principles of pharmacokinetics prof. kršiak department of pharmacology, third faculty of medicine,...
DESCRIPTION
ABSORPTION DISTRIBUTION ELIMINATION Clearance Volume of distribution WHAT HAPPENS TO DRUGS INSIDE THE BODY Administered Absorbed „Hidden“ Eliminated ActingTRANSCRIPT
Principles of pharmacokinetics
Prof. Kršiak
Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague
Cycle II, Subject: General pharmacology Lecture: 8th November 2012 8:00-9:30 , Syllaba Hall, Ruská
87, Prague
Charles University in Prague, Third Faculty of Medicine
1. Fate of drugs in the body1.1 absorption 1.2 distribution - volume of distribution1.3 elimination - clearance
2. The half-life and its uses
3. The uses of the half-life
4. Plasma concentration-effect relationship
M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague, 2008
ABSORPTION
DISTRIBUTION
ELIMINATION Clearance
Volume of distribution
WHAT HAPPENS TO DRUGS INSIDE THE BODY
Administered
Absorbed
„Hidden“
Eliminated
Acting
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
Depends on:
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)
VOLUME OF DISTRIBUTIONVd = Amount of drug in body / Concentration of drug in plasma
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
EXCRETIONkidneys 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)
Bathtube in a hotelwith 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?
Example – analogy for utilization of information on volume of distribution (Vd) and clearance (CL):
the half-life is the time taken for the plasma concentration to fall by half [plasmatic half-life]
Volume of distributiont ½ = 0,69 . Clearance
Linear kinetics (First order)
[t 1/2 is stable]
In most drugs after therapeutic doses: plasma concentration falls exponentially
The rate of elimination is proportional to the concentration
In most drugs after therapeutic doses:plasma concentration falls exponentially because elimination processes are not saturated
[some robustness to dose increase]
Elimination is the bigger the higher is the level
Cmax
Cmin
Linear kinetics (First order)
The rate of elimination is proportional to the concentration
Elimination processes are saturated e.g. in alcohol, after higher doses of phenytoin, theophyllin
[unstable t 1/2 ]
Non-linear (Zero-order, saturation) kinetics
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
The rate of elimination is constant
In a few drugs at therapeutic doses or in poisoning, elimination processes are saturated
elimination is constant, limited
Cmax
Cmin
Non-linear (Zero-order, saturation) kinetics
[low robustness to dose increase]
Kinetics
Half-life(plasmatic)
for anytherapeutic
dose
Robustnessto doseincrease
Predictability
Linear (First-order) stable good goodNon-linear(saturation,zero-order)
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
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 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)
THE USES OF THE HALF-LIFE
„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
Plas
ma
conc
e ntr
atio
n
Interval Administered Initial plasmaconcentration atthe beginning of
intervalmicrog/ml
Remains atthe end of
intervalmicrog/ml
[Eliminatedduringinterval
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
Attainment of steady state (SS) during multiple dosing of drug at intervals of 1 half-life
Why SS is attained after 4-5 half-lifes?
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)
THE USES OF THE HALF-LIFE
Elimination of a drug during 5 half-lifes
of initial level % of total elimination
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
REPEATED ADMINISTRATION OF DRUGS
Steady-state concentrations are proportional to dose
Linear kinetics - diazepamplasma concentrations
daily
daily
daily
Time (days)
toxic
therapeutic
Time (days)
therapeutic
toxic
plasma concentrationsNon-linear, saturation kinetics - phenytoin
daily
daily
daily
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
REPEATED ADMINISTRATION OF DRUGS
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.)
by administering a total dose (e.g. a daily dose) in parts at shorter intervals (mostly inconvenient)
or
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