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

1
Q

therapeutic index

A

difference between therapeutic and toxic ranges

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2
Q

pharmacodynamics

A

effects of the administered drug
desired = efficacy
undesired = toxicity

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3
Q

pharmacokinetics

A

getting the drug to the right place in the right amount

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4
Q

components of pharmacokinetics

A

absorption
distribution
metabolism
excretion

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5
Q

absorption

A

how a drug gains entry into systemic circulation

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6
Q

passive diffusion

A

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

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7
Q

carrier mediated transport

A

transporters facilitate movement
structural selectivity
competition by similar molecules
saturable

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8
Q

facilitated diffusion

A

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

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9
Q

active transport

A

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

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10
Q

important sites of active transport

A
enterocytes
hepatocytes
neuronal membranes
renal tubular cells
blood brain barrier
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11
Q

absorption of APAP

A

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

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12
Q

blood

A

very large molecules

highly charged molecules

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13
Q

extracellular water

A

large
very polar
water soluble

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14
Q

total body water

A

smaller
water soluble
*acetaminophen

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15
Q

adipose tissue

A

lipid soluble

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16
Q

bone and teeth

A

ions

chelators

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17
Q

other tissues

A

specific uptake mechanisms or binding proteins lead to drug accumulation

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18
Q

apparent volume of distribution

A

the compartment where a drug appears to distribute

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19
Q

C0

A

extrapolated concentration of drug in plasma at time 0 after equilibration

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20
Q

Vd

A

amount of drug/C0

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21
Q

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

A

plasma
ECF
total body water
tissue concentration

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22
Q

what factors influence distributions

A

gender
age
body fat
edema

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23
Q

what does Vd really represent?

A

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

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24
Q

what does a large Vd indicate?

A

high drug concentrations in one or more tissues

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25
why is Vd qualitatively important in clinical use?
indicates ration of plasma concentrations to concentrations in tissues
26
why is Vd quantitatively important in clinical use?
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
27
primary parameters
clearance and Vd | inherent properties
28
clearance
primary parameter for elimination (metabolism + excretion)
29
secondary parameters
half life | elimination rate constant
30
Kel
CL/Vd
31
t0.5
0.693*Vd/CL
32
amt of drug in body at any time
Vd*plasma concentration
33
APAP Vd
0.7 L/kg | total body water
34
metabolism (biotransformation)
many drugs are hydrophobic, but efficient excretion requires water solubility metabolism increases water solubility and excretion
35
phase 1 metabolism
introduce/unmask a functional group relatively few atoms involved oxidation, reduction, or hydrolysis
36
phase 2 metabolism
synthetic reactions addition of molecules require specific functional groups
37
do drugs always undergo both phase 1 & 2 metabolism?
no, can do either, both, or neither
38
what are 2 different outcomes of phase 1 metabolism?
1. drug metabolite w modified activity produced | 2. inactive drug metabolite produced
39
types of phase 2 metabolism
``` water soluble: -glucuronidation -sulfate conjugation -glycine conjugation lipid soluble: -acetylation -methylation detoxification: -glutathione conjugation ```
40
dominant phase 1 metabolic enzymes
``` CYP family (cytochrome p450) high activities in enterocytes and liver contribute to first-pass effect ```
41
dominant phase 2 metabolic enzymes
UGTs SULTs NATs
42
what are the 3 metabolic pathways of APAP
sulfation catalyzed by SULTs glucuronidation catalyzed by UGTs oxidation catalyzed by CYP2E1 + conjugation of oxidation product catalyzed by GSTs
43
what transporters are involved in APAP metabolism
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
44
excretion
how xenobiotics or their metabolites are eliminated from the body
45
amount excreted by any process per unit time is proportional to...
rate of elimination for that process | concentration of drug in plasma
46
drug concentration in plasma is inversely proportional to....
volume of distribution - larger volumes eliminated slower - lower volumes eliminated faster
47
renal excretion
generally smaller MW favored by high aqueous solubility excretion by active and passive processes
48
hepatic/biliary excretion
generally larger MW less polar environment excretion by active and passive processes
49
excretion of APAP
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
50
elimination rate (mg/hr)
CL (L/hr) * C (mg/L)
51
what is one way to think about clearance?
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
52
total body clearance...
sum of hepatic and renal clearance
53
first order kinetics
``` absorption rate= kabs[drug] distribution rate=kdis [drug] metabolism rate=kmet [drug] excretion rate=kexc [drug] -parameters proportional to concentration of drug ```
54
zero order kinetics
elimination rate = k | no proportionality, constant over all concentrations
55
rate limiting part of first order kinetics
drug concentrations
56
how do drug concentrations change in first order kinetics?
by some constant fraction per unit time
57
half life of first order kinetics
constant (independent of dose) dose-independent pharmacokinetics log plasma conc. vs. time is straight line
58
catalyzed or facilitated processes are....
saturable
59
at low concentrations or a catalyzed/facilitated process
``` first order kinetics rates proportional to dose Vd constant clearance constant half life constant ```
60
at saturating drug concentrations of a catalyzed/facilitated process
``` zero order kinetics rates are constant regardless of dose Vd may vary clearance may vary half life varies ```