Lecture 8 - Drugs and Receptors; Pharmacokinetics Flashcards
how do drugs exert an effect?
bind to a receptor - mostly proteins
where do antimicrobial and antitumour drugs bind?
dna
list drug targets and proportions
enzymes 47% gpcr 30% ion channels 7% transporters 4% nuclear hormone receptors 4% other receptors 4% integrins 1% miscellaneous 2%
what is the relevance of concentration of drug molecules?
drugs of equivalent molar concentrations have same concentration of drug molecules
drugs of equivalent concentrations may not
how do molecular weight, molarity and grams/litre link?
mol. weight x molarity = g/l
molarity = g/l / mol. weight
what is affinity?
likelihood of a ligand binding to its target
what is efficacy?
likelihood of activation
what are agonists?
have both affinity and efficacy
what are antagonists?
have affinity but not efficacy
how can binding information be obtained?
using a radioligand
[drug] is usually logarithmic on the binding curve
what is bmax?
maximum binding capacity
gives idea of number of receptors
what is kd?
dissociation constant
measure of affinity - concentration needed for 50% occupancy
lower kd = higher affinity
what is the difference between a concentration and dose response curve?
concentration used when measuring a response in cells/tissues
dose used when measuring a response in a whole animal
what is emax?
maximum response
what is ec50?
effective concentration giving 50% of maximal response
measure of potency
what is potency?
combination of both affinity and efficacy
governed by number of receptors
how is efficacy measured?
in relative terms, no absolute scale
how does emax affect efficacy?
agonists with different emax have different efficacy
agonists with the same emax may not have identical efficacy if the drugs differ in affinity (so relationsip between occupancy and response is different)
how is asthma treated?
have to activate beta 2 adrenoceptors to relax airways
salbutamol and salmeterol
how does salbutamol work?
beta 2 adrenoagonist with kd of 20 micromoles for beta 1 and 1 micromole for beta 2
kd for beta 2 is lower so has higher affinity
beta 2 selective efficacy and route of adminstration limits beta 1 activation and side effects
how does salmeterol work?
longer acting beta 2 adrenoagonist
no selective efficacy, preventing beta 1 activation and side effects purely through difference in affinity
kd of 1900 nm for beta 1 and 0.55 nm for beta 2
lower kd value for beta 2 gives 3455 times greater affinity than for beta 1
what are spare receptors?
sometimes, less than 100% occupancy gives 100% response
what is the relevance of spare receptors?
increase sensitivity
allow for response at low concentration of agonist
number of receptors affects potency
what is a partial agonist?
drugs that cant produce a maximal response, even with full occupancy
ec50 = kd
what is the potency of a partial agonist compared to a full agonist?
can be less or more because potency depends on affinity and efficacy
is a partial agonist always a partial agonist?
no
depends on the tissue and the biological response
how are partial agonists used clinically?
opiods act primarily through mu-opiod receptor (gpcr) including heroin and can cause respiratory depression leading to death
morphine is a full agonist of the receptor
buprenorphine is a partial agonist of the receptor which higher affinity but lower efficacy than morphine
advantageous as can provide adequate pain control without as much respiratory depression
what are the three types of antagonist?
- reversible competitive
- irreversible competitive
- non competitive
what is reversible competitive antagonism?
relies on dynamic equilibrium between ligand and receptor
can be overcome by high concentrations of agonist causing a parallel shift to right of agonist concentration-response curve
what is a therapeutic example of a reversible competitive antagonist?
naloxone
high affinity, competitive antagonist of mu-opioid receptor
used to reverse opioid mediated respiratory depression - competes with opioids
what is ic50?
concentration of antagonist giving 50% inhibition
what is irreversible competitive antagonism?
the antagonist dissociates slowly or not at all
cause a parallel shift to the right of agonist concentration-response curve
at high concentrations suppresses maximal response as spare receptors are filled by antagonist so no longer enough receptors for maximal response
what is a therapeutic example of an irreversible competitive antagonist?
phenoxybenzamine
non selective irreversible alpha 1 adrenoceptor blocker used in hypertension episodes in pheochromocytoma
what is non competitive antagonism?
allosteric binding of antagonist to a receptor (ie not at the ligand binding site)
