Pharmacodynamics- Drug Receptor Interactions

Question 1

Binding site

Answer 1

Can bind a substance but are not themselves capable of initiating a subsequent response

Question 2

Receptors

Answer 2

Can bind a substance and are capable of initiating a subsequent response

Question 3

Receptor fractional occupancy

Answer 3

Dependent only on the drug’s affinity and concentration (or dose)

Question 4

Kd

Answer 4

Equilibrium dissociation constant
Koff/Kon

Measure of drug’s propensity to bind to a given receptor (aka AFFINITY). More affinity, lower value

Question 5

Dose-response relationship

Answer 5

Correspondence between the amount of drug and the magnitude of the effect
Increasing the dose, increases the effect in a graded manner

Question 6

Potency

Answer 6

Concentration or dose of drug needed to produce 50% of that drug’s maximal response
EC50 or ED50 value
Depends on affinity for receptor and efficiency with which the receptor activation is coupled to response

Question 7

Maximal efficacy

Answer 7

Maximal response produced by the drug

Question 8

Competitive antagonism

Answer 8

Surmountable
Shift to the right in DR curve
Increase in ED50
No change in Emax

Question 9

Non-competitive antagonism

Answer 9

Insurmountable
Decrease in Emax
No change in ED50

Question 10

Quantal dose response curve

Answer 10

Relationship between drug dose and a specified effect in a population of individuals
Can determine median effective dose

Question 11

Therapeutic Index

Answer 11

TI = Toxic Dose50/ Effective Dose50

Question 12

Therapeutic Window

Answer 12

Dosage range between minimum effective therapeutic dose and minimum toxic dose

Question 13

Pharmacophore

Answer 13

Drug recognition site on receptor

Question 14

Ligand-Regualted Transmembrane Enzyme Receptors

ie Protein Tyrosine Kinase

Answer 14

Polypeptides that cross membrane once
Phosphorylate tyrosines or serines on various downstream proteins
Autophosphorylation of tyrosines on receptor’s cytoplasmic side can intensify/prolong the duration of activations
Ex of substances: insulin, EGF, ANF

Question 15

Cytokine Receptors

Answer 15

Resemble tyrosine kinase receptors but utilize a SEPARATE protein tyrosine kinase that binds non-covalently and is NON-INTRINSIC to the receptor
The protein can then dissociate and travel to nucleus to regulate gene transcription

Question 16

Ligand-Gated Channel Receptors

Ie Nicotinic Cholinergic Receptor

Answer 16

Drug binds to subunit and produce a conformational change and opens the channel
Allows ions or substances to pass into the cell
Very fast

Question 17

G-Protein Linked Receptors

Answer 17

Single polypeptide chain that transverse membrane 7 times
3rd intracellular loop regulates the ability to interact with specific G-proteins (activation of G protein conveys effects of drug to 2nd messenger enzymes)
Carboxyl terminus contain serine residues that can be phosphorylated and regulate receptor function

Question 18

Activation of Adenylyl Cyclase

Answer 18

1. Multiple G proteins activated
2. Activation of catalytic units of adenyl cyclase
3. Conversion of ATP to cAMP
4. cAMP activates multiple cAMP dependent kinases (PKA)
5. PKA phosphorylates multiple downstream proteins
6. Amplified final response

Question 19

Activation of Phosphoionositide Hydrolysis Pathway

IP3 and DAG

Answer 19

1. Multiple G proteins activated
2. Activation of catalytic units of Phospholipase C
3. Conversion of PIP2 to TWO second messengers DAG and IP3
4. DAG activates multiple PKC enzymes (>9)
5. Multiple PKCs phosphorylate various downstream proteins
6. IP3 release of large intracellular stores of Ca2+
7. Ca2+ activates multiple Calmodulin dependent kinases (PKA)
8. Multiple PKAs phosphorylate multiple downstream proteins
9. HIGHLY AMPLIFIED/DIVERSE FINAL RESPONSE

Question 20

Tachyphalaxis

Answer 20

Rapid development of diminished responsiveness to a drug

Question 21

Pharmacodynamic Tolerance (desensitization)

Answer 21

Decreased responsiveness to hormonal stimulation that occurs SLOWLY over time

Desensitization is NOT restricted to only the receptor population activated by the drug (think about heterlogous desensitization)

Question 22

Supersensitivity

Answer 22

Compensatory receptor mechanism where loss of activity on receptors leads to an increase in receptor density and/or enhanced receptor-effector coupling