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

1. ClinicalPK-steady state concentration
and half -life
Dr Kalpana Tiwari

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

7. Two compartment model.
•Drugs which exhibit a slow equilibration with
peripheral tissues, are best described

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

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

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)

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)

28. Steady State

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

34. References
•PRINCIPLES of PHARMACOLOGY THE
PATHOPHYSIOLOGIC BASIS OF DRUG
THERAPY third edition by GOLAN
•13th edition 2018 Goodman & Gilman
•Rang and Dale 8th