Pharmacokinetics Lecture: Clinical Applications and Dosage Regimens
Pharmacokinetics
Lec-4
Presented by
Oula Mohammed Sami
M.B.Ch.B/ MSc. Clinical pharmacology
Mainly used
post operation
… 1*3
Clinical situations resulting in changes in drug half-life
Patients who may have an
increase
in
drug half-life
(يتراكم بالجسم)
include those
with :
1)
Decreased metabolism
, for example, when a concomitant drug
inhibits
metabolism
or in
hepatic insufficiency
, as with
cirrhosis
.
2)
Diminished
renal or hepatic
blood flow
, for example, in cardiogenic shock, heart
failure, or hemorrhage
3) Decreased ability to extract drug from plasma (P.P.B), for example, in
renal disease
.
These patients may
require a decrease in dosage or less frequent dosing
intervals.
In contrast, the half-life of a drug may be
decreased
(يخرج بسرعة)
by
increased
hepatic
blood flow
,
increased metabolism
, or
decreased protein binding
.
This may
necessitate higher doses or more frequent dosing
intervals.
Design and Optimization of Dosage Regimen
Selection of a regimen depends on various
patient
and
drug factors
,
including how
rapidly therapeutic levels of a drug must be achieved.
Therapy may consist of a
single dose
of a drug, for example, a
sleep-inducing agent
,
such as
zolpidem
.
More commonly
, drugs are
continually administered
, either as an
IV infusion
(Continuous)
or in
IV or oral
fixed-dose/fixed-time interval regimens (repeated
administration
)
(for example, “one tablet every 4 hours”).
Continuous
or
repeated administration
results in
accumulation
of the drug until
a
steady state occurs.
Steady-state concentration
is reached when
the rate of drug
elimination is equal to the rate of drug administration
, such that plasma and tissue
levels
remain relatively
constant
.
Continuous infusion regimens
With continuous IV infusion,
the rate of drug entry into the body is constant
.
Most
drugs
exhibit
first-order
elimination, that is, a
constant fraction
of the drug is
cleared per unit of time.
Therefore, the rate of drug
elimination increases proportionately
as the plasma
concentration increases.
Following initiation of a
continuous IV infusion
, the plasma
concentration of a drug
rises until a steady state
(rate of drug
elimination equals rate of drug administration) is reached,
at which
point the plasma concentration of the drug remains constant.
Influence of infusion
rate
on steady-state concentration
•
The steady-state plasma concentration
(Css)
is
directly
proportional
to the
infusion rate. For example,
if the infusion rate is doubled, the Css is doubled.
•
Furthermore, the
Css is
inversely
proportional to the clearance of the drug
. Thus,
any factor that
decreases clearance
, such as liver or kidney disease,
increases the
Css of an infused drug
(assuming Vd remains constant). Factors that
increase
clearance, such as increased metabolism, decrease the Css . ( t1/2 … CL)
Ro = rate of drug infusion
Css = steady-state concentration.
تسريع قطرات جهاز الاعطاء لا
يؤثر على الوقت وانما على التركيز
للوصول الى الفائدة الدوائية
Time to reach steady-state drug concentration
The
concentration
of a drug rises from
zero at the start of the infusion
to
its ultimate steady-
state level,
Css
.
The
rate constant for
attainment of
steady state
is the
rate constant for
total body
elimination
of the drug.
Thus, 50% of Css of a drug is observed after the time elapsed, since the infusion, t, is equal to
t1/2 , where t1/2 is the time required for the drug concentration to change by
50%.
After another half-life, the drug concentration approaches
75%
of Css . The drug concentration
is
87.5%
of Css at 3 half-lives and
90% at 3.3 halflives.
Thus, a drug reaches steady state in about 4 to 5 half-lives
The sole determinant of the rate that a drug achieves steady state
is the
half-life (t1/2 )
of the
drug, and this rate is influenced only by factors that affect half-life.
The rate of approach
to steady state is
not affected by the rate of infusion.
When the infusion is stopped
, the
plasma concentration of a drug declines
(washes out)
to zero with the same time course observed in approaching steady state
.
pharmacokinetic study of a new antihypertensive drug is being
conducted in healthy human volunteers. The
half-life of the drug
after
administration
by continuous intravenous infusion
is
12
hours
.
Which of the following best approximates the
time
for the drug to
reach steady state
?
. 24 hours
B. 48 hours
C. 72 hours
D. 120 hours
E. 240 hours
Fixed-dose/fixed-time regimens
Administration of a drug by fixed doses rather than by continuous infusion is often more
convenient
. However, fixed doses of
IV or oral
medications given at fixed intervals result in
time-dependent
fluctuations
in the circulating level of drug, which contrasts with the
smooth
ascent of drug concentration with
continuous
infusion
.
Multiple IV injections
When a drug is given
repeatedly at regular intervals
, the plasma
concentration increases until a steady state is reached . Some drug from the first dose
remains in the body when the second dose is administered, some from the second dose
remains when the third dose is given, and so forth.
Therefore, the drug accumulates until,
within the dosing interval, the rate of drug elimination equals the rate of drug
administration and a steady state is achieved at 4-5 t 1/2
(Rule of five)
Effect of dosing frequency
With
repeated administration
at regular intervals, the plasma
concentration of a drug oscillates
about a mean. Using
smaller doses
at shorter intervals
reduces the amplitude of fluctuations
in drug
concentration. However, the
dosing frequency
changes
neither
the
magnitude of Css
nor
the
rate of achieving Css
.
Example of achievement of steady state using different dosage
regimens
Curve B shows the amount of drug in the body when 1 unit of a drug is administered IV and
repeated at a dosing interval that corresponds to the half-life of the drug.
At the end of the
first dosing interval, 0.50 units of drug remain from the first dose when the second dose is
administered.
At the end of the second dosing interval, 0.75 units are present when the third
dose is given. The minimal amount of drug remaining during the dosing interval progressively
approaches a value of 1.00 unit, whereas the maximal value immediately following drug
administration progressively approaches 2.00 units. Therefore, at the steady state, 1.00 unit
of drug is lost during the dosing interval, which is exactly matched by the rate of
administration.
That is, the “rate in” equals the “rate out.”
As in the case for IV infusion,
90%
of the steady-state value is achieved in 3.3 half-lives.
Most drugs
administered on an
outpatient
basis are
oral
medications taken at a specific
dose one, two, or more times
daily. In contrast to IV injection,
orally administered drugs may be
absorbed slowly
, and the
plasma
concentration of the drug is
influenced by both the rate of
absorption and the rate of
elimination
Multiple oral administrations
Optimization of dose
If the therapeutic window of the drug is small (for example,
digoxin
or
lithium
), extra
caution
should be taken in selecting a
dosage
regimen, and
drug levels should be monitored to
ensure
attainment of the therapeutic range.
Drug regimens are administered as a
maintenance dose
and may
require a
loading
dose if rapid effects are warranted
Loading dose
Sometimes
rapid
obtainment of
desired plasma levels is needed
(for example, in
serious
infections or arrhythmias
). Therefore, a “loading dose” of drug is
administered to achieve the desired plasma level
rapidly
,
followed by a maintenance
dose to maintain the steady state .
Loading dose = (Vd ) × (desired steady-state plasma concentration)/F
Disadvantages of loading doses include increased risk of drug
toxicity
and a longer
time for the plasma concentration to fall if excess levels occur.
Maintenance dose
Drugs are generally administered to
maintain
a Css within the therapeutic
window.
It takes 4 to 5 half-lives for a drug to achieve Css
.
To achieve a given concentration, the
rate of administration and the rate of
elimination
of the drug are important.
The dosing rate can be determined by knowing the target concentration in plasma
(Cp), clearance (CL) of the drug from the systemic circulation, and the fraction (F)
absorbed (bioavailability):
A 64-year-old female patient (60 kg) is treated with
experimental Drug A for type 2 diabetes. Drug A is available
as tablets with an oral
bioavailability of 90%.
If the
Vd is 2
L/kg
and the desired
steady-state plasma concentration is
3.0 mg/L
, which of the following is the most appropriate
oral loading dose of Drug A?
A.
6 mg
B.
B. 6.66 mg
C.
C. 108 mg
D.
D. 360 mg
E.
E. 400 mg
loading dose = [(Vd ) × (desired steady-state plasma concentration)/F]. The Vd in this case is
corrected to the patient’s weight is 120 L. The F value is 0.9 (because bioavailability is 90%,
that is, 90/100 = 0.9). Thus, loading dose = (120 L × 3.0 mg/L)/0.9 = 400 mg.
Accumulation of drug administered orally without a loading dose and with a single oral
loading dose administered at t = 0.
Dose adjustment
For drugs with a defined therapeutic range,
drug concentrations
are measured, and
the
dosage
and
frequency
are adjusted to obtain the desired levels. When
determining a dosage adjustment,
Vd
can be used to calculate the amount of drug
needed to achieve a desired plasma concentration.
For example, assume a
heart failure patient
is not well controlled due to inadequate
plasma levels of
digoxin
.
Suppose the concentration of digoxin in the plasma is C1 and
the desired target concentration is C2 , a higher concentration.
The following calculation can be used to determine how much additional digoxin
should be administered to bring the level from C1 to C2 . (Vd )(C1 ) = Amount of drug
initially in the body (Vd )(C2 ) = Amount of drug in the body needed to achieve the
desired plasma concentration The difference between the two values is the additional
dosage needed, which equals Vd (C2 − C1 ).
A 74-year-old man was admitted to the hospital for treatment of
heart failure. He received 160 mcg of digoxin intravenously, and the
plasma digoxin level was
0.4 ng/mL
. If the desired plasma
concentration of digoxin for optimal therapeutic activity in heart
failure
is 1.2 ng/mL
, and the patient has an estimated
Vd
of 400 L
,
calculate the additional dose of digoxin needed for this patient to
achieve the desired plasma concentration.
A.
128 mcg
B.
B. 160 mcg
C.
C. 320 mcg
D.
D. 480 mcg
E.
E. 640 mcg
the desired plasma concentration can be calculated using the equation Vd (C2 – C1 ).
Pharmacogenetics
P
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a
r
m
a
c
o
g
e
n
e
t
i
c
s
:
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e
s
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o
f
g
e
n
e
t
i
c
f
a
c
t
o
r
s
t
h
a
t
u
n
d
e
r
l
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e
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a
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i
a
t
i
o
n
i
n
d
r
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g
r
e
s
p
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n
s
e
.
•
Genetic variations in enzymes
•
Genetic variations in immune system function
•
Polygenic effects
•
Others
Genetic variations in enzymes
Phase I enzymes:
CYP2C19 “poor metabolizers”
have a diminished antiplatelet effect,
clopidogrel
is a
prodrug
, and CYP2C19 activity is required to convert it to the active
metabolite.
Phase II enzymes:
diclofenac
, undergo extensive
glucuronidation
. Allelic variants of
UGT2B7appeared to predispose individuals to the formation and accumulation of
reactive diclofenac metabolites leading to
hepatotoxicity
.
Other enzymes :
Glucose 6-phosphate dehydrogenase
(G6PD) deficiency
is a
hereditary abnormality in the activity of an erythrocyte enzyme. This enzyme (G6PD),
is essential for assuring a normal life span for red blood cells. The deficiency may
provoke sudden destruction of RBCs and lead to hemolytic anemia with jaundice
following the intake of fava beans, infection and various drugs
aspirin
Sulfonamides
.
clopidogrel
(prodrug ) CYP2C19 active
↓
antiplatelet effect
diclofenac
, undergo extensive
glucuronidation
. Allelic variants of
UGT2B7
appeared
to predispose to
hepatotoxicity
.
Hypersensitivity reactions to various drugs can range from mild
rashes to severe skin toxicities. Among the worst hypersensitivity
reactions are liver injury, toxic epidermal necrosis (TEN), and
Stevens-Johnson syndrome (SJS). E.g.
Abacavir
is associated with SJS,
of unknown mechanism.
Genetic variations in immune system function
Warfarin
, a
vitamin K antagonist
, oral
anticoagulant
.
The pharmacologic action of warfarin is mediated through
inactivation of VKORC1
.
Individuals with
decreased VKORC1 expression
, are at increased
risk
for
excessive anticoagulation
.
Furthermore, patients with
reduced-function CYP2C9
genotypes are
at increased risk for
bleeding
due to decreased metabolic clearance.
Polygenic effects
Others
Malignant hyperthermia
: is autosomal
dominant
mutation
of the
ryanodine receptor (type1),
located within
skeletal
muscle cells that
stores
calcium
level .
Exposure to triggering agents
in these patients
may lead to unregulated passage of calcium from the sarcoplasmic
reticulum into the intracellular space, leading to an
acute malignant
hyperthermia crisis
.
It is triggered by the volatile inhalational anesthetic agents
(
halothane
) and the muscle relaxant
succinylcholine
.
Explore the pharmacokinetics lecture focusing on clinical implications such as changes in drug half-life in various patient conditions. Learn about dosage regimen design and optimization, including considerations for achieving therapeutic drug levels. Discover clinical situations requiring dosage adjustments and the importance of steady-state concentration in drug therapy.
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Presentation Transcript
Pharmacokinetics Lec-4 Presented by Oula Mohammed Sami M.B.Ch.B/ MSc. Clinical pharmacology
Mainly post 1*3 used operation
Clinical situations resulting in changes in drug half-life Patients who may have an increasein drug half-life with : ) ( include those 1) Decreased metabolism, for example, when a concomitant drug inhibits metabolism or in hepatic insufficiency, as with cirrhosis. 2) Diminished renal or hepatic blood flow, for example, in cardiogenic shock, heart failure, or hemorrhage 3) Decreased ability to extract drug from plasma (P.P.B), for example, in renal disease. These patients may require a decrease in dosage or less frequent dosingintervals. In contrast, the half-life of a drug may be decreased hepatic blood flow, increased metabolism, or decreased protein binding. ) ( by increased This may necessitate higher doses or more frequent dosing intervals.
Design and Optimization of Dosage Regimen Selection of a regimen depends on various patient and drug factors, including how rapidly therapeutic levels of a drug must be achieved. Therapy may consist of a single dose of a drug, for example, a sleep-inducing agent, such as zolpidem. More commonly, drugs are continually administered, either as an IV infusion (Continuous) or in IV or oral fixed-dose/fixed-time interval regimens (repeated administration) (for example, one tablet every 4 hours ). Continuous or repeated administration results in accumulation of the drug until a steady state occurs. Steady-state concentration is reached when the rate of drug elimination is equal to the rate of drug administration, such that plasma and tissue levels remain relatively constant.
Continuous infusion regimens With continuous IV infusion, the rate of drug entry into the body is constant. Most drugs exhibit first-order elimination, that is, a constant fraction of the drug is cleared per unit of time. Therefore, the rate of drug elimination increases proportionately as the plasma concentration increases.
Following initiation of a continuous IV infusion, the plasma concentration of a drug rises until a steady state (rate of drug elimination equals rate of drug administration) is reached, at which point the plasma concentration of the drug remains constant. 3.3 t1/2
Influence of infusion rate on steady-state concentration The steady-state plasma concentration (Css) is directly proportional to the infusion rate. For example, if the infusion rate is doubled, the Css is doubled. Furthermore, the Css is inversely proportional to the clearance of the drug. Thus, any factor that decreases clearance, such as liver or kidney disease, increases the Css of an infused drug (assuming Vd remains constant). Factors that increase clearance, such as increased metabolism, decrease the Css . ( t1/2 CL) Ro = rate of drug infusion Css = steady-state concentration.
Time to reach steady-state drug concentration The concentration of a drug rises from zero at the start of the infusion to its ultimate steady- state level, Css . The rate constant for attainment of steady state is the rate constant for total body elimination of the drug. Thus, 50% of Css of a drug is observed after the time elapsed, since the infusion, t, is equal to t1/2 , where t1/2 is the time required for the drug concentration to change by 50%. After another half-life, the drug concentration approaches 75% of Css . The drug concentration is 87.5% of Css at 3 half-lives and 90% at 3.3 halflives. Thus, a drug reaches steady state in about 4 to 5 half-lives The sole determinant of the rate that a drug achieves steady state is the half-life (t1/2 ) of the drug, and this rate is influenced only by factors that affect half-life. The rate of approach to steady state is not affected by the rate of infusion. When the infusion is stopped, the plasma concentration of a drug declines (washes out) to zero with the same time course observed in approaching steady state .
pharmacokinetic study of a new antihypertensive drug is being conducted in healthy human volunteers. The half-life of the drug after administration by continuous intravenous infusion is 12 hours. Which of the following best approximates the time for the drug to reach steady state? . 24 hours B. 48 hours C. 72 hours D. 120 hours E. 240 hours
Fixed-dose/fixed-time regimens Administration of a drug by fixed doses rather than by continuous infusion is often more convenient. However, fixed doses of IV or oral medications given at fixed intervals result in time-dependent fluctuations in the circulating level of drug, which contrasts with the smooth ascent of drug concentration with continuousinfusion. Multiple IV injections When a drug is given repeatedly at regular intervals, the plasma concentration increases until a steady state is reached . Some drug from the first dose remains in the body when the second dose is administered, some from the second dose remains when the third dose is given, and so forth. Therefore, the drug accumulates until, within the dosing interval, the rate of drug elimination equals the rate of drug administration and a steady state is achieved at 4-5 t 1/2 (Rule of five)
Effect of dosing frequency With repeated administration at regular intervals, the plasma concentration of a drug oscillates about a mean. Using smaller doses at shorter intervals reduces the amplitude of fluctuations in drug concentration. However, the dosing frequency changes neither the magnitude of Css nor the rate of achieving Css .
Example of achievement of steady state using different dosage regimens Curve B shows the amount of drug in the body when 1 unit of a drug is administered IV and repeated at a dosing interval that corresponds to the half-life of the drug. At the end of the first dosing interval, 0.50 units of drug remain from the first dose when the second dose is administered. At the end of the second dosing interval, 0.75 units are present when the third dose is given. The minimal amount of drug remaining during the dosing interval progressively approaches a value of 1.00 unit, whereas the maximal value immediately following drug administration progressively approaches 2.00 units. Therefore, at the steady state, 1.00 unit of drug is lost during the dosing interval, which is exactly matched by the rate of administration. That is, the rate in equals the rate out. As in the case for IV infusion, 90% of the steady-state value is achieved in 3.3 half-lives.
Multiple oral administrations Most drugs administered on an outpatient basis medications taken at a specific dose one, two, or more times daily. In contrast to IV injection, orally administered drugs may be absorbed slowly, and the plasma concentration of the drug is influenced by both the rate of absorption and the rate of elimination are oral
Optimization of dose If the therapeutic window of the drug is small (for example, digoxin or lithium), extra cautionshould be taken in selecting a dosage regimen, and drug levels should be monitored to ensure attainment of the therapeutic range. Drug regimens are administered as a maintenance dose and may require a loading dose if rapid effects are warranted
Loading dose Sometimes rapid obtainment of desired plasma levels is needed (for example, in serious infections or arrhythmias). Therefore, a loading dose of drug is administered to achieve the desired plasma level rapidly, followed by a maintenance dose to maintain the steady state . Loading dose = (Vd ) (desired steady-state plasma concentration)/F Disadvantages of loading doses include increased risk of drug toxicity and a longer time for the plasma concentration to fall if excess levels occur.
Maintenance dose Drugs are generally administered to maintain a Css within the therapeutic window. It takes 4 to 5 half-lives for a drug to achieve Css . To achieve a given concentration, the rate of administration and the rate of elimination of the drug are important. The dosing rate can be determined by knowing the target concentration in plasma (Cp), clearance (CL) of the drug from the systemic circulation, and the fraction (F) absorbed (bioavailability):
A 64-year-old female patient (60 kg) is treated with experimental Drug A for type 2 diabetes. Drug A is available as tablets with an oral bioavailability of 90%. If the Vd is 2 L/kg and the desired steady-state plasma concentration is 3.0 mg/L, which of the following is the most appropriate oral loading dose of Drug A? A. 6 mg B. B. 6.66 mg C. C. 108 mg D. D. 360 mg E. E. 400 mg loading dose = [(Vd ) (desired steady-state plasma concentration)/F]. The Vd in this case is corrected to the patient s weight is 120 L. The F value is 0.9 (because bioavailability is 90%, that is, 90/100 = 0.9). Thus, loading dose = (120 L 3.0 mg/L)/0.9 = 400 mg.
Accumulation of drug administered orally without a loading dose and with a single oral loading dose administered at t = 0.
Dose adjustment For drugs with a defined therapeutic range, drug concentrations are measured, and the dosage and frequency are adjusted to obtain the desired levels. When determining a dosage adjustment, Vd can be used to calculate the amount of drug needed to achieve a desired plasma concentration. For example, assume a heart failure patient is not well controlled due to inadequate plasma levels of digoxin. Suppose the concentration of digoxin in the plasma is C1 and the desired target concentration is C2 , a higher concentration. The following calculation can be used to determine how much additional digoxin should be administered to bring the level from C1 to C2 . (Vd )(C1 ) = Amount of drug initially in the body (Vd )(C2 ) = Amount of drug in the body needed to achieve the desired plasma concentration The difference between the two values is the additional dosage needed, which equals Vd (C2 C1 ).
A 74-year-old man was admitted to the hospital for treatment of heart failure. He received 160 mcg of digoxin intravenously, and the plasma digoxin level was 0.4 ng/mL. If the desired plasma concentration of digoxin for optimal therapeutic activity in heart failure is 1.2 ng/mL, and the patient has an estimated Vd of 400 L, calculate the additional dose of digoxin needed for this patient to achieve the desired plasma concentration. A. 128 mcg B. B. 160 mcg C. C. 320 mcg D. D. 480 mcg E. E. 640 mcg the desired plasma concentration can be calculated using the equation Vd (C2 C1 ).
Pharmacogenetics Pharmacogenetics: : the study of genetic factors that underlie variation in drug response. Genetic variations in enzymes Genetic variations in immune system function Polygenic effects Others
Genetic variations in enzymes Phase I Phase II others
Genetic variations in enzymes Phase I enzymes: CYP2C19 poor metabolizers have a diminished antiplatelet effect, clopidogrel is a prodrug, and CYP2C19 activity is required to convert it to the active metabolite. Phase II enzymes: diclofenac, undergo extensive glucuronidation. Allelic variants of UGT2B7appeared to predispose individuals to the formation and accumulation of reactive diclofenac metabolites leading to hepatotoxicity. Other enzymes : Glucose 6-phosphate dehydrogenase (G6PD) deficiency is a hereditary abnormality in the activity of an erythrocyte enzyme. This enzyme (G6PD), is essential for assuring a normal life span for red blood cells. The deficiency may provoke sudden destruction of RBCs and lead to hemolytic anemia with jaundice following the intake of fava beans, infection and various drugs aspirin Sulfonamides.
clopidogrel (prodrug ) CYP2C19 active antiplatelet effect
diclofenac, undergo extensive glucuronidation. Allelic variants of UGT2B7appeared to predispose to hepatotoxicity.
Genetic variations in immune system function Hypersensitivity reactions to various drugs can range from mild rashes to severe skin toxicities. Among the worst hypersensitivity reactions are liver injury, toxic epidermal necrosis (TEN), and Stevens-Johnson syndrome (SJS). E.g. Abacavir is associated with SJS, of unknown mechanism.
Polygenic effects Warfarin, a vitamin K antagonist, oral anticoagulant . The pharmacologic action of warfarin is mediated through inactivation of VKORC1. Individuals with decreased VKORC1 expression, are at increased risk for excessive anticoagulation . Furthermore, patients with reduced-function CYP2C9 genotypes are at increased risk for bleeding due to decreased metabolic clearance.
