Lecture 15- Pharmacodynamic receptor theory Flashcards
drug targets include
- Mainly GPCR
- Ion channels
- Kinases
- Few nuclear receptors
- Enzymes
drugs are
ligands for a receptor
how many GOCRs in man
800
- 400 olfactory receptors e.g. sigh and smell
- non-olfactory receptors
olfactory receptors are regulated by
light, odorants, hormones, NT and ions
what is critical in determining drug action
the concentration of drug moelcule around receptors
uM
10-6M
nM
10-9M
pM
10-12M
how many moles in a uM
100,000
most drugs bind to receptors in an
irreversible manner
drugs either act
as antagonists
as agonists
antagonists
block the binding of endogenous agonists
agonists
activate the receptor
to bind to a receptor (as an antagonist or agonist)
drug must have affinity
higher affinity= stronger binding
mode of action: antagonists
- goverened by affinity
- no intrinisc efficacy
intrinsic efficacy and antagonists
wont switch the receptor to active state
mode of action of agonists
have both affinity and intrinsic efficacy
ligands bind tor eceptor due to
affinity
- both antagonists and agonists
intrinsic efficacy means that
ligand activates rthe recpetor and causes a response inside the cell
pharmacology efficacy
if drug causes blood vessel to dilate
clinical efficacy
if the drug actually lowes BP
lock and key analogy of antaognists and agonists
both bind due to affinity
Agonists- cause activation of receptor and repsosne inside cell (intrinsic efficacy)
Antagonists- have affinity but do not have intirnsic efficacy (block response of effector)
two ways the effect of drug concnenreation can be looked at
1) binding to the receptor
2) functional response
how do we measure binding
- Many cells/ many receptors e.g. 10,000- 1000,0000 receptors per cell
- Incubate radioligand and receptors —> binding
- Low ligand conc= low binding
- High ligand conc= high ligand binding
quantifying binding
using conentration of drug vs proption of bound receptors graph
Bmax
the maximum binding capacity
- gives info about receptor no.
Kd
dissociation constat
- concentration of ligand needed to occupy 50% of available receptors
the lower the Kd
the higher the affinity the ligand has for the receptor
high affinity (low kd) allows
binding at low conc of ligand
to treat morphine or heroin overdose
- Naloxone used to treat overdose :
- High affinity antagonist of u-opioid receptors
- Outcompetes opioid
nalaxone
has a higher affinity for the receptor than morphine or heroine (antagonist)
[drug] on graph usually presented
in logarithmic and not linear way
Log10 of a no.
power by which 10 has to be raised to get that number
e.g. 0.001 or 1mM = 10-3
scale on a logarithmic graph for receptor binding
between -11 and -7 ( ligand concentration at receptors usually <<1M
response by a cell requries
drug efficacy - onyl agonists give this
conenctration reponse curve
graphs which plot receptor binding usually use the sigmoidal log curve
Emax
maximum effect evoked by a ligand (intrinsic activity)
EC50
effecitve concetration giving 50% of the maximal response
EC50 is a measure of agonist
Potency
depends on both affintiy and intrinsic efficacy
concentration is the
known concentration of drug at site of action e.g. in cells and tissue
- usually unknown*
- so we use DOSE*
dose
concentrationa t site of action generally unknown
however we can quanitify have much of a drug a patient is getting in mg or mg/kg
