Module 2: Pharmacodynamics & Drug Receptors

Question 1

Ligand-gated ion channels

Answer 1

• has ligand binding site and when ligand binds to channel, it opens briefly allowing ions to move through the membrane
• response time: FAST, milliseconds
• creates important drug target

Question 2

G protein-coupled receptor

(seven transmembrane)

Answer 2

• passes through the membrane seven times and has alpha, beta, and gamma subunits
• requires use of GTP to activate
• increases secondary messenger
• amplification of signal
• Response Time: seconds

Question 3

Intracellular/ Soluble Receptor

Answer 3

• receptors are not bound to the membrane and are intracellular
• ligands are lipid soluble and can passively diffuse across plasma membrane
• alters transcription and translation
  
  • ex. steroid hormones, vitamin D, thyroid hormone
• Consequences:
  
  • Response time: SLOW, can take at least 30 min
  • the effects can persist for hours or days

Question 4

Enzyme-linked receptors

Answer 4

• extracellular binding site
• when ligand attaches, it stimulates enzymatic activity
• most commonly tyrosine kinase
  
  • add a phosphate group to tyrosine
• these display kinase activity
• Response time: hours

Question 5

Full Agonist

Answer 5

Elicits a maximal tissue response

Question 6

EC₅₀

Answer 6

the concentration of a drug that will produce 50% of the normal response

• tells us how potent the drug is
• Drug A is more potent than Drug B because it has a lower EC₅₀

Question 7

Efficacy Graph, how can you tell which drug is more efficacious

Answer 7

Drug A is more efficacious because it reaches 100% pharmacological effect where as drug B does not

Question 8

ED₅₀

Answer 8

50% Effective Dose

• dose at which 50% of individuals in a population are responding

Question 9

LD₅₀

Answer 9

50% Lethal Dose

• the dose at which 50% of animals die

Question 10

TD₅₀

Answer 10

50% Toxic Dose

• the dose at which 50% of the humans developed toxicity

Question 11

Partial Agonist

Answer 11

Response is submaximal even if 100% of the receptors are occupied

Question 12

Inverse Agonist

Answer 12

Stabilizes the receptor and will eliminate any basal activity that is occuring

Question 13

Competitive Antagonist

Answer 13

Competing with the agonist

• potency of agonist is reduced
• requires more agonist in order to overcome the competitive antagonist

ex. morphine, naloxone

Question 14

Non-competitive Antagonist

Answer 14

• bind to allosteric (separate) binding site that will cause conformational change of the agonist binding site.
• will also bind to same active site as agonist
• reduces efficacy of the agonist
• does not change the EC₅₀ of the agonist

Question 15

Neutral Antagonist

Answer 15

• blocks the docking of the agonist but does not trigger an effect

Question 16

Uncompetitive Antagonist

Answer 16

agonist binds to the active site which opens a new site for the antagonist to bind

• different from non-competitive since they require the agonist to bind and activate the separate site

Question 17

Affinity

Answer 17

• the tendency of a drug to bind to a receptor
• directly proportional to efficacy and potency
• mostly influenced by the rate of dissociation (K_D)
  
  • the lower K_D the higher the affinity

Question 18

Therapeutic Index (TI)

Answer 18

• Therapeutic index for animals = LD₅₀/ED₅₀
• Therapeutic index for humans = TD₅₀/ED₅₀
• this is a measure of drug safety
  
  • higher therapeutic index safer than lower therapeutic dose

Question 19

Tachyphylaxis

Answer 19

• rapidly diminishing response to successive doses of a drug, making it less effective
• AKA decreased effectiveness of drug with continued doses administered
• very common with drugs acting on nervous system
• Causes:
  
  • change in drug concentration at receptor site
  • change in concentration of soluble receptors
  • change in # or function of transmembrane receptors
  • change in components different from receptor (i.e. disease compensatory mechanism)

Question 20

Factors affecting variation in drug responsiveness

Answer 20

• Tachyphylaxis
• Age, gender, body size
• Dz state, genetics
• Co-administration with other drugs

Question 21

Homologous desensitization

Answer 21

• decreased response to stimulation by a drug or ligand at a single type of receptor
  
  • only the activated receptors are turned off
  • agonist-dependent
  • rapid (seconds-minutes)
  • receptor stays in the plasma membrane (usually)

Question 22

Heterologous desensitization

Answer 22

• decreased response at two or more types of receptors
  
  • i.e. activation of one receptor resulted in the inhibition of another
  • agonist-independent
  • “cross-desensitization”:
    
    • unresponsiveness to a variety of other agonists after prolonged stimulation by one agonist
  • slow (min-hours)
  • receptor is usually internalized

Question 23

Inactivation

Answer 23

• the loss of the ability of a receptor to respond to stimulation by a drug or ligand
  
  • completely turning off the receptor may result from phosphorylation of the receptor
    
    • completely block the signaling activity
    • lead to the removal of a receptor from the cell surface

Question 24

Quantal response curve

Answer 24

• needed to measure the variability of response in a population
• plot of the cumulative % of response vs. log of the dose
  
  • aka dose-percent curve

Question 25

General Receptor Characteristics

Answer 25

• specialized target macromolecule that will allow a drug or ligand to bind to it and mediate pharmacologic action
• have structural features that allow for drug specificity
• must have both
  
  • drug-binding domain
  • effector (active) domain

Question 26

K_D

Answer 26

rate of dissociation

the lower the K_D the higher the rate of dissociation

Question 27

Allosteric Activator

Answer 27

• these act at a separate site to increase the response to the agonist