Practicals: pharmacokinetics
MUDr. P. Potměšil, Ph.D.
1) Quiz
2) Clin. examples and solutions
3) Demonstrations in computer
programme
4) Theory
Quiz – questions
1/ What is a biological half-life of
drug ?
Quiz – answers, explanations
1/ What is a biological half-life of
drug?
After one half-life the concentration of
drug will have fallen to half of the initial
concentration;
after two half-lives it will have fallen to
one quarter of the initial concentration
and so on.
Quiz – questions
2/ What is a biological availability
(bioavailability)
Quiz – answers, explanations
2/ What is a biological availability
(bioavailability)
Bioavailability is the fraction of the
administered dose of a drug that
reaches the systemic circulation.
Quiz – answers, explanations
2/ What is a bioavailability
Bioavailability can be calculated by
comparing the plasma concentration
achieved by giving an i.v. dose with
the plasma concentration over time
following administration of the same
dose of a drug given orally.
Rate of drug absorption and first-pass
metabolism in the liver are main influences
on bioavailability.
Quiz – questions
3/ What is a distribution volume?
Quiz – answers, explanations
3/ What is a distribution volume?
The volume in which a drug would
need to be uniformly distributed to
produce the same concentration
throughout the body as found in
plasma.
Vd = Dose / concentration in plasma
Distribution volume
(apparent)
Vd is arbitrary value useful as a
guide when comparing the
relative concentration of the
drug in plasma with the rest of
the body and should not be
thought of as an actual physical
volume of fluid.
Distribution volume
Low Vd indicates drug is mainly
distributed in plasma, larger
indicates drug has been
distributed to additional
compartments.
Features of drugs that cause them to
predominate in each fluid compartment
Intravascular (plasma = 4L)
Interstitial fluid (14 L)
• High mol. weight,
bound to albumin:
Warfarin
Benzodiazepines
Penicilin
• Low mol. weight,
hydrophilic
Epinephrine
Features of drugs that cause them to
predominate in each fluid compartment
Intracellular ( = 42L)
Tissue binding (49 L)
• Low mol. Weight,
hydrophobic:
ethanol
• Binds to high affinity
site in tissues, high
lipid solubility
Digoxin
Tetracyclines
Quiz – questions
4/ What is TDM?
Quiz – answers, explanations
4/ What is TDM?
Therapeutic drug monitoring
For ex.:
• Digoxin (inotropic drug)
• Gentamicin (aminoglycoside antibiotic)
• Valproate (antiepileptic, mood stabiliser)
• Lithium (mood stabiliser)
Clinic example 1:
• A 53 yrs old man has swollen ankles,
shortness of breath, fatigue upon mild
exercise.
• He is observed:
- severe pitting edema of lower extremities,
distended neck veins with prominent pulsation
- Sinus tachycardia 105 beats/min. at rest,
normal blood pressure
• He is diagnosed as being in congestive heart
failure
• renal function is normal (creatinine CL=115 mL/min)
Clin. Example 1 - continued
• If treatment is begun with oral digoxin
(inotropic drug) with a maintenance dose
0,25mg once daily how long should you
wait before increasing the dose if his
initial response appears inadeaquate?
• You know that biological half-life of
digoxin is approx. 36 hours.
a/ approx. 2 hours
b/ approx. 1 day
c/ approx. 2 days
d/ approx. 1 week
Clin. Example 1 - solution
• Summary of dosing regimen with digoxin
without use of loading dose
•
•
•
•
Initial (starting) dose 0,25mg
Maintenance dose 0,25mg
Dosing interval: 24 hrs. (once daily)
Biol. half life approx. 36 hrs. (1,5 day)
Calculation: steady state concentration wil
be in plasma after time of 4-5 biol. half-lives
4 x 36/ 24 = 6 days
Correct answer in test is:
d/ approx. 1 week
Clin. Example : solution using programme
PK-SIM
Graph of digoxine dosing without loading dose
(in programme PK-SIM)
Dosing of digoxine with loading dose,
normal renal function (progr. PK-SIM)
Graph of digoxine dosing with loading dose
normal renal function (in progr. PK-SIM)
Graph of digoxine dosing with loading dose,
if renal failure is present (progr. PK-SIM)
Graph of digoxine dosing with reduced loading and
maintenance dose and prolonged dosing interval,
severe renal failure is present
Graph of digoxine dosing with reduced loading and
maintenance dose and dosing interval 24 hrs,
severe renal failure is present
Clinical example 2:
• Cooperating patient with problems of
addiction to alcohol desires to try treatment
with acamprosate instead of disulfiram.
• How often should be appropriate to use
acamprosate, if we know that biol. half-life
of acamprosate is approx. 13 hours?
• multiple choice test
a/ once daily
b/ twice daily
c/ three times daily
Accumulation: dose, dose interval
and fluctuation of plasma level
Plasma concentrations of drugs
with irregular dosing
Genetic variants in PK
Where can be PK data found?
• In section 5.2 „Pharmacokinetic properties“
of SPC = summary of product
characteristics
5. Pharmacologic properties
5.1 Pharmacodynamic prop.
5.2 Pharmacokinetic prop.
• SPC is available on the EMA (european
medicines agency) web
www.ema.europa.eu or web pages of
marketing authorisation holder
Recommended literature
• Rang, Dale, Ritter:
Pharmacology 7ed., 2012
• Mark A. Simmons:
Pharmacology - an illustrated review,
2012
Acknowledgements and used literature
(information sources)
Lectures,
presentations:
• Prof. M. Kršiak
• MUDr. J. Šedivý, CSc.
• Prof. J. Bultas
Books:
• Lullman, Mohr:
Color atlas of
pharmacology, 2011
• M. A. Simmons:
Pharmacology illustrated review,
2012
Lecture on pharmacokinetics
M. Kršiak Department of Pharmacology, Third Faculty of Medicine,
Charles University in Prague, 2008
1. Fate of drugs in the body
1.1 absorption
1.2 distribution - volume of distribution
1.3 elimination - clearance
2. The half-life and its uses
3. The uses of the half-life
4. Plasma concentration-effect relationship
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION
ABSORBED
DISTRIBUTION
„HIDDEN“
ELIMINATED
ACTING
ELIMINATION
1.1 ABSORPTION
Depends on:
• lipid solubility
• ionization (depends on pH)
non-ionized (non-polar), local changes in the pH
• routes of administration
- per os
- presystemic elimination
FIRST-PASS EFFECT
- pharmaceutical technology
BIOAVAILABILITY, bioequivalence
- parenteral
FIRST-PASS EFFECT:
loss of a drug by a metabolism mostly in
the liver that occurs en route from the gut
lumen to the systemic circulation
e.g. in nitroglycerin, morphine
Clinical consequence of the first-pass effect:
• limited effect after oral administration
• great interindividual differences in dosage
BIOAVAILABILITY:
the proportion of drug that reaches the
systemic circulation
It is usually calculated from the AUC
(Area Under the Curve)
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION
ABSORBED
DISTRIBUTION
„HIDDEN“
ELIMINATED
ACTING
ELIMINATION
1.2 DISTRIBUTION
Depends on:
- membrane penetration
- protein binding
-plasma proteins
-tissue proteins
ONLY A FREE DRUG ACTS!
The bound drug is inactive.
Free and bound drug are in equilibrium.
Displacement: drug-drug interactions
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION
ABSORBED
DISTRIBUTION
„HIDDEN“
ELIMINATED
ELIMINATION
ACTING
1.3 ELIMINATION:
METABOLIC (biotransformation)
mostly in the liver
ENZYME INDUCTION/ INHIBITION
oxidase enzymes - cytochrom P450
(CYP2D6 etc)
GENETIC POLYMORPHISM
EXCRETION
kidneys metabolites or unchanged
(almost completely unchanged e.g. digoxin, gentamycin)
GIT... enterohepatic circulation
e.g. tetracyclines
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION depends on
- membrane penetration which depends on
ABSORBED
-lipid solubility
DISTRIBUTION depends
on:
- ionization (depends on pH)
„HIDDEN“
- routes of administration
FIRST-PASS EFFECT BIOAVAILABILITY
- membrane penetration
- protein binding
ELIMINATED
ONLY A FREE DRUG ACTS!
ELIMINATION
ACTING
- metabolic
- excretion
VOLUME OF DISTRIBUTION
Depends on:
protein binding
-plasma proteins
-tissue proteins
ONLY A FREE DRUG ACTS!
The bound drug is inactive.
Free and bound drug are in equilibrium.
Displacement: drug-drug interactions
VOLUME OF DISTRIBUTION
Vd = Amount of drug in body / Concentration of drug in plasma
Because the result of the calculation may be a volume greater than that of
the body, it is an APPARENT (imaginary, not actual) volume
For example, Vd of digoxin is about 645 liters for a 70 kg man (i.e. about 9
times bigger than his actual volume)
Clinical importance of volume of distribution:
• When Vd of a drug is big it takes long time to
achieve effective plasma concentration of the drug.
•In such cases a loading dose may be given to boost
the amount of drug in the body to the required level.
This is followed by administration of lower
maintenance dose.
METABOLIC (biotransformation)
mostly in the liver
the drug is made more hydrophilic – this increases its
excretion in the urine
EXCRETION
mostly by the kidneys
metabolites or unchanged
GIT... enterohepatic circulation e.g. tetracyclines
CLEARANCE
Clearance (CL) is the volume of
plasma totally cleared of drug in unit
of time (ml/min/kg)
CLtot total
CLR renal
CLH hepatic
CLNR nonrenal (= Cltot - CLR)
Example – analogy
for utilization of information on volume of distribution (Vd) and clearance (CL):
Bathtube in a hotel
with two holes, no plugs,
and a plate indicating Vd= 1000 L, CL = 100 mL/min
How would you regulate supply of water (water tap) to fill the bath in order to
take a bath soon and for a longer time?
the half-life is the time taken for the
plasma concentration to fall by half
[plasmatic half-life]
t½
= 0,69 .
Volume of distribution
Clearance
In most drugs after therapeutic doses:
plasma concentration falls exponentially
Linear kinetics (First order)
The rate of elimination is
proportional to the concentration
[t 1/2 is stable]
In most drugs after therapeutic doses:
plasma concentration falls exponentially because elimination processes
are not saturated
Linear kinetics (First order)
Cmax
[some robustness to
dose increase]
Cmin
Elimination is the bigger the higher is
the level
The rate of elimination is
proportional to the concentration
Elimination processes are saturated e.g.:
in alcohol, after higher doses of phenytoin, theophyllin
Non-linear (Zero-order,
saturation) kinetics
The rate of elimination is constant
[unstable t 1/2 ]
For example, in alcohol the
rate of metabolism remains
the same at about 1 g of
alcohol for 10 kg of body
weight per hour
In a few drugs at therapeutic doses or in poisoning, elimination
processes are saturated
Cmax
[low robustness to
dose increase]
Cmin
elimination is constant,
limited
Non-linear (Zero-order, saturation) kinetics
Kinetics
Linear
(First-order)
Non-linear
(saturation,
zero-order)
Half-life
Robustness Predictability
(plasmatic)
to dose
for any
increase
therapeutic
dose
stable
good
good
unstable
poor
poor
T1/2 as a guide to asses:
1/ At a single-dose: duration of drug action
2/ During multiple dosing:
•to asses whether a drug is accumulated in the
body (it is - if the drug is given at intervals shorter
than 1,4 half-lifes) and
•when a steady state is attained (in 4-5 half-lifes)
3/ After cessation of treatment: to asses the time
taken for drug to be eliminated from the body (in 4-5
half-lifes)
[t1/2 = 1 - 2 h]
Ampicillin - single dose
THE USES OF THE HALF-LIFE
T1/2 as a guide to asses:
1/ At a single-dose: duration of drug action
2/ During multiple dosing:
• to asses whether a drug is accumulated in the
body (it is accumulated if the drug is given at
intervals shorter than 1,4 half-lifes) and
• when a steady state is attained (in 4-5 halflifes)
3/ After cessation of treatment: to asses the time
taken for drug to be eliminated from the body (in 4-5
half-lifes)
„PRINCIPLE OF 4-5 HALF-LIFES“:
If a drug is administered in intervals shorter than 1.4 half-life, then a
steady state is attained after approximately 4-5 half-lifes
The time to attain the steady state is independent of dose.
Steady state
t1/2
Why Stead State is attained after 4-5 half-lifes?
Attainment of steady state (SS) during multiple dosing of drug at intervals of 1 halflife
Interval
Administered
Initial plasma
concentration at
the beginning of
interval
microg/ml
Remains at
the end of
interval
microg/ml
[Eliminated
during
interval
microg/ml]
1.
100 mg
100
50
50
2.
100 mg
150
75
75
3.
100 mg
175
88
88
4.
100 mg
188
94
94
5.
100 mg
194
97
97
THE USES OF THE HALF-LIFE
T1/2 as a guide to asses:
1/ At a single-dose: duration of drug action
2/ During multiple dosing:
•to asses whether a drug is accumulated in the
body (it is - if the drug is given at intervals shorter
than 1,4 half-lifes) and
•when a steady state is attained (in 4-5 half-lifes)
3/ After cessation of treatment: to asses the time
taken for drug to be eliminated from the body (in 4-5
half-lifes)
Elimination of a drug during 5 half-lifes
of initial level
% of total elimination
REPEATED ADMINISTRATION OF DRUGS
TIME TO STEADY STATE (attained after 4-5 half-lifes)
independen of dose
FLUCTUATIONS
• proportional to dose intervals
• blunted by slow absorption
STEADY-STATE LEVELS (CONCENTRATIONS)
proportional to dose
t1/2
Steady-state concentrations are proportional to dose
Linear kinetics - diazepam
toxic
plasma concentrations
daily
therapeutic
daily
daily
Time (days)
Non-linear, saturation kinetics - phenytoin
plasma concentrations
toxic
daily
daily
therapeutic
daily
Time (days)
REPEATED ADMINISTRATION OF DRUGS
TIME TO STEADY STATE (attained after 4-5 half-lifes)
independen of dose
FLUCTUATIONS
• proportional to dose intervals
• blunted by slow absorption
STEADY-STATE LEVELS (CONCENTRATIONS)
proportional to dose
t1/2
How to reduce fluctuations in drug
concentrations?
by administering drugs slowly, continually, e.g.:
slow i.v. injection,
infusion,
sustained–release (SR) tablets,
slow release from depots
(e.g. from patches transdermally, depot antipsychotics injected i.m.)
or
by administering a total dose (e.g. a daily dose) in parts at shorter intervals
(mostly inconvenient)
Effects of drug
• correlate with plasma concentrations
Therapeutic Drug Monitoring (TDM) (eg. gentamicin, lithium, some
antiepileptics)
• do not correlate with plasma concentrations
- „hit and run“
- tolerance or sensitisation
- active metabolites
The *.ppt set of this lecture will appear at:
http://vyuka.lf3.cuni.cz
1st Teaching Unit (ID9234)