Pharmacodynamics

1. Q: What is pharmacodynamics?

A: What the drug does to the body.

2. Q: What is the basic sequence of pharmacodynamic action?

A: Drug → receptor → signal → cellular response → clinical effect.

3. Q: What is a receptor?

A: A protein that a drug binds to and changes cellular activity.

4. Q: Does every drug require a receptor?

A: No. Some drugs act chemically without receptors; e.g., antacids neutralize gastric acid.

5. Q: What generally happens as the number of drug-receptor complexes increases?

A: The cellular response generally increases.

6. Q: What are the two basic receptor states?

A: R = inactive and R* = active. They normally exist in equilibrium: R ⇌ R*.

7. Q: What is an agonist?

A: Binds and activates the receptor, shifting it toward R*.

8. Q: What is an antagonist?

A: Binds the receptor but does not activate it; stabilizes the inactive state. Intrinsic activity = 0.

9. Q: What is a partial agonist?

A: Activates the receptor but produces a response less than a full agonist. Intrinsic activity is between 0 and 1.

10. Q: What is an inverse agonist?

A: Stabilizes the inactive receptor and decreases activity below baseline. Intrinsic activity is < 0.

11. Q: What is the intrinsic activity spectrum?

A: Inverse agonist < antagonist < partial agonist < full agonist
< 0 → 0 → 0–1 → 1

12. Q: What is the key difference between an antagonist and inverse agonist?

A: Antagonist blocks without activating; inverse agonist actively decreases constitutive receptor activity below baseline.

13. Q: What are the four major receptor families in order from fastest to slowest?

A:

1. Ligand-gated ion channel → milliseconds

2. GPCR → seconds–minutes

3. Enzyme-linked receptor → minutes–hours

4. Intracellular receptor → hours–days

14. Q: What is the easiest way to remember receptor speed?

A: Ion channel → G protein → enzyme → gene
As you move down, responses become slower but generally longer-lasting.

15. Q: How do ligand-gated ion channels work?

A: Drug binds receptor → ion channel opens/closes → very rapid response.

16. Q: What is an important example of a ligand-gated ion channel?

A: Nicotinic ACh receptor: Na⁺ enters/K⁺ exits → depolarization → action potential/muscle contraction.

17. Q: What happens when GABA binds the GABA-A receptor?

A: Cl⁻ enters → hyperpolarization → ↓ likelihood of action potential.

18. Q: What type of receptor do local anesthetics block?

A: Voltage-gated Na⁺ channels → ↓ Na⁺ influx → ↓ neuronal conduction.

19. Q: What are the structural characteristics of GPCRs?

A: 7 transmembrane domains and an associated G protein containing α, β, and γ subunits.

20. Q: What happens to the α subunit when a GPCR is activated?

A: It binds GTP.

21. Q: What is the general GPCR signaling pathway?

A: Receptor → G protein → effector → second messenger → cellular response.

22. Q: What does Gs do?

A: ↑ adenylyl cyclase → ↑ cAMP.

23. Q: What does Gi do?

A: ↓ adenylyl cyclase → ↓ cAMP.

24. Q: What does Gq do?

A: ↑ phospholipase C → IP₃ + DAG.

25. Q: What do IP₃ and DAG do?

A: IP₃ → ↑ intracellular Ca²⁺; DAG → activates protein kinase C (PKC).

26. Q: What is the easiest way to memorize Gs, Gi, and Gq?

A:

• Gs = stimulates cAMP

• Gi = inhibits cAMP

• Gq = calcium pathway → IP₃/DAG

27. Q: How do enzyme-linked receptors generally work?

A: Ligand binds → intracellular enzyme, usually tyrosine kinase, is activated → protein phosphorylation.

28. Q: What are examples of enzyme-linked receptors?

A: Insulin receptor and many growth factor receptors.

29. Q: What is the key word associated with enzyme-linked receptors?

A: Phosphorylation.

30. Q: What type of drug generally binds an intracellular receptor?

A: A lipid-soluble drug that can cross the cell membrane.

31. Q: How do intracellular receptors produce their effects?

A: Drug → intracellular receptor → DNA transcription → mRNA → protein.

32. Q: What are examples of drugs/hormones acting through intracellular receptors?

A: Steroid hormones, thyroid hormone, vitamin D.

33. Q: What is the typical timing of intracellular receptor effects?

A: Slow onset: hours–days, but effects are generally long-lasting.

34. Q: What is signal amplification?

A: Activation of a small number of receptors can produce a large cellular response because one receptor can activate many signaling molecules.

35. Q: What are spare receptors?

A: Receptors that do not need to be occupied to produce a maximal response.

36. Q: What is an important example of a receptor system with spare receptors?

A: Insulin receptors have a large receptor reserve.

37. Q: What is desensitization?

A: Repeated stimulation causes a receptor to become less responsive.

38. Q: What is downregulation?

A: Chronic agonist stimulation causes fewer receptors to be available.

39. Q: What is an example of downregulation?

A: Chronic morphine → ↓ opioid receptor responsiveness/number → tolerance → more drug needed for the same effect.

40. Q: What is upregulation?

A: Chronic antagonist exposure causes more receptors to be inserted into the membrane, increasing sensitivity to agonists.

41. Q: What happens with chronic agonist vs. chronic antagonist exposure?

A:

• Chronic agonist → ↓ sensitivity / ↓ receptors

• Chronic antagonist → ↑ receptors / ↑ sensitivity

42. Q: What is Emax?

A: The maximum effect a drug can produce.

43. Q: What is potency?

A: How much drug is needed to produce an effect.+

44. Q: What measures potency?

A: EC50.

45. Q: What does a lower EC50 mean?

A: Higher potency because less drug is needed to produce 50% of maximum effect.

46. Q: What is efficacy?

A: The maximum effect a drug can produce.

47. Q: What measures efficacy?

A: Emax.

48. Q: What is the key distinction between potency and efficacy?

A: Potency = amount needed.
Efficacy = maximum effect.

49. Q: Drug A works at 10 mg and Drug B at 100 mg, but both produce the same maximum effect. Which is more potent?

A: Drug A. They have the same efficacy.

50. Q: Why is efficacy generally more clinically important than potency?

A: A drug must be capable of producing the desired maximum therapeutic effect; needing a smaller dose does not compensate for inadequate maximum efficacy.

51. Q: What is affinity?

A: How strongly a drug binds to its receptor.

52. Q: What is Kd?

A: The equilibrium dissociation constant, reflecting receptor-ligand binding affinity.

53. Q: What does a low Kd mean?

A: High affinity; the drug binds strongly and is less likely to dissociate.

54. Q: What is the difference between affinity and potency?

A: Affinity = strength of binding.
Potency = amount required to produce an effect.
They are related but not identical.

55. Q: What characterizes a full agonist?

A: Fully activates the receptor, has intrinsic activity = 1, and can produce the maximum Emax.

56. Q: What characterizes a partial agonist?

A: Activates the receptor but has intrinsic activity between 0 and 1 and a lower Emax than a full agonist.

57. Q: Can a partial agonist produce a maximal response if 100% of receptors are occupied?

A: No. Its intrinsic activity is insufficient to produce the full maximum response.

58. Q: How can a partial agonist act as an antagonist?

A: In the presence of a full agonist, the partial agonist occupies receptors that the full agonist could occupy → ↓ overall response.

59. Q: What are the key characteristics of an antagonist?

A: Binds receptor, does not activate it, intrinsic activity = 0, and reduces agonist effects.

60. Q: What is a competitive antagonist?

A: A reversible antagonist that binds the same receptor site as the agonist.

61. Q: Can competitive antagonism be overcome?

A: Yes. Increasing agonist concentration can overcome the antagonist.

62. Q: What happens to the dose-response curve with a competitive antagonist?

A:

• EC50 ↑

• Emax unchanged

• Curve shifts right

• ↓ potency of agonist

63. Q: What is the high-yield memory rule for competitive antagonists?

A: Competitive = right shift → ↑ EC50, Emax unchanged.

64. Q: What is a noncompetitive antagonist?

A: An antagonist whose effect cannot be overcome simply by increasing agonist concentration.

65. Q: What are two mechanisms of noncompetitive antagonism?

A:

• Irreversible antagonist: covalently binds receptor.

• Allosteric antagonist: binds a different site and prevents receptor activation.

66. Q: What happens to the dose-response curve with a noncompetitive antagonist?

A: ↓ Emax, usually with no major change in EC50 → ↓ efficacy.

67. Q: What is the key difference between competitive and noncompetitive antagonism?

• Competitive → ↑ EC50, Emax unchanged → ↓ potency

• Noncompetitive → ↓ Emax → ↓ efficacy

68. Q: What is functional antagonism?

A: Two drugs act at different receptors but produce opposing physiological effects.

69. Q: Give the example of functional antagonism from the notes.

A: Histamine → H1 → bronchoconstriction; epinephrine → β₂ → bronchodilation. Therefore, epinephrine functionally antagonizes histamine.

70. Q: What does a graded dose-response curve measure?

A: How much effect a drug produces in one system/person.

71. Q: Give an example of a graded response.

A: Drug produces a 20%, 50%, or 80% decrease in blood pressure.

72. Q: What does a quantal dose-response curve measure?

A: Whether a desired effect occurs or does not occur in a population.

73. Q: What does ED50 mean?

A: The dose producing the desired therapeutic effect in 50% of the population.

74. Q: What is the therapeutic index?

A: TI = TD50 / ED50

75. Q: What do ED50 and TD50 represent?

A:

• ED50 = effective dose in 50% of population

• TD50 = toxic dose in 50% of population

76. Q: What does a high therapeutic index mean?

A: Greater safety margin; larger separation between effective and toxic doses.

77. Q: What does a low therapeutic index mean clinically?

A: Therapeutic and toxic doses are close → careful dosing and monitoring required.

78. Q: Give examples of a low-TI and high-TI drug from the notes.

78. Q: Give examples of a low-TI and high-TI drug from the notes.

79. Q: What is the receptor occupancy equation?

A:
[DR]/[Rₜ] = [D]/(Kd + [D])

Most important concept: lower Kd = higher affinity.

80. Q: What is the effect equation?

A:
E/Emax = [D]/(Kd + [D])

81. Q: What is the therapeutic index equation?

A:
TI = TD50 / ED50

82. Q: What does a higher TI indicate?

A: Greater safety margin.

83. Q: What are the four receptor families from fastest → slowest?

A: Ligand-gated ion channel → GPCR → enzyme-linked → intracellular.

84. Q: What are the three major G proteins?

A: Gs → ↑ cAMP; Gi → ↓ cAMP; Gq → IP₃/DAG → ↑ Ca²⁺.

85. Q: What determines potency?

A: EC50. Lower EC50 = greater potency.

86. Q: What determines efficacy?

A: Emax. Higher Emax = greater efficacy.

87. Q: What determines affinity?

A: Kd. Lower Kd = greater affinity.

88. Q: What does a competitive antagonist do to EC50 and Emax?

A: ↑ EC50; Emax unchanged.

89. Q: What does a noncompetitive antagonist do to Emax?

A: ↓ Emax.

90. Q: What happens with chronic agonist exposure?

A: Desensitization/downregulation → ↓ responsiveness/tolerance.

91. Q: What happens with chronic antagonist exposure?

A: Upregulation → ↑ receptor number/sensitivity.

92. Q: What is the difference between full and partial agonists?

A: Full agonist → Emax/intrinsic activity = 1. Partial agonist → lower Emax/intrinsic activity 0–1.

93. Q: What is the key distinction between antagonist and inverse agonist?

A: Antagonist = 0 activity; inverse agonist = activity below baseline.

94. Q: What is the most important partial-agonist concept?

A: A partial agonist can antagonize a full agonist when both compete for the same receptors.

95. Q: What is the most important therapeutic-index concept?

A: Higher TI = safer drug; lower TI = greater need for monitoring.