pcol2 pharmacokinetics
TRANSCRIPT
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Pharmacokinetics
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Absorption of Partially-Ionized
Drugs
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Aspirin pka = 3
Paracetamol pka = 9.5
Ibuprofen pka = 4.4
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Percent ionized
pka - pH If anion (weak acid) If cation (weak base)
- 4 99.99 0.01
- 3 99.94 0.06
- 2 99.01 0.99
- 1 90.91 9.09
- 0.9 88.81 11.19
- 0.8 86.30 13.70- 0.7 83.37 16.63
- 0.6 79.93 20.07
- 0.5 75.97 24.03
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Percent ionized
pka - pH If anion (weak acid) If cation (weak base)
- 0.4 71.53 28.47
- 0.3 66.61 33.39
- 0.2 61.32 38.68
- 0.1 55.73 44.27
0 50.0 50.0
+ 0.1 44.27 55.73+ 0.2 38.68 61.32
+ 0.3 33.39 66.32
+ 0.4 28.47 66.61
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Percent ionized
pka - pH If anion (weak acid) If cation (weak base)
+ 0.5 24.03 75.97
+ 0.6 20.07 79.93
+ 0.7 16.63 83.37
+ 0.8 13.70 86.30
+ 0.9 11.19 88.81
+ 1 9.09 90.91+ 2 0.99 99.01
+ 3 0.06 99.94
+ 4 0.01 99.99
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For acidic drugs, the lower the pka the
stronger the acid
Forbasic drugs the higher the pka thestronger the base
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The relation between ionization and pH is
sigmoidal
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pH-partition hypotheses
If the pH on one side of a cell membrane
differs from the pH on the other side of
the membrane, then:
1. The drug will ionize to different degrees
on respective sides of the membrane
2. The total drug conc. (ionized + non-
ionized) will be unequal on either sides of
the membrane
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pH-partition hypotheses
3. The compartment in which the drug is
more highly ionized will contain the
greater total drug conc.
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Goal
To deliver the right amount (dose) of drug
that is safe & effective at the right place
(target organ) and at the right time (onset
& duration of action).
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First-order and zero-order
kinetics
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Time of
collection (hrs)
Drug A (ug/mL) Drug B (ug/mL)
1 2000 2000
2 1500 1000
3 1000 500
4 500 250
5 0 125
6 0 63
7 0 31
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Which drug is eliminated by first-order
kinetics? Which one is zero-order kinetics?
Which one is concentration-dependentand which one is concentration-
independent?
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The rate of a chemical reaction or
pharmacokinetic process is the velocity
with which it occurs
The orderof a reaction is the way in which
the concentration of a drug in a chemical
reaction affects the rate
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Zero-order reaction
Drug conc. changes with respect to time at
a constant rate
dC/dt = -ko
C = -kot + Co
ko = zero-order rate constant
(conc./time)
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First-order reaction
Change in drug conc. with respect to time
equals the product rate constant and the
concentration of drug remaining
dC/dt = -kC
k = first-order rate constant
(reciprocal time)
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Integration yields:
C = Coe-kt
ln C = -kt + ln Co
log C = -kt/2.3 + log Co
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Biologic half-life (t1/2)
Time required for the concentration of a
drug to decrease by one half
Formula:
t =
Half-life is a constant and is related to the
first-order rate constant
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Biologic half-life (t1/2)
Unit: mins., sec., hrs.
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Elimination rate constant (k or kel)
Drug elimination is a first-order kinetic
process
Sum of the rate constants for removal ofthe drug from the body, including the rate
constants for renal excretion and
metabolism (biotransformation)
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Elimination rate constant (k or kel)
Not affected by the route of administration
Affected by physiologic or pathologic
conditions of the patient (e.g. liver failure,age)
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Elimination rate constant (k or kel)
Formula:
kel = ke + km
ke = rate constant for renal excretion; km =rate constant for metabolism
kel =
Unit: reciprocal time (sec-1, mins-1,
hrs.-1)
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Drug distribution
Reversible transfer of drug from one
location to another within the body
Most drugs do not distri
bute uniformlythroughout the body
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Apparent Volume of Distribution
(Vd)
Hypothetical volume ofbody fluid in
which the drug is dissolved
Not a true anatomic or physical volume
Is needed to estimate the amount of drug
in the body relative to concentration of
drug in the plasma
Measure of the apparent space in the
body available to contain the drug
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Apparent Volume of Distribution
(Vd)
Can vastly exceed any physical volume
(since it is hypothetical) in the body
Reflects the volume necessary to containthe amount of drug homogenously at the
conc. found in the plasma, blood or water
(after giving a dose and getting the plasma
conc.)
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Apparent Volume of Distribution
(Vd)
Formula:
Vd x Cp = Ab
Vd = apparent volume of distribution (L, mL)
Cp = plasma drug concentration (mg/mL,
ug/mL)
Ab = amount of drug in the body (mg, g)
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Apparent Volume of Distribution
(Vd)
Reflects the amount of drug in the tissues,
not in the plasma
Inversely proportional in relation to thedrug plasma concentration
Unit: volume (mL, L)
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Apparent Volume of Distribution
(Vd)
To calculate the Vd after intravenous bolus
injection
Vd =Ab
/Cp
Ab = dose of drug given by intravenous bolus (g,
mg)
Cp = extrapolated drug concentration at zero time onthe y-axis, after the drug equilibrates (ug/mL,
mg/mL)
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Apparent Volume of Distribution
(Vd)
Influenced by:
1. binding affinity of a drug forblood ortissue elements
2. blood flow (i.e., delivery of drug to thetissues)
3. ability to cross biomembranes
4. physicochemical properties (lipophilicity,extent of ionization, pH, pka) thatdetermine partitioning to tissues
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Importance of Vd
Directly proportional to the half-life prolongs the half-life ___________
duration of action ??
Used for the computation of the loadingdose of a drug
Determine or predict the distribution of
drugs (is it predominantly in the plasma orin the body tissues?)
Compare the distribution characteristics of
various drugs
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Apparent Volume of Distribution
(Vd)
A drug which is more bound to plasma
proteins than tissue proteins will ___ Cp
and ___ Vd
A drug which has a high affinity for
adipose tissues than plasma proteins will
___ Cp and ___ Vd
Vd of a lipophilic drug is large in an obese
patient
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Total body clearance (ClT, CL)
Measure of the ability of the body to
eliminate the drug
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Total body clearance (ClT, CL)
Irreversible removal of drug from the body
by an organ of elimination
Units are flow
volume per time (mL/min,L/hr)
Defined as the volume ofblood irreversibly
cleared of drug per unit of time
Influenced by pathologic conditions and
age of the patient
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Total body clearance (ClT, CL)
Product ofblood flow to the organ (Q) and
extraction ratio (ER) of that organ
CL organ = Q x ER Extraction ratio fraction of drug that is
irreversibly removed by an organ or tissue as
the plasma-containing drug perfuses that tissue
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Total body clearance (ClT, CL)
Drug elimination rate divided by the
plasma concentration
ClT = rate of drug eliminationplasma concentration
= dDe/dt
CpdDe/dt = rate of drug elimination (mg/min, g/hr)
Cp = drug plasma conc. (mg/mL)
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Total body clearance (ClT, CL)
According to the concept of clearance, the
body contains an apparent volume
distribution in which a drug is dissolved
(Vd) and a constant portion of this is
cleared or removed from the body per unit
time (kel or ke)
ClT =
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Total body clearance (ClT, CL)
ClT = FDo
AUC
F= absolute bioavailability
Do = amount of drug administered (mg, g)
AUC = area under the curve, rate and extent of
drug absorbed in the systemic circulation
(mg.hr/mL)
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Total body clearance (ClT, CL)
Sum of all clearances of the bodyCLT = CLR + CLNR
CLT = total body clearance
CLR = renal clearanceCLNR= non-renal clearance is often equated to
hepatic clearance (CLH)
It is always assumed that the drug iseliminated/cleared by first-order kinetics
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Total body clearance (ClT, CL)
In relation to biologic half-life
ClT = keVd
ClT = 0.693Vdt 1/2
t = 0.693Vd
ClT
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Total body clearance (ClT, CL) is
influenced by:
Body surface area/ body weight
Cardiac output
Drug-drug interactions (renal or hepatic) Extraction ratio/ blood flow
Genetics
Plasma protein binding Hepatic and renal function
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Importance of ClT
Computation of the maintenance dose
Determine or predict the duration of action
of a drug
good orb
ad outcome
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Bioavailability
Measurement of the rate & extent
(amount) to which the active ingredient or
active moiety becomes available at the
site of action
Measure of the rate & extent of
therapeutically active drug that is
systemically absorbed
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For drugs not intended to be
absorbed in the bloodstream
Bioavailability may be assessed by
measurements intended to reflect the rate
& extent to which the active ingredient or
active moiety becomes available at the
site of action
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Pharmacokinetic studies in
determining bioavailability
Acute pharmacologic effect
Plasma drug concentration
Urinary drug excretion Comparative clinical trials
In vitro measurements ofbioequivalence
(e.g. dissolution testing)
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Acute pharmacologic effects
Changes in BP, heart rate, clotting time
Used if there is no assay for plasma drug
conc. is availab
le Used if the plasma conc.______________
to the pharmacologic response
Quantitation of pharmacologic effect
versus time profile can be used as a
measure
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Acute pharmacodynamic effect
Onset time
Intensity (proportional to what??)
Duration of action Therapeutic window
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Plasma drug concentration
tmax
Cmax
AUC
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Plasma-level time curve
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Urinary drug excretion
Is most accurate if the active therapeuticmoiety is __________________________
Assumed that a drug is eliminated by
______-order kinetics Cumulative amount of active drug
excreted in the urine (DU) - extent of
systemic drug ab
sorption Rate of drug excretion in the urine(dDU /dt)
rate of systemic drug absorption
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Urinary drug excretion
Time of the drug to be completely excreted
(t ) total time of the drug to be
systemically absorbed and completely
excreted after administration
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Correlating the plasma drug conc.
with cumulative drug excretion
C drug is completely eliminated, plasma
conc. approaches zero, max. amt. of drug
excreted in the urine
B max. rate of drug excretion, A & C
minimum rate of drug excretion
Proof: ClT = dDu/dt
Cp
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Correlating the plasma drug conc.
with cumulative drug excretion
Graph comparing rate of drug excretion
with plasma-level time curve of the same
drug appearance???
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Plasma data Urine data
t max t infinity
C max dDu/dt max
AUC Du at infinity
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Extent of drug bioavailability decreases
Plasma data Urine data Change
t max t infinity same
Cmax dDu/dt max
AUC Du at infinity
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Rate of drug bioavailability decreases
Plasma data Urine data Change
t max t infinity
Cmax dDu/dt max
AUC Du at infinity same
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Comparative clinical trials
Can be used to measure bioavailability
quantitatively
Highly v_________ and less precise than
other methods because of individual
differences in drug pharmacodynamics
and subjective measurements
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In vitro measurements
Rate of drug dissolution in vitro for certain
drug products correlate with drug
bioavailability in vivo (if it is stastically
adequate to be used as a predictor)
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Loading dose
Loading dose = Vd x Cp
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Maintenance dose
Intended to sustain a certain plasma conc.
(Ctarget)
Administered as a constant rate infusion
Ctarget = MD/Cl MD = R = Ctarget x Cl
MD = Ctarget x Cl x X
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Multiple doses
Drugs are given intermittently in a multiple-
dosage regimen for continuous or
prolonged therapeutic activity
Regimen is used to treat chronic diseases
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Multiple doses
If drug doses are given frequently before
the previous dose is completely eliminated
plasma drug conc. accumulate and
increase to a steady-state level
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Multiple doses
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Multiple doses
AUC of a dosing interval at steady state is
equal to AUC of a single dose of the drug
At steady state, plasma drug conc.
fluctuates between a maximum (Cmax) and
minimum (Cmin) value
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Multiple doses
When a multiple-dose regimen is
designed, only the dosing rate can be
adjusted easily
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Dosing rate
R = Dose
dosing interval
R = Do
X
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Dosing rate
Based on the size of the dose (Do) and
the interval between the doses (X) or the
frequency of dosing
As long as the dosing rate is the same, the
expected average drug conc. at steady
state (Cave) is the same
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Dosing rate
600 mg dose is given every 12 hour:
dosing rate 600 mg/12 hrs or 50 mg/hr
Dose: 300 mg every 6 hr or 200 mg every
4 hr also gives the same dosing rate (50
mg/hr) with the same expected Cave;
however, the Cmax and Cmin values will bedifferent
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Dosing rate
For a larger dose given over a longer
interval (e.g. 600 mg every 12 hr), the Cmaxis higher and the Cmin lower compared with
a smaller dose given more frequently (e.g.200 mg every 4 hr)