Pharmacodynamics II: Receptor regulation + Drug tolerance

Question 1

agonist adaptation

Answer 1

cells exposed to an agonist over time will reduce receptor function in an attempt to overcome continuous presence of the agonist

Question 2

abrupt agonist removal

Answer 2

insufficient stimulation by endogenous agonist

Question 3

antagonist adaptation

Answer 3

cells exposed to an antagonist over time will increase receptor number and response

Question 4

abrupt antagonist removal

Answer 4

exaggerated response by endogenous agonist

Question 5

receptor adaptation clinical examples

Answer 5

drug = clonidine
used as a second line drug for hypertension
functions as an alpha 2 receptor agonist
Recall: alpha 2 receptor inhibits NE release
abrupt removal may cause hypertensive crisis

drug = glucocorticoid
used as anti inflammatory and immunosuppressor
the body will synthesise less endogenous glucocorticoid
abrupt removal = not enough glucocorticoid in the body
and adrenal crisis

Question 6

desensitisation/tachyphylaxis

Answer 6

in a lab setting where prolonged exposure can induce desensitisation

Question 7

tolerance

Answer 7

in the clinical setting where prolonged exposure can induce tolerance

Question 8

mechanisms of tolerance

Answer 8

1. accelerated drug clearance at the receptor e.g. up-regulated expression of CYP 450 enzymes by auto inducers
2. reduced receptor response due to receptor modification e.g. conformational change in receptor, phosphorylation or intracellular region, GPCR sensitisation
3. reduced number of receptors e.g. receptor internalisation/re-uptake or reduced gene expression of receptor protein
4. depletion/exhaustion of mediators e.g. NA pool in the brain with prolonged use of amphetamines
5. physiological changes

Question 9

example of reduced receptor response to agonist due to modification

enzyme: beta adrenoceptor kinase
protein: beta arrestin

Answer 9

in the normal state:
the intracellular tail of the beta adrenoceptor has several critical amino acid residues with hydroxyl groups which undergo conformational change when exposed to an agonist and signal to Gs G proteins

after prolonged exposure:
intracellular enzyme beta adrenoceptor kinase will phosphorylate the amino acid hydroxyl group on the beta adrenoceptor tail.

the phosphorylated receptor will now attract another protein from the cytosol: beta arrestin

this adaptation is reversible with enzyme phosphatase cleaving the phosphate groups formed on the beta adrenoceptor and beta arrestin protein dissociates

Question 10

receptor trafficking: receptor internalisation

Answer 10

endocytosis of receptors at the membrane.

where receptors are activated by ligand binding for prolonged period of time then they can become phosphorylated.

phosphorylated receptors migrate in the plane of the membrane and then cluster in coated pits and associate with one another forming a raft of activated receptors

this attracts intracellular protein = clathrin

eventually the membrane becomes endocytosed and these receptors can become:
> broken down inside the cell
> their ligand can be removed and reverted to their original state
> maintained within the cells in vesicles as a reserve of receptors

Question 11

agonist vs maximal response curve

Answer 11

hyperbolic/rectangular curve

EC50 value refers to the potency of the drug and is a measure of how much drug is required to produce 50% of maximal response.

Question 12

agonist vs maximal response semi log curve

Answer 12

sigmoidal curve

allows to compare the EC50 value of different drugs

Question 13

full agonists

Answer 13

differing full agonists may have different potency values but will always produce a maximal response in the tissue at sufficiently high concentration

efficacy (epsilon) = 1

will have a higher affinity for the activated state there by shifting to an increased drug response

Question 14

partial agonists

Answer 14

will never be able to stimulate the tissue to produce maximal response

efficacy (epsilon) < 1

will have less of an extreme preference for the activated state and will bind to resting state to some degree also, therefore it will never achieve 100% maximal response

Question 15

antagonist

Answer 15

will never ever stimulate a response (just maintain normal response levels at equilibrium)

efficacy (epsilon) = 0

antagonist has equal preference for both activation and resting state and will therefore bind equally readily to both states of the receptor i.e. it will not disturb the equilibrium

the basal response will not be effected

BUT: it will prevent the receptor from binding to an endogenous ligand by competitively binding to ligand binding site on the receptor.

Question 16

inverse agonsit

Answer 16

will have an extreme preference for the resting state and will therefore reduce response towards inactivation levels

Question 17

competitive antagonism

Answer 17

competes with agonist for binding site, it will shift the response curve to the right but maximal response is NOT affected.

response curve shifts to the right because it means that a higher concentration of the agonist is required to achieve the same EC50 response as normal conditions.

maximal response can still be achieved if concentration of agonist is increased to outcompete the antagonist.

Question 18

non-competitive antagonism

Answer 18

doesnt compete with agonist for the binding site.

shifts the dose response curve downwards as maximal response can never be achieved even by the use of a full agonist.

i.e. even at very high concentrations of the agonist, the maximal response can no longer be achieved.