Week 4 Nordgren - Principles of Pharmacodynamics

Question 1

What is the basic definition of Pharmacology?

Answer 1

The study of substances (“drugs”) that interact with living systems through chemical processes.

(deals with both the beneficial & adverse effects)

Question 2

How does Toxicology relate to Pharmacology?

Answer 2

Toxicology is viewed as a branch of pharmacology which deals with adverse effects on living systems.

“science of poisons”

Question 3

What is a drug receptor?

Answer 3

A cellular macromolecule that interacts with a drug and in doing so initiates a series of biochemical events that result in the characteristic action of the drug.

Question 4

What are the functions of the receptor?

Answer 4

• Recognition
  
  • the receptor binds a drug or endogenous ligand
• Signal transduction
  
  • transfer of information
  • recognition of the drug needs to be communicated to the cell

Question 5

What does the term “selectivity” mean in the context of drug-receptor interactions?

Answer 5

The drug binds to one receptor or a small number of receptor types.

The tissue localization of different receptor types imparts specificity of drug action.

Question 6

Why is the drug-receptor interaction based on selectivity and specificity?

Answer 6

It would not be helpful if a drug bount to all receptors.

The drug is intended to exert a distinctive influence on the body.

Question 7

What is receptor-mediated signal transduction?

Answer 7

The interaction of a drug with its receptor propagates a signal, i.e. it converts the “drug signal” into a tissue response.

Question 8

What are the three ways transduction propagates a signal?

Answer 8

1. Alters receptor function
2. Generates a second messenger
3. Impacts gene transcription

Question 9

What were the four transduction mechanisms discussed in class?

Answer 9

1. G-protein coupled receptor signal
2. Ligand-Gated ion channel
3. Receptors as enzymes
4. Receptors regulating nuclear transcription

Question 10

What do G-protein coupled receptors (GPCRs) do?

Answer 10

• regulate second messengers
  
  • cAMP, cGMP, Ca²⁺, DAG, IP₃,
• most common drug receptor group
• specific subunits dissociate and have their own characteristic actions
  
  • ex. up/down regulation

Question 11

What is the mechanism of Ligand-Gated Ion Channels?

Answer 11

• Ligand binds → channel opens → ions flow through and down electrochemical gradient
  
  • drugs will interact with this channels
  • cationic & anionic
  • can lead to depolarization of the cell membrane

Question 12

How do “receptors as enzymes” work?

Answer 12

• Intrinsic enzyme activity phosphorylates diverse effector proteins.
  
  • phosphorylation proteins (kinases) at specific AA residues
  • Cleave phosphate off (phosphatases)
• lots of receptors possess enzymatic activity
• can be inactivated or activated by ligand binding

Question 13

How do “receptors regulating nuclear transcription” work?

Answer 13

• Receptors have the ability to bind directly to DNA
• Regulate expression of adjacent genes
• Often associate with a chaperone protein
  
  • when receptor bound by ligand, will inactivate the chaperone
• Examples: sense steroids, thyroid hormones, etc.
  
  • control development, homeostasis, & metabolism

Question 14

What are the five major attributes of drug receptor-mediated processes?

Answer 14

1. Highly compartmentalized
2. Self-limiting on relatively short time scales
3. Organized into opposing systems
4. Provide opportunities for signal amplification
5. Operate through a relatively small number of second messenger systems

Question 15

What two attributes of drug receptor-mediated processes contribute to drug-drug interactions?

Answer 15

• Receptor-based processes tend to be organized into opposing systems.
• A large number of different receptors may operate through a much smaller number of secondary messenger systems.

Question 16

What are the non-receptor modes of drug action discussed in class?

Answer 16

• Drugs interacting chemically with small molecules
  
  • EDTA, dimercaprol
• Drugs producing physicochemical effects
  
  • Mannitol, MgSO₄
• Drugs that target rapidly dividing cells
  
  • chemotherapeutic agents, cell cycle specific drugs, and cell cycle non-specific drugs that act on dividing cells

Question 17

What are the two underlying assumptions of the Occupancy Theory?

Answer 17

1. Effect is proportional to receptor occupancy
2. Interaction is monovalent

Question 18

What is EC₅₀?

Answer 18

The concentration of drug producing 50% of the maximal response and is an estimate of the drug’s K_D.

Question 19

What is ED_50?

Answer 19

The dose of the drug producing 50% of the maximal response.

Question 20

What does affinity mean??

Answer 20

The ability of a drug to form a complex with a receptor.

• The greater the affinity, the lower the drug concentration required to produce an effect and occupy the receptor.
  
  • small K_Dand EC₅₀
• 1/K_D

Question 21

What is potentcy as it pertains to drugs?

Answer 21

A comparative term used to describe the relative positions of several agonist dose-response curves.

• High potency does NOT confer on a drug any inherent benefit.

Question 22

What is efficacy as it pertains to drugs?

Answer 22

Capacity to produce a response.

(a. k.a. Intrinsic Activity)
* Response induced by the interaction of a drug and receptor is a function of BOTH the affinity of the drug for the receptor and the efficacy of the drug-receptor complex to produce a response.

Question 23

What is a full antagonist drug?

Answer 23

A drug capable of inducing a maximum response.

(alpha = 1)

Question 24

What is a partial agonist?

Answer 24

A drug whose maximal response is only a fraction of the maximum that can be elicited.

(0 < alpha < 1)

Question 25

What is a "pure" antagonist?

Answer 25

A drug that can bind to a receptor (has affinity for the receptor), but induces no response. i.e. zero efficacy (alpha = 0)

Question 26

What are the effects of a competitive antagonist on the dose-response graph?

Answer 26

* Shifts to the right * apparent affinity of agonist is reduced * slope does not change * maximal response can still be produced * REVERSIBLE

Question 27

What are the effects of a non-competitive antagonist on the dose-response curve?

Answer 27

* Slope reduced * apparent affinity changes very little, if at all * apparent numbers of receptors decreased * maximal response reduced * IRREVERSIBLE

Question 28

What are physiological mechanisms of drug antagonism?

Answer 28

Distinct from the type of antagonism described before, as it involves interaction between regulatory pathways mediated by different receptors. * does not involve binding to the same receptor * counteract an effect by using a different pathway * ex. insulin vs. glucocorticoids

Question 29

What is an inverse agonist?

Answer 29

* A drug that preferentially binds to the inactive form, shifting equilibrium to the inactive form. * This results in an effect the opposite of that produced by an agonist.

Question 30

Describe the two-state theory of drug-receptor interactions.

Answer 30

* Postulates that the receptor exists in an active and inactive form. * An equilibrium exists between these forms which results in a basal or "constitutive" level of activity in the absence of the drug.

Question 31

What are spare receptors?

Answer 31

* A system behaves as if it has "spare" receptors * more than it needs * different EC₅₀ and K_D values * violation of simple occupancy theory * may involve amplification and persistence of the original binding signal * possible that limitations on the response to receptor occupancy exist "downstream" of the ligand-receptor interaction itself

Question 32

Describe the Quantal Dose Effect.

Answer 32

* All or None * quantal dose-effect curve is a frequency distribution curve of the **population response** to a drug

Question 33

What information do/don't quantal log dose-response curves provide?

Answer 33

* Do: * Median effective dose (ED₅₀) - the dose required to produce the response in 50% of the population. * provides information on variability in the response of a population * can be used to judge a drug's potency relative to that of another drug * Don't: * provide info on a drug's KD value or maximum efficacy

Question 34

What is the therapeutic index (TI) of a drug?

Answer 34

The ratio of the median lethal dose to the ED₅₀ * a measure of relative safety of a drug

Question 35

What is the Certain Safety Factor of a drug?

Answer 35

The ratio of the dose producing death in 1% of the population (LD₁) to the dose of drug producing the therapeutic response in 99% of the population (ED₉₉).