Drug distribution: The reversible transfer of a drug between the blood and the extravascular fluids and tissues of the body.
Drugs come into the circulation after absorption. From plasma, drugs have to cross the capillary membrane to come to interstitial space. And then need to cross the cell-membrane to enter into the intracellular fluid.
Distribution is a passive process, for which, the driving force is concentration gradient between the blood and the extravascular tissues.
The process occurs by diffusion of free drugs only until equilibrium is achieved.
As the pharmacological action of a drug depends upon its concentration at the site of action, distribution plays a significant role in the onset, intensity and sometimes duration of drug action.
FACTORS AFFECTING DISTRIBUTION OF DRUGS:
Tissue Permeability of the Drug
Physicochemical Properties of the drug like Molecular size, pKa and o/w Partition coefficient.
Physiological Barriers to Diffusion of Drugs.
Organ / Tissue Size and Perfusion Rate
Binding of Drugs to Tissue Components
binding of drug to blood components
binding of drug to extracellular components
Miscellaneous Factors
Age, Pregnancy, Obesity, Diet, Disease states, and Drug Interactions…
Tissue Permeability of the Drug:
Off the many factors listed above, the two major rate-determining steps in the distribution of drugs are:
Rate of tissue permeation, and
Rate of blood perfusion.
If the blood flow to the entire body tissues is rapid and uniform, differences in the degree of distribution between tissues will be indicative of differences in the tissue penetrability of the drug and the process will be tissue permeation rate-limited.
Tissue permeability of a drug depends upon the physicochemical properties of the drug as well as the physiological barriers that restrict diffusion of drug into tissues.
A. Physicochemical Properties:
The physicochemical properties of drugs that influence drug distribution are,
Molecular size, pKa and o/w Partition coefficient.
Molecular size:
Mol wt less than 500 to 600 Dalton easily passes capillary membrane to extracellular fluid.
Entry of drug from ECF to cells is function of Mol size, ionization constant & lipophilicity of the drug.
Large mol size is restricted or requires a specialized transport system.
Degree of Ionization (pKa):
The pH at which half of a drug remains unionized is called pKa.
Most of the drugs are weak acids or bases & their degree of ionization depends upon pKa.
The PH of Blood plasma, extracellular fluid and CSF is 7.4(constant) except in acidosis and alkalosis.
All the drugs ionize at plasma pH (i.e. Polar, Hydrophilic Drugs) Can not penetrate the Lipoidal cell membrane hence the distribution is limited for such drugs.
o/w permeability:
Polar and hydrophilic drugs are less likely to cross the cell membrane.
Nonpolar and hydrophobic drugs are more likely to cross the cell membrane.
Only unionized drugs that are generally lipophilic can cross the cell membrane.
Among the drugs having the same o/w partition coefficient but differ in extent of drug Ionization, the drug which is less ionized is absorbed or has greater permeability than that of more ionized form.
Ex- Salicylic acid & phenobarbitone have same o/w Partition coefficient but phenobarbitone is more unionized and hence distributed rapidly.
B. PHYSIOLOGICAL BARRIERS:
Simple capillary endothelial barrier
Simple cell membrane barrier
Blood brain barrier
Blood CSF barrier
Blood placental barrier
Blood testis barrier
1. The simple capillary endothelial barrier
Capillaries supply the blood to the inner tissues.
All drugs ionized or unionized molecular size less than 600D diffuse through the capillary endothelium to interstitial fluid.
Only drugs that are bound to that blood component can’t pass through this barrier Because of the larger size of the complex.
2. Simple cell membrane barrier
Once the drug diffuses through capillary to extracellular fluid, its further entry into cells of most tissue is limited.
Simple cell Membrane is similar to the lipoidal barrier (absorption)
Nonpolar & hydrophilic drugs will pass through it (passively).
Lipophilic drugs with 50-600 D molecular size & Hydrophilic, Polar drugs with ‹50 D will pass this membrane
3. BLOOD-BRAIN BARRIER (BBB):
Unlike the capillary found in other parts of the body, the brain capillaries are made of tight junctions of capillary cells.
The brain capillaries consist of endothelial cells which are joined to one another by continuous tight intercellular junctions comprising what is called as the blood-brain barrier.
As a result the intercellular passage is blocked and for a drug to enter from capillary it has to pass THROUGH the cells rather BETWEEN them.
Since BBB is lipoidal barrier, it allows only the drugs having high o/w partition coefficient to diffuse passively.
3 different approaches have been utilized successfully to promote crossing the BBB by drugs:
a. use of permeation enhancers (dimethyl sulfoxide)
b. osmotic disruption of the BBB by infusing internal carotid artery with mannitol
c. using dihydropyridine redox system as drug carrier (active transport).
4. Blood-cerebrospinal fluid barrier:
The cerebrospinal fluid (c.s.f) is formed mainly by the choroid plexus and is similar in composition to the ECF of the brain.
Here the capillary endothelium that lines the c.s.f has open junctions, and drugs can flow freely into the extracellular spaces between capillary wall and choroidal cells.
But the choroidal cells are joined to each other by tight junctions forming the blood-csf barrier which has permeability characters similar to that of BBB.
Although the mechanism for diffusion of drugs into CNS and CSF is similar, the degree of uptake may vary significantly.
5. PLACENTAL BARRIER:
The maternal and fetal blood vessels are separated by a number of tissue layers made of fetal trophoblast basement membrane and the endothelium which together constitutes the placental barrier.
Many drugs having molecular weight of less than 1000 D and moderate to high lipid solubility can cross the barrier by simple diffusion process.
This shows that the placental barrier is not as effective a barrier as BBB.
6. BLOOD-TESTIS BARRIER:
This barrier is located not at the capillary endothelium level but at sertoli-sertoli junction; it is the tight junction between the neighboring sertoli cells that act as the blood-testis barrier.
This barrier restricts the passage of drugs to spermatocytes and spermatids.
C) ORGAN/TISSUE SIZE AND PERFUSION RATE:
Distribution is permeability rate-limited in the following cases:
a. When the drug under consideration is ionic, polar or water-soluble.
b. Where the highly selective physiological barriers restrict the diffusion of such drugs to the inside of the cell.
In contrast, distribution will be perfusion rate-limited when:
i. The drug is highly lipophilic.
ii. The membrane across which the drug is supposed to diffuse is highly permeable such as those of the capillaries and the muscles.
Perfusion rate is defined as the volume of blood that flows per unit time per unit volume of the tissue. It is expressed in ml/min/ml of the tissue.
D) BINDING OF DRUGS TO TISSUE COMPONENTS:
A drug in the body can bind to several components such as the plasma proteins, blood cells and hemoglobin (i.e. blood components) and extravascular proteins and other tissues.
E) Miscellaneous Factors:
1) Age:
Differences in distribution pattern of a drug in different age groups are mainly due to differences in:
a) Total body water-which is greater in infants.
b) Fat content-is also higher in infants and elderly.
c) Skeletal muscles-are lesser in infants and elderly.
d) Plasma proteins: low albumin content in both infants and elderly.
2) Diet:
A Diet high in fats will increase the free fatty acid levels in circulation thereby affecting binding of acidic drugs such as NSAIDS to Albumin.
3) Obesity:
In Obese persons, high adipose tissue content can take up a large fraction of lipophilic drugs.
4) Pregnancy:
During pregnancy the growth of the uterus, placenta and fetus increases the volume available for distribution of drugs.
5) Disease States:
Altered albumin or drug – binding protein conc.
Altered or reduced perfusion to organs /tissues
Altered Tissue pH
6) Drug Interactions:
Drug interactions that affect distribution are mainly due to differences in plasma protein or tissue binding of drugs.
Commonly Asked Questions.
Define Distribution of drugs, discuss various factors affecting distribution of drugs.
Write a short note on physiological barriers to distribution of drugs.