Distribution of Drug
Distribution of drug start after a drug is absorbed, it is distributed to various body tissues and fluids. Drugs which easily pass through cell membrane achieve wide distribution. Drugs which do not pass through cell membrane are limited in their distribution. Movement of drug proceeds until an equilibrium is established between unbound drug in plasma and tissue fluids.
Apparent Volume of Distribution (V) of Drug:
Presuming that the body behaves as the single homogenous compartment, with volume V into which drug gets immediately and uniformly distributed.
The volume that would accommodate all the drug in the body, if the concentration throughout was the same as in plasma. Pathological states e.g. congestive heart failure, uracemia, cirrhosis of liver etc. can alter the V of many drugs by altering distribution of body water, permeability of membranes, binding of proteins or by accumulation of metabolites that displace the drug from binding sites.
Entry into Central Nervous System
Entry of drugs into central nervous system is limited by blood brain – barrier. It is a hypothetical barrier which exists between plasma and extracellular surface of brain. Only lipid soluble non ionized drugs readily pass trough this barrier. Example-dopamine does not enter into brain but its precursor levodopa can enter, so it is used in parkinsonism instead of dopamine.
Entry into Foetal Circulation
Entry of drugs into foetal circulation is restricted by blood – placental barrier. It is also a hypothetical barrier which exists between maternal and foetal circulation. It permits the entry of only lipid soluble and non ionized form of drug. E.g. morphine.
Plasma Protein Binding
Most drug possess physicochemical affinity for plasma proteins. Acidic drugs generally bind to plasma albumin and basic drugs to α1 acid glycoprotein. Example-
- Albumin α1 acid glycoprotein
- Barbiturates Bupivacaine
- NSAID’S Lignocaine
- Valproic acid Imipramine
- Sulphonamides Prazosin
- Tetracyclines Verapamil
The clinically significant of Plasma – Protein Bindings are:
- High degree of protein binding generally makes the drug long acting, because bound fraction is not available for metabolism or excretion.
- One drug can bind to many sites on the albumin molecule. Conversely, more than drug can bind to the same site. Drug bound with higher affinity will displace that bound with lower affinity. E.g. salicylates displace methotrexate.
A drug can get stored at different areas of body. Slow release of the drug from these areas can produce prolonged effects. E.g.
- Skeletal muscle and heart ——— Digoxin, Emetine.
- Liver ———————– Chloroquine, Mepacrine, Emetine, Tetracyclines
- Kidney ———————– Chloroquine, Digoxin, Emetine .
- Thyroid ———————– Iodine.
- Brain ———————– Chlorpromazine, Acetazolamide, Isoniazid.
- Retina ———————– Chloroquine.
- Iris ———————– Ephedrine, Atropine.
- Bone and teeth ——————- —- Tetracyclines, Heavy metals.
- Adipose tissue ——————– — Ether, Phenoxy Benzamine.
Factors Affecting Drug Distribution
- The distribution of drug can be affected by the following factors-
- Lipid water partition coefficient of the drug.
- Pka value of the drug.
- Degree of plasma protein binding.
- Affinity for different tissues.
- Disease like CHF and liver cirrhosis.