Half life of drugs

The time by which a means would come to its half is called the half of that
measure where the measure may be a) concentration of a drug b) effect of
a drug c) excretion of a drug. Thus the half life may be classified into 3
categories namely

1. Plasma half life

The time by which the concentration of a drug would come to its half is
called the plasma half life.

2. Biological half life

The time by which the effect of a drug would decline by one half is called
the biological half life.

With drugs that act competitively on receptors (alpha & beta

adrenoreceptor agonist & antagonists), this biological half life can be
provided with reasonable accuracy. However, with antimicrobials when
the number of infecting organisms & their sensitivity determine the
outcome, the biological half life cannot be provided.

3. Elimination half life

The time by which the excretion of a drug would come to its half is called
the elimination half life.

Half life is expressed by t1/2

Example: 4 mg of a drug is administered. Blood concentration becomes 2

mg (50%) after 10 minutes. So, plasma half life is 10 minutes.

In the simplest case & the most useful in designing drug dosage regimens-
the body may be considered as a single compartment of a size equal to the
volume of distribution Vd.
The time course of a drug in the body would be directly proportional to the
volume of distribution & inversely proportional to the overall rate of
clearance. The equation is written as

t1/2= (o.693 x Vd)/CL

The half-life of a drug in plasma or serum is frequently taken as indicating

the persistence of the drug in its volume of distribution; this interpretation
may be incorrect unless the material can move freely and rapidly from
one fluid compartment of the body to another, and is not bound or stored
in one or another tissue. The term "biological half-life" should not be used
instead of the specific terms "plasma half-life" or "serum half-life". The
tissue for which the half-life of a drug is determined should always be
specified, e.g., "serum half-life"; the half-life of a drug in muscle, kidney,
etc., or in the whole organism can be determined. Drug half-lives are
frequently based on the results of chemical analyses, i.e., the results of the
reaction of a reagent with a specific chemical group of a drug molecule; it
should be remembered that detection of the group per se does not
necessarily imply its continuous existence as part of a biologically active
drug.
A drug molecule that leaves the plasma may have any of several fates: it
can be destroyed in the blood; it can be eliminated from the body; or it can
be translocated to a body fluid compartment other than the intravascular
to be stored, bio-transformed, or to exert its pharmaco-dynamic effects.

When the plot of log plasma or serum concentration (during the period of
its decline) against time is composed of two straight line segments, the
inference may be made that two first order processes are involved in the
distribution and biotransformation and elimination of the drug. The
earlier phase - represented by the line segment of greater slope - is termed
the distributive phase, and corresponds to the period during which
translocation of the drug to its ultimate volume of distribution occurs and
is the dominant process; the later phase - represented by the line of lesser
slope - is termed the eliminative phase, and corresponds to the period
when biotransformation and elimination of drug are dominant processes.
For two-phase systems, three phase systems, etc., half-lives of the drugs in
the various phases can be determined only after more sophisticated
analysis of the data than that described above.

Figure 1 shows the time course of drug accumulation during a constant

rate drug infusion & the time course of drug elimination after stopping an
infusion that has reached steady state.

Disease states can affect both of the physiologically related primary

pharmaco kinetic parameters, volume of distribution & clearance. A
change in half life would not necessarily reflect a change in drug
elimination e.g. patients with chronic renal failure have decreased renal
clearance of digoxin but also a decreased volume of distribution; the
increase in digoxin half life is not as great as might be expected based on
the change in renal function. The decrease in volume of distribution is due
to the decreased renal & skeletal muscle mass & consequent decreased
tissue binding of digoxin to Na+/K+ATPase

Rule of Five

Generally, 5x the elimination ½ life = time at which the drug is

completely (97%) eliminated from the body (assuming that
The drug was given in a single original dose
1x ½ life - 50% of the original drug removed
2x ½ life - 75%
3x ½ life - 87.5%
4x ½ life - 93.75%
5x ½ life - 96.875%
Factors affecting Half Life

1. Routes of administration: If the routes are Oral, Subcutaneous & IM

then the plasma half life would be more.

2. Plasma protein binding: increases half life.

3. Tissue binding of drug: increases half life.

4. Metabolism of drug: decreases half life.

5. Excretion of drug: decreases half life.

6. Pathology in kidney & liver: increases half life.

7. Distribution of a drug: increases half life.

8. Amount of drug administered (dose):

Low dose Phenytoin t1/2 = 10-15 hrs

High dose Phenytoin t1/2 = >60 hrs

9: In infancy & old age: renal elimination & hepatic metabolism is

impaired if compared to other ages

Drugs Neonates Adults

Ampicillin 4h 1-2h

Gentamicin 18h 2h

Diazepam 25-10h 15-25h

10. Genetic factors:

Isoniazid Slow acetylators t1/2 = 3h

Isoniazid Fast acetylators t1/2 = 1.5h

Importance of plasma half life

1. It gives idea about a) duration of action of drugs b) Amount of drugs to

be administered c) frequency of administration d) management of drug
overdose

2. Useful in estimating time to steady state: approximately 4 half lives are

required to reach about 94% of a new steady state

3. Useful in estimating time required for drug removal from the body

4. Useful for estimation of appropriate dosing interval

Clinical situations resulting in increased half life of drug

The drug half life can be increased in the following conditions:

1. With diminished renal plasma flow e.g. a) cardiogenic shock b) heart

failure c) hemorrhage

2. With addition of 2nd drug which displaces the 1st from its plasma protein
binding by increasing the volume of distribution e.g. Digoxin+Quinine

3. In some kidney diseases

4. With decreased metabolism e.g. another drug inhibiting its

biotransformation (enzyme inhibitor)
Significance by comparing half lives of 2 drugs:

Let we consider two drugs of different half lives, 3hrs & 12 hrs
respectively. Now the following changes would be visible in the
comparing:

t1/2=12 hrs t1/2=3hrs

The conc. of drug in the plasma The conc. of drug in the plasma
would decline to half by 12 hrs would decline to half by 3 hrs

Slow absorption Rapid absorption

High plasma protein binding Less plasma protein binding

Slow metabolism Rapid metabolism

Less excretion Rapid excretion

Slow & sustained action Rapid action

Suitable in chronic case Suitable in emergency case

Good compliance Less compliance

Less frequency of administration High frequency of administration

More cumulative effect Less cumulative effect