
Lithium
ED= 1 mM
LD= 3 mM
TI=3
