1. Distribution Siva Nageswararao Mekala Assistant professor
Dept. of clinical pharmacology
Faculty of medicine

2. DISTRIBUTION
Distribution is defined as the reversible transfer of drugs
between body fluid compartments
Depends upon lipid solubility of the drug, ionization at
physiological pH, extent of binding to plasma proteins, and
tissue proteins, blood flow to tissues.

3. Volume of Distribution
An abstract concept
Gives information on HOW the drug is distributed in the body
Used to calculate a loading dose

4. 3 L

5. Apparent volume of distribution (aVd):
aVd is defined as the hypothetical volume of the body fluid into which a drug
is uniformly distributed at a concentration equal to that in plasma ,assuming
the body to be a single compartment.
TOTAL AMOUNT OF DRUG IN THE BODY
aVd = ………………………………………………………..
CONCENTRATION OF THE DRUG IN PLASMA
Lipid insoluble drugs do not enter cells, so aVd is approximates ECF volume .
Drugs extensively bound to plasma proteins eg: warfarin, phenylbutazone, are largely restricted to vascular compartment and have low values

7. Clinical importance of Vd :
Aspirin Vd = L/Kg ; Pethidine Vd = 280 L/Kg
Hemodialysis is useful only for drugs with small volume of
distribution e.g. aspirin

8. Factors governing volume of distribution
1. Physicochemical properties of the drug:
Lipid soluble and unionized form of drugs readily cross the
cell membrane and are widely distributed.
Eg: Lignocaine ,Propranolol
2. Degree of plasma protein binding:
Drugs that are highly bound to plasma proteins have a low
volume of distribution
Eg: warfarin, phenytoin

9. 5. Fat : Lean body mass ratio: Highly lipid soluble drugs
3. Tissue storage :
Certain drugs can get sequestrated in some tissues. such drugs
have a large Vd
Eg: Digoxin is sequestrated in heart, muscle ,liver etc and has Vd
is 63L/Kg
4. Disease states:
The volume of distribution of drugs can be altered in certain
diseases
Eg: In CHF ,the Vd of some drugs can be increase due to increase in
ECF volume
5. Fat : Lean body mass ratio: Highly lipid soluble drugs
get distributed to the adipose tissue.

10. Redistribution
Highly lipid soluble drugs such as Thiopentone sodium , on I.V
administration immediately gets distributed to areas of high
blood flow such as Brain and causes general anesthesia .
Immediately with in a few minutes ,it recrosses the BBB and
gets distributed into the blood and then to the less perfused
tissues such as muscle and adipose tissue .
This is called redistribution ,which results in termination of
drug action.

11. Blood Brain Barrier (BBB)
The capillary boundary that is present between the blood and brain is called BBB
Barbiturates, diazepam, volatile anesthetics, amphetamine etc – cross BBB

12. The unique characteristics of brain capillary endothelial cells and pericapillary glial cells constitute the blood-brain barrier.
The lipid insoluble and ionized particles do not cross the BBB.
EG: Dopamine , Aminoglycosides
Meningitis, encephalitis - increase the permeability of the BBB
eg. penicillin in normal conditions has poor penetration
through BBB, but its penetrability increases during
meningitis and encephalitis.

13. Placental Barrier :
The lipid membrane between the mother and fetus is called placental barrier.
Unionized and lipid soluble drugs can freely cross the placental barrier. e.g. anesthetics, alcohol, morphine etc.
Quaternary ammonium compounds e.g.. d-TC and substances with high molecular weight e.g.. insulin cannot cross the placental barrier.
The fetal plasma is slightly more acidic than that of the mother (pH 7.0 to 7.2 versus 7.4), so that ion trapping of basic drugs occurs.

14. Certain drugs when given during pregnancy may cross the
placenta and cause various dangerous effects in the foetus
called teratogenic effect.
Eg: Thalidomide -Phocomelia
Tetracyclines – Yellowish discoloration of the teeth
Anti thyroid drugs – Foetal goiter

15. Plasma protein binding
To albumin
(Acidic drugs )
Barbiturates
Benzidiazepines
NSAIDS
Valproicacid
Phenytoin
Penicillins
Sulfonamides
Tetracyclines
Tolbutamide
Warfarin
To alpha 1 glycoprotein
(Basic Drugs )
Beta blockers
Bupivacaine
Lignocaine
Disopyramide
Imipramine
Methadone
Prazocin
Quinidine
Verapamil

16. Importance of plasma protein binding
1) high plasma protein binding drugs have lower volumes of
distribution .
2) bound fraction is not available for action but in equilibrium
with free drug in plasma.
3) high degree of plasma binding makes drug longer acting.

17. 4)generally expressed conc. of the drug refer to both bound
and free conc. of the drug.
5)one drug can bind to many sites of plasma protein and a
plasma protein can bind to many drugs.
6) Displacement of drugs is seen. More than one drug bing to the same site
on Albumin . The drug with higher affinity will displace the one having
lower affinity and may results in a sudden increase in the free
concentration of the drug with lower affinity .
E.g.: phenylbutazone and salicylates displace tolbutamide.
Indomethacin and phenyl butazone displace warfarin.

18. 7) pathological states like hypoalbuminemia binding is reduced
(severe liver disease or the nephrotic syndrome )
In cases of acute-phase reaction response (e.g., cancer, arthritis,
myocardial infarction, and Crohn's disease) lead to elevated levels of a1-
acid glycoprotein and enhanced binding of basic drugs.
Highly protein bound drugs have a longer duration of action and hence
difficult to remove.
In cases of poisoning, highly plasma protein bound drugs are difficult to be removed by Hemodialysis.

19. Tissue storage: Skeletal muscle,heart - digoxin,emetine
Liver choloroquine, Tetracyclines
Kidney chloroquine,digoxin
Thyroid iodine
Brain chlorpromazine, Isoniazid
Bone and teeth tetracyclines,metals
Adipose tissue thiopentone , ether