Chapter 2 Basic Pharmacologic Principles
Pharmacokinetics
3. What factors govern drug absorption?
4. How is absorption via buccal mucosa significantly different from drug absorption via the stomach?
5. What aspects of absorption make transdermal drug delivery distinct from other modes of drug delivery? Name some examples of drugs for which a transdermal application is clinically important.
6. What is the mechanism for the offset of local anesthetic effects following nerve block?
7. What is “first order” transfer? How does doubling the dose of a drug affect the shape of a plot of drug absorbed versus time?
8. How does absorption rate from its delivery site affect peak plasma concentration of a drug? What does absorption rate mean regarding the relative safety of intercostal nerve blocks?
9. Define distribution. Define volume of distribution.
10. Distinguish central volume of distribution from peripheral volume of distribution.
11. What factors increase a peripheral volume of distribution for a drug?
12. What are two empiric models of peripheral volumes of distribution that are clinically useful?
13. Generally speaking, what is clearance of a drug? What is the difference between systemic clearance and “intercompartmental” clearance?
14. How are most anesthetic drugs removed from the body?
15. What processes are used in the liver to metabolize drugs?
16. What drugs are metabolized by cytochrome CYP 3A4?
17. What drugs or substances induce CYP 3A4? What drugs or substances inhibit CYP 3A4?
18. What function important to anesthesia does CYP 2D6 have? What drugs inhibit CYP 2D6, and what clinical implication does this have?
19. Why do remifentanil, succinylcholine, and esmolol generally vanish from the plasma so quickly after intravenous administration?
20. Why is the pharmacokinetics of succinylcholine less predictable than other drugs cleared by ester hydrolysis?
21. Define “linear” pharmacokinetics.
22. Describe the formula for rate of drug metabolism in terms of liver blood flow.
23. What is an extraction ratio? What is the formula for clearance in terms of hepatic blood flow? What are the units for clearance?
24. In the case of a drug exhibiting “linear” pharmacokinetics, what is significant about the constant relationship between metabolic rate and drug concentration?
25. What does it mean to say that a drug’s metabolism is “flow limited Name a drug whose metabolism is “flow limited.”
26. What does it mean to say that a drug’s metabolism is “capacity limited What effect does an alteration of blood flow to the liver have on drugs whose metabolism is “capacity limited
27. How is the maximum metabolic rate (Vm) of the liver defined? What is Km?
28. What factors may alter the maximum metabolic rate for a drug in the liver? How do changes in maximum metabolic rate for a drug alter the clearance of “flow limited” and “capacity limited” drugs?
29. What does it mean for a drug to have saturable pharmacokinetics?
30. What class of drugs significant to anesthesia practiceare eliminated by the kidneys?
31. Why is a normal serum creatinine value in an elderly person not a reliable indicator of the individual’s ability to clear drugs in the kidney?
32. Describe the clearance of propofol from the bloodstream following intravenous injection.
33. What is distribution clearance? What is the clinical significance of this phenomenon?
34. What is the capacity for plasma proteins to bind most anesthetic drugs? How does the number of protein binding sites for a drug in plasma influence the amount of a drug in the plasma bound to proteins?
35. What effect does a change in plasma protein concentrations have on the apparent potency of a drug?
36. Sketch a graph plotting time versus the amount of drug for a first order pharmacokinetic process. What does it mean to say that a first order pharmacokinetic process demonstrates exponential decay?
37. What do the rate constants between pharmacokinetic compartments relate?
38. For anesthetic drugs, which compartment model best reflects their pharmacokinetic behavior? What about anesthetic drug pharmacokinetics makes this model appropriate? What do the “compartments” correspond to?
39. Why is it impossible to achieve a steady state drug concentration with a bolus of drug followed by a simple infusion when a drug is best described by a multiple compartment model?
40. What is the time course of drug effect? Why does this exist for anesthesia drugs, and what pharmacokinetic properties does this process exhibit?
41. Define context-sensitive half-time. What are its limitations? Why is context-sensitive half-time a more meaningful concept with regards to the offset of anesthetic drug effects than drug half-life?
42. Why is morphine not an appropriate choice for continuous infusion during anesthesia? Define context-sensitive effect site decrement time.
Pharmacodynamics
43. When a drug’s concentration is equal to its dissociation constant for the binding of a certain receptor, what may be said regarding occupation of those receptors? If a dissociation constant is relatively high, what does this mean regarding the nature of the binding between a receptor and a drug?
44. Define receptor full agonist. What is a partial agonist?
45. Define receptor antagonist. What is an inverse agonist?
46. Distinguish efficacy from affinity.
47. What is the difference between competitive and noncompetitive antagonism?
48. How does binding of a receptor by a drug result in drug effect?
49. What three types of receptors are of most significance to anesthesia? For each type of receptor, name several drugs important in anesthesia whose effects are mediated by that receptor type.
50. Sketch a graph plotting the dose of a drug (or measure of exposure) versus its response (drug effect). If a dose-response curve is “shifted to the left,” what does this mean regarding drug (or exposure) potency?
51. Define ED50, LD50, and therapeutic index. Why is a drug with a higher therapeutic index safer?
52. Describe the interaction of hypnotics and opioids, specifically with regard to fentanyl and isoflurane MAC.
53. What is a response surface?
54. Define additive drug interactions, supraadditive interactions, and infraadditive interactions.
Answers
1. Pharmacokinetics is the process by which the body “disposes” of drugs via absorption, distribution, metabolism, and elimination. It can be thought of as “what the body does to the drug.” (35)
2. Pharmacodynamics is the process by which drugs interact with specific receptors in the body to produce pharmacologic effects. It can be thought of as “what the drug does to the body.” (35)
Pharmacokinetics
3. Drug absorption is governed by route of delivery, bioavailability of the drug, and possibly first-pass metabolism. (36)
4. Drug absorption via buccal mucosa differs from absorption from lower in the gastrointestinal tract because presence of food does not hinder delivery of drug to the mucosa. Also, venous outflow from the buccal mucosa returns directly to the systemic circulation, thereby avoiding the potential for the first-pass hepatic effect that is present for drugs absorbed in the stomach, which first enter the portal venous system. (36)
5. Transdermal drug delivery is distinct in that skin is designed to be a significant barrier to absorption. This means that drugs delivered transdermally will have a markedly delayed onset of action following administration. Also, the skin serves as a depot of the drug, resulting in prolonged drug effect following removal of the skin application. Examples of drugs delivered transdermally include clonidine, scopolamine, nitroglycerin, and fentanyl. (36)
6. Local anesthetics applied in nerve blocks have their pharmacologic effects ended by movement of the drug away from the site of action. The process by which the body absorbs this locally applied bolus of drug, thus ending its local effects, is the same by which the body absorbs drugs injected into tissues for the purpose of eliciting systemic drug effects that follow absorption. (36)
7. “First order” transfer is when the rate of drug absorption is proportional to the concentration gradient. Doubling the dose of a drug does not affect the shape of the curve (absorption over time) when a “first order” transfer is occurring. Concentrations will be exactly twice as high at all times, but peak absorption will occur at the same time and the shape of the curve will be identical. (36)
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