Pharmacodynamics Flashcards
What are the different names a drug can have and what one should we care about?
Chemical name, generic name, commercial name
We need to know the generic name
What do organisms rely on to control tissue function?
Multicellular organisms rely upon intercellular signalling molecules to control tissue function
Features of receptors for drug interactions (4)
-The signalling molecules interact with proteins (receptors) in the plasma membrane to regulate biochemical pathways in the cytoplasm
-Each cell typ expreses a unique selection of receptors
-More than 1k PM receptors are known in 20 families
-Most drugs act by stimulating or blocking membrane receptors
What are the three things drugs need to possess adequately to interact with receptors?
Size, charge, shape and atomic composition
What are the lower and upper limits related to drug size?
Lower limit = minimum size needed to impart SPECIFICITY of action (100 MW)
Upper limit = size limit allowing reasonable movement in the body to sites of action (1000MW)
What is special about the administration of large drugs?
They must be administered directly into the compartments where the target receptors are located (bc they are too big to be able to leave otherwise)
How do drugs and receptors interact related to chemical forces or bonds?
Drugs that interact w receptors through WEAK BONDS are MORE SELECTIVE
What is drug affinity
Relative ability to bind to the receptor
What are the two common types of bonds and their features?
Electrostatic
-weaker than covalent
-includes electrostatic, hydrogen, van der wal bonds
-Many D-R interactions involve this bond
Hydrophobic
-Usually quite weak
-Probs most important with lipid interactions and highly lipid soluble drugs
-Many D-R interactions involve these bonds
Which type of bond has the weakest/more selectivity?
Hydrophobic
What bonds are important for highly lipid soluble drugs?
Hydrophobic
What do many drugs exist as?
Enantiomers (left and right handed versions of molecule)
Usually one of them is more portent and reflects a better fit with a receptor
Why do drugs modify signal transduction after binding to receptors?
To initiate, enhance, diminish, and terminate cellular chemical pathways
What do the effects of binding depend on?
Effects depend on actions of effector proteins and often second messengers that modulate cellular targets
What is drug effect proportional to?
Proportional to the percentage of receptors occupied by drug
What does the fraction of drug receptors that are occupied depend on?
Fraction of drug receptors occupied by drug is dependent on drug concentration in ECF
What are the five main mechanisms of transmembrane signalling that account for the majority of drug effects?
- Lipid-soluble drug binds to cytoplasmic receptor
- Transmembrane enzyme
- Transmembrane non-enyzme
- Drug binds to and opens/blocks an ion channel
- G-protein coupled receptors
Feature of cytoplasmic receptors and how it works
-Receptor possess a DNA binding domain as well as a ligand-binding site
D-R complex translocates to nucleus -> binds to response elements -> MODULATE GENE TRANSCRIPTION
Examples of lipid soluble drugs that bind to cytoplasmic receptors
Steroids (progesterone, estrogen, glucocorticoids)
Biological effects persist after drug has left body (hours,days)
How do transmembrane enzymes work?
D-R complex activates enzymatic activity on cytoplasmic face of receptor
How do transmembrane non-enzymes work?
Receptor activation allows mobile enzymes to bind to the cytoplasmic face of the receptor, activating the enzyme
includes cytokine receptors
What are the key neurotransmitters that modulate ion channels? How they work?
-GABA, 5-HT, glutamate
Effects are very rapid and they transduce signal across a membrane by allowing ions to cross membrane and alter cell excitability
What is the most abundant receptor type
G protein coupled receptor
How do GPCR work?
THey bind to a family of heterotrimeric GTP binding regulatory proteins termed G proteins. Activation results in exchange of GDP for GTP and subsequent downstream effects
What are second messengers?
Cytoplasmic molecules that translate D-R interaction into a change in cellular activity.
What does most second messengers entail
Entail reversible phosphorylation of key targets which allows for amplification of signal and flexible regulation of signalling
What is the purpose of giving drugs therapeutically? (2)
Stimulate receptors in hypofunctional states
Block receptors in hyperfunctional states
What does an agonist do?
Activates receptor = cellular response
What does an partial agonist do?
Agonist that is not able to fully activate the receptor
What does an antagonist do?
Binds to but doesnt activate the receptor = prevents agonists from stimulating receptor
What does an inverse agonist do?
Reduces basal activity of receptor
What is the dose response curve?
Its a depiction of the observed drug effect (% maximal response) as a function of drug concentration
What is potency?
The concentration of drug required to produce a given effect
What defines potency?
Normally defined by the half-maximal effective concentration (EC50)
How can you measure relative potency?
Relative potency of different drugs acting at the same receptor can be measured by comparing EC50 values
Are the most potent drugs the most efficacious?
Not necessarily
When is low potency a concern?
Its a concern if the volume of the required dose is too large to be convenient
What is efficacy?
The magnitude of the cellular response produced when all the receptors of a given type are occupied by the ligand
Defined by maximal response (Emax) of the drug
What gives a measure of relative efficacy?
Comparison of maximal responses of drugs acting at the same receptors
What is the parameter of greatest interest to the clinician
Efficacy
Why do hormones typically have a lag time for their effects?
Because there is a time required for the synthesis of new proteins.
What is the main characteristic of a competitive receptor antagonist?
It has affinity for the receptor but no efficacy, competing with the agonist at the site.
How can the effects of a fixed dose of antagonist be overcome?
By increasing the concentration of the agonist.
What effect does a competitive antagonist have on the dose-response curve?
It produces a parallel rightward shift in the dose-response curve
What happens to the EC50 value in the presence of a competitive antagonist?
The EC50 value increases (is larger), indicating decreased potency of the agonist.
Does the competitive antagonist change the Emax of the agonist?
No, there is no change in Emax
How does a non-competitive antagonist bind to the receptor?
It binds irreversibly to the receptor or dissociates very slowly.
Can a higher concentration of agonist overcome the effects of a fixed dose of non-competitive antagonist?
No, a higher concentration of agonist cannot overcome the effects.
What happens to Emax in the presence of a non-competitive antagonist?
Emax is reduced, meaning the agonist’s efficacy is decreased.
Is there always a change in EC50 when a non-competitive antagonist is present?
There may or may not be a change in EC50.
What is the process of an allosteric antagonism?
-Primary ligand/drug binds to main binding site on receptor
-Allosteric antagonist binds to a different site on the receptor, a conformational change in the receptor then inhibits binding of drug at the main receptor
What type of antagonism is allosteric antagonism an example of?
Non-competitive antagonism
What is tolerance in the context of drug administration?
Tolerance is the gradual decrease in responsiveness to chronic drug administration.
What are some mechanisms that contribute to tolerance? (3)
- Temporary inactivation of receptors (e.g., phosphorylation).
- Sequestration of receptors in the cell (internalization).
- Reduced synthesis of new receptors.
What happens to responsiveness after the drug is discontinued?
Responsiveness returns to basal levels after some time, depending on the drug.
What is tachyphylaxis and when does it occur?
Tachyphylaxis is a rapid (acute) form of tolerance to a drug.
It can occur with some drugs after the second dose
What is supersensitivity?
Supersensitivity is an increase in response to a ligand.
What usually causes supersensitivity?
It is typically due to chronic under-stimulation of a receptor type, leading to an unusually high number of receptors being expressed.
When may supersensitivity occur?
It may occur when a receptor antagonist has been used chronically and is suddenly withdrawn.
