Lecture 9

Question 1

Pharmacokinetics (PK)

Answer 1

Before drug receptor actions

Question 2

Pharmacodynamics (PD)

Answer 2

After drug receptor actions

Question 3

Mechanisms of Drug Action Direct effect:

Answer 3

– No specific receptor involved.
– e.g., antacid (base) neutralizes excess acid in stomach.

Question 4

Mechanisms of Drug Action Indirect effect:

Answer 4

Drug interacts with receptor and initiates a sequence of events.

Question 5

lock and key

Answer 5

• Lock  receptor surface.
• Key  drug or ligand.

Question 6

Drug Receptor Current Model

Answer 6

• Receptors are fluid, flexible surfaces or pockets.
• Changes in receptor conformation as ligand docks.
• Structural change causes a functional change.
• Most drug receptors are also sites for natural ligands.
• The actual receptor is usually a small portion of a macromolecule.
• Most receptors are proteins, located in cell membrane, cytoplasm, or
  nucleus.

Question 7

Irreversible covalent bonding

Answer 7

– Active site-directed irreversible inhibition; covalent bond strengths range
from 40-140 kcal.
– Anticancer agents, e.g., alkylating agents.
– Enzyme inhibitors such as the MAOI tranylcypromine.
– Antibacterial agents such as the beta-lactamase inhibitors:

Question 8

Reversible drug-receptor complex

Answer 8

– Generally more desirable than covalent modification, since drug
can eventually be excreted and effect controlled.
– Requires weaker receptor/drug interactions:
* Hydrogen bonds: 1 to 7 kcals.
* Ionic bonding: 5 to 10 kcals.
* Ion-dipoles bonds: 1 to 7 kcals.
* Dipole-dipole bonds: 1 to 7 kcal.
* Van der Waals: 0.5 to 1 kcal.
* Hydrophobic bonding: 1 kcal.
– Bond strength typically 10 to 30 kcal.

Question 9

Forces Involved in Drug-Receptor Interaction

Answer 9

• Molecular surfaces must be close and complementary.
• G° = -RTlnKeq
• Change in G° of -5.5 kcal/mol drives binding
  equilibrium from 1% to 99% for drug-receptor complex.
• Forces in drug-receptor complex are generally weak and
  noncovalent.

Question 10

Requirements of a Drug Receptor: Recognition

Answer 10

• Receptor must exist in a conformational state that allows for
  recognition of the drug and must satisfy the following
  criteria:
  – Saturability.
  – Reversibility.
  – Stereoselectivity.
  – Specificity.

Question 11

Requirements of a Drug Receptor: Transduction

Answer 11

• The binding of an agonist must be transduced into some kind of
  response.
• Different receptor types are linked to effector systems:
  – Ligand-gated ion channels.
  – Single-transmembrane receptors.
  – Transmembrane GPCRs.
  – Soluble steroid hormones.

Question 12

Affinity

Answer 12

Binding strength (kcal) of a drug and receptor.

Question 13

Intrinsic activity (IA):

Answer 13

– Maximal effect of a drug as compared to the endogenous ligand.
– Full agonist: IA = 1.
– Antagonist: IA = 0.
– Partial agonist: IA > 0 and <1

Question 14

Intrinsic efficacy:

Answer 14

Measure of a drug’s ability to bind a receptor and elicit a full response (%).

Question 15

Potency

Answer 15

Ability of a drug to cause a functional change at specific doses (ED50).

Question 16

Agonists

Answer 16

– Interact with and activate receptors; possess both affinity and efficacy.
– Full agonist: An agonist with maximal efficacy.
– Partial agonist: An agonist with less then maximal efficacy

Question 17

Antagonists

Answer 17

– Interact with the receptor but do not result in transduction; i.e., have affinity
but no efficacy.
– Competitive: Binds to active site reversibly.
– Irreversible or Pseudoirreversible: Binds to active site irreversibly or
essentially irreversibly.
– Allosteric: Does not bind to active site

Question 18

G-Protein Coupled Receptors

Answer 18

• Structure:
  o Single polypeptide chain threaded
  back and forth resulting in 7
  transmembrane -helices.
  o G-protein attached to the
  cytoplasmic side of the membrane
  functions as a switch.