Lec3-5 Flashcards
1
Q
lipophilicity
A
solubility in lipid relative to water
2
Q
lipophilicity is measured by
A
oil/water partition coefficient (drug conc in oil v water)
3
Q
drugs with carboxylate reside undergo ionization and become ____
what is their solubility to water and lipid now
A
anions
more soluble to water
less soluble to lipid
4
Q
drugs with amine undergo ionization and become ____
what is their solubility to water and lipid now
A
cation
less soluble to water
more soluble to lipid
5
Q
quaternary ammonium with fixed positive charge (such as ACH) has what type of lipophilicity
A
lipophilicity is low
high solubility in water
low solubility in lipid plasma membranes
6
Q
very large MW drugs
A
> 1000 (tend to be proteins)
7
Q
small MW drugs
A
<1000
8
Q
pharmacokinetics is concerned with
A
the time course of
- absorption
- distribution
- eliminiation
9
Q
absorption
A
drug from site of administration into the blood stream
10
Q
why is conc of plasma important
A
bc it’s what we can measure (blood)
11
Q
distribution
A
from blood stream into tissues in body
12
Q
elimination
A
getting out of body in form of molc it was administered
13
Q
4 major types of biotransport
A
passive diffusion throguh plasma membrane
filtration
carrier-mediated transport
receptor-mediated endocytosis
14
Q
what order kinetics is passive diffusion and is the half life or rate dependendant on dose conc
A
first order
half life NOT dependent on conc
rate IS dep on conc gradient
15
Q
transport in bulk flow of aqueous fluid is known as
A
filtration
16
Q
filtration rate is dependent on ? (3)
A
hydrostatic pressure
MW, size, charge
tissue porosity
17
Q
what type of transport can be active transport of a molc that wouldn’t cros w/o it
A
carrier-mediated transport
18
Q
drug transporter whose efflux pump causes resistance to some antitumor drugs
A
MDR p-glycoproteins
19
Q
biotransporter that is important for big molecules
A
receptor-mediated endocytosis
20
Q
rate of receptor mediated endocytosis is dependent on
A
receptor expression and membrane insertion
21
Q
what protein therapeutics is receptor-mediated endocytosis a mechanism for
A
monoclonal antibodies (iGg)
22
Q
time course of transport from site of administration to systemic circulation
A
absorption
23
Q
bioavailability is the
A
% dose absorbed (what % gets into bloodstream)
24
Q
only route of admin that’s 100% bioavailabity
A
intravenous bc all put into vasculature
25
route of admin with fastest possible input rate
intravenous
26
during subcutanrous or intramuscular routes of admin where do low MW lipophilic drugs enter
where do high MW compounds enter
low - into blood
| high - into lymphatics
27
subcutaneous and intramuscular has better biovailability than ____ for ____ drugs
than oral route
| for polar & high MW drugs
28
during inhalation route of admin, rapid absorption of gases and vapors is due to
high pulmonary blood flow
| low diffusional distance from alveolus to blood
29
which route of admin do we want no bioavailability
inhalation
30
why is absorption through skin (topical route) generally slow
moves through surface layers of dead, keratinized cells
31
which route avoids the first pass effect
topical (i.e. transdermal)
32
why might bioavailabity of oral route be low
```
mucosa as barrier
high MW
low lipophilicity
carrier-mediated extrusion
first pass effect
```
33
biotransformation during the absorption process
first pass effect
34
is bioavailability low or high in a drug with NO first pass effect
high bioavailability
35
time course of transport from vasculature to tissue space
distribution
36
what determines equilibration rate during distribution
blood flow
37
highly perfused organs?
intermed?
low?
```
high:
lung
liver
brain
kidney
```
inter:
skeletal muscle
low:
fat
38
which is equilibrated faster? highly perfused structures or low
highly bc equilibrate in mins while low does in hours
39
determinants of equilibrium gradient in distribution
vascular permability
macromolc binding in plasma and tissue
MW, lipophilicity, carrier affinity
40
BBB has what 2 things that allow drugs to pass
tight junctions and transporters
41
what does a drug binding to albumin do & whats its effect on equilibrium gradient
it prevents the complex from moving out of the vascular compt
as drug distributed, dissociated from albumin and incr drug distribution (high equilibrium gradient)
42
monoclonal antibody likely to distribute into a space like that of
albumin (in plasma)
43
volume of the body into which the drug appears to have distributed once equilibrium is obtained
volume of distribution
44
(plasma) concentration is
amount (g) / volume (L)
45
volume of distribution is determinant of
plasma concentration
46
one compt model v 2
1 compt - drug ditributes entire volume and reaches equilibrium v quickly
2 compt - equilibrates slowly
47
high lipid solubility means ____ Vd
high
48
high MW(proteins) - ___ Vd
small MW and polar(charge) - ____ Vd
small MW and lipophilic - _____ Vd
highly lipophilic and accumulates in fat - ____ Vd
small (Vd about plasma vol, 4%)
Vd like sucrose (Vd about extracell fluid vol, 17%)
Vd like water (Vd about total BW, 58%)
more than body water (>>58%)
49
mechanism by excretion or biotransformation
elimination
50
molc in same chemical configuration as the form it was injected in is by
excretion
51
clearance is what over what
volume of plasma cleared over unit time
52
what is the extraction ratio & what is it's range of values
Cp arterial - Cp venous
0=nothings removed
1=all of drug is removed
53
what determines the elimination rate of a drug from the body
total clearance
54
elimination rate (amt of drug in body/time) =
Cl Total x Cp
| where Cp=plasma conc
55
elimination rate changes in parallel w
plasma conc
56
total clearance = sum of
renal and nonrenal clearance
57
renal clearance refers to
nonrenal
urinary excretion unchanged
all other routes and mechanisms
58
nonrenal clearance participates in biotransformation where critical enzymes are lumped into phase 1 and phase 2
-whats the general difference
1- oxidation, reduction, hydrolysis
| 2-conjugations
59
pathway of biotransformation
drug --phase 1 --> metabolite --phase 2--> conjugated metabolite
60
main enzyme for phase 1
CYP450
61
2 isozymes of CYP450
3A4 and 2D6
62
how do CYP450 familu isozymes differ
substrate specificity
inducers
inhibitors
63
what happens to clearance of some drugs when theres biotransfortmation w an inducer
increases clearance
64
what are good ligands for phase 2 conjugation
OH
65
good ligands for phase 1
CH3
66
phase 2 conjugating MOieties (6)
```
GMS GAG
glucoronic acid
methyl groups
sulfate
glutathione
acetyl group
glycine
```
67
phase 2 enzymes that are transferase creater metabolites with ___ compared to parent
higher MW
68
volume of plasma cleared by excretion unchanged into urine
renal clearance
69
mechanisms of renal clearance
Glomerular filtration of unbound low MW drug
prox tube secretion mediated by oatp and mdr
passive reabsorption of uncharged, lipophilic drug
70
why is renal clearance small
bc readily reabsorbed
71
equation for renal clearance
urinary excretion rate / Cp
Cp=plasma conc
72
if renal clearance is 0-120 (
not filtered and/or lots of reabsorption or bound to macromolc in plasma
73
if renal clearance is 120 (GFR) it's mechanism of excretion was
filtration and NO reabsorption
74
if renal clearance is 120-640 (RPF) it's mechanism of excretion was
filtration and secretion
NO net reabsorption
*>GFR only happens if secreted into nephron in prox tubule and no net reabsorption
75
renal clearance is most likely what for:
| high albumin binding
<120
76
renal clearance is most likely what for:
| lipophilic drug
<120
| filtered but reabsorbed
77
renal clearance is most likely what for:
| acidic drug w affinitiy for OATP, high urine pH
>120
OATP means likely to be secreted so incr ClR
if drug is anion (wk acid) then it's more charged in high pH --> less reabsorption --> incr ClR
78
renal clearance is most likely what for:
| acidic drug w low urine pH
<120
| would want a more basic pH if drug is acidic
79
what type of distribution? drug rapidly equilibrates into volume of distribution
single compartment distribution
80
type of elimination?
drug is cleared at constant fractional rate
Kel (elimination constant) is fraction eliminated per unit time
first order elimination
81
does total clearance depend on dose
no
82
how do you linearize plasma conc
take ln
83
bioavailability with iv
100%
84
compute vol of distribution
dose/Cp0
85
elimination half life is function of both
Vd and clearance
86
tiem to eliminate 50% of a drug from plasma
half life
87
is half life dose depend or independ? what order of elimination?
dose independent
| first order
88
if you incr Vd what happens to half life
larger Vd --> lower Cp0 --> (longer or) incr half life
89
increase clearance what happens to half life
```
faster clearance (higher ClT) so shorter half life
* no effect on CP0
```
90
how are Cp, Vd, ClT, and half life affected with dose
Cp incr w dose
| rest do not change
91
with iv admin, 1st order elimination, 1 compt distribution, rapid reversible effect, and no active metabolits
if you double dose, what happens to duration
duration increases by addition of one half life
92
what type of elimination has Cp v time as linear without log transformation
zero order
93
in zero order kinetics, how does biotransformation time change w conc
50% biotransformation time incr w conc
94
main diff bn first ortder and zero order Cp v time
first order has fractional elimination like it decr by half
| zero order has constant rate of elimination like decr by 20 every hour
95
is eliminiation happening from the central or peripheral compt? what are central organs? peripheral?
central
central: lung liver kidney brain
peripheral: fat and skeletal muscle
96
Cp v time curve for two compt model has 2 phases, what are they and what do they describe
alpha - initial rapid decline that describes distribution of drug from central in peripheral comp
beta - linear
97
which most similarly acts/looks like the plasma conc v time curve of a 2 compt model? highly perfused or poorly perfused tissue concentration
highly perfused tissue (central compt like brain)
98
what happens to conc of poorly perfused tissue as Cp decreases
they rise/ incr til reach equilibirum
99
duration of action for multi-compartments is dependent on
distribution into and out of compt where target is located
100
what do lipophilic drugs that act in the brain duration of action depend on
redistribution out of brain to slowly perfused tissues
| **not on elim by kidney or liver
101
can duration of action be short if elimination half life is long
yes
102
half life is always elimination
false theres an absorption half life
103
plasma conc time curve is influenced by what 3 things
absorption rate constant
elimination rate constant
bioavailability
104
the faster the absorption (i.e. the shorter the half life of absorption), the ___ Cp max and the ____ t max
higher Cp max
| earlier the tmax (so the time for that peak is shorter)
105
fraction of dose that gets into plasma conc is known as
bioavailability
106
what is proportional to bioavailability
area under the curve of Cp v t
107
integral of Cp = AUC = ?
Fx D / ClT
bioavailability x dose / total clearance
*ClT is constant
108
the absolute bioavailability is determined for
a new drug
109
the relative bioavailability is determined for
generic in comparison to proprietary formulation of drug
| *comparing one manufacturers formualtion to anoteher
110
eq for absolute bioavailability and relative
abs: AUC nonIV dose / AUC IV dose
rel: AUC formualtion 1/AUC formualtion 2
111
during continuous infusion, at steady state what 2 rates equal each other
input rate = output rate
112
input rate =
Cp steady state * ClT
*also true for output rate equation
113
equation that relates Cpss w infusion rate
Cpss=infusion rate / ClT
114
the higher the ClT the ____ the Cpss
lower the Cpss
| *unless you increase the infusion rate to get a desired CPss
115
tiem to achieve steady state level achieved by infusion depends SOLELY on
elimination half life
116
time to reach 50% of Cpss take how many elimination half life
one
117
time to reach 93% of Cpss take how many elimination half life
four
118
when prescribe a drug by continuous IV infusion, which drug will reach steady state mor quickly? shorter half life or longer
shorter half life
119
Cmin is called a
trough
120
CmaxSS to CminSS is
therapeutic window
121
when is loading dose important
for rapid onset of effect is needed
if drug elimination half life is LONG and slowly attains SS
122
diff bn multiple dose kinetics and IV infusion
multiple is not continuous, it's pulsatile
123
equation for multiple dose kinetics
maintenance dose / dosing interval
124
extent of accu,ulation from first dose to SS depends on
ration bn elimination half life and dosing interval
125
if dosing interval is 7 times the elimination half life, how much accumulation?
none
126
if dosing interval = elimination half life, how much accumulation?
2 fold accumulation
127
calculate Cp average
input rate / clearance
| (D/t) / Cl T
128
compare the Cp avg of small dose at frequent intervals and high dose at long intevals
they're about the same
