Transcript in 4-5 half

Charles University in Prague, Third Faculty of Medicine
Cycle II, Subject: General pharmacology
Lecture: 8th November 2012 8:00-9:30 , Syllaba Hall, Ruská
87, Prague
Principles of pharmacokinetics
Prof. Kršiak
Department of Pharmacology, Third Faculty of Medicine,
Charles University in Prague
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
WHAT HAPPENS TO DRUGS INSIDE THE BODY
Administered
Absorbed
ABSORPTION
DISTRIBUTION
„Hidden“
Volume of distribution
Eliminated
Acting
ELIMINATION
Clearance
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
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
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 halflifes)
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 SS is attained after 4-5 half-lifes?
Attainment of steady state (SS) during multiple dosing
of drug at intervals of 1 half-life
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 halflifes)
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