Download Test Yourself! - Department of Health Science and Technology

General Principles of
Pharmacology and Toxicology
Parisa Gazerani, Pharm D, PhD
Assistant Professor
Center for Sensory-Motor Interaction (SMI)
Department of Health Science and Technology
Aalborg University
Pharmacokinetics II
2
Pharmacokinetics made easy!
•
In pharmacokinetics the body is represented as a single or multiple
compartments in to which the drug is distributed.
Volume of Distribution = Dose/Plasma Concentration
Clearance = Elimination Rate Constant x Volume of Distribution (CL = kV)
Loading dose = Cp(Target) x VD
Maintenance Dose = CL x CpSSav (target average steady state drug
concentration)
3
Question 1
What Is the is the loading dose required for drug A if:
Target concentration is 10 mg/L
VD is 0.75 L/kg
Patients weight is 75 kg
Answer is on the next slide
4
Answer – Loading Dose of Drug A
VD = 0.75 L/kg x 75 kg = 56.25 L
Target Conc. = 10 mg/L
Loading Dose = Target Concentration x VD
Loading Dose = 10 mg/L x 56.25 L = 565 mg
This would probably be rounded to 560 or even 500 mg.
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Question 2
What maintenance dose is required for drug B if:
Target average SS concentration is 10 mg/L
CL of drug A is 0.015 L/kg/hr
Patient weighs 75 kg
Answer is on the next slide
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Answer – Maintenance Dose of Drug B
Maintenance Dose = CL x CpSSav
CL = 0.015 L/hr/kg x 75kg = 1.125 L/hr
Dose = 1.125 L/hr x 10 mg/L = 11.25 mg/hr
So will need 11.25 x 24 mg per day = 270 mg
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•
Half-life is the time taken for the drug concentration to fall to half its
original value
The elimination rate constant (k) is the fraction of drug in the body
which is removed per unit time.
Drug Concentration
•
C1
C2
Time
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t1/2 = 0.693/k
Log Concn.
C0
C0/2
t1/2
t1/2
t1/2
Time
Time to eliminate ~ 4 t1/2
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Steady-state (SS)
•
Steady-state occurs after a drug has been given for approximately five
elimination half-lives.
•
At steady-state the rate of drug administration equals the rate of
elimination and plasma concentration - time curves found after each
dose should be approximately superimposable.
•
Rate in = Rate Out
•
Reached in 4 – 5 half-lives (linear kinetics)
•
Important when interpreting drug concentrations in TDM or assessing
clinical response
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Accumulation to Steady State 100 mg given every half-life
175
187.5
194 …
200
150
100
87.5 94
97
…
100
75
50
11
C
Cpav
t
Four half lives to reach steady state
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Test Yourself!
Elimination of a drug refers to:
Excretion of its breakdown products in the urine
Renal excretion of the unchanged drug
Uptake of drug from the blood into the liver
Metabolism of the drug in the liver
Distribution of the drug into fat
Correct answers: b, d
a)
b)
c)
d)
e)
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Test Yourself!
The elimination rate of a drug is:
A constant for a particular drug and patient
The extent to which it is excreted in urine
Directly proportional to the plasma drug concentration
Directly proportional to the clearance
The extent to which the drug is excreted in the faeces
Correct answers: c, d
a)
b)
c)
d)
e)
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Test Yourself!
Clearance:
a) Depends on the elimination rate
b) Refers to the efficiency of elimination of drug by an organ or the
whole body
c) Cannot be greater than blood flow to an organ
d) Determines the steay state drug concentration during constant
dosing
e) Is determined by the half-life
Correct answers: b, c, d
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Test Yourself!
Two definition of clearance are:
a) The volume of blood or plasma irreversibly cleared of drug per unit
time
b) The time taken to reduce the plasma concentration by half
c) The constant relating the rate of elimination of a drug to the plasma
drug concentration
d) The amount of drug metabolized per unit time
e) The amount of drug excreted in urine per unit time
Correct answers: a, c
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Test Yourself!
Volume of distribution is:
a)
b)
c)
d)
The total volume of the body
The volume of the extracellular fluid
Equal to the volume of total body water
The constant relating amount of drug in the body to the plasma drug
concentration
e) The volume of the body minus the blood volume
Correct answer: d
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Test Yourself!
The loading dose of a drug is determined by:
The clearance
The elimination rate
The target plasma drug concentration
The volume of distribution
The molecular weight of drug
Correct answers: c, d
a)
b)
c)
d)
e)
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Test Yourself!
The rate of distribution of a drug can determine:
The volume of distribution
The onset of drug effect
The rate of drug elimination
The duration of drug effect
The clearance
Correct answers: b, d
a)
b)
c)
d)
e)
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Test Yourself!
Volume of distribution can be measured using:
a) The plasma drug concentration extrapolated back to zero time after
administration
b) The rate of elimination at a particulatr time after the dose
c) The clearance
d) The rate of onset of drug effect
e) The duration of drug effect
Correct answer: a
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Test Yourself!
Half-life:
Is the time taken for the plasma concentration to fall by half
Has units of ”per hour”
Is the time taken for the amount of drug in the body to fall by half
Decreases as elimination constant increases
Increases as the elimination constant increases
Correct answers: a, c, d
a)
b)
c)
d)
e)
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Test Yourself!
After a single dose of a drug which has a half life of 12 hours, what
percentage of the dose is still in the body after 1 day?
87.5%
75%
50%
25%
12.5%
Correct answer: d
a)
b)
c)
d)
e)
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Test Yourself!
During a constant rate intravenous infusion of a drug with an elimination
rate constant of 0.173 per hour, the plasma drug concentration will
be what percentage of steady state after 16 hours?
25%
50%
75%
87.5%
93.75%
Correct answer: e
a)
b)
c)
d)
e)
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Test Yourself!
Half-life determines:
The loading dose
The time to reach steady state
The drug concentration at steady state during constant dosing
The duration of action after a single dose
The flactuation in plasma drug concentration during a dosing interval
Correct answers: b, d, e
a)
b)
c)
d)
e)
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Test Yourself!
Bioavailability:
a)
b)
c)
d)
Is the extent to which a drug is absorbed from the gut
Is the fraction of the drug metabolized first pass by liver
Is the fraction of the dose reaching the systemic circulation intact
Is a measure of both first-pass metabolism and absorption from the
gut
e) Only refers to intravenous drug administration
Correct answers: c, d
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Test Yourself!
A new generic drug is tested in a bioavailability study against the
innovator brand. The AUC oral for the generic is 1200 mg*hour/L and
that for the innovator brand is 1000 mg*hour/L
a) The relative bioavailability of the generic formulation compared to the
innovator brand is 1.2
b) The absolute bioavailability of the innovator brand is 1.0
c) The generic formulation would usually be regarded as bioequivalent
to the innovator brand
d) The absolue bioavailability of the innovator brand is 0.83
e) The generic brand is better than the innovator brand
Correct answers: a, c
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Test Yourself!
Which of the following routs of administration completely avoid first-pass
clearance?
Buccal
Sublingual
Rectal
Oral
Transdermal
Correct answers: a, b, e
a)
b)
c)
d)
e)
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Test Yourself!
With respect to the renal clearance of drugs by glomerular filtration:
a) Glumerular filtration rate is about 40% of renal blood flow
b) Only unbound drug is filtered
c) Drug clearance by glumerular filtration is equal to glomerular filtration
rate
d) Both bound and unbound drug can be filtered
Correct answer: b
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Test Yourself!
The proportion of drug re-absorbed from the renal tubule depends on:
The glomerular filtration rate
The urine flow rate
The extent of drug secretion into the renal tubule
The liphophilicity of the non-ionized drug
The urine pH
Correct answers: b, d, e
a)
b)
c)
d)
e)
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Test Yourself!
The renal clearance of a lipophilic drug which is a weak acid with a pKa
of 5.0 is likely to be:
Reduced by cimetidine
Reduced by probenecid
Increased by acidifying the urine
Increase by alkalinizing the urine
Increased by an increase in urine flow rate
Correct answers: b, d, e
a)
b)
c)
d)
e)
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Test Yourself!
The fraction of a drug unbound in plasma is:
Usually not affected by the drug concentration
Independent of the concentration of binding protein
Dependent on the affinity of drug for the binding protein
Usually increased as drug concentration increases
Usually decreases as drug concentration increases
Correct answers: a, c
a)
b)
c)
d)
e)
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Test Yourself!
The AUC for the plasma concentration versus time curve of a drug after
a single intravenous dose is determined by:
Volume of distribution
Dose
Half-life
Clearance
bioavailability
Correct answers: b, d
a)
b)
c)
d)
e)
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Test Yourself!
Calculation of the volume of distribution of a drug after a single oral
dose requires which of the following parameters?
The time of max plasma concentration
The clearance
The elimination rate constant or half-life
The bioavailability
The absorption rate constant
Correct answers: b, c, d
a)
b)
c)
d)
e)
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Explore it!
Table gives plasma drug
concentrations (Cp) obtained following
an intravenous bolus administration of
a 250 mg dose of a drug that exhibited
the characteristics of a onecompartment model and was
eliminated exclusively by urinary
excretion.
Time (h)
Plasma Con.
(ug/mL)
0.5
68.0
1.0
54.0
2.0
30.0
3.0
18.5
5.0
6.0
7.0
1.8
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Plotting the data revealed the following:
a) The elimination half life (t1/2) =1.275 h
b) The overal elimination rate constant (K) = 0.543/h
c) The intial plasma concentration (Cp)0 = 90 ug/mL
Drug conc
100
Intercept = initial
plasma conc.
Slope= -K/2.303
10
5
t1/2
1
Time (h)
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Questions
a) The apparent volume of distribution (Vd)?
V = Dose/(Cp)0
b) The drug plasma concentration at 75 min following the administration
of a 2.5 mg/kg dose to a subject weighting 70 kg?
c) The time at which the plasma concentration of the drug will fall below
20 ug/mL, following the administration of a 275 mg dose?
Cp = (Cp)0 e –Kt or Cp/(Cp)0 = e –Kt or Ln (Cp/(Cp)0)/-K = t
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Answer
V = Dose/(Cp)0 V= 250/90= 2.77 L
(Cp)0 = Dose/V
(Cp)0 = 175/2.77 = 63.176
Cp = (Cp)0 e –Kt Cp = 63.176 e 0.543 x 75min or 1.25 h = 31.956
(Cp)0 = Dose/V
(Cp)0 = 275000ug/2770 mL = 99.277 ug/mL
t = Ln (Cp/(Cp)0)/-K
t = Ln (20/99.277) 0.543 = 2.94 h
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Take a closer look!
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with answers in this book.
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