Drug Distribution
It is the process by which the drug reversibly leaves the bloodstream and enters tissues.
it depends on:-
1- capillary permeability
determined by capillary structure and chemical nature of the drug.
-The capillary wall consists of an endothelial cell layer and abasement membrane enveloping the endothelial cell layer .Capillary structure varies widely in terms of the basement membrane that is exposed by slit (tight) junction between endothelial cells In the brain, the capillary structure is continuous, and there are no slit junctions The capillaries of the brain are surrounded by a thick lipid membrane. Polar and ionic hydrophilic drugs cross this barrier slowly In order to enter the brain, drugs must be actively transported through the endothelial cell so repass through the endothelial cells of the capillaries of the central nervous system (brainand spinal cord).
Ionized or polar drugs generally fail to enter the CNS, since they are unable to pass through the endothelial cells of the CNS.
-drug structure
The chemical nature of the drug strongly influences its ability to cross cell membranes. Hydrophobic drugs (lipophilic drugs),readily move across most biological membranes. The major factor influencing the hydrophobic drug's distribution is the blood flow to the area. By contrast, hydrophilic drugs, do not readily penetrate cell membranes and must go through the junctions of endothelial cells in capillary beds .Small drug molecules can freely diffuse out of the blood vessel while large drug molecules are confined to the plasma
2- blood flow
The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs.3- the degree of binding of the drug to plasma proteins
Albumin is the major drug-binding and may act as a drug reservoir , when the drug eliminated by metabolism or excretion the bound drug dissociate from protein.-volume of distribution
The volume of distribution is is the ratio of the amount of a drug in the body to its concentration in the plasma or blood.Amount of drug in the body (Q)
volume of distribution (Vd)= ------------------------------
Plasma drug concentration(C)
-large molecular weigh drug or extensively bind to plasma proteins drugs are too large to pass through capillaries and trapped within the plasma . in this case the drug distributes in plasma which is about 6% of the body weight ( 4L in 70 kg individual )
-low molecular weight & hydrophilic can move through capillaries slit junctions into interstitial fluid
however hydrophilic cannot pass through the lipid cell membrane to enter the water phase of the cell so this drugs distribute in the volume ( plasma water + interstitial fluid) (extracellular fluid ) about 20 % of the body weight ( 14 L in 70 kg individual)
-low molecular weight & hydrophobic can move through the endothelial slit junction into interstisial fluid and can pass through the cell membrane into the intracellular fluid the drug, therefore, distribute in the total body water about 60% of body weight (42L in 70kg individual)
-in pregnancy extremely lipid soluble drug distribute to placenta and thus increase Vd .
sometimes drug(2) can take the place of drug(1)that binds to the plasma proteins so the concentration of drug 1 will increase and may reach the toxic concentration .
-ex:-
1-Chloral hydrate ,clofibrate ,phenybutazone can displace coumarin which is anticoagulant so if we take any drug of this 3 drugs with Coumarin it will cause bleeding.
2-Salicylates can displace Tolbutamide which is a hypoglycemic drug so Hypoglycemic shock will happen if we take both drugs with each other.
-drugs of high Vd have high half-life .
4- the degree of binding of the drug to tissue proteins.
some drugs prefer to accumulate in specific tissues for ex:-Chlorpromazine prefer Brain
Digitoxin prefer Liver ,Kidney & Heart
Tetracycline prefer Bones & Teeth
Calcium prefer Collagen
Arsenic prefer Keratin
Iodine prefer Thyroid gland .... and so on
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