Lecture 1 - Pharmacodynamics Flashcards
What is a receptor?
A protein that interacts with drugs (ligands*) and imitates chain of events causing a form of cellular response.
(Proteins that can bind to drugs, hormones, neurotransmitters, cytokines, and other ligands)
List some examples of drug targets in cells?
- G-protein coupled receptors
- transort proteins
- ion channels
- tyrosine kinase receptor
- intracellular enzymes
- nuclear DNA
*drugs target these and then they activate or inhibit cellular functioning
Where can receptors be located? (3)
- cell membrane
- cytoplasm
- nucleus
Explain v briefly how drugs trigger biological responses
Receptor-ligand bonding either activates or inhibits post-receptor signalling (a signal transduction cascade) and further triggers biological responses.
boom roasted
Does lipid-solubility matter when determining which receptors a drug can bind to?
Yes.
- If lipid-soluble then it can penetrate the cell membrane and bind to receptors inside the cell membrane.
- If not lipid-soluble - it cannot penetrate the cell membrane and will be forced to bind to receptors outside of the cell membrane.
Receptors are ____ for drugs.
Targets
What determines the quantitative relation between the conc of a drug and it’s biological effect?
receptors man
What properties effect the relationship between drug dose and the pharmacologic response?
potency
efficacy
agonists
antagonists
T or F: receptors determine both the therapeutic and toxic effects of drugs in pts
true
List the 4 receptor families
1-G protein-coupled receptors (GPCRs)
2-ion channels
3-enzyme-linked receptors
4-Intracellular receptors
What receptor type is the biggest family of receptors and 30% of drugs act on members of this family.
GPCRs
What are the most common site of drug action – most targeted by drugs?
GPCRs
Describe the structure of the receptor
- single alpha helical peptide with 7 transmembrane domain
- extracellular domain contains the ligand-binding area
a G protein has 2 subunits - what are they?
- alpha
- beta gamma
What are the 3 different isoforms of the alpha subunit?
G - alpha stimulatory
G - alpha inhibitory
Gq
What two things can alpha subunit bind to?
- GDP
- GTP
What does the beta gamma subunit inhibit?
It inhibits the alpha subunit.
Describe v briefly the function and regulation of GPCRs
1 - unoccupied receptor doesn’t bind with G protein
2 - occupied (by a hormone or neurotransmitter) receptor changes shape and interacts with the G protein and G protein releases GDP and binds with GTP.
3 - alpha subunit of G protein dissociates and activates adenylyl cyclase
4 - hormone or neurotransmitter is now not present and the receptor reverts back to it’s resting state, GTP on the alpha subunit is hydrolyzed back to GDP, and adenylyl cyclase is deactivated
**see slide 12
**this also affects second messengers
Give some examples of second messengers
cAMP (cyclic adenosine monophosphate)
IP3 (inositol-1,4,5 triphosphate)
DAG (diacylglycerol)
Calcium
What 2 things are activated by GPCRs?
AC (adenylyl cyclase)
PLC (phospholipase C)
MEMORIZE SLIDE 13
OK MAN
What ions are more abundant outside of the cell?
Na+
Ca2+
Cl-
What ions are more abundant inside of the cell?
A-protein
K+
What are the 2 types of ion channels?
- ligand gated
- voltage gated
Extracellular domains of a ligand-gated channel bind to a _____.
ligand obvs
Explain the function and regulation of ligand-gated ion channels.
when the ligand binds to the channel - it triggers a conformational change in the receptor and then the channel opens
*direction of movement determined by electrochemical gradient
Ion channels are _____.
selective
Give 3 examples of ligand-gated channels? (specific to their ions)
1 - nicotinic ACh receptor
(ligand-gated Na+ channel)
2 - glutamate N-methyl-D-aspartate (NMDA) receptor
(ligand-gated Ca2+ channel)
3 - Gamma-aminobutyric acid (GABA) receptor
(ligand-gated Cl- channel)
*slide 18 for more details
What are voltage-gated ion channels activated by?
changes in electrical membrane potential
Where are voltage gated channels more likely to be found?
presynaptic
Where are ligand gated channels more likely to be found?
postsynaptic
Explain the presynaptic and postsynaptic channels using Ca2+ as an example
presynaptic (voltage gated channel) - activation of neurotransmitter release
postsynaptic (ligand gated channel) - activation of calcium dependent enzymes (because calcium is now present and able to activate other enzymes and trigger a biological response)
Example of a voltage-gated Ca2+ channel
amplodipine (for high blood pressure)
Example of a voltage-gated Na+ channel
Phenytoin
Explain what an ion pump is
- it’s a transmembrane protein that moves ion though a plasma membrane AGAINST their concentration gradient (low to high conc) (i.e. uses energy)
- ion channels move ions with the concentration gradient (high to low)
Where are ion pumps located?
in cell membrane
What is the purpose of an ion pump?
to re-establish ion gradients
What are the 2 types of enzyme-linked receptors?
1 - cell membrane
2 - intracellular
cell membrane enzyme-linked receptors are known as ____ _____ receptors
tyrosine kinase
Explain the structure of cell-membrane enzyme-linked receptors
- spans the membrane
- extracellular domain binds to a LIGAND
- intracellular domain has cytosolic enzyme activity which induces tyrosine phosphorylation
Explain the function and regulation of cell-membrane enzyme-linked receptors
- ligand binding = conformational change
- forms dimers
- converts kinases from inactive forms to active forms
- induces receptor tyrosine auto-phosphorylation
- recruit protein targets
- metabolism, growth and differentiation are controlled by these types of receptors (cell-membrane enzyme-linked receptors)
Where are intracellular enzyme-linked receptors located?
in the cytoplasm
Describe the structure of an intracellular enzyme-linked receptor
-forms a heterodimer composed of an alpha and a beta subunit
- contains an:
- RD (regulatory domain)
- CCD (coiled-coil domain)
- CD (cyclase domain)
What are intracellular enzyme-linked receptors activated by?
nitric oxide (NO)
In intracellular enzyme-linked receptors:
- NO activates initially
- ultimately cGMP is activated
In GPCR’s:
- receptor binding activates initially
- ultimately cAMP is activated
ok man
KNOW SLIDE 24 mini mechanism !!!
Intracellular receptors have two binding domains - what are they?
- ligand binding domain
- DNA binding domain
Where are intracellular receptors frequently located?
nucleus
Receptor ligands are ____ soluble?
lipid
so they can diffuse into the cell to interact with the nuclear receptor
Duration of action for:
ion channels
milliseconds
Duration of action for:
GPCR’s (G protein coupled receptors)
seconds to minutes
Duration of action for:
enzyme-linked receptors
-guanylyl cyclase
seconds to minutes
Duration of action for:
enzyme linked receptors
-receptor tyrosine kinases
minutes to hours
Duration of action for:
-intracellular nuclear receptors
hours to days
see review slide (28 & 29)
okay man
Bmax
maximal specific binding of ligand to a receptor
(top of normal graph)
(plateau of log graph)
*indicates the total concentration of receptor sites
Kd
eqbm dissociation constant between ligand and receptor
*represents the concentration of drug at which half-maximal binding (50%) is observed
Affinity
ability of a drug to bind to a receptor
When Kd decreases, affinity ______
increases!
inverse relationship
Selectivity
degree to which a drug acts on a given site relative to other sites
*describes preference for one receptor over the other
Emax
maximal effect induced by a drug (full agonist)
EC50
the concentration of drug producing an effect that is 50 perfect of the maximum
Potency
a measure of the amount of drug required to produce an effect of given magnitude
What is potency determined by?
EC50
EC50 and potency have an ____ relationship
INVERSE
higher EC50 = ____ potency
lower
Efficacy
measure of the ability of a drug to elicit a biological response by agonist
What is efficacy determined by?
Emax
Emax and efficacy have a ____ relationship
DIRECT
higher Emax = ____ efficacy
higher
When determining what drug is better - is efficacy or potency a better measure?
EFFICACY
-always look at efficacy and then potency
What is an agonist?
-mimics the action on the original endogenous ligand on the receptor
What are the 3 types of agonists?
full
partial
inverse
Agonists can be blocked by ______
antagonists
Define: full agonist
a drug that binds to a receptor and produces MAXIMAL biological response (that mimics response to endogenous ligand)
*good efficacy
Define: partial agonist
- less than max
- less than 100%
-have affinity for receptor but have LOW EFFICACY
What happens when partial and full agonist are administered together?
partial agonist reduces the effects of the full agonist
Define: inverse agonists
- have affinity for the receptor but have negative effect
* exert opposite pharmacological effect of receptor agonist
What is the difference between an inverse agonist and an antagonist?
Antagonist - fails to produce a biologic response
Inverse Agonist - produces a biologic response/pharmacological effect but in the exact opposite form of what is desired
What are antagonists?
a drug that has affinity for the receptor but no efficacy
affinity = yes efficacy = no
T or F: an antagonist always a biological effect regardless of whether or not an agonist is present
FALSE MAN
-an antagonist has no biological effect if an agonist is not present
Describe the two mechanisms of competitive antagonists.
they bind to the same site on the receptor with the agonist
-they prevent an agonist from binding to its receptor
OR
- they bind to an allosteric site (other than the agonist-binding site)
- which prevents the receptor from being activated even if the agonist is attached to the active site
If competitive antagonist binds to same site - what happens?
no changes in Emax or efficacy
-increase EC50 of agonist (decrease potency)
If competitive antagonist binds to different site - what happens?
decrease Emax (decrease efficacy)
see slide 42 for summary
adverse effect
undesired or harmful effect resulting from a medication (drug)
What are 4 types of adverse effects?
- overdose (too much therapeutic effect)
- poor tissue selectivity
- poor receptor selectivity
- drug interactions
How do we measure drug safety?
therapeutic index
TD50
ED50
TD50
drug dose that produces a toxic effect or adverse effect in 50% of patients taking drug
ED50
drug dose that produces a therapeutic effect or desired response in 50% of patients taking drug
What is the difference between ED50 and EC50?
ED50 - drug dose that produces therapeutic effect in 50% of Pt’s taking drug
EC50 - concentration of drug producing an effect that is 50% of the maximum
What ratio is used for therapeutic index (TI)
TD50/ED50
TI is high = ?
- therapeutic window is wide
- safety is high
- less adverse effects
high affinity + high selectivity = ??
high TI (therapeutic index)
Idiosyncratic
individuals exhibit an unusual drug response
Tachyphylaxis
an acute rapid loss of response to a drug (ex. pt took it yesterday, now today dose must be increased)
receptor desensitization
mechanism that reduces the receptor response to an agonist
see slide 47 for examples
clinical trials are always done on ___
humans
Briefly describe the 4 phases of a clinical trial
1 - for safety
- small number of healthy volunteers (20-100)
- find max tolerated dose
2 - (100-200)
-identify therapeutic dose and study efficacy
3-larger # of pt’s
-further establish and confirm safety and efficacy
4 - large # of pt’s
- post marketing studies
- monitor safety of new drug
- safety studies during sales
SEE SUMMARY PAGE
slide 51 & 52
ok man
