B2.070 Pharmacokinetics: Relationships Among Dose, Exposure, and Effects

Question 1

therapeutic index

Answer 1

difference between therapeutic and toxic ranges

Question 2

pharmacodynamics

Answer 2

effects of the administered drug
desired = efficacy
undesired = toxicity

Question 3

pharmacokinetics

Answer 3

getting the drug to the right place in the right amount

Question 4

components of pharmacokinetics

Answer 4

absorption
distribution
metabolism
excretion

Question 5

absorption

Answer 5

how a drug gains entry into systemic circulation

Question 6

passive diffusion

Answer 6

direct passage through lipid bilayers of cell membrane
driven by concentration gradient
most common way for drugs to cross cell membranes
smaller, less polar molecules

Question 7

carrier mediated transport

Answer 7

transporters facilitate movement
structural selectivity
competition by similar molecules
saturable

Question 8

facilitated diffusion

Answer 8

a type of carrier mediated transport
facilitates passage of polar or charged molecules
does NOT require energy
moves DOWN gradient

Question 9

active transport

Answer 9

energy dependent carrier mediated transport
transport coupled to ATP hydrolysis (primary) or co transport substrate down a gradient (secondary)
can move AGAINST gradient
most rapid

Question 10

important sites of active transport

Answer 10

enterocytes
hepatocytes
neuronal membranes
renal tubular cells
blood brain barrier

Question 11

absorption of APAP

Answer 11

passive diffusion
max plasma concentrations at 0.5-1 hr
F = 0.7-0.9

Question 12

blood

Answer 12

very large molecules

highly charged molecules

Question 13

extracellular water

Answer 13

large
very polar
water soluble

Question 14

total body water

Answer 14

smaller
water soluble
*acetaminophen

Question 15

adipose tissue

Answer 15

lipid soluble

Question 16

bone and teeth

Answer 16

ions

chelators

Question 17

other tissues

Answer 17

specific uptake mechanisms or binding proteins lead to drug accumulation

Question 18

apparent volume of distribution

Answer 18

the compartment where a drug appears to distribute

Question 19

C0

Answer 19

extrapolated concentration of drug in plasma at time 0 after equilibration

Question 20

Vd

Answer 20

amount of drug/C0

Question 21

list in order of smallest to largest Vd: ECF, total body water, plasma water, tissue conc

Answer 21

plasma
ECF
total body water
tissue concentration

Question 22

what factors influence distributions

Answer 22

gender
age
body fat
edema

Question 23

what does Vd really represent?

Answer 23

relative distribution between plasma and the rest of the body
Amt = Vd * C0
Amt = (VpCp)+(VaCa)+(Vb*Cb)

Question 24

what does a large Vd indicate?

Answer 24

high drug concentrations in one or more tissues

Question 25

why is Vd qualitatively important in clinical use?

Answer 25

indicates ration of plasma concentrations to concentrations in tissues

Question 26

why is Vd quantitatively important in clinical use?

Answer 26

allows calculations of total amount of drug in body supports dose determination to achieve a target concentration key determinant of half life *more useful than qualitative

Question 27

primary parameters

Answer 27

clearance and Vd | inherent properties

Question 28

clearance

Answer 28

primary parameter for elimination (metabolism + excretion)

Question 29

secondary parameters

Answer 29

half life | elimination rate constant

Question 30

Kel

Answer 30

CL/Vd

Question 31

t0.5

Answer 31

0.693*Vd/CL

Question 32

amt of drug in body at any time

Answer 32

Vd*plasma concentration

Question 33

APAP Vd

Answer 33

0.7 L/kg | total body water

Question 34

metabolism (biotransformation)

Answer 34

many drugs are hydrophobic, but efficient excretion requires water solubility metabolism increases water solubility and excretion

Question 35

phase 1 metabolism

Answer 35

introduce/unmask a functional group relatively few atoms involved oxidation, reduction, or hydrolysis

Question 36

phase 2 metabolism

Answer 36

synthetic reactions addition of molecules require specific functional groups

Question 37

do drugs always undergo both phase 1 & 2 metabolism?

Answer 37

no, can do either, both, or neither

Question 38

what are 2 different outcomes of phase 1 metabolism?

Answer 38

1. drug metabolite w modified activity produced | 2. inactive drug metabolite produced

Question 39

types of phase 2 metabolism

Answer 39

``` water soluble: -glucuronidation -sulfate conjugation -glycine conjugation lipid soluble: -acetylation -methylation detoxification: -glutathione conjugation ```

Question 40

dominant phase 1 metabolic enzymes

Answer 40

``` CYP family (cytochrome p450) high activities in enterocytes and liver contribute to first-pass effect ```

Question 41

dominant phase 2 metabolic enzymes

Answer 41

UGTs SULTs NATs

Question 42

what are the 3 metabolic pathways of APAP

Answer 42

sulfation catalyzed by SULTs glucuronidation catalyzed by UGTs oxidation catalyzed by CYP2E1 + conjugation of oxidation product catalyzed by GSTs

Question 43

what transporters are involved in APAP metabolism

Answer 43

no transporters for APAP no transporters for glutathione conjugate and metabolites of glutathione conjugate ATP driven active transport for secretion of glucuronide and sulfate conjugates from hepatocyte into bile or blood

Question 44

excretion

Answer 44

how xenobiotics or their metabolites are eliminated from the body

Question 45

amount excreted by any process per unit time is proportional to...

Answer 45

rate of elimination for that process | concentration of drug in plasma

Question 46

drug concentration in plasma is inversely proportional to....

Answer 46

volume of distribution - larger volumes eliminated slower - lower volumes eliminated faster

Question 47

renal excretion

Answer 47

generally smaller MW favored by high aqueous solubility excretion by active and passive processes

Question 48

hepatic/biliary excretion

Answer 48

generally larger MW less polar environment excretion by active and passive processes

Question 49

excretion of APAP

Answer 49

APAP excreted in urine glutathione conjugate is metabolized and excreted in urine glucuronide and sulfate conjugates mostly excreted in urine, with lesser amount in feces

Question 50

elimination rate (mg/hr)

Answer 50

CL (L/hr) * C (mg/L)

Question 51

what is one way to think about clearance?

Answer 51

all drug being taken out of a set amount of plasma in a set amount of time -volume of plasma cleared of drug per unit time

Question 52

total body clearance...

Answer 52

sum of hepatic and renal clearance

Question 53

first order kinetics

Answer 53

``` absorption rate= kabs[drug] distribution rate=kdis [drug] metabolism rate=kmet [drug] excretion rate=kexc [drug] -parameters proportional to concentration of drug ```

Question 54

zero order kinetics

Answer 54

elimination rate = k | no proportionality, constant over all concentrations

Question 55

rate limiting part of first order kinetics

Answer 55

drug concentrations

Question 56

how do drug concentrations change in first order kinetics?

Answer 56

by some constant fraction per unit time

Question 57

half life of first order kinetics

Answer 57

constant (independent of dose) dose-independent pharmacokinetics log plasma conc. vs. time is straight line

Question 58

catalyzed or facilitated processes are....

Answer 58

saturable

Question 59

at low concentrations or a catalyzed/facilitated process

Answer 59

``` first order kinetics rates proportional to dose Vd constant clearance constant half life constant ```

Question 60

at saturating drug concentrations of a catalyzed/facilitated process

Answer 60

``` zero order kinetics rates are constant regardless of dose Vd may vary clearance may vary half life varies ```