3 - Pharmacodynamics Flashcards
What are the five different types of drug receptor classifications?
1 - Intracellular receptors
2 - Receptors with intrinsic enzymatic activity
3 - Receptors that directly associate with intracellular enzymes
4 - Ligand-gated ion channels
5 - 7 membrane spanning receptors (7MSR)
Describe intracellular receptors
- Intracellular receptors (meaning they are located within the cell) only bind ligands which are lipophillic
- This is because the ligand needs to first diffuse through the cell membrane (only lipophillic can do that)
- The receptors are located in either the nucleus or the cytoplasm
- Lipophillic ligands which commonly bind to intracellular receptors include steroids, thyroid hormones and vitamins A and D
- Once a ligand binds to an intracellular receptor, it typically increases or decreases gene expression
Describe a receptor with intrinsic enzymatic activity
- These receptors are found in the cell membrane and contain an extracellular and intracellular domain
- A ligand outside of the cell binds to the extracellular domain
- The intracellular domain has an enzymatic activity which changes a substrate within the cell (ex. A –> B)
What are some examples of receptors with intrinsic enzymatic activity?
- tyrosine kinases (i.e. insulin receptors, epidermal growth factor receptor)
- serine/threonine kinases (i.e. transforming growth factor-beta receptors)
- tyrosine phosphatases (i.e. CD45 receptors)
- guanylyl cyclases (atrial natriuretic peptide receptors)
Describe a receptor that directly associates with intracellular enzymes
Very similar to receptors with intrinsic enzymatic activity, but these don’t have their own enzymatic activity, instead they associate with an enzyme
What are some examples of receptors that directly associate with intracellular enzymes?
For example, theses receptors can associate with kinases or proteases and include receptors such as the interleukin-3 receptor, erythropoietin receptor, and leptin receptor
Describe a ligand-gated ion channel receptor
- Composed of several transmembrane proteins that form a “barrel” in the cell membrane
- Typically bind with neurotransmitters or hormones
- The pore or center of the barrel is hydrophilic and allows molecules in or out of the cell
- Typically only one of the proteins serves as the receptor for the ligand
Give an example of a ligand-gated ion channel receptor
One example of this type of receptor includes the nicotinic acetylcholine receptor (nAchR).
Describe 7 membrane-spanning-receptors or 7MSRs
- Drug receptors that have 7 transmembrane domains
- The extracellular domain is the N-terminus
- The intracellular domain is the C-terminus
- Bind with an array of ligands including hormones and neurotransmitters
- The signalling can either be G protein coupling (GDP –> GTP) or independent of G proteins
- If independent of G proteins, signalling usually includes transcription factors or transcriptional regulators
Define agonist
- They “go into” the receptor
- Agonist: a drug or ligand that binds to a receptor and produces a molecular, cellular, or physiological response
Define antagonist
- They “tag out” something trying to get into the receptor
- Antagonist: a drug or ligand that binds to a receptor and inhibits the response produced by an agonist
Define competitive antagonist
agonist and antagonist compete for the same binding site
Define non-competitive antagonist
agonist and antagonist bind to different sites, but antagonist induces a conformation change to alter binding site
Define partial agonist
a drug that produces a lower maximal response as compared to the agonist
Define ED50
ED50 (median effective dose): dose at which 50% of individuals exhibit a specific quantal effect.
Define TD50
TD50 (median toxic dose): dose at which a specific toxic effect occurs in 50% of the individuals tested.
Define LD50
LD50 (median lethal dose): dose that is lethal for 50% ov individuals tested. This is experimentally defined with animal models.
Define the therapeutic index (TI)
From the quantal dose-effect curve an indicator of safety related to a particular drug can be derived. This indicator is referred to as the therapeutic index (TI).
How do you calculate therapeutic index?
TI = TD50/ED50
The greater the ratio or the greater the window between the TD50 and the ED50, the safer the drug is for a patient.
What is K(d)?
The dissociation constant of a ligand in relation to its receptor
The Kd represents the point at which half of the receptors are occupied with ligand and half the receptors are free
What can K(d) be used for?
The Kd represents the affinity of a ligand for its receptor. This can then be used to compare the binding affinity of two ligands that bind to the same receptor. The lower the Kd (or the less drug required for half maximal occupancy), the greater the binding affinity of that drug.
What is B(max)?
B(max) represents full receptor occupancy (saturation)
Be able to draw and label a ligand binding affinity curve
Look at page 4 of the pharmacodynamics handout
- y-axis = receptor-bound drug
- x-axis = drug concentration
- K(d) = point on the x-axis (concentration of a drug) where the y-axis is at 0.5 (or 50% of the drug is bound)
- B(max) = point on the y-axis where receptor-bound drug is 100% or 1.0 on the graph
How can you use a ligand binding affinity curve to distinguish the affinities between two drugs?
Recall from the definition of K(d) that you can use the K(d) (represents the affinity of a ligand for its receptor) to compare two ligands in terms of their binding potential.
This is most easily visualized when plotted as bound drug vs. the log of drug concentration (still a ligand binding affinity curve)
This just converts the hyperbolic curve into a sigmoidal curve and is best for comparison purposes
