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DRUG DISTRIBUTION BARRIERS AND PLASMA PROTIEN BINDING
Introduction

Once a drug has gained excess to the blood stream, the drug is subjected to a number of processes called as Disposition Processes that tend to lower the plasma concentration.
Distribution which involves reversible transfer of a drug between compartments.
Elimination which involves irreversible loss of drug from the body. It comprises of biotransformation and excretion.
DISTRIBUTION BARRIERS
THE SIMPLE CAPILLARY ENDOTHELIAL BARRIER

All the drug ,ionized or unionized, with a molecular size less than 600 daltons,it will diffuse through the capillary endothelium and into the interstitial fluid.
Only drugs bond to the blood components are restricted because of the large molecular size of complex.
SIMPLE CELL MEMBRANE BARRIER
Once a drug diffuses from the capillary wall into the extracellular fluid, it s further entry into cells of most tissues is limited by it s permeability through the membrane that lines such cells.
It is similar to the lipoidal barrier.
PENETRATION OF DRUGS THROUGH BLOOD BRAIN BARRIER
A stealth of endothelial cells lining the capillaries.
It has tight junctions and lack large intra cellular pores.
Further, neural tissue covers the capillaries.
Together , they constitute the BLOOD BRAIN BARRIER.
Astrocytes : Special cells / elements of supporting tissue are found at the base of endothelial membrane.
The blood-brain barrier (BB) is a separation of circulating blood and cerebrospinal fluid (CSF) maintained by the choroid plexus in the central nervous system (CNS).
Since BB is a lipoidal barrier,
It allows only the drugs having high o/w partition coefficient to diffuse passively where as moderately lipid soluble and partially ionized molecules penetrate at a slow rate. Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria ) and large or hydrophilic molecules into the CSF, while allowing the diffusion of small hydrophobic molecules (O2, CO2, hormones). Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins.
Various approaches to promote crossing BB:
Use of Permeation enhancers such as Dimethyl Sulfoxide.
Osmotic disruption of the BB by infusing internal carotid artery with Mannitol.
Use of Dihydropyridine Redox system as drug carriers to the brain ( the lipid soluble dihydropyridine is linked as a carrier to the polar drug to form a prodrug that rapidly crosses the BB )
PENETRATION OF DRUGS THROUGH PLACENTAL BARRIER
Placenta is the membrane separating Fetal blood from the Maternal blood.
It is made up of Fetal Trophoblast Basement Membrane and the Endothelium.
Mean thickness in early pregnancy is (25 ) which reduces to (2 ) at full term.
Many drugs having mol. wt. < 1000 Daltons and moderate to high lipid solubility e.g. ethanol, sulfonamides, barbiturates, steroids, anticonvulsants and some antibiotics cross the barrier by simple diffusion quite rapidly .
Nutrients essential for fetal growth are transported by carrier mediated processes.
Blood Cerebrospinal Fluid Barrier:
The Cerebrospinal Fluid (CSF) is formed mainly by the Choroid Plexus of lateral, third and fourth ventricles.
The choroidal cells are joined to each other by tight junctions forming the Blood CSF barrier which has permeability characteristics similar to that of BB.
Only high lipid soluble drugs can cross the Blood CSF barrier.
Blood Testis Barrier:
It has tight junctions between the neighboring cells of sertoli which restricts the passage of drugs to spermatocytes and spermatids.
PLASMA PROTEIN BINDING
PLASMA PROTIEN BINDING

Following entry of drug in to systemic circulation , the first thing with it can interact are blood components like plasma protein blood cells and hemoglobin .
BINDING OF DRUGS TO HUMAN SERUM ALBUMIN
The human serum albumin having a molecular weight of 65000 , is the most abundant plasma protein with a large drug binding capacity
Four different sites on HSA have been identified for drug binding :
Site 1 : warfarin and azapropazone binding site.
Site 2 : diazepam binding site.
Site 3 : digitoxin binding site.
Site 4 : tamoxifen binding site.
SITE 1 : WARFARIN AND AZAPROPAZONE BINDING SITE
It represents the region to which large number of drugs are bound ,
Example :
NSAIDs (phenyl butazone , indomethacin)
Sulphonamides
Phenytoin
Sodium valproate
SITE 2 : DIAZEPAM BINDING SITE.
Drug which bind to this region include :
Benzodiazepines
Medium chain fatty acids
Ibuprofen
Ketoprofen
Tryptophan
Cloxacilin , etc ..
Binding of drug to globulin
Binding of drug to blood cells
Clinically significant of plasma protein biding
Highly plasma protein bound drugs are largely restricted to the vascular compartment because protein bound drug does not cross membranes .they tend to have smaller volumes of distribution.
The bound fraction is not available for action. It is equilibrium with the free drug in plasma and dissociates when the concentration of the latter is reduced due to the elimination.thus,it is called as the storage of the drug.
High degree of protein binding generally makes the drug long acting, because bound fraction is not available for the metabolism or excretion, unless it is actively extracted by liver or kidney tubules.
We can increase the half life of the drug with using the plasma protein binding.
Generally expressed plasma concentrations of the drug refer to bound as well as free drug.