Pharmacokinetics & Pharmacodynamics Flashcards Preview

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Flashcards in Pharmacokinetics & Pharmacodynamics Deck (79):
1

Michaelis-Menten kinetics graph

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3

Lineweaver-Burk Plot

  • X-axis: 1/[S]
  • Y-axis: 1/{V]
  • X-int = (1/-Km)
  • Y-int = (1/Vmax)
  • Slope = (Km/Vmax)

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Michaelis-Menten kinetics

  • Km (enzyme conc at 1/2 Vmax) is inversely related to enzyme affinity for substrate
    • higher affinity → get to 1/2 Vmax faster
  • Vmax is directly proportional to enzyme conc
  • Most enzymatic rxns follow hyperbolic curve (MM kinetics)
    • Rxns w/sigmoid curve usually indicate cooperative kinetics (hemoglobin)

5

Enzyme inhibition graph

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7

Lineweaver-Burk Plot interpretation

  • Higher Y-int = lower Vmax
  • X-int closer to 0 = lower affinity → higher Km

9

Reversible Competitive Inhibitor Characteristics & Effects

  • Resemble substrate, bind active site
  • Can be overcome by increasing substrate concentration
  • Vmax: unchanged
  • Km: increased
  • Pharmacodynamics: decreased potency

10

Irreversible Competitive Inhibitor Characteristics & Effects

  • Resemble substrate, bind active site
  • CANNOT be overcome by increasing substrate concentration
  • Vmax: decreased
  • Km: unchanged
  • Pharmacodynamics: decreased efficacy

11

Noncompetitive Inhibitor Characteristics & Effects

  • Does not resemble substrate
  • Binds site other than active site
  • CANNOT be overcome by increasing substrate concentration
  • Vmax: decreased
  • Km: unchanged
  • Pharmacodynamics: decreased efficacy

12

Bioavailability (F)

  • Fraction of administered drug reaching systemic circulation unchanged
  • IV dose: F = 100%
  • Orally: F

13

Volume of Distribution (Vd) Definition

  • Theoretical volume occupied by total amount of drug in the body relative to its plasma concentration
  • Apparent Vd of plasma protein-bound drugs can be altered by liver and kidney disease
    • Decreased protein binding, increased Vd
  • Drugs may distribute in more than one compartment

14

Vd equation

Vd = (amount of drug in the body / plasma drug concentration)

15

Low Vd means what?

  • Drug mainly in blood
  • Drug is Large, Charged, and/or Plasma Protein-Bound

16

Medium Vd means what?

  • Drug mainly in ECF
  • Drug is small and hydrophilic

17

High Vd means what?

  • Drug in all tissues, incl. fat
  • Drug is small and lipophilic, and/or bound to tissue protein

18

Total body water volume and percentage of body mass

  • Vol: 42L
  • 60% of body mass

19

Intracellular fluid volume and percentage of body mass

  • Vol: 28L
  • 40% of body mass

20

Extracellular fluid volume and percentage of body mass

  • Vol: 14L
  • 20% of body mass

21

Plasma volume and percentage of body fluid

  • Vol: 3.5L
  • 25% of ECF

22

RBC volume

2.8L

23

Blood volume and contents

  • Vol: 5.5L
  • Plasma: 55%
  • Blood cells (Hct): 45%

24

How is plasma volume measured?

substances that distribute in plasma but not interstitial fluid, b/c too large to cross capillary walls

  • Radiolabeled albumin
  • Evans blue

25

How is ECF measured?

Large molec weight sugars or anions can't cross cell memb → distributed in ECF but not ICF

  • Mannitol
  • Inulin
  • Sulfate

26

Normal body fluid osmolality

Osmolality = 285–295 mOsm/kg H2O

27

Total Body Water Graph

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28

ECF compartments

  • Plasma (25%)
  • Interstitial fluid (75%)

29

Major cations in ECF

Na+ (balanced by Cl- and HCO3-)

30

Major cations in ICF

K+ and Mg2+ (balanced by proteins and organic phosphates)

32

Types of Volume Changes in Body Fluid Disturbances

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33

Diarrhea causes what kind of volume change?

Isoosmotic volume contraction: loss of isoosmotic fluid

  • Decreased ECF volume
  • Increased Hct
  • Increased Plasma Protein
  • No change in ICF volume or Osmolarity

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34

Water Deprivation / Dehydration causes what kind of volume change?

HypERosmotic volume contraction: loss of hypOosmotic fluid (sweat)

  • Decreased ECF volume (fluid lost)
  • Decreased ICF volume (shift to ECF)
  • Increased Osmolarity
  • Increased Plasma Protein
  • No change in Hct

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35

Sweating and/or fever causes what kind of volume change?

HypERosmotic volume contraction: loss of hypOosmotic fluid

  • Decreased ECF volume
  • Decreased ICF volume
  • Increased Osmolarity
  • Increased Plasma Protein
  • No change in Hct

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36

Diabetes insipidus causes what kind of volume change?

HypERosmotic volume contraction: loss of hypOosmotic fluid

  • Decreased ECF volume
  • Decreased ICF volume
  • Increased Osmolarity
  • Increased Plasma Protein
  • No change in Hct

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37

Adrenal insufficiency causes what kind of volume change?

HypOosmotic volume contraction: aldosterone deficiency → excess naturiesis

  • Decreased ECF volume
  • Increased ICF volume
  • Decreased Osmolarity
  • Increased Hct
  • Increased Plasma Protein

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38

Isotonic NaCl infusion causes what kind of volume change?

Isoosmotic volume expansion: gain of isoosmotic fluid

  • Increased ECF volume
  • Decreased Hct
  • Decreased Plasma Protein
  • No change in ICF volume or Osmolarity

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39

High NaCl intake causes what kind of volume change?

HypERosmotic volume expansion:

  • Increased ECF volume
  • Decreased ICF volume (shift to ECF)
  • Increased Osmolarity
  • Decreased Hct
  • Decreased Plasma Protein

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40

SIADH causes what kind of volume change?

HypOosmotic volume expansion: ADH promotes water reabsorption w/o solutes

  • Increased ECF
  • Increased ICF
  • Decreased Osmolarity
  • Decreased Plasma Protein
  • No change in Hct (RBC volume increase compensates for dilution)

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41

60-40-20 Rule

  • 60% of body weight is water
    • 40% is ICF
    • 20% is ECF

42

How is total body water measured?

Distributes everywhere:

  • Isotopic Water (D2O)
  • Titriated Water (THO)
  • Antipyrine

43

How is ICF measured?

ICF = Total body water - ECF

44

How is interstitial fluid measured?

IF = ECF - Plasma

47

What percent of drug is left after 1, 2, 3, and 4 half-lives?

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53

Zero-Order Elimination

  • Rate of elimination is constant regardless of Cp
    • constant amount of drug eliminated per unit time
  • Cp decreases linearly with time
  • Drugs:
    • Phenytoin
    • Ethanol
    • Aspirin (at high/toxic concentrations)

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55

Zero-Order elimination graph

  • Linear elimination
  • Depends on body capacity to eliminate constant amount of drug

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57

Clearance (CL) Definition

  • volume of plasma cleared of drug per unit time
  • may be impaired w/defects in cardiac, hepatic, or renal function

58

First-Order Elimination

  • Rate of elimination is directly proportional to drug concentration
    • constant fraction of drug eliminated per unit time
  • Cp decreases exponentially with time

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59

Clearance equation

CL = (elimination rate / plasma drug conc) = (Vd x Ke)

60

First-Order Elimination Graph

  • Exponential elimination
  • Depends on concentration

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61

Half-life (t1/2) Definition

  • Time required to change amount of drug in body by 1/2 during elimination or constant infusion
  • Property of 1st-order elimination

62

Half-life equation

t1/2 = (0.693Vd) / CL

63

How many half-lives to reach steady state?

about 5 (w/constant infusion rate)

64

How many half-lives to reach 90% of steady state?

3.3

66

Loading dose definition

  • initial higher dose of a drug that may be given at the beginning of a course of treatment
  • most useful for drugs w/long t1/2

67

Weak acids

  • Donate protons to form anions (A-)
  • Low pKa
  • Diffuse across memb @ low pH
  • Trapped (excreted) @ high pH
  • Rx overdose: HCO3-

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68

Weak bases

  • Accept protons to form cations (HB+)
  • High pKa
  • Diffuse across memb @ high pH
  • Trapped (excreted) @ low pH
  • Rx overdose: NH4Cl

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69

Loading Dose equation

LD = (Cp x Vd) / F

 

Cp = target plasma conc at steady state

70

Maintenance Dose equation

MD = (Cp x CL x dose interval) / F

71

Time to steady state depends primarily on what?

t1/2

  • independent of dose and dosing frequency

72

How do loading and maintenance dose change in pts w/renal or liver disease?

  • Loading dose: unchanged
  • Maintenance dose: decreased

74

Drugs eliminated by Zero-Order kinetics

  • Phenytoin
  • Ethanol
  • Aspirin (at high/toxic concentrations)

76

Efficacy

  • Maximal effect a drug can produce
  • Represented by y-value (Vmax)
    • Increased y-value = Increased Vmax = Increased efficacy
  • Unrelated to potency
    • efficacious drugs can have high or low potency
  • Partial agonists have less efficacy than full agonists

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77

Drug Efficacy Graph

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78

Drug Potency Graph

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79

Potency

  • Amount of drug needed for a given effect.
  • Represented by the x-value (EC50).
    EC50 = effective conc at 50% max effect
    • Increased potency (EC50) = less drug needed.
    • Left-shifting = decreased EC50 = increasedpotency.
  • Unrelated to efficacy (potent drugs canhave high or low efficacy)

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80

Capacity-Limited Elimination

= Zero-Order Elimination

81

Flow-Dependent Elimination

= First-Order Elimination

83

Drugs eliminated by First-Order kinetics

Most drugs

85

What types of molecules are cleared quickly in urine?

  • Ionized species are trapped in urine and cleared quickly.
  • Neutral forms can be reabsorbed.

86

most drugs absorbed by what method?

Passive diffusion

87

OATPs

  • organic anion transporting proteins
  • transporters that facilitate uptake

88

PGPs

P-glycoproteins:

  • Efflux transporters that actively remove drugs from epithelial cells and prevent absorption
  • Essential mechanism to prevent toxin absorption
  • Can also lead to chemotherapeutic drug resistance

89

what form of drug can cross lipid membranes?

Only non-ionized form

90

What does pKa tell you?

pH value at which drug is ½ ionized and ½ non-ionized

93

Examples of weak acid drugs

  • phenobarbital
  • methotrexate
  • aspirin
  • TCAs

94

Examples of weak base drugs

amphetamines

95

Drug Metabolism

2 phases:

  1. P450 processing
  2. Conjugation

96

Phase I Drug Metabolism

  • Reduction, oxidation, hydrolysis w/cyt P-450
  • → slightly polar, water-soluble metabolites (often still active)
  • Geriatric pts lose this phase first

97

Phase II Drug Metabolism

  • Conjugation: Glucuronidation, Acetylation, Sulfation
  • → very polar, inactive metabolites (renally excreted)
  • Pts who are slow acetylators have more S/E from certain drugs because of decreased rate of metabolism

98

Geriatric pts often deficient in which phase of drug metabolism?

Phase I (P450 processing)

99

Slow acetylators have a difference in which phase of drug metabolism?

Phase II (conjugation)