Revision 8: Drugs and Receptors/Pharmacokinetics

Question 1

Discuss affinity and efficacy, as well as salbutamol and salmeterol

Answer 1

Affinity: likelihood of a ligand binding to its target

Efficacy: likelihood of activation of target by ligand

Agonist has high values of both

Antagonist has high value of aff, low value of eff

Salbutamol (short term emergency relief eg COPD): K_d: 20 micromoles for beta 1 and 1 micromole for beta-2 - higher affinity for beta-2

-in addition, beta-2 selective efficacy and oral spray route of administration limit beta-1 activation and potential side effects

Salmeterol (long term chronic conditions eg asthma): no selective efficacy between beta adrenoceptors, K_d of 1900nm for beta 1 and 0.55 for beta-2, therefore 3455 times greater affinity for beta-2

Question 2

explain drug-receptor interactions

Answer 2

Information is normally obtained through the binding of a radioligand (radioactive ligand)

B_max: maximum binding capacity, gives info. about no. of receptors

K_d: dissociation constant, conc. needed for 50% occupancy, K_d is inversely proportional to affinity

conc. of drug is normally expressed logarithmically

Question 3

explain conc. or dose response curves

Answer 3

conc. : used when measuring a response in cells/tiss.
dose: measuring a response in a whole animal

E_max: maximal response

EC₅₀: effective conc. giving 50% of maximal response - measure of potency which is combo of aff., eff. and no. of receptors

Question 4

spare receptors

Answer 4

sometimes <100% occupancy will result in 100% response -> ie K_d>EC₅₀ - the conc. for 50% of the maximum response takes less than the conc. required for 50% receptor occupancy

-this can be due to amplification from 2nd messengers, as well as the properties of the tissue

some tissues have more receptors than needed to produce a maximal response - spare receptors -> these inc. sensitivity -> allow for responses at lower conc. of agonist

Question 5

Partial agonists

Answer 5

drug that cannot produce a maximal effect even w/ full receptor occupancy

-K_d=EC₅₀

Can become full agonists depending on the tissue and biological response

can be more/less potent than full agonists, as potency is a measure of both eff. and aff.

uses: buprenorphine: an opioid with a higher aff. but lower eff. than morphine, so it provides adequate pain control while producing less respiratory depression

Question 6

different types of antagonists

Answer 6

Reversible competitive: IC₅₀ - conc. of antagonist that leads to 50% inhibition, K_d - conc. of antagonist needed to give 50% occupancy

• can be overcome by high levels of agonists
• eg. Naloxone: high aff. competitive antagonist at mu-opioid receptors, used to reverse opioid mediated respiratory depression, high aff. means it can compete effectively w/ agonists eg heroin for receptors

Irreversible competitive: antagonist dissociates slowly/not at all

• cause a parallel shift to the right of the graph, as well as nihibitng the max. response at high conc.s
• Phenoxybenzamine: non-selective irreversible alpha-1 adrenoceptor blocker used in hypertension episodes of pheochromocytoma (tumour of adrenal glands -> inc. (N)Adr secretion -> vasoconstriction

Non-competitive: allosteric binding of an antagonist to a receptor (ie not at the ligand binding site)

Question 7

reversible competitive antagonist

Answer 7

IC50 - conc. of antagonist that leads to 50% inhibition, Kd - conc. of antagonist needed to give 50% occupancy

• can be overcome by high levels of agonists
• eg. Naloxone: high aff. competitive antagonist at mu-opioid receptors, used to reverse opioid mediated respiratory depression, high aff. means it can compete effectively w/ agonists eg heroin for receptors

Question 8

irreversible competitive antagonist

Answer 8

antagonist dissociates slowly/not at all

• cause a parallel shift to the right of the graph, as well as nihibitng the max. response at high conc.s
• Phenoxybenzamine: non-selective irreversible alpha-1 adrenoceptor blocker used in hypertension episodes of pheochromocytoma (tumour of adrenal glands -> inc. (N)Adr secretion -> vasoconstriction

Question 9

type of inhibition

Answer 9

reversible competitive antagonist

as, even though the conc. of antagonist inc.s, a max. response from the tiss. can always be produced by high conc.s of agonists

Question 10

type of inhibition

Answer 10

irreversible competitive inhibition

as high levels of the antagonist will eventually cause the max. response to lower

Question 11

Which: (a) Which agonist has the highest potency?

(b) Which of the response curve(s) result(s) from activation of all receptors present?
(c) Which agonist(s) are full agonists?
(d) What is the EC₅₀ for agonist A?

Answer 11

a) B
b) B
c) A, C
d) 10^-7 M

Question 12

homo/heterologous desensitisation of a receptor

Answer 12

Homologous desensitisation – the process by which only the signal from the stimulated receptor is reduced

Heterologous desensitisation – the process when receptors for several agonists become less effective even when only one has been continuously stimulated.