Plasma Half Life and factor affecting

2. Dr. Tayaba Farooq
PGT Pharmacology

3. The Half life (t1/2)is the time it takes for the drug plasma
concentration to be reduced by 50% to its original value
after reaching its peak.
t1/2 ≅ 0.693 X Vd/CL or
t1/2 = 0.7 X Vd/CL
t1/2 = Vd
t1/2 = 1/CL

4. Aspirin 4.3 hr
Digoxin 39hr
Diazepam 43 hr
Gentamicin 3hr
Lidocaine 1.8hr

5. The process of slow equilibration of the drugs
between body compartment that will produce a
prolongation of the half-life of the drug.

6. With prolonged dosing (or with high drug
concentrations), a drug may penetrate beyond the
central compartment into “deep” or secondary body
compartments that equilibrate only slowly with the
plasma.
When the infusion or dosing stops, the drug will be
initially cleared from plasma as expected but will
eventually drop to a point at which net diffusion from the
secondary compartments begins, and this slow
equilibration will produce a prolongation of the half-life of
the drug, referred to as the terminal half-life.

7. Gentamicin has a t1/2 of 2–3 h following a single
administration, but a terminal t1/2 of 53 h because drug
accumulates in spaces such as kidney parenchyma
(where this accumulation can result in toxicity).
Biliary cycling probably is responsible for the 120-h
terminal value for indomethacin.

8. Volume Of Distribution
Clearance
Type of kinetics

9. 1. VOLUME OF DISTRIBUTION
Plasma protein binding
Lipid solubility
Binding to tissue protein
Age
Pregnancy
Pathology CCF, Liver disease
Fat, lean body mass ratio

10. 2. CLEARANCE:
Kidney function
Liver function
Age
Enterohepatic circulation
3. TYPES OF KINETICS:
First order
Zero order

11. t 1/2 = 0.7 X Vd/CL
t1/2 will increase as long as the volume of distribution
remains unchanged.
For example, the t1/2 of diazepam increases with increasing
age; however, this does not reflect a change in clearance but
rather a change in the volume of distribution.

12. Clearance is the measure of the body’s capacity to eliminate
a drug;
For example, changes in protein binding of a drug (e.g.,
hypoalbuminemia) may affect its clearance as well as its
volume of distribution, leading to unpredictable changes in
t1/2 as a function of disease.
Most of the drugs are eliminated after 4-5 half lives

13. “A constant fraction (instead of amount) of a drug
is being absorbed, distributed, metabolized and
eliminated per unit time”
The rate of elimination is directly proportional to the
drug concentration.

14.  The metabolic transformation of drugs is catalysed by enzymes, and
most of the reactions obey Michaelis-Menten kinetics, where Km is
Michaelis constant (drug concentration at which rate of elimination is
50% of Vmax).
 .
 In most clinical situations, the concentration of the drug, [C], is much
less than the Michaelis constant, Km, and the Michaelis-Menten
equation reduces to

15. That is, the rate of drug metabolism and elimination is directly
proportional to the concentration of free drug.
This means that a constant fraction of drug is
metabolized per unit of time (that is, with each half-life, the
concentration decreases by 50%).
First-order kinetics is also referred to as linear kinetics.

17. This applies to majority of drugs which do not saturate the
elimination processes (transporters, enzymes, etc.) over the
therapeutic concentration range.
However, if the dose is high enough, elimination pathways of
all drugs will get saturated. Few drugs normally saturate
eliminating mechanisms and are handled by-Zero order
Kinetics

18. With a few drugs, such as aspirin, ethanol, and phenytoin,
the doses are very large. Therefore, [C] is much greater than
Km, and the velocity equation becomes.

19. The enzyme is saturated by a high free drug concentration,
and the rate of metabolism remains constant over time.
This is called zero-order kinetics (also called nonlinear
kinetics).
A constant amount of drug is metabolized per unit of
time & the rate of elimination is constant and does not
depend on the drug concentration.
Zero-order kinetics can also occur at high (toxic)
concentrations as drug-metabolizing capacity becomes
saturated.

21. ZERO ORDER KINETICS FIRST ORDER KINETICS
 Rate of elimination proportional
to plasma concentration.
 Constant fraction of drug
eliminated per unit time.
 Clearance can be estimated
 Half life is constant.
 Steady state concentration can
be achieved in 4 -5 half lives.
 Examples; most of drugs in
therapeutic doses.
 Constant rate of elimination
regardless of plasma
concentration.
 Constant amount of drug is
eliminated per unit time
 Clearance can not be estimated
 Half life is not constant,
increases with dose.
 Steady state concentration can
not be achieved in 4-5 half lives.
 Examples; alcohol above
10mg/dl, phenytoin and aspirin

22. Indicates how quickly a drug is removed from the plasma
Indicates duration of a drug action
Determines the frequency of dosing of the drug
Knowledge of half life prevents excess administration
causing toxicity.
Indicate the time required to reach steady state
concentration.

23. When the drug elimination (the product of clearance and
concentration) will equal the rate of drug availability
or
When the rate of drug administration equals the rate of drug
elimination.
steady-state concentration eventually will be achieved
when a drug is administered at a constant rate, dose &
interval

24. As noted, repeated administration of a drug more frequently
than its complete elimination will result in accumulation of
 the drug to or around a steady-state level.
When a constant dosage is given, reaching a steady-state
drug level (the desired therapeutic concentration) will take
four to five elimination half lives.

25. This period can be too long when treatment demands a more
immediate therapeutic response.
In such a case, one can employ a loading dose, one or a
series of doses given at the onset of therapy with the aim of
achieving the target concentration rapidly

26. The loading dose is calculated as
For IV infusion, the bioavailability is 100%, and the equation
becomes

27. For example, consider the case for treatment of arrhythmias
with lidocaine,
The t1/2 of lidocaine is usually 1–2 h.
Arrhythmias encountered after myocardial infarction may be
life threatening, and one cannot wait four half-times (4–8 h)
to achieve a therapeutic concentration of lidocaine by
infusion of the drug at the rate required to attain this
concentration.
Hence, use of a loading dose of lidocaine in the coronary
care unit is standard

29. The particularly sensitive individual may be exposed abruptly
to a toxic concentration of a drug that may take a long time to
decrease (i.e., long t1/2)
Loading doses tend to be large, and they are often given
parenterally and rapidly; this can be particularly dangerous if
toxic effects occur as a result of actions of the drug at sites
that are in rapid equilibrium with plasma.

30. This occurs because the loading dose calculated on the
basis of Vss subsequent to drug distribution is at first
constrained within the initial and smaller “central” volume of
distribution.
It is therefore usually advisable to divide the loading dose
into a number of smaller fractional doses that are
administered over a period of time.

31. It is dose of a drug required per unit time to maintain a
desired steady state level in the plasma in order to sustain a
specific therapeutic effect
In most clinical situations, drugs are administered in a series
of repetitive doses or as a continuous infusion to maintain a
steady-state concentration of drug associated with the
therapeutic window.

32. To maintain the chosen steady-state or target concentration,
the rate of drug administration is adjusted such that the rate
of input equals the rate of loss
This relationship is expressed here in terms of the desired
target concentration: