Lecture 8 - Drugs and Receptors; Pharmacokinetics

Question 1

how do drugs exert an effect?

Answer 1

bind to a receptor - mostly proteins

Question 2

where do antimicrobial and antitumour drugs bind?

Answer 2

dna

Question 3

list drug targets and proportions

Answer 3

enzymes 47%
gpcr 30%
ion channels 7%
transporters 4%
nuclear hormone receptors 4%
other receptors 4%
integrins 1%
miscellaneous 2%

Question 4

what is the relevance of concentration of drug molecules?

Answer 4

drugs of equivalent molar concentrations have same concentration of drug molecules
drugs of equivalent concentrations may not

Question 5

how do molecular weight, molarity and grams/litre link?

Answer 5

mol. weight x molarity = g/l

molarity = g/l / mol. weight

Question 6

what is affinity?

Answer 6

likelihood of a ligand binding to its target

Question 7

what is efficacy?

Answer 7

likelihood of activation

Question 8

what are agonists?

Answer 8

have both affinity and efficacy

Question 9

what are antagonists?

Answer 9

have affinity but not efficacy

Question 10

how can binding information be obtained?

Answer 10

using a radioligand

[drug] is usually logarithmic on the binding curve

Question 11

what is bmax?

Answer 11

maximum binding capacity

gives idea of number of receptors

Question 12

what is kd?

Answer 12

dissociation constant
measure of affinity - concentration needed for 50% occupancy
lower kd = higher affinity

Question 13

what is the difference between a concentration and dose response curve?

Answer 13

concentration used when measuring a response in cells/tissues
dose used when measuring a response in a whole animal

Question 14

what is emax?

Answer 14

maximum response

Question 15

what is ec50?

Answer 15

effective concentration giving 50% of maximal response

measure of potency

Question 16

what is potency?

Answer 16

combination of both affinity and efficacy

governed by number of receptors

Question 17

how is efficacy measured?

Answer 17

in relative terms, no absolute scale

Question 18

how does emax affect efficacy?

Answer 18

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)

Question 19

how is asthma treated?

Answer 19

have to activate beta 2 adrenoceptors to relax airways

salbutamol and salmeterol

Question 20

how does salbutamol work?

Answer 20

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

Question 21

how does salmeterol work?

Answer 21

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

Question 22

what are spare receptors?

Answer 22

sometimes, less than 100% occupancy gives 100% response

Question 23

what is the relevance of spare receptors?

Answer 23

increase sensitivity
allow for response at low concentration of agonist
number of receptors affects potency

Question 24

what is a partial agonist?

Answer 24

drugs that cant produce a maximal response, even with full occupancy
ec50 = kd

Question 25

what is the potency of a partial agonist compared to a full agonist?

Answer 25

can be less or more because potency depends on affinity and efficacy

Question 26

is a partial agonist always a partial agonist?

Answer 26

no

depends on the tissue and the biological response

Question 27

how are partial agonists used clinically?

Answer 27

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

Question 28

what are the three types of antagonist?

Answer 28

1. reversible competitive
2. irreversible competitive
3. non competitive

Question 29

what is reversible competitive antagonism?

Answer 29

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

Question 30

what is a therapeutic example of a reversible competitive antagonist?

Answer 30

naloxone
high affinity, competitive antagonist of mu-opioid receptor
used to reverse opioid mediated respiratory depression - competes with opioids

Question 31

what is ic50?

Answer 31

concentration of antagonist giving 50% inhibition

Question 32

what is irreversible competitive antagonism?

Answer 32

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

Question 33

what is a therapeutic example of an irreversible competitive antagonist?

Answer 33

phenoxybenzamine

non selective irreversible alpha 1 adrenoceptor blocker used in hypertension episodes in pheochromocytoma

Question 34

what is non competitive antagonism?

Answer 34

allosteric binding of antagonist to a receptor (ie not at the ligand binding site)