Fa: Pharmacology - Pharmacokinetics & Dynamics

Front 1

What is the graph of most enzymatic reactions following Michaelis-Menten kinetics? What do the axises represent?

Back 1

Most follow a hyperbolic curve; however, enzymatic reactions that exhibit a sigmoid curve usually indicate cooperative kinetics (eg, hemoglobin)

Y-axis = Velocity (V)
X-axis = [S]

Front 2

According to the Michaelis-Menten equation, what does Km equal?

Back 2

Km = [S] at 1/2 Vmax

Front 3

What is Km (of the Michaelis-Menten equation) related to?

Back 3

Related to the affinity of the enzyme for its substrate

Front 4

What is Vmax (of the Michaelis-Menten equation) related to?

Back 4

Directly proportional to the enzyme concentration

Front 5

What is the slope on a Lineweaver-Burk plot? What do the axises represent?

Back 5

Slope = Km / Vmax

Y-axis = 1/V
X-axis = 1/[S]

Front 6

What is the X-intercept on a Lineweaver-Burk plot?

Back 6

1 / -Km

Front 7

What is the Y-intercept on a Lineweaver-Burk plot?

Back 7

1 / Vmax

Front 8

What value changes as the Y-intercept increases on a Lineweaver-Burk plot?

Back 8

As Y-intercept ↑, Vmax ↓

Remember Y-intercept = 1 / Vmax

Front 9

What value changes as the X-intercept increases (gets closer to zero) on a Lineweaver-Burk plot?

Back 9

The further to the right the x-intercept, the greater the Km and the lower the affinity

Remember X-intercept = 1 / -Km

Front 10

What happens to the lines of competitive inhibitors on a Lineweaver-Burk plot?

Back 10

Competitive inhibitors cross each other competitively

Front 11

What happens to the lines of non-competitive inhibitors on a Lineweaver-Burk plot?

Back 11

Non-competitive inhibitors do not cross each other

Front 12

Which types of inhibitors resemble the substrate? Which do not?

Back 12

Resemble substrate:
- Competitive reversible inhibitors
- Competitive irreversible inhibitors

Do not resemble substrate:
- Non-competitive inhibitors

Front 13

Which types of inhibitors can be overcome by ↑ [S]? Which are not?

Back 13

Overcome:
- Competitive reversible inhibitors

Not overcome:
- Competitive irreversible inhibitors
- Non-competitive inhibitors

Front 14

Which types of inhibitors canbind the active site? Which do not?

Back 14

Bind active site:
- Competitive reversible inhibitors
- Competitive irreversible inhibitors

Do not bind active site:
- Non-competitive inhibitors

Front 15

What is the effect of the different inhibitors on Vmax?

Back 15

Unchanged:
- Competitive reversible inhibitors

Decreased:
- Competitive irreversible inhibitors
- Non-competitive inhibitors

Front 16

What is the effect of the different inhibitors on Km?

Back 16

Increased:
- Competitive reversible inhibitors

Unchanged:
- Competitive irreversible inhibitors
- Non-competitive inhibitors

Front 17

What is the pharmacodynamic effect of the different inhibitors?

Back 17

↓ Potency:
- Competitive reversible inhibitors

↓ Efficacy:
- Competitive irreversible inhibitors
- Non-competitive inhibitors

Front 18

What is pharmacokinetics?

Back 18

The effects of the body on the drug (ADME):
- Absorption
- Distribution
- Metabolism
- Excretion

Front 19

What is pharmacodynamics?

Back 19

The effects of the drug on the body
- Includes concepts of receptor binding, drug efficacy, drug potency, and toxicity

Front 20

Which term encompasses the effects of the body on the drug?

Back 20

Pharmacokinetics, eg:
- Absorption
- Distribution
- Metabolism
- Excretion

Front 21

Which term encompasses the effects of the drug on the body?

Back 21

Pharmacodynamics, eg:
- Concepts of receptor binding, drug efficacy, drug potency, and toxicity

Front 22

What is the term for the fraction of the drug that reaches the systemic circulation unchanged?

Back 22

Bioavailability (F)

Front 23

What is the bioavailability? What drug/administration has a bioavailability (F) of 100%?

Back 23

Fraction of administered drug that reaches the systemic circulation unchanged

For IV dose, F = 100%

Front 24

What causes decreased bioavailability of orally administered drugs?

Back 24

F typically <100% because of incomplete absorption and first-pass metabolism in the liver

Front 25

What is the volume of distribution (Vd)?

Back 25

Theoretical volume occupied by the total absorbed drug amount at the plasma concentration

Front 26

What can affect the apparent Volume of Distribution (Vd)?

Back 26

Apparent Vd of plasma protein-bound drugs can be altered by LIVER and KIDNEY disease (↓ protein binding, ↑ Vd)

Front 27

How do you calculate the volume of distribution?

Back 27

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

Front 28

What are the compartments in which a drug may distribute?

Back 28

- Blood
- Extracellular Fluid (ECF)
- All tissues including fat

Front 29

What compartment is a drug in that has a low Vd? Drug characteristics?

Back 29

Drug is in blood (4-8 L)
- Large / charged molecules
- Plasma protein bound drugs

Front 30

What compartment is a drug in that has a medium Vd? Drug characteristics?

Back 30

Drug is in ECF
- Small hydrophilic molecules

Front 31

What compartment is a drug in that has a high Vd? Drug characteristics?

Back 31

Drug is in all tissues, including fat
- Small lipophilic molecules, especially if bound to tissue protein

Front 32

What is the half-life of a drug?

Back 32

The time required to change the amount of drug in the body by 1/2 during elimination (or constant infusion)

Front 33

A half-life is a property of what type of elimination?

Back 33

First-order elimination

Front 34

How long does an infused drug infused at a constant rate take to reach a steady state?

Back 34

Takes 4-5 half-lives to reach steady state

Front 35

How many half-lives does it take to reach 90% of the steady state level?

Back 35

3.3 half-lives

Front 36

How do you calculate the half-life of a drug?

Back 36

t1/2 = 0.693 * Vd / CL

CL = Clearance
Vd = Volume of distribution

Front 37

How much drug is remaining (%) after 1, 2, 3, and 4 half-lives?

Back 37

- 1: 50%
- 2: 25%
- 3: 12.5%
- 4: 6.25%

Front 38

What does the clearance of a drug represent?

Back 38

The volume of plasma cleared of drug per unit time

Front 39

What can impair clearance of a drug?

Back 39

Defects in:
- Cardiac function
- Hepatic function
- Renal function

Front 40

How do you calculate the clearance of a drug?

Back 40

CL = (rate of elimination of drug) / (plasma drug concentration)
CL = Vd * Ke

Ke = Elimination Constant

Front 41

How do you calculate what the loading dose should be?

Back 41

Loading dose = (Cp * Vd) / F

Cp = target plasma concentration at steady state
Vd = volume of distribution
F = bioavailability

Front 42

How do you calculate what the maintenance dose should be?

Back 42

Maintenance dose = (Cp * CL * π) / F

Cp = target plasma concentration at steady state
CL = clearance
π = dosage interval (time between doses), if not administered continuously
F = bioavailability

Front 43

What is Cp?

Back 43

Target plasma concentration at steady state

Front 44

What happens to the relative maintenance dose in a patient with renal or liver disease?

Back 44

Maintenance dose ↓

Front 45

What happens to the relative loading dose in a patient with renal or liver disease?

Back 45

Loading dose is unchanged usually

Front 46

What determines the time to steady state?

Back 46

Depends primarily on t1/2 and is independent of dose and dosing frequency

Front 47

What are the types of elimination of drugs?

Back 47

- Zero-order elimination
- First-order elimination

Front 48

What type of elimination is characterized by a constant rate of elimination regardless of Cp (constant amount of drug eliminated per unit time)?

Back 48

Zero-Order Elimination

Front 49

What limits Zero-Order Elimination?

Back 49

Capacity-limited elimination

(rate is constant no matter what the concentration is)

Front 50

What happens to the concentration of a drug with time with Zero-Order Elimination?

Back 50

Concentration decreases linearly with time

Front 51

What drugs have Zero-Order Elimination?

Back 51

PEA (a pea is round, shaped like the "0" in "zero-order")
- Phenytoin
- Ethanol
- Aspirin (at high or toxic concentration)

Front 52

What type of elimination is characterized by a rate of elimination directly proportional to the drug concentration (ie, constant fraction of drug eliminated per time)?

Back 52

First-Order Elimination

Front 53

What limits First-Order Elimination?

Back 53

Flow-Dependent Elimination

Front 54

What happens to the concentration of a drug with time with First-Order Elimination?

Back 54

Cp decreases exponentially with time

Front 55

What gets trapped in urine and is cleared quickly?

Back 55

Ionized species

Front 56

What drugs are weak acids? How does this affect their elimination?

Back 56

- Ex: phenobarbital, methotrexate, aspirin
- Weak acids are trapped in BASIC environments

Front 57

How do you treat an overdose of a weak acid drug (eg, phenobarbital, methotrexate, aspirin)?

Back 57

Bicarbonate

Front 58

What drugs are weak bases? How does this affect their elimination?

Back 58

- Ex: amphetamines
- Trapped in ACIDIC environment

Front 59

How do you treat an overdose of a weak base drug (eg, amphetamines)?

Back 59

Treat overdose of weak base with ammonium chloride

Front 60

What are the phases of drug metabolism?

Back 60

- Phase I
- Phase II

Front 61

What happens in phase I drug metabolism? What does it yield?

Back 61

- Reduction
- Oxidation
- Hydrolysis with cytochrome P-450
- Usually yields slightly polar, water-soluble metabolites (often still active)

Front 62

What happens in phase II drug metabolism? What does it yield?

Back 62

- Conjugation (glucuronidation, acetylation, sulfation)
- Usually yields very polar, inactive metabolites (renally excreted)

Front 63

What phase of drug metabolism do geriatric patients lose first?

Back 63

Phase I
- Reduction
- Oxidation
- Hydrolysis w/ cytochrome P-450

Front 64

What phase of drug metabolism do geriatric patients usually still have?

Back 64

Phase II
- Conjugation (glucuronidation, acetylation, sulfation)

Geriatric patients have GAS

Front 65

What type of abnormal drug metabolism in a patient causes greater side effects from certain drugs? Why?

Back 65

Slow acetylators - decreased rate of metabolism

Front 66

What is meant by drug "efficacy"?

Back 66

Maximal effect a drug can produce

Front 67

What is meant by drug "potency"?

Back 67

Amount of drug needed for a given effect

Front 68

What are some examples of high efficacy drug classes?

Back 68

- Analgesic (pain) meds
- Antibiotics
- Antibiotics
- Antihistamines
- Decongestants

Front 69

What mediates increased potency of a drug?

Back 69

Increased affinity for receptor

Front 70

What are some examples of high potency drug classes?

Back 70

- Chemotherapeutic (cancer) drugs
- Anti-hypertensive (blood pressure) drugs
- Lipid-lowering (cholesterol) drugs

Front 71

What is the effect of a competitive antagonist on potency and efficacy?

Back 71

- Shifts curve to right (decreased potency)
- No change in efficacy

Front 72

How can you overcome a competitive antagonist?

Back 72

Increase the concentration of agonist substrate

Front 73

What is the effect of a non-competitive antagonist on potency and efficacy?

Back 73

Shifts curve down (decreased efficacy)

Front 74

How can you overcome a non-competitive antagonist?

Back 74

Cannot be overcome by increasing agonist substrate concentration

Front 75

What is the effect of an irreversible antagonist on potency and efficacy?

Back 75

Shifts curve down (decreased efficacy)

Front 76

How can you overcome an irreversible antagonist?

Back 76

Cannot be overcome by increasing agonist substrate concentration

Front 77

What is the effect of a partial agonist on potency and efficacy?

Back 77

- Acts at same site as full agonist, but with lower maximal effect (decreased efficacy)
- Potency is an independent variable

Front 78

What is the relationship of flumazenil to diazepam?

Back 78

Competitive antagonist at GABA receptor

Front 79

What is the relationship of ketamine to glutamate?

Back 79

Non-competitive antagonist at NMDA receptor

Front 80

What is the relationship of phenoxybenzamine to norepinephrine?

Back 80

Irreversible competitive antagonist on α receptors

Front 81

What is the relationship of buprenorphine on morphine

Back 81

Partial agonist at opioid µ receptors

Front 82

What measurement is used to assess drug safety?

Back 82

Therapeutic Index

Front 83

How do you calculate the therapeutic index (TI)?

Back 83

TI = (TD50 / ED50) = (median toxic dose) / (median effective dose)

TITE: Therapeutic Index = TD50 / ED50

Front 84

What is the therapeutic window?

Back 84

Measure of clinical drug effectiveness for a patient

Front 85

What relative Therapeutic Index value do safer drugs have?

Back 85

Higher Therapeutic Index values

Front 86

What are some drugs with low Therapeutic Index values?

Back 86

- Digoxin
- Lithium
- Theophylline
- Warfarin

Front 87

What value often replaces TD50 in animal studies?

Back 87

LD50 (lethal median dose)