Pharmacodynamics Flashcards
What is the most common target for human drugs?
Proteins! 95% of drug targets in the human body are proteins
What types of proteins are most commonly targeted by drugs?
Kinase proteins and GPCRs
How could a drug affect a receptor protein?
It can act as an agonist (activate the receptor. could be a partial agonist (not able to elicit full response) or a full agonist), an antagonist (inhibit the receptor. could be competitive, non-competitive, or an irreversible inhibitor), or an inverse agonist (binding reduces basal activity of receptor and can, in some cases, also act as a competitive inhibitor.
An agonist would bind to the receptor protein as if it were the natural ligand. A competitive inhibitor would bind to the receptor as if it were the natural ligand. A non-competitive inhibitor would bind to an allosteric site. An irreversible inhibitor would bind and “lock” to the ligand site. An inverse agonist could do either.
How could a drug affect an ion channel protein?
It could physically block the ion channel’s opening. It could also modify the ion channel’s ability to pass ions through by increasing or decreasing the channel’s probability of being open (shape change caused by binding of drug)
How could a drug affect an enzyme protein?
It could use the enzyme to create an active form of the drug. It could act as a false substrate for the enzyme. It could block the enzyme from functioning. It could lead to the phosphorylation or dephosphorylation of the enzyme, activating or deactivating the enzyme.
How could a drug affect a carrier protein?
The drug could use the carrier protein to get into a cell, or it could inhibit the carrier protein from letting other stuff into the cell.
What is non-competitive inhibition?
The inhibitor binds to an allosteric site on the protein, which decreases its function but does not decrease the ability of substrate to bind to the protein. The Vmax decreases and Km does not change in MM graphs. In Hill dose response graphs the Kd would be unchanged but the max response would decrease.
What is competitive inhibition?
The inhibitor binds to the protein where its natural ligand would have bound. This keeps the substrate from binding. When a substrate is able to bind, the outcome is normal. Competitive inhibition changes Km (increases) but does not change Vmax
What is irreversible non-competitive inhibition?
The inhibitor binds and locks onto the protein. Nothing else can bind that protein, and it is a permanent change. This would increase Km and not change Vmax, because presumably as long as you can find an open enzyme you’d be able to get the optimal response from that enzyme.
How does competitive inhibition impact a michaelis menten or Hill dose-response curve?
Increase Km (Kd in Hill), no change in Vmax (Response in Hill)
What is an antagonist?
A drug that stops agonists (anti-agonist) from engaging fully or at all with a target protein.
What is an agonist?
A drug that stimulates the activity of a target protein
What is an inverse agonist?
A drug that stops basal receptor activity (receptors can be randomly active even when not bound with ligands) while allowing agonists to still bind (or if it’s a competitive inhibitor it would also be an antagonist). Inverse agonists are not called antagonists because they have an independent effect on receptors, where agonist can only block other ligands from doing their thing.
Why do inverse agonists impact receptor activity?
Many of our receptors have natural levels of activity even when not bound to their signaling molecules. This allows for a sustainable “base” level of activity in the cell (you can’t survive without some PKA being active even when glucagon isn’t around). Inverse agonists interrupt that basal activity.
How does noncompetitive inhibition impact dose-response (Hill) or michaelis menten graphs?
It would decrease Vmax (or maximum response in Hill) while not affecting Km (Kd). This is true for irreversible binding as well, because any enzyme that’s still functional would be able to reach maximum velocity. It’s assuming you don’t bind enough enzymes to totally shut the system down though.
What is Kd?
Kd is the drug concentration at which 50% of receptors are occupied. A lower Kd means your drug has a stronger binding affinity for the receptor. A higher Kd means you have a lower binding affinity.
What are ED50, TD50, and LD50 in dosage response curves?
ED50 is the drug dose at which you get 50% of maximal therapeutic impact. TD50 is the drug dose at which you get 50% of the maximal toxic effect. LD50 is the dosage at which 50% of people using the drug die.
What are the axes for a dosage response curve?
y axis = %maximum response.
x axis = drug concentration. it is often logarithmic.
Which axis in dose response or michaelis menten curves is often on a logarithmic scale?
X axis (drug concentration). This is because sometimes it takes magnitudes larger dosages to get an appreciable change in effect, especially as you get towards the maximal response. Your graph would be gargantuan with a big asymptotic line if you did a linear x-axis. Doing a logarithmic X-axis will make the graph look like an S
What are full agonists? Partial agonists? Neutral antagonists? Inverse agonists?
Full agonists are agonists which, when flooded in a system, can elicit a maximal response from the receptor protein. Partial agonists are agonist which, when flooded in a system, can only elicit a partial response. Neutral antagonists are antagonists which inhibit receptor activity with other ligands without causing any increase in activity (some antagonists block ligands but cause a minor amount of activity themselves). An inverse agonist cuts back the basal activity.
