1. School of Pharmacy, University of Nizwa
Half Life of Drug, Volume of Distribution and Therapeutic Drug Monitoring
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture-11
October 19, 2011

2. Half Life of Drug
The duration of action of a drug is known as its half life
It is the time taken for a drug to become 50% of concentration
Biological half-life is an important pharmacokinetic parameter and is usually denoted by the abbreviation t½

3. Half Life of Drug 2 4 6 8 10 7.5 Conc. (mg/L) 5 2.5 time (h) 1.25
2.5 5
7.5 10 2 4 6 8
time (h)
Conc. (mg/L)
1.25
0.625

4. Use of Half Life
To predict how long it will take from the start of dosing to reach steady state levels (CSS)
Time for a drug to be removed from the body. It takes about 6 t½ for near complete elimination
Means to estimate the appropriate dosing interval
Can be used to predict how long it will take a drug concentration to decline from one specific value to another

5. Steady State Drug Levels
CSS of a drug is the concentration of the drug where the rate of absorption of drug into the systemic circulation is equal to the rate of elimination from the body
Two questions can be asked about achieving the steady-state
what is the relationship between the rate of drug infusion and the plasma concentration of drug achieved at the steady state?
Second, what length of time is required to reach the steady state drug concentration?

6. Multiple i.v. bolus dose administration : drug accumulation in plasma until the steady state is achieved
During multiple dosing or continuous IV infusion, it takes 4 t½ to reach CSS.

7. Immediately effective treatment
Use of a loading dose
Immediately effective treatment
The delay in reaching the CSS can be overcome by giving a loading dose e.g. digoxin. Loading Dose= Vd x desired Css

8. Volume of Distribution (Vd)
The Vd is a hypothetical volume of fluid into which the drug is disseminated
The apparent Vd: A drug rarely distribute into one of the water compartments of the body. Instead, the vast majority of drugs distribute into several compartments. Therefore, the volume into which drugs distribute is called the apparent Vd

9. Vd = Amount / Concentration in plasma
Vd=D/C, where D= total amount of drug in the body and C= concentration of drug in the plasma
Most drugs are distributed unevenly into the body. Some drugs (digoxin) are extensively distributed and bound in tissues, leaving low concentrations in the plasma, thus the body as a whole appears to have a large volume of distribution.

10. Water Compartments in the Body
Once a drug enters the body, it has the potential to distribute into any one of three functionally distinct compartments of body water
Plasma compartment
Extracellular fluid
Total body water

11. Plasma Compartment
If a drug has a very large molecular weight or binds to plasma proteins, it is too large to move out through the endothelial slit junctions of the capillaries and thus is effectively trapped within the plasma compartment.
Plasma volume is about 4% of the body weight or, in a 70-kg individual, about 3 L of body fluid.

12. Extracellular Fluid
If the drug has a low molecular weight, but is hydrophilic, it can move through the endothelial slit junctions of the capillaries into the interstitial fluid
However, hydrophilic drugs cannot move across the membranes of cells to enter the water phase inside the cell.
Extracellular fluid= Plasma water + Interstitial fluid
This is about 20% of the body weight, or about 14 L in a 70-kg individual

13. Total Body Water
If the drug has a low molecular weight and is hydrophobic, it can not only move through the slit junctions but can also move thought the cell membranes into the intracellular fluid
Total body water= Plasma water + Interstitial fluid + Intracellular fluid
This volume is about 60% of body weight, or about 42 L in a 70-kg individual.

14. Body water
Intra-vascular
Interstitial
Intra-cellular

15. Distribution - Evan’s Blue Intra-vascular space only

16. Distribution - Inulin Extracellular water

17. Distribution - Ethanol All water

18. Distribution - Evan’s Blue Intra-vascular space only
V = D/C
C is very high, so V is small (3 L)
Small V tells us drug does not tend to spread beyond the blood.

19. Distribution - Inulin Extracellular water
V = D/C
C is lower, so V is higher (14 L)
Higher V tells us some of the drug leaves the blood.

20. Distribution - Ethanol All water
V = D/C
C is even lower, so V is now quite high (42 L)
High V tells us much of the drug leaves the blood.

21. Distribution - Quinacrine Concentration into cells
V = D/C
C is very low, so V is enormous
Huge V tells us most of the drug leaves the blood.