Transcript T 1/2 as a guide to asses

Charles University in Prague, Third Faculty of Medicine
Cycle II, Subject: General
Pharmacology
INTRODUCTION TO PHARMACOKINETICS
M. Kršiak
Department of Pharmacology, Third Faculty of Medicine,
Charles University in Prague,
2014-2015
http://vyuka.lf3.cuni.cz
CVSE3P0012 General Pharmacology
ID 15034
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION depends on
DISTRIBUTION-
ABSORBED
- membrane penetration depends on
-lipid solubility
Volume of distribution
- ionization (depends on pH)
- routes of administration
„HIDDEN“
-
depends on
membrane penetration
FIRST-PASS EFFECT, BIOAVAILABILITY
- protein binding (reversible)
ONLY A FREE DRUG ACTS!
ELIMINATED
ELIMINATION - Clearance
ACTING
- metabolic
- excretion
PRIMARY PHARMACOKINETIC PARAMETERS:
Volume of distribution, Clearance
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
per os:
paracetamol 90% > morphine 30% > buprenorphine ≈0%
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
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:
because elimination
processes are not saturated
plasma concentration falls exponentially
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
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 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
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
How to reduce fluctuations in drug
concentrations?
by administering drugs continually, e.g.:
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