Pharmacodynamics Flashcards
What are the primary targets of most drugs and why?
G-protein couples receptors
Receptors themselves are the body’s endogenous way to “drug” itself (i.e. regulate itself and achieve homeostasis)
What are the efects of ligand binding on the mu-opioid receptor? (e.g. repiratory depresseion etc)
___ and endorphins are examples of endogenous ligands for the mu-opioid receptor. ___ is a pro-drug that gets converted to ___, which itself is an exogenous ligand for the mu-opioid receptor
Respiratory depression
Euphoria
Analgesia
GI symptoms
Met-enkephalin and endorphins are examples of endogenous ligands for the mu-opioid receptor. Heroin is a pro-drug that gets converted to morphine, which itself is an exogenous ligand for the mu-opioid receptor
Describe a typical binding experiment and how you would determine binding affinity
In the petri dish: some source of drug target (tissue, purified drug etc) >> add drug in >> see what sticks >> measure bound amt
Affinity can be described as ___ and ___. Essentially, affinity is a measure of how long a drug stays in the receptor’s binding pocket
Affinity can be described as the rate of binding and the rate of dissociation. Essentially, affinity is a measure of how long a drug stays in the receptor’s binding pocket
Using the concepts of on/off rates, explain how fentanyl and buprenorphine (both bind to the mu-opioid receptor) can both have high affinity for the receptor
Fentanyl has higher on rate (access binding pocket more readily) = binds receptor w/ high affinity
Buprenorphrine: has similar on rate but once bound, stays in docking site longer (low off rate)
A higher on rate equates to a higher affinity because the drug can access the binding pocket more readily
A lower off rate also equates to a higher affinity because once the drug accesses the binding pocket, it stays docked for a longer period of time
Describe the meaning of the following variables on the curve below
Koff
Kon
Kd
[L] [R] vs [LR]
What do the plots for a binding experiment look like? How do you find the Kd?
What would the plot of a drug with 2 binding sites on the receptor look like? How would you tell which target the drug prefers?
If measuring drug binding on drug with 2 binding sites; you’ll get 2 bumps (the 2nd one = second binding site)
The bigger the difference between Kd’s; the more selective the drug is for the initial target
What is the significance of the therapeutic index and what would the curve to find the index look like?
Therapeutic index – difference between the Ed50 and the Td50; therapeutic window before he drug reaches toxicity in patients
How would you perform a dose response experiment?
Define efficacy
Dose response experiment: similar experiment to binding experiment but you measure effect you get from binding at varying drug doses (efficacy)
Draw a histogram showing a receptor in various states in the abscence of ligand
What would the curve look like when an agonist binds the receptor? What is its effect on the receptor’s ative state?
Agonist: shifts histogram to active state (activating drug; shows preferential binding to active conformation; will bind pocket when it moves to active state and will stabilize it in the active form)
For the curve of the agonist below, explain the following:
EC50
Potency
The significance of the difference in potencies between two agonists
Are these drugs full or partial agonists? Explain your answer
Concentration of drug to get half of maximal response= effective conc for half maximal efficacy (EC50)
When 2 different agonists elicit same response, they’ll have different EC50s
Agonist that has a higher EC50=less potent (potency – amt of drug needed to elicit response); difference in EC50 between 2 agonists = difference in potency
2 drugs can have the same efficacy but different potency
Both are full agonists because they reach max efficacy. A partial agonist would never reach max efficacy.
What is the difference between a competitive antagonist and an agonist? The site at which a competitive antagonist binds is called an ___ site.
Draw the histogram for a competitve antagonist
Competitive antagonist bind (orthosteric binding site) same site as agonist but shows NO preference for any form (active or not) or receptor; it blocks binding site NOT the active state
Draw the curve of a competitive antagonist in the presence and abscence of a ligand/agonist
What would you need to do, if anything, to elicit the same response as the agonist alone?
In the absence of ligand, nothing will happen if you add comp antagonist
Once you add a ligand and you add a comp antagonist, there’ll be change in dose response curve of agonist
Need higher concentration of agonist to outcompete antagonist to get back to same level of efficacy
Contrast a non-competitive antagonist and a competitive antagonist. What effect does a non-competitive antagonist have on the dose response curve in the presence of an agonist?
Non comp antagonists don’t care about conformation of receptor but they can’t be outcompeted by agonist, which happens in the case of a competitive inhibitor
(On the histogram, the curve shifts DOWN because the presence of the inhibitor knocks out the total # of receptors available for binding
Another way is for the inhibitor to bind to an ALLOSTERIC site.
Binding to the allosteric site affects the receptor shape such that the ligand can no longer bind to the orthosteric site, in which case, the total number of receptors available for ligand binding doesn’t change, it’s just that they can’t bind their usual site because the actual receptor itself has changed conformation)
On dose response curve, the curve will have a downward shift (if inh is a negative modulator) or an upwardshift (if inh is a pos modulator)
When a max response saturates with only a small percentage of receptors needing activation, what would the curve look like for the agonist and the non competitive inhibitor?
Non comp antagonists can behave like a competitive antagonist (response is maxed out by engaging fraction of those receptors); when you have an agonist, you need to increase the agonist
Explain the ability to achieve max efficacy and the later reduction of efficacy in the curve below
Here you have an alkylating agent which is an antagonist for smooth muscle
Control: just histamine
+ conc” adding the alkylating agent
As you increase the conc of non comp antagonist, you still get max response with slightly higher doses of histamine but once you increase the conc of non comp inhibitor enough, you can see reduction of efficacy because at that point, there are not enough receptors available for the ligand to bind and elicit the same response
Describe the function of a partial agonist. What effect will it have on binding at baseline?
At baseline, when you add a partial agonist, you’re going to shift the distribution such that the curve flattens out but the net effect is activation
If you start out with an agonist, then you add a partial agonist, what is the net effect?
If you have full agonist and then you add a partial agonist, you’ll see resemblance of competitive inhibition due to reduction in maximal efficacy
**recall that partial agonists bind the active site and mostly show preference for the active conformation but they can also show preference for inactive states as well, in which case they lock the receptor in the inactive state so you can never reach max response even with increased concentration of the agonist**
Using the diagram below (and what you should already know), explain why:
You would give naloxone to someone that’s had a heroin overdose
You would use buprenorphine for opioid replacement therapy/to help with withdrawal
Buprenorphine has the highest binding affinity of the 3 but because it’s a partial agonist(and thus some preference for the inactive state, it’ll never reach the efficacy of morphine)
Naloxone also has very high affinity but as a competitive antagonist, it has no preference for the active state which is why you give naloxone in the case of heroin overdose to remove morphine off of the mu-opioid receptor
Buprenorphine helps with opioid withdrawal (but won’t completely block mu-opioid receptor signaling so withdrawal symptoms are milder)
Beta blockers: full antagonists of beta adrenergic receptors but one drug acts as a partial antagonist so it’ll never block fully
Why would you give pindolol, a partial agonist type of beta blocker instead of a regular full agonist beta blocker?
Pindolol is a partial agonist that partially blocks epinephrine signaling from the beta-adrenergic receptor but won’t block fully, which is why it works well for pts who need a beta blocker but you don’t want to risk them developing bradycardia (i.e. those with partial heart block)
Describe an inverse agonist. How is it different from an antagonist? What effect does adding an inverse agonist have?
Opposite of regular agonist – shows preference of inactive state (not like an antagonist): will shift distribution of receptors even in complete absence of agonist
Meaning: that shifting between states is prevented by the inverse agonist
Examples: anti-histamines; mutation in receptor that makes it constitutively active – if you added an antagonist, it wouldn’t change anything but if you added an inverse agonist, you’d be able to shut the signaling off
Explain how an inverse agonist would work when you have constitutive activity vs no constitutive activity
When there is detectable baseline activity (i.e. an inverse agonist will work to decrease efficacy BELOW ZERO)
In cases where receptors have no constitutive activity, inverse agonists would function as competitive antagonists because there could never be suppression below zero
How does a bias agonist differ from a full or partial agonist?
A bias agonist has a “bias” over a specific SIGNALING PATHWAY as opposed to a conformational state, like the other types of agonists
