Transcript Document

59-291 Section 1, Lecture 6
Single-dose kinetics
Plasma [Drug] curve
Upon administration
[drug]plasma reaches a max
Then begins to decline as the
Drug is eliminated
Cpmax =max plasma [drug]
tmax = time to reach Cpmax
AUC= area under the curve=
These measures are useful for comparing the bioavailability of
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different pharmaceutical formulation
Bioavailability- the fraction of the administered dose that reaches
the systemic circulation= AUCoral/AUCIV
AUCoral can be affected by:
-rate of tablet disintegration
-drug solubility
-sequestration by food
-gastric acid and gut
enzyme inactivation
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Continuous and multiple dose kinetics
Steady-State Principle: for drugs exhibiting first-order
pharmacokinetics
[Drug]
Rate of
administration or
absorption
[Drug]plasma
rate= [Drug] x kabs
Rate of
elimination
[Drug]urine,
rate= [Drug]plasma x ke
Initially rate of admin. or absorption greater than rate of elimination
because initially [Drug]plasma is low
-rate of elimination gradually increases as [Drug]plasma increases
and reaches a plateau. This is termed the steady-state concentration.
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Since the time to reach steady-state is composed of 2 first-order
processes, it also obeys the rules of 1st order reactions.
It takes 5 half-lives to complete a 1st order process:
(1/2n)= 1/ 2x2x2x2x2= 1/32= 0.03 or 3% remains or 97% produced
after 5 half-lives
Time required to reach the steady state is independent of the drug4
dose and frequency of drug administration
Half-Life
• The time it takes for one half of the original amount of a drug in the body
to be removed
• A measure of the rate at which drugs are removed from the body
Dug concentration 100
50
25
12.5
6.25
3.125
Hours after peak
concentration
0
8
16
24
32
40
Number of half0
lives
Percentage of drug 0
removed
1
2
3
4
5
50
75
88
94
97
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Steady-State concentration depends on:
-drug dose/unit time; and t ½ of the drug
-if you double either, you get the same effect
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-an intermittently administered drug will accumulate to a steadystate at the same rate as a drug given by continuous infusion BUT
the fluctuations in [drug]plasma will be less with the latter method
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Dosage Calculations;
Loading dose- dose to establish a rapid therapeutic [drug]plasma
= Vd x desired [drug]plasma
dose/Cp0
In the case of toxic drugs (digitalis) Loading dose is divided into
several portions and given over a long time
Maintenance dose= dose required to maintain a desired steady-state
Rate of elimination (in hours) x dosage interval in hours
At steady state: rate of elimination=rate of administration
(absorption)
rate of elimination = Cl x avg [Drug]steady-state plasma
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Example for Gentamicin:
[Gentamicin]steady-state plasma= 2 mg/L
Clgentamicin=100 mL/min
rate of elimination = Cl x avg [Drug]steady-state plasma
= 0.1 L/min x 2 mg/L
= 0.2 mg/min
What is the maintenance dose for administration once every 8 h?
Maintenance dose = Rate of elimination (in hours) x dosage
interval in hours
= 0.2 mg/min x 60 min/h x 8h
= 96 mg
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Practice questions
• Define bioavailability and list the
parameters that are useful for comparing
different formulations
– the fraction of the administered dose that
reaches the systemic circulation=
AUCoral/AUCIV
– CPmax
– Tmax
– AUCoral
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• List the parameters that affect bioavailability
of orally administered drugs
–
–
–
–
rate of tablet disintegration
drug solubility
sequestration by food
gastric acid and gut enzyme inactivation
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