clinical pharmacokinetics half-life first-order elimination zero order elimination steady-state conc applied aspect of steady-state applied aspect of half-life advantage and disadvantage
2. Learning objectives-
To explain concept
Measurement and significance of kinetics of drug
elimination
Measurement and significance of half life
Measurement and significance of steady state conc
3. Clinical Pharmacokinetics….
Relation between concentration of the drug & its pharmacological
effects, as these change in time
Pharmacological effects :Desired /adverse effect
To know Quantitative relationship between dose &
effect
Adjust drug concentration in biological fluids through
changes in dosing
clinical
pharmacokinetics
Bioavailability, Volume of distribution,
Clearance, Elimination t1/2
Important
parameters
4. Linear/non-linear pharmacokinetics
Doses are increased for most drugs steady-state
concentrations increase in a proportional fashion
leading to linear pharmacokinetics
When steady-state concentrations change in a
disproportionate fashion after the dose is altered
nonlinear pharmacokinetics
5. Pharmacokinetics models
Compartmental model
Compartmental models are categorized by number of
compartments needed to describe drug's behavior in body
One- compartment, Two-compartment and
Multicompartment models
Compartments do not represent a specific tissue or fluid
but may represent a group of similar tissues or fluids
Models can be used to predict time course of drug
concentrations in body
6. one compartment model
• Drug is evenly distributed throughout the body into a single
compartment
• This model is only appropriate for drugs which rapidly and
readily distribute between the plasma and other body
tissues
8. Solid line shows serum concentration/time graph for drug
that follows one-compartment model PK
Dashed line represents serum concentration/time plot
for drug that follows two- compartment model PK after
intravenous bolus is given
9. Importance of two-compartment models
For many drugs multicompartment kinetics may be
observed for significant periods of time
Failure to consider distribution phase can lead to
significant errors in estimates of clearance and in
predictions of appropriate dosage
Also difference between "central" distribution volume is
important in deciding a loading dose strategy
10. Half life
• Amount of time over which drug conc.in plasma decrease to
one half of its original value
t1/2=0.693Vd/ Clearance
11. Plasma half life (t1/2)
• Generally it is measured by –
• The time to decline plasma concentration of a drug Plasma half life
(t1/2) of drug
• Time to decline conc. from 100 to 50 = 2 hr t1/2 of this drug is 2 hr
12.
13. Plasma half life (t1/2) of drug
Generally a drug will be completely eliminated
after 6 half lives-
After 1 half-life the conc. will be 50%
After 2 half-lives it will be 25%
After 3 half-lives 12.5% and
After 4 half-lives 6.25%
After 5 half-lives 3.125%
After 6 half-lives 1.56%
14. Why is half-life important ?
Half-life is a major determinant of
Duration of action after a single dose
Time required to reach steady state
Dosing frequency
Importance of( t 1/2 A)
Estimation of dosing schedule
It defines time interval between doses, and is very
important in design of infusion systems
Estimation of time to drug elimination
It gives idea to estimate time to total drug elimination
Generally most drugs will be eliminated in approximately
six half-lives
15. Kinetics of drug elimination
Rate and pattern of drug elimination follow
First order
Zero order
Mixed Order Kinetics
16. First order kinetics
Majority of the drugs follow this type of elimination
A constant fraction of the drug is eliminated at a constant
interval of time. eg: Plasma concentration declining at a rate
of 50% per two hours
100 µg/ ml 50 µg/ml
25 µg/ ml
12.5 µg/ml and so on
17. First order kinetics: (contd.)
Rate of drug elimination is directly proportional to the
plasma concentration eg: 200-> 100-> 50-> 25-> 12.5
so on
t ½ of any drug would always remain constant
irrespective of the dose
18. First order kinetics: (contd.)
Plasma concentration is plotted against time , the resultant
“ plasma fall-out curve” curvilinear
Log of plasma concentration are plotted against time
resultant curve - linear
19. Zero order kinetics
A constant or a fixed quantity of drug is eliminated per unit
time rate of elimination is independent of the concentration
of drug in plasma
Ethyl alcohol exhibit zero order at virtually all plasma
concentrations
For eg: if plasma concentration falls at a rate of 25 µg per
hour then 50mg
25mg
nil
t ½ of a drug following zero order is never constant
20. Zero order kinetics
If such a fall in plasma concentration is plotted against
time the resultant “plasma fall-out curve” is steeply linear
if logarithm of plasma concentration are plotted against
time then the curve becomes curvilinear
21.
22. Mixed Order Kinetics/ Saturation Kinetics
Dose-dependent kinetics - smaller doses are eliminated by
first order kinetics as plasma concentration reaches higher
values rate of drug elimination- zero order
Phenytoin, warfarin After a single dose administration if
plasma concentrations are plotted against time resultant
curve remains linear in beginning (zero order) and then
become predominantly exponential ( curvilinear i.e. first
order)
23.
24. Clinical Importance:
Drugs having very short half-life are given by constant i.v.
infusion to maintain steady state concentration
For drugs having longer t ½, with high Vd & slow rate of
clearance also are cumulative in nature
To reach steady state Loading dose given Maintenance
dose
Loading dose= Desired plasma conc. x aVd
25. Clinical Importance:
Digoxin 0.25 mg given/24 hour 5 days a week considering
its nature of accumulation
Lignocaine in cardiac arrhythmia- loading dose given
irrespective of shorter t ½
Loading dose also necessary in case of certain antibiotics
to keep the plasma conc. higher than MIC
26. Fixed-Dose Drug Combination
Rationale fixed-drug formulation of two drugs can be
advantageous drug should have equal t ½ Eg Cotrimoxazole
(Sulfamethoxazole [t ½ 11 hr]) & Trimethoprim [t ½ 10 hr]
Ratio of dose depends on aVd & plasma conc. Of individual
drug eg t ½ & Vd of Amoxycillin (1-2hr 0.21 L/kg) matches
with t ½ &Vd of Clavulanic acid (1-1.5hr 0.20 L/kg )
Advantage of Fixed-dose formulation
Convenient dose schedule
Better patient compliance
Enhanced effect
Minimal side effect
27. Steady State
Amount of drug administered is equal to amount of drug
eliminated within one dosing interval resulting in a plateau
or constant serum drug level
Drugs with short half-life reach steady state rapidly
Drugs with long half-life take days to weeks to reach
steady state
Drug bioavailability, clearance, dose, and
Dosing interval (the frequency of administration)
Why is it important ?
Rate in = Rate Out
Reached in 4 – 5 half-lives (linear kinetics)
29. Applied Steady State
Effective pharmacological management of diseases
Serum concentrations of antibiotics need to remain within a
clinically effective range for optimal treatment
Concentrations below range could fail to treat infections and
levels above range could cause toxicity
General anesthesia in totally intravenous anesthesia (TIVA)
of propofol and remifentanil are used to maintain a constant
blood concentration and therefore a predictable
concentration at site effector (brain)
30. Applied Steady State
longer half life high Vd and slow rate of clearance (Digoxin
40 hr),chloroquine (40hr 130L) need 5 half life to reach SSC
leads several days to achieve therapeutic range
If there is clinical emergency like CHF cause fatal for patient
in such case loading dose is required followed by MD to
achieve steady state
Drug very short half life (dopamine epinephrine) usually
given by a constant IV infusion to maintain steady state PC
31.
32.
33.
34. References
•PRINCIPLES of PHARMACOLOGY THE
PATHOPHYSIOLOGIC BASIS OF DRUG
THERAPY third edition by GOLAN
•13th edition 2018 Goodman & Gilman
•Rang and Dale 8th