Pharmacokinetics Flashcards
1
Q
What are the basic processes of pharmacokinetics?
A
ADME
Absorption, Distribution, Metabolism, Excretion
2
Q
What is the difference between pharmacokinetics and pharmacodynamics?
A
Kinetics: effects of body on drug
Dynamics: how drugs affect body
3
Q
What factors affect absorption?
A
Rate of dissolution (how long to break down)
Surface area
Blood flow
Lipid solubility (how quickly cross membrane)
pH partitioning (ion trapping)
4
Q
What route is suitable for large volumes and easily adjusted?
A
IV (bypass absorption barriers)
5
Q
Which routes are suitable for oily substances and suspensions?
A
IM
SQ
6
Q
Most common transport mechanism for drugs
A
simple diffusion
~non-protein
7
Q
3 ways drugs and cross cell membrane
A
facilitated diffusion (rare)
active transport
direct penetration= simple diffusion (most common)
8
Q
What transport system kicks drugs out of cells?
A
P-glycoprotein
9
Q
Which type of drugs can easily cross the cell membrane?
A
nonpolar drugs
10
Q
Which drugs can’t dissolve in or cross cell membranes easily?
A
polar drugs
11
Q
In what form can weak acids and bases cross membranes?
A
only in unionized form
12
Q
Lower pH, more likely…
A
molecule has H+ attached
–>ion trapping
13
Q
Where is a weak base trapped?
A
acidic compartments–> so many H in solution, it can’t ditch one to become ionized
14
Q
Where is a weak acid trapped?
A
basic compartments–> can’t find H to stabilize since not enough in solution
15
Q
Where are weak acids absorbed readily?
A
acidic–> stomach
16
Q
Are weak acids readily absorbed in the stomach?
A
No since stomach is acidic
17
Q
What body fluids can ion-trap drugs?
A
Urine Breast milk Jejunum, ileum Stomach Prostate Vagina
18
Q
What is Ka?
A
rate constant for absorption
per unit time
19
Q
What is S?
A
Salt factor
drugs often given as their salt
20
Q
What is the S value?
A
less than 1
21
Q
What is F?
A
bioavailability
= amount of drug that reaches bloodstream
22
Q
What is the value of F?
A
less than 1
23
Q
What is the equation to find bioavailability (F)?
A
Area under curve of route used/ AUC IV
24
Q
How to configure amount of drug absorbed
A
S * F * Dose
25
What is volume distribution (Vd)
amount of drug in body divided by plasma concentration
26
What happens to Vd when there is a lot of drug in the body
gets very large although there is very little in the plasma
know how much you gave, not in the plasma so must be elsewhere in the body
27
What is Cp?
concentration of drug in plasma
28
How to calculate Cp for 1 compartment model
S * F * Dose / Vd
29
What comprises extracellular volume?
plasma and interstitial
30
What comprises total body water?
extracellular + intracellular volumes
31
TBW of lean male
60% body weight (kg)
32
TBW of lean female
55% body weight (kg)
33
How to calculate extracellular volume
1/3 TBW
34
How to calculate plasma volume
25% of extracellular volume
35
How to calculate Cp for 2 compartment model
Once distributed, calculate t 1/2 for elimination
36
Site of peripheral drug concentration
Fat
Tissue
Bone
Transcellular reservoir (stomach)
37
What peripheral site stores lipid-soluble drugs
fat
38
Where do tetracycline abx accumulate
bone
39
How is stomach a transcellular reservoir
stores drugs that are slowly absorbed or undergoing enterohepatic circulation
40
When is Vd larger than TBW?
drug concentrates in a body compartment instead of plamsa--> apparent Vd
tetracycline, etc.
41
When is Vd lowest?
when in plasma
plasma< extracellular< intracellular < TBW < peripheral site
42
What affects drug distribution
ability of drugs to enter cells (same as absorption)
blood flow to tissues
ability of drugs to exit vasculature (lipid easier)
43
When is a drug bioactive?
when free in blood (alpha)
44
Why is alpha (drug bioactivity) important?
potential toxicity
new drugs displace bound and cause more drug to be free
--> if drug 90% bound, new drug added and now 80% bound, alpha doubled (eventually eliminated but double concentration for a period of time)
45
What is the blood brain barrier a barrier against?
ionized or polar drugs UNLESS they have a transporter
46
Where is the primary site of biotransformation (metabolism)
liver
47
What is the function of liver in regards to metabolism in ADME
primarily inactivates drug, but can activate pro-drugs
48
Why is the liver so important in terms of excretion?
lipophilic drugs must be made polar so they can be trapped in the renal tubular fluid
49
What are secondary areas of metabolism of drugs?
```
kidney
lungs
intestines
testes (Sertoli)
skin epithelia
brain
plasma
```
50
Stages of Phase 1 Metabolism
oxidation
reduction
hydrolysis
51
What is the purpose of phase 1 of drug metabolism?
make polar metabolites
| add or unmask group
52
What enzymes are vital to phase 1 of metabolism and where are they located?
Cytochrome P450 in SER
-->oxidative process
53
What do inducers of CYP450 do?
increase enzyme levels--> speed up metabolism so lower total plasma levels below MEC
54
Examples of CYP450 inducers
phenobarbital
carbamazepine
ethanol
cigarette smoke
55
What do CYP450 inhibitors do?
inhibit enzyme-->slow metabolism--> toxic levels
56
Examples of CYP450 inhibitors
erythromycin
ketoconazole
metronidazole
grapefruit juice
57
What specific CYP450 enzyme does grapefruit juice inhibit?
CYP3A4
58
What is the mechanism of grapefruit juice in metabolism?
inhibits CYP3A4 in intestinal epithelial cells
increase BIOAVAILABILITY of other drugs so more enter blood
59
What 3 processes can occur in phase 2 of biotransformation?
conjugation
acetylation
methylation
60
What is the function of acetylation and methylation in metabolism?
make drug LESS water soluble--> REDUCE drug activity
AKA inactivates drug
61
What is the major route of metabolism for drugs and endogenous compounds that occurs in the ER?
Glucuronidation
62
What is another major route of drug metabolism that occurs in the cytoplasm?
sulfation
63
What is the function of conjugation in phase 2 metabolism?
add highly POLAR molecule to make drug MORE water soluble and more excretable
64
What is the difference between conjugation and acetylation/methylation?
conjugation adds polar group to make MORE water soluble
acetylation/methylation makes drug LESS water soluble to inactivate it
65
Which aspect of conjugation is inducible?
glucuronidation
66
Why does first-pass metabolism decrease bioavailability of oral drugs?
since the drug goes to the GI tract then the liver, small amount of drug is transferred to blood
-->why IV used if need more or fast drug
67
What is the major route of drug elimination?
Kidney
68
What are minor routes of drug elimination?
bile
sweat
breath
breast milk
69
What are the steps in drug elimination?
Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
70
What drugs don't filter in the glomeruli?
protein-bound drugs
71
What drugs are reabsorbed passively in tubular reabsorption during elimination?
lipid soluble drugs
unionized weak acids and bases
72
How do we eliminate protein-bound drugs?
active tubular secretion
-->when drug temporarily displaced from protein binding sites near proximal tubule
73
What modify renal drug excretion?
pH-dependent ionization (affects passive)
competition for active tubular transport
age (GFR decreases)
74
What is the excretion rate?
mass eliminated per unit time
75
Excretion rate _____ as plasma concentration increases
increases
76
What is clearance?
plasma volume of solute removed per time
FLOW RATE
77
Clearance _____ as plasma concentration change
remains constant
78
If clearance decreases by half, solute_____
doubles
79
eGFR
(140-age) x BW / 72 * serum creatinine
80
What to do to eGFR equation if female
multiply by .85
81
What is special about allergy or hypersensitivity drug effect?
not dose related
requires prior sensitization
82
What are the most serious drug allergies to?
penicillin family most serious
sulfa drugs common
83
Lack of plasma esterase and succinylcholine
apnea of long duration
84
Lack of NADH methemoglobin reductase and nitrites, sulfonamides, primaquine
hereditary methemoglobinemia
85
low liver acetyl transferase and isoniazid (treats TB)
increased toxicity
86
lack of G6P dehydrogenase (low GSH) and primaquine
drug-induced hemolytic anemia (favism)
87
Deficiency of porphobilinogen deaminase and barbiturates, estrogens, sulfonamides, chloroquine
acute intermittent porphyria
88
Hepatotoxic drugs
```
lipid-lowering
antiseizure
TB
antiretroviral
oral hypoglycemics
antifungal
immunosuppressants
acetaminohpen
```
89
Terfenadine (seldane) caused
QT prolongaiton, torsades de pointes-->drop dead
90
What drugs have greatest carcinogenic potential
cancer chemotherapeutic drugs
--> diethylstilbestrol (DES)
used to prevent miscarriage, caused uterine and vaginal cancer in daughters
91
Neonate and infants have __________ TBW c/t adults
increased
92
metabolism of drugs is ___ in children
faster but similar ADE
93
Describe ADME in infants
A increased or decreased
D: low albumin so higher protein bound drugs, BBB not developed so drugs can cross
M: decreased (adjust downward)
E: decreased (adjust downward)
94
What fraction of patients respond to placebo
1/3
95
What percent of patients respond to placebo when used for pain
75%
96
Describe drug therapy physiologic changes during pregnancy
decreased bowel tone and motility--> increased time for drug absorption
increased hepatic metabolism
increased GFR
97
Which kinetics describes amount of drug eliminated is independent of drug concentration
zero order
98
Which kinetics is constant amount eliminated per unit with drug elimination saturated
zero
99
equation for zero order kinetics
change in plasma concentration over change in time= constant (k)
100
Example of zero order drug
ethanol
101
Which kinetics is constant fraction eliminated per unit time
first order
102
Which kinetics is not saturated, where mass of drug eliminated is DIRECTLY related to the concentration
first order
103
Equation for first order kinetics
change in plasma concentration over change in time= constant (k) multiplied by plasma concentration
104
Which kinetics is the more typical form of drug elimination
first order
105
In first order kinetics, each subsequent half-life_____ the concentration
halves
```
1= 50%
2= 25%
3= 12.5%
```
106
97% drug eliminated in ____ half-lives
5
107
first order kinetics calculation
0.693= k*t1/2
108
what is tau
dosage interval
qd-> 24 tau
109
CPss (ave)
plasma concentration at steady-state plateau where input=output
110
clearance equation
clearance= Kel (first order elimination rate constant) * Vd
OR
S * F * (dose/tau)/ Cp
111
When do you see hockey stick kinetics graph
drugs at high concentrations
| starts out as 0--> 1
112
Rate of elimination equation
Vmax * Cp/ Km + Cp
113
Steady-state concentrations proportional to...
dose/dosage interval OR F/Cl
114
Cpss (ave) =
dosing rate/ clerance
1.44 * S * F * D * t 1/2 / tau * Vd
115
loading dose equation
Cpss (ave) * Vd / (S * F)
116
Plasma concentration with varying dosages
have proportional changes in peak concentration
117
Plasma concentration with varying absorption rates
more rapid absorption give higher peak (line goes below average as times goes on)
if 1/3, goes above with time
118
Plasma concentration with varying elimination rates
higher peak with slower elimination, line above average
