2. Principles of drug actions

Question 1

Every drug has a ………

Answer 1

Target

Question 2

What is a drug?

Answer 2

A drug is a chemical applied to a physiological system that affects its function in a specific way.

Question 3

Drugs act on target proteins.

What are some examples of target proteins?

Answer 3

• Target proteins:
  
  1. Receptors
  2. Enzymes
  3. Carriers/Transporters
  4. Ion Channels

Question 4

Exceptions

Answer 4

• Drugs act on target proteins.
• There are always exceptions to the rules (e.g. osmotic diuretics, purgatives, antacids, & DNA).
• These do NOT affect target proteins.
  
  1. Osmotic Diuretics → act on osmotic potential in kidneys
  2. Purgatives → act on gut
  3. Antacids → act on stomatch
  4. DNA

Question 5

What are receptors?

Answer 5

Receptors are the sensing elements in the system of chemical communication in the body.

Question 6

What binds to a receptor?

Answer 6

1. Agonist
2. Antagonist

Question 7

What’s the difference between agonist & antagonist?

Answer 7

• Agonist:
  
  1. activates
  2. turns on the receptor
• Antagonist:
  
  1. blocks
  2. turns off the receptor

Question 8

Agonist

Answer 8

1. Ion channel opening/closing
2. Transduction mechanisms:​
   
   • ​​Enzyme activation or inhibition
   • Ion channel modulation
   • DNA transcription

Question 9

Antagonist

Answer 9

1. No effect
2. Endogenous mediators blocked

Question 10

What are ion channels?

Answer 10

• Ion channels are gateways in cell membranes that allow the selective passage on specific ions.
• Ion channels may be:
  
  1. Ligand-gated channels → ligand binds & opens a channel (e.g., Calcium)
  2. Voltage-gated channels → based on membrane potential

Question 11

Ion Channels

“Blockers”

Answer 11

Blockers → Permeation blocked

Question 12

Ion Channels

“Modulators”

Answer 12

Modulators → Increased or decreased opening probability

Question 13

Drugs & Enzymes

{ ​​Inhibitors }

Answer 13

1. Inhibitor:

• Drugs may be a substrate analogue that acts as a:
  
  1. competitive inhibitor of the enzyme
  2. irreversible non-competitive inhibitor
• Example:
  
  1. Aspirin irreversibly inhibits cyclo-oxygenase.
  2. Ibuprofen reversibly inhibits cyclo-oxygenate.

Question 14

Drugs & Enzymes

{ False Substrate }

Answer 14

• Drugs may also be a false substrate for the enzyme which results in a compound that subverts normal metabolic pathways.
• Example: Fluorouracil replaces uracil but cannot be converted to thymidylate thus blocking DNA synthesis & preventing cell division.

Question 15

Drugs & Enzymes

{ Prodrug }

Answer 15

• Some drugs require activation by enzymes (prodrugs).
• Example: Enalapril is converted by esterases to enalaprilat to inhibit ACE.
• ACE: Angiotensin converting enzyme.

Question 16

Transporter

Answer 16

• Movement of ions & small polar organic molecules across a cell membrane requires a channel or transport protein.
• In many cases hydrolysis of ATP provides energy to transport a substrate against an electrochemical gradient.
• Transport may be coupled with the transport of ions either in the same direction (symport) or the opposite direction (antiport).

Question 17

Drug-Receptor Binding Forces

Answer 17

Van der waals & hydrogen bonds are more important

Question 18

Drug-Receptor Interactions

Answer 18

• Affinity: Both agonist & antagonist
• Efficacy: Only agonist
• Affinity: (bind K+ / unbind K-)
• Efficacy: (activation β / deactivation α )
• Agonist → Response
• Antagonist → No response

Question 19

Acetylcholine

Answer 19

• Acetylcholine channels are either:
  
  1. Nicotinic acetylcholine receptor ⇔ (Ligand)
  2. Muscarinic acetylcholine receptor ⇔ (G-protien)

Question 20

Ligand-gated ion channels

Answer 20

• Location: Membrane
• Effector: Ion Channel
• Coupling: Direct
• Examples:
  
  1. Nicotinic Acetylcholine Receptor
  2. GABA_A receptor
• Structure: Oligomeric assembly of subunits surrounding central pore.

Question 21

G protein-coupled receptor

Answer 21

• Location: Membrane
• Effector: Channel or Enzyme
• Coupling: G protein or arrestin
• Examples:
  
  1. Muscarinic acetylcholine receptor
  2. Adrenoceptors
• Structure: Monomeric or oligomeric assembly of subunits comprising seven transmembrane helices with intracellular G protein-coupling domain.

Question 22

Receptor Kinases

Answer 22

• Location: Membrane
• Effector: Protein Kinases
• Coupling: Direct
• Examples:
  
  1. Insulin
  2. Growth factors
  3. Cytokines receptors.
• Structure: Single transmembrane helix linking extracellular receptor domain to intracellular kinase domain

Question 23

Nuclear Receptors

Answer 23

• Location: Intracellular
• Effector: Gene transcription
• Coupling: Via DNA
• Examples: Steroid receptors
• Structure: Monomeric structure with receptor & DNA-binding domains.

Question 24

Measurement of Drug Effect

Answer 24

1. Graded Response (Incremental Response)
   
   • Increase dose → Increase effect
   • Small increment in dose causes a corresponding increase in effect:
     
     1. muscle contraction
     2. insulin secretion
     3. cAMP production
   • Applicable to cells, tissues, organs or whole animals.
   • Expressed in response units, % maximal response or fold-change.
     
     1. Contraction → Force
     2. Secretion → Concentration
     3. CAMP production → Moles
2. Quantal Response (Yes or No Response)
   
   • Drug effect is measured on an all or nothing basis (e.g. sleep, death or a defines endpoint.)
   • Applicable to populations only & expressed as the % population responding.

Question 25

Dose-Response Curves

Answer 25

• EC_{<strong>50</strong>:} half maximum effective conc. that gives you E_max.
• E_max: maximum response of given drug in system used to compare efficacy.

Question 26

Therapeutic Index

Answer 26

• TI=LD₅₀/EC₅₀
• Therapeutic Index of a drug: is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response.
• TD₅₀ = the dose of drug that causes a toxic response in 50% of the population.
• ED₅₀ = the dose of drug that is therapeutically effective in 50% of the population.
• LD₅₀ = the dose that kills 50% of the population.
• EC₅₀=
  
  • 50% of conc. that gives E_max.
  • half maximum effective conc. that gives you E_max.
    ​

Question 27

Therapeutic Index

Answer 27

• Low TI → EC₅₀ & LD₅₀ are similar
• High TI → EC₅₀ & LD₅₀ are different
• If the TI is small (the difference between the two concentrations is very small), the drug must be dosed carefully and the person receiving the drug should be monitored closely for any signs of drug toxicity.
• The larger the (TI) → the safer the drug is.

Question 28

Dose-Response Curves

Answer 28

• E_{<strong>max</strong>}: The maximum response to a drug in a given tissue/assay. A measure of efficacy.
• EC₅₀ (or ED₅₀): The concentration (or dose) of a drug that produces 50% of the maximal response (or a pre-determined end-point in 50% of the test population in the case of quantal response).
• LD₅₀: The dose that results in the death of 50% of the test population.
• TD_50: The dose that results in a pre-determined toxic effect in 50% of the test population.
• Therapeutic Index (TI): The ratio of LD₅₀ to ED₅₀. It is a measure of the safety margin of a drug.

Question 29

E_max

Answer 29

A measure of efficacy

Question 30

Therapeutic Index (TI)

Answer 30

A measure of the safety margin of a drug