5. Pharmacodynamics: how drugs act Flashcards
what are drug targets
drugs produce effects by binding to protein molecules
what are the 4 main drug targets
receptors, enzymes, carrier proteins and ion channels
do drugs act at non protein targets
yes eg DNA
receptors have how many binding sites
at least one binding site
what are ligands
chemicals which bind to receptors
what does binding require
affinity
what does the binding of endogenous and some exogenous ligands result in
result in activation of intracellular signaling pathways (signal transduction)
drugs can act by ___ or ____ the process of ____
inhibiting/promoting
signal transduction
for a ligand/agonist to have an effect what does there need to be
signaling system
binding needs to alter something in the cell
what are the 4 classes of receptors
iontropic
metabotropic
kinase linked
nuclear/intracellular
what are ionotropic receptors linked to
ion channels
what are metabotropic receptors linked to
G proteins (GPCRs)
what are kinase linked receptors linked to
certain enzymes
where are receptors found and what is the exception
on the membrane of cells unless they are nuclear receptors which are on the inside of the cell
what is an example of ionotropic receptors
ligand gated ion channels
what is the response time for ligand gated ion channels ionotropic receptors
quick - millisec
what does GPCR do
activate G proteins and leads to opening of ion channel/activation of enzyme that leads to cascade in cell and cellular effects
what is the response time for G protein metabotropic receptors
quick - within seconds
where are kinase receptor enzymes
and what does it do
on transmembrane protein
catalyze phosphorylation of target molecules
what is the response time for kinase linked receptors
slower - within hours
what do nuclear receptors do
promote gene transcription and synthesis new proteins
what is the response time for nuclear receptors
days to hours
what are ligand gated ion channels made up of
multi subunit complexes
what are the 3 important properties of ligand gated ion channels
activated in response to certain ligands
conduct ions through the otherwise impermeable cell membrane
select among different ions
what happens when an agonist bonds to the subunits of the ligand gated ion channels
causes conformational change to receptor and allows ions to flow into cell
what are 3 endogenous ligands for ionotropic receptors
what do they do
acetylcholine
GABA
glutamate
regulate flow of ions in and out of cells
what is altered when ligands bind to ionotropic receptors
electrical potential across membrane
what happens when an agonist binds to the receptor in a GPCR situation
activates signalling protein called G protein
what does the activation of a G protein lead to in the cell
what 2 things are achieved/changed
cascade of events activated in the cells
changes the activity of an element usually in an enzyme or ion channel
changes conc of the IC second messenger
how many times does the GPCRs span the membrane
7 times
how many subtypes of muscarinic acetylcholine receptors are there
5
what does M1 subtype of the muscarinic acetylcholine receptors in control of
neural - CNS and peripheral
cns excitation and gastric secretion
what does M2 subtype of the muscarinic acetylcholine receptors in control of
cardiac
cardiac inhibition and neural inhibition
what does M3 subtype of the muscarinic acetylcholine receptors in control of
glandular/smooth muscle
gastric and salivary secretions, smooth muscle contraction and vasodialtion
what does M4/5 subtype of the muscarinic acetylcholine receptors in control of
CNS
m4 = enhanced locomotion m5 = not well known
what are 2 examples of drugs that act through GPCRs
atropine and hyoscine at muscarinic receptors
what does non selective antagonists mean
non selective = act on all receptors so effect on drugs have a range of effect
what happens when you have a high conc of atropine and hyoscine
toxicity due to their increased effects
what is hyoscine butylbromide
what does it do and what does it allow
buscopan
muscarinic receptor antagonist
poorly absorbed and cannot cross the BBB and used to facilitate gastrointestinal radiology as it relaxes the GI smooth msucles
for tyrosine kinase receptors what do they consist of
extracellular part that binds the ligand and the intracellular part that functions as a kinase
what does the receptor function as in tyrosine kinase receptors
functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins (phosphorylation)
what does phosphorylation do to protein function
controls protein function by changing an enzymes activity which then leads on to produce a cellular effect
what does tyrosine kinases mediate the actions of
growth factors, cytokines and certain hormones
what is kinase
enzyme that transfers phosphate groups
what is vascular endothelial growth factor receptors essential for
essential for angiogenesis during development, pregnancy and wound healing
what are the main types of vascular endothelial growth factor
VEGFR1
VEGFR2
VEGFR3
what is VEGFR2 overexpressed in
cancer
how is VEGFR 2 linked to treating cancers
selective antagonists for VEGFR2 can interrupt the signaling pathways involved in tumor angiogenesis
where are nuclear receptors located
intracellularly in cytoplasm or nucleus
what does the activated nuclear receptor do when it is activated
function as transcription factor
in the absence of ligands where are nuclear receptors located
in the cytoplasm
when ligands are bound, where are nuclear receptors located
travel to nucleus and stimulate transcription of target genes
what is affinity
attraction of ligand/drug for a receptor
what is efficacy
do all drugs that bind to receptor have affinity and effect
what does 0 and 1 mean
intrinsic activity
Drugs ability to initiate biological activity as result of binding, some ligands bind to receptor (affinity) and lead to max effect but some will bind and have affinity for receptor but wont have an effect
1 = max effect 0 = no effect
what is an agonist
have affinity and efficacy - mimics
what is an antagonist
have affinity but no efficacy - prevents
Binds to receptor and prevents effects or binding of endogenous ligands
for a drug conc vs % effect graph as the conc of the drug increases what happens to the effect
increases
for a drug conc vs % effect graph at low conc increases in drug conc will result in what for the effect
proportional increase in effect
for a drug conc vs % effect graph at high conc increases in drug conc will result in what for the effect
increases in drug conc is no longer proportional and reaches a plateau so the effect is independent of conc
for a drug conc vs % effect graph at high conc why is the effect independent of the drug conc
limited amount of receptors in tissue, so in high conc, more and more receptors will be occupied/saturated and maximum effect is seen
the higher the affinity what happens to the conc at which it produces a given level of receptor occupany
lower conc
why are conc response curves not good measure of affinity
as relationship between receptor occupancy and response is not strictly proportional
why are relationship between receptor occupancy and response not strictly proportional
amplification may exist so may only take a low level of receptor occupancy to cause a max response in some tissues
many factors downstream of receptor binding may interact to produce the final response
the response to a drug can be classified by what 2 parameters
EC50 and Emax
what is the potency of an agonist measured by
EC50
what is the EC50
effective conc of an agonist that produces 50% of the max response
the more potent the agonist, the ___ the EC50
lower the EC50
antagonist potency is measured by what prinicple
IC50 - conc of drug required to produce 50% inhibition
what is the relationship with the efficacy and receptor for agonists
a drug with positive efficacy will activate a receptor to promote cellular response
what is the relationship with the efficacy and receptor for inverse agonist
drug with negative efficacy will activate a receptor to promote cellular response
what is the relationship with the efficacy and receptor for inverse agonists
drug with negative efficacy will bind to receptors to decrease basal receptor activity
what is the relationship with the efficacy and receptor for anatagonist
a drug with no efficacy will bind to receptors by have no effect on activity
what is the Emax
point reached beyond which no further increase in response occurs
what efficacy do agonists have
positive
what efficacy do inverse agonists have
negative
what efficacy do antagonists have
no efficacy
how do you judge the efficacy of a drug
Emax
how do you judge the potency of a drug
EC50 - how much conc of drug is needed to reach 50% of effects
what are full agonists
drugs that elicit the max tissues response
what are partial agonists
drugs that produce less than the max response
can partial agonists produce max response even at 100% receptor occupancy
why or why not
no never as it binds to receptor it partially activates receptor so produces some effects but competes with full agonists to block some of full agonists to take effect
what is the max response of a tissue to a drug determined by
efficacy and tissue properties
can drugs be a partial agonist in one tissue and a full agonist in another
yes
what effect do inverse agonists produce
opposite effect to full agonists
what effect does antagonists have
no activity on its own but can block activity of agonists and inverse agonists
what are antagonists
compound that binds but doesn’t activate/inactivate the receptor
do antagonists have affinity and effcacy
have affinity but no efficacy
what is the type of antagonists defined by
how they bind to receptor
what are the 3 main types of antagonists
competitive reversible antagonists
competitive irreversible antagonists
non competitive antagonists
how do competitive reversible antagonists work
Competitive antagonist compete for same receptor site and binds so prevents agonist from binding to cause effect
how do non competitive reversible antagonists work
Non competitive antagonist can prevent effect of agonist without binding to same site as agonist so acts on downstream factors that are needed to produce effect
what is irreversible antagonism and how does it work
bind covalently to receptor and is nor reversible
reduces the number of receptors avail to agonist so reduces the max response that an agonist can produce
for irreversible antagonism can it be reversed by increasing conc
Increase in conc cant overcome this blockade as it Is irreversible
what does irreversible antagonism do to the max response and shifting of the curve
Binding is irreversible so max bio response decreases
Reduce max response and shifts curve downwards
what are reversible competitive antagonists and how do they work
bind to receptor in a reversible manner to compete directly with agonist binding
what effect does increasing the conc of reversible competitive antagonists have on the agonist response curve
If you increase the competitive reversible agonist, will shift curve to right, competitive reversible antagonist makes agonist less potent by shifting dose response in right direction
Agonist and antagonist compete for same receptor as increase conc of agonist, increase chance that agonist will bind and produce effect, at a high enough agonist conc the antagonist wont have a change as it is outnumbered
since antagonists have no effects on their own, how can you observe it
what effect does it have on the EC50
Can only observe by looking at its effect on agonist
EC 50 are increased so same max effect is achieved but higher conc is needed to achieve max response
what does a irreversible antagonist look like for a response conc curve at low doses
why does it look like this
looks like reversible antagonist
Shows that the number of receptors avail exceeds the number req to produce the max response - oversupply of receptor to begin with but eventually high conc of irreversible antagonist result in downward shift in conc response curve
what is selectivity for receptor subtypes
preferential binding to a certain subtype leads to greater effect at that subtype than others
what does the lack of selectivity for drugs lead to
unwanted drug effects
what are 3 non receptor protein targets
enzymes
carrier proteins
ion channels
what are the effects of cyclo-oxygenase inhibition - what does NSAID inhibition of COX1 and 2 lead to
decrease in inflammation, pain and fever
reduction in homeostatic pathways involved in kidney function and maintenance of gastric mucosa
what is NSAIDS universally inhibited by
cyclo-oxygenase
what does inhibition of COX 1 do
unwanted actions including GI effects
what does inhibition of COX 2 do
anti inflammatory action
what does theophylline do - to phosphodiesterase
inhibits phosphodiesterase so stops conversion of cAMP -> AMP
what does theophylline do - cAMP
increases cAMP levels relax bronchial muscle
what does theophylline do - A receptors
antagonist at A receptor so blocks effects of adenosine = bronchoconstriction and inflammation
what are examples of drugs that interact with carrier proteins
drugs that act on monoamine neurotransmitters (serotonin, dopamine and norepinephrine) uptake proteins
what do drugs taht act on ion channels do
change ability to open and close ion channels
what are the 2 voltage gated ion channels
Na+ channel blockers
Ca2+ channel blockers
what is the dose response relationship
dose vs conc
what is the relationship of drug conc and dose administered for dose response relationship
proportional
is there EC50 for a dose response relationship
ED50
what is the difference between dose response curves and conc effect curves
Conc effect curve describe pharmacodynamics, purely dependent on drugs pharmacodynamic characteristics
Dose response curve is function of both pharmacodynamics and pharmacokinetic characteristics
for the dose response curve what is the median effective dose
ED50
dose at which 50% of individual exhibit specified quantile effect
for the dose response curve what is the median toxic dose
dose required to produce toxic effect in 505 of subjects
for the dose response curve what is the median lethal dose
Median lethal dose is dose req to kill 50% of subjects
for the dose response curve what are the 2 parameters used to calculate the therapeutic index of drugs
what is the limitation of the therapeutic index
LD 50 and ED 50 are used to calculate therapeutic index of drugs
this index has limitation as LD50 cant be measured In humans and were done in humans but animals are not the same as humans so is a poor guide. It has ethical issues
