Transcript in 4-5 half

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. Repeated administration of drugs
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 that 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.
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)
Clinical importance of clearance
•Determines the maintenance dose
•Drugs eliminated mainly through the
kidney need measures (e.g. dosage
adjustment) in renal insufficiency
•Drugs eliminated mainly through the liver
need protective measures in liver
insufficiency
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
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)
[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 - 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
This time 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
STEADY STATE
attained after 4-5 half-lifes
FLUCTUATIONS
• proportional to dose intervals
• blunted by slow absorption
STEADY-STATE CONCENTRATIONS
proportional to dose
t1/2
Fluctuations of concentrations are
the bigger the longer are intervals
between administrations (of parts of
total dose)
Time (h)
Administration of parts of total dose at
short intervals
• produces smaller fluctuations of drug
concentrations (levels)
• an omission of a particular dose*
does not need to cause an undesirable
fall in drug concentrations (levels)
*noncompliance
How to reduce fluctuations in drug
concentrations?
by administering:
• The total dose in parts at short intervals –
mostly inconvenient
• Sustained-release preparations, infusions
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)
Effects of drug
• correlate with plasma concentrations
Therapeutic Drug Monitoring (TDM)
• do not correlate with plasma concentrations
- „hit and run“
- tolerance or sensitisation
- active metabolites