Receptors
This type of receptor needs a *blank* to bind & it binds extracellularly. It is not the most common, and when it binds it changes conformation.
ligand gated ion channels
what does basal state mean and what is the ratio?
the activity that occurs when there is no ligand bound. The ratio is 95-5% (more inactive than active).
What is a quantal response? How do you get the ED50?
what is a side effect? adverse effect?
side effect: any other effect apart from the therapeutic effect; most (not all) side effects of drugs are adverse effects.
adverse effect: means it is HARMFUL.
*all adverse effects are side effects but not all side effects are adverse effects*
describe toxicity, idiosyncratic, allergic, teratogenic, fetopathic effects.
toxicity: if the concentration of the drug in the blood was increased
idiopathic: effects due to some genetic differences
allergic: immune system is activated due to hypersensitivity
teratogenic: harm to the fetus
fetopathic: death to the fetus
What are transmembrane targets? Name 5
-Sodium/Potassium Pump
-GPCR
-muscarinic M2
-NE transporters
-unable to bind G-proteins
-most energetically favorable state
-at basal state there is 95% receptors in this state
Active State (Ra):
-can bind G-proteins
-generate second messengers
-at basal state there is 5% receptors in this state
Name the 5 ligands a drug could be.
Full Agonist: moves the receptor into the ACTIVE state
Partial Agonist: moves the receptor mainly into the ACTIVE state but some of the receptors will also go into the INACTIVE state.
Neutral Agonist/Antagonist: will move the same number of receptors into the active state as in the inactive state. 50-50.
Partial Inverse Agonist: moves receptors primarily into the INACTIVE state but will move some into the ACTIVE.
Inverse Agonist: moves the receptors into the INACTIVE conformation.
true or false: adverse effect means toxic effect.
false. toxic is due to too Hugh of a dose or slow elimination of the drug from the body. this is due to excessive effects of the drug in the body.
when raising the concentration in the blood the more selective drug will:
mention the risk & benefit of this
but by doing this its running the risk of more off-target adverse effects b/c the drug is occupying more of other proteins --> especially noticeable when we have a less selective drug
but we also expect an increase in therapeutic effect its occupying more of the target.
Name the G-proteins and what they do/activate.
Gs: stimulate adenylyl cyclase --> activate cAMP
Gi: inhibit adenylyl cyclase --> reduce the amount of cAMP
Gq: stimulate phospholipase C which breaks down PIP2 into DAG & IP3.
Describe the kD and put the units in order of smallest to largest.
kD is the affinity a drug has for a receptor. The smaller the kD the HIGHER the affinity, and the higher the affinity the STRONGER the bond.
pico<nano<micro<milli
True or False: *IF FALSE EXPLAIN HOW YOU CAN CORRECT IT*
1. Additivity is when you add two active substances together and it yields the combined response (simply add).
2. Synergy is the response of adding one active substance and one inactive substance. the combined effect will yield 2.
3. Potentiation is when you add two active substances and the response yields something greater than we expected.
1. true
2. false. synergy is adding 2 active substances together and it yielded a response GREATER than 2.
3. false. potentiation is adding one active and one inactive substance which yields a responser greater than the one active substance on its own.
what are the two type of adverse effects?
mechanism based:
-mechanism of action of a drug--> how it works in the body. the drug binds to a receptor and activates it. This is due to a target of a drug (receptor) is found in many locations of the body.
off-target:
-have nothing to do with the mechanism.
-it bind to something else besides the target; some of those proteins have a better affinity for the drug than the intended receptor.
what is the LD50?
LD50 is the lethality; FDA requires this to be tested on at least 2 species of animals. it is the dose that causes DEATH in half of the population.
What does DAG and IP3 do?
DAG stimulates PKC
IP3 binds to receptors on the sarcoplasmic reticulum and releases Ca2+ to be released.
What is a full agonist and is it able to do? What happens when you add more and more of an agonist?
A full agonist is a ligand that is able to ACTIVATE a receptor. It is able to move the receptors into the ACTIVE conformation; it has a higher affinity for the active confirmation.
When you add MORE agonists, the total number for active receptors start to increase; the inactive receptors are transitioning to the active form
Describe competitive antagonism and what it would do to the curve on the graph and the ED50.
when we repeat the agonist concentrations with low concentrations of an antagonist, the dose response curve is shifted a bit to the right. The agonist appears to be less potent in the presence of the agonist; the ED50 will be higher numerically because the antagonist will make it appear less potent. This is preferred clinically because we can reverse the effects.
what is selectivity? and why is poor selectivity a problem?
what receptor a drug binds to; the drug will be selective towards the target (receptor) but it will bind to any of that receptor, not just on one target.
poor selectivity is a problem because the affinity for another protein is what causes some adverse effect; higher the number, lower the affinity. we want a drug to be as selective as possible.
how do you calculate the therapeutic index in animals and in humans? And what is the ideal TI?
animals:
TI= LD50/ED50
humans:
TI= ED50(adverse effect)/ED50(therapeutic effect
**THE BIGGER THE TI THE SAFER THE DRUG**
what kind of kinases are PKG and PKA?
serine-threonine kinases
A graded response is a numerical value we can measure. It gives us the Emax which is the maximal effectiveness, where it plateaus (we look at the Y-axis).
The ED50 is the dose that produces half of the maximal response; where it intersects the curve! Relates the POTENCY of a drug. The more potent a drug, the less the ED50.
Describe non-competitive antagonist and what it looks like on a graph & what do we see a huge decrease of.
an antagonist that works irreversibly or in a non-competitive manner. When an irreversible agonist is added, the curve shifts to the right. There is a huge decrease in maximal efficacy. The higher the concentration of receptors, the more irreversibly they will be bound to the antagonist, now the receptors to the agonist will be lowered, due to not having any agonist available.
what is specificity?
which organ the drug acts upon; if there is a receptor in only one organ and a drug is made for it, it will be specific for that target and it will not act anywhere else. it is very difficult to find something for the target and nothing else in the body.
Where does drug metabolism take place? What are the 2 types of enzymes responsible? What are their roles?
Liver
cytochrome p450 & transferases
p450: phase I metabolites; responsible for metabolic rxns like oxidation/reduction/demethylation
transferases: phase II metabolites; responsible for the transfer/conjugation of a large endogenous substance onto the phase I metabolite. goes from lipophilic to more hydrophilic.