Pharmacodynamics Lecture Sep 17 Flashcards
What is the study of pharmacology?
What is the study of pharmacodynamics?
Pharmacokinetics?
study of drugs that interact wiht living systems through chemical processes
Pharmacodynamics is how the drugs affect the body.
Pharmacokinetics is how the body affects the drugs.
How does a drug produce an effect?
It interacts with a receptor on or within a cell. It acts to increase or decrease cell function–it does not confer new function.
What is an agonist?
a drug that activates molecular, biochemical, and physiological events associated with the interaction
What are the two main functions of receptors?
- recognition of the ligand/drug - confers specificity
- Signal transduction - the message has to be transmitted to the cell to elicit an effect
What imparts selectivity of drug binding?
What confers specificity of drug action?
Receptor recognition of a drug imparts selectivity of drug binding–a drug will only bind one or a small number of receptor types
The tissue localizaiton of different receptor types imparts specificity of drug action - the drug exerts a distinctive influence on the body because the receptors are located in distinctive organs/systems
True or false: most drugs bind their receptors covalently.
False
If a drug binds to its receptor permanently, it essentially takes the receptor out of circulation because the bond is pretty much permanent. THe body would have to synthesize more receptor sin order to rescue the response.
SOme drugs actualy do this, but most bind noncovalently through H bonding, ionic interactions, etc. THey still need to fit appropriately into the active site, however.
What are most receptors composed of?
The majority are proteins (including enzymes, ion channels, structural, and regulatory)
Some are nucleic acids, but not many
In general terms, what are the 3 ways a receptor can propogate its signal?
- Alter receptor function
- Generates a second messenger (like cAMP)
- Impacts gene trasncription
Give an example of a receptor that propogates its signal through second messengers.
G protein-coupled receptor signalling
A durg binds to the G protein
Subunits separate and have their own characteristic puposes, such as increases or decreases cAMP, initiating calcium release, etc.
About half of the drugs we use today act through this mechanism
How do ion channels work?
You get a ligand/drug binding to the channel
this causes a conformational change and the channel opens
ions will flow through the channels down the electrochemical gradient
this could cause the depolarization of the membrane or the ion itself will be the secondary messenger
Explain how a receptor can act as an enzyme.
Many receptors possess enzymatic activity.
Very commonly, the ligand will bind receptor
receptors will dimerize
After the dimerization, the receptor can become an enzyme to catalyze reactions
these reacions are often phosphorylations (such as for the tyrosine kinase receptors) or dephosphorylation (like the tyrosine phosphatase receptors)
Explain how receptors can regulate nuclear transcription.
Many steroid hormones operate through this mechanism.
You have a receptor typically located in the cyotplasm or in the nucleus bound to chaperone (like a heat shock protein)
WHen the drug/ligand binds the receptor, the chaperone is inactivated and falls off.
This allows the receptor to interact with a hormone response element on the DNA
The receptor bound to the DNA will then recruit transcription machinery to alter gene expression
**note: these drugs are often moderatly lipophylic because they need to be able to travel across cell membranes easily.
What are 5 important attributes of receptor-mediated processes?
- THey are highly compartmentalized (receptors are expressed only in certain tissues)
- They are self-limiting on relatively short time scales (this is extremely important otherwise they wouldn’t make for very good signalling pathways)
- THey are often organized into opposing systems (one end will turn on a cascade and the other will turn it off)
- They provide opportunities for signal amplification (this is characteristic of GPCR - they snowball the effect)
- They operate through a relatively small number of 2nd messenger systems (many receptors will operate through the same signalling pathway, often simultaneously)
Some drugs don’t interact with receptors. WHat are some examples of things they react with?
- interact with small molecules
- produc physicochemical effects (move water around, alter pH, etc)
- target rapidly dividing cells
Why are drug drug interactions so common?
DD interactions are common because a large number of receptors may operate through a small number of secondary messenger systems
What are some of the ways cell cycle-specific drugs will be tosic to cells that are cycling?
- Can be structural analogs of endogensou compounds (like 5-fluouracil or methotrexate) that act by interfering with DNA/RNA synthesis
- THey can bind to DNA causing strand breaks (like the ABx bleomycin)
- Others target the cellular machinery needed for cell division (like tubulin)
What is inverse agonism?
This also doesn’t jive with occupancy theory.
It’s the idea that for a system that always have some level of constitutive activation, if you give an inverse agonist, you will actually get a DECREASE in response.
You can add in an normal agonist, which will increase the activation if you can swamp out the inverse agonist.
To further this point, if you give a pure antagonist to this type of system, activation will not respond to either an inverse agonist or a normal agonist.
