Factors Affecting the Drug Distribution

The drugs entered into the bloodstream is subjected to several processes called disposition processes, which tend to lower the plasma concentration of the drugs. 

The drug disposition processes are:

1. Distribution - This involves the reversible transfer of a drug between compartments.

2. Elimination - This involves irreversible loss of drug from the body by biotransformation and excretion.


Definition

Drug Distribution is the reversible transfer of a drug between one compartment (blood) to another (extravascular tissue).

Distribution is a passive process in which the driving force is the concentration gradient between the blood and the extravascular tissues.

This process occurs by diffusion of the free drug until equilibrium is attained. 

Distribution of a drug involves the following two steps:

Permeation of free drug present in the blood through the capillary wall & entry into the interstitial/extracellular fluid (ECF).

Permeation of drugs from ECF to intracellular fluid (ICF) through the membrane of tissue cell. This step is rate-limiting and depends on two factors:

Rate of Perfusion to the ECF, and

Membrane Permeability of the Drug.


    Factors affecting Drug Distribution

    The factors that affect drug distribution are as follows:

    1. Tissue Permeability of Drugs.

    a) Physicochemical Properties of the drug.

    b) Physiological barriers to the diffusion of drugs.

    2. Organ/tissue size and perfusion rate.

    3. Binding of drugs to tissue components.

    a) Binding of the drug to blood components

    b) Binding of the drug to extracellular components

    4. Miscellaneous factors.

    a) Age.

    b) Pregnancy.

    c) Obesity.

    d) Diet.

    e) Disease states.

    f) Drug interactions. 


    Tissue Permeability of Drugs

    Tissue permeability of drugs includes the following: 


    a) Physicochemical Properties of the Drug

    Physicochemical properties of the drug that influence distribution are: Molecular size, degree of ionization, partition coefficient, and stereochemical nature.


    Molecular Size

    The penetration of drugs from ECF to cells is the function of Molecular size, ionization constant & lipophilicity of drugs.

    Molecular weights less than 500 to 600 Dalton will easily pass the capillary membrane to the extracellular fluid.

    From extracellular fluid to cross the cell membrane through aqueous filled channels, need particle size less than 50dalton (small) with the hydrophilic property.

    A large molecular size is restricted or requires a specialized transport system.


    Degree of Ionization (pKa)

    The pH at which half of the drug is unionized is called pKa.

    The PH of Blood plasma, extracellular fluid, and Cerebrospinal Fluid is 7.4 (constant). Except in acidosis and alkalosis conditions, all the drugs ionize at plasma pH (i.e., Polar, Hydrophilic Drugs), and cannot penetrate the Lipoidal cell membrane.


    Partition Coefficient

    Hydrophilic and polar drugs are less likely to cross the cell membrane, whereas hydrophobic and nonpolar drugs are more likely to cross the cell membrane.

    In the case of polar drugs where permeability is the rate-limiting step, the driving force is the effective partition coefficient of a drug that can be calculated by the below formula:


    Effective Ko/w = Fraction unionized at pH 7.4 x Ko/w of unionized drug.


    Lipoidal drugs penetrate the tissue rapidly. 

    Among the drugs with the same Ko/w but different in ionization at blood pH, one with less ionization shows a better distribution. 

    E.g., Phenobarbital has better distribution than the salicylic acid since it is more unionized at blood pH and highly specialized than the salicylic acid even though both are having the same Ko/w.


    Stereochemical Nature

    The stereochemical nature of the drug will influence the distribution of the drug when it tends to interact with macromolecules like the proteins.

    Tissue localization of some drugs may be an indication of stereoselectivity in drug distribution.


    b) Physiological Barriers to Distribution of Drugs

    There are several physiological barriers that interfere with the distribution of drugs. They are:


    Simple Capillary Endothelial Barrier

    All drugs, both ionized or unionized with molecular size, less than 600dalton diffuse through the capillary endothelium to interstitial fluid.

    Only drugs that are bound to the blood components can't pass through this barrier because of the larger size of the complex.


    Image Source: SlideShare | By Kailas Mail 


    Simple Cell Membrane Barrier

    Once the drug diffuses through capillary to the extracellular fluid, its further entry into the cells of most tissues is limited.

    The simple cell membrane is similar to the lipoidal barrier (absorption).

    Nonpolar & hydrophilic drugs will pass through it (passively).

    Lipophilic drugs with 50 to 600dalton molecular size & hydrophilic, Polar drugs with < 50dalton will pass this membrane.


    Image Source: SlideShare | By Kailas Mail 


    Blood-Brain Barrier

    The capillaries in the brain are highly specialized and less permeable to water-soluble drugs.

    Blood-Brain Barrier is the brain capillaries that consist of endothelial cells that are joined to one another by continuous tight intercellular junctions.

    The presence of special cells called pericytes and astrocytes at the base of the endothelial membrane acts as a supporting tissue. 

    The specific areas like the trigger area and the hypothalamic eminence of the brain do not have BBB. 



    A Solute passes the BBB by either of the following pathways:

    1. Passive diffusion through the lipoidal membrane - The drugs with high o/w partition coefficient diffuse passively but, the drugs with less or intermediate partition coefficient passes slowly.

    2. Active transport of essential nutrients like sugars and amino acids, hence the similar drugs can also pass the BBB by this mechanism.


    The different approaches that promote drugs to cross BBB are:

    1. Use of permeation enhancers like dimethyl sulphoxide (DMSO).

    2. Osmotic disruption of the BBB by infusion of mannitol into the internal carotid artery.

    3. Use of a carrier system like dihydropyridine redox system for delivery of steroidal drugs to the brain.


    Blood-Cerebrospinal Fluid Barrier

    The cerebrospinal fluid (CSF) which is formed by the choroid plexus of the lateral, third, and fourth ventricles & it is similar to the composition of ECF of the brain.

    The drug can flow freely into the extracellular space between the capillary endothelium wall and the choroid cells.

    The choroidal cells join to each other by tight junctions to form the blood CSF barrier that has the permeability and diffusion of the drug similar to BBB but, the degree of uptake may vary significantly.

    The drug that enters the CSF slowly cannot achieve a high concentration as the bulk flow of CSF continuously removes the drug.

    CSF concentration may be higher than its cerebral concentration. 

    E.g., Sulfamethoxazole and trimethoprim and vice versa in other cases like beta-blockers.


    Image Source: Pinterest.com | By Nimrah Ali


    Blood-Placental Barrier

    The maternal (mother) and fetal blood vessels are separated by a fetal trophoblast basement membrane and the endothelium that together constitute the placental barrier.

    The human placental barrier has a mean thickness of 25microns during early pregnancy and reduces to 2microns at full term but does not reduce its effectiveness. 

    The drugs having a molecular weight less than 1000Daltons and moderate to high lipid solubility can cross the barrier rapidly by simple diffusion. 

    E.g., Ethanol, sulphonamides, barbiturates, gaseous anesthetics, steroids, narcotic analgesics, anticonvulsants, and some antibiotics. 

    It is not as effective as BBB.

    The nutrients essential for fetal growth are transported by carrier-mediated processes, and the immunoglobulins are transported by endocytosis.

    The agent that causes toxic effects on the fetus is called teratogen & the fetal abnormalities caused by the administration of such agents during pregnancy is called Teratogenicity.



    Blood-Testis Barrier

    This barrier is present at the Sertoli-Sertoli cell 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.


    Image Source: Quora.com | By Gary Larson


    Organ/Tissue Size and Perfusion Rate

    Distribution is permeability rate-limited in the following cases:

    When the drug is ionic, or polar, or water-soluble, the highly selective physiological barrier restricts the diffusion of such drug to the inside of a cell.

    The distribution will be perfusion rate-limited in the following cases:

    When the drug is highly lipophilic. 

    When the membrane is highly permeable.

    Perfusion rate is the volume of the blood that flows per unit time per unit volume of the tissue (ml/min/ml).

    Distribution rate constant (Kt) and distribution half life are calculated as follows:


    `\text {Kt} = \frac {\text {Perfusion rate}}{K}`


    `\text {Distribution half life} = \frac {\text {0.693}}{Kt}`



    The greater the blood flow, the faster will be the distribution.

    Highly lipophilic drugs can cross the most selective barrier like BBB, E.x. Thiopental.

    The highly permeable capillary wall permits the passage of almost all drugs, except those bound to plasma protein.

    Highly perfused tissues like the Lungs, Kidneys, Liver, Heart, Brain are rapidly equilibrated with the lipid-soluble drugs.

    The drug is distributed in a particular tissue or organ depending upon the size of tissue (Volume) & tissue/blood partition coefficient E.x. Thiopental IV infusion (lipophilic drug) has a high tissue/blood partition coefficient towards brain & adipose tissue. But the brain is a highly perfused organ, so the drug is distributed fast and shows a rapid onset of action than poorly perfused adipose tissue.


    Binding of the Drug to Tissue Components

    Drugs can bind to the different components of tissue; they may be intracellular or extracellular.

     

    a) Binding of the Drug to Blood Components

    Drugs can bind to many of the blood components, which influences the distribution of the drugs.


    Plasma Protein Bindings

    Human serum albumin: All types of drugs.

    Alpha Acid glycoprotein: Basic drugs.

    Lipoproteins: Basic, lipophilic drugs (chlorpromazine).

    Alpha 1-Globulin: Steroids like corticosterone, vitamin B12.

    Alpha 2-Globulin: vitamin - A, D, E, K, cupric ions.

    Hemoglobin: Phenytoin, phenothiazines.

    The binding of the drug to the plasma protein is reversible.

    The order or extent of binding of drugs to various plasma proteins is:


    Albumin > Alpha-acid glycoprotein > Lipoproteins > Globulins.



    Blood Cells Bindings

    The RBC comprises of 3 parts, each of which can bind to drugs:

    Hemoglobin.

    Carbonic Anhydrase.

    Cell Membrane.

    40% of blood comprises blood cells, and 95% of these cells are RBC (RBC has hemoglobin).

    Drugs like phenytoin, phenobarbitone bind to hemoglobin.

    Drugs like imipramine, chlorpromazine bind to the RBC Cell wall.


    b) Binding of the Drug to Extracellular Components

    Extracellular Components

    40% of total body weight comprises vascular tissues.

    Tissue-drug binding results in the localization of drugs at a specific site in the body and serves as a reservoir.

    As binding increases, it also increases the biological half-life.

    Irreversible binding leads to drug toxicity.

    The order of drug binding to the extracellular components is:


    Liver > Kidney > Lungs > Muscle > Skin > Eye > Bone > Hair > Nails.


    Miscellaneous factors

    The miscellaneous factors may include age, pregnancy, diet, obesity, diseases a person has, etc.


    a) Age

    The distribution pattern of a drug in different age groups is mainly due to differences in:

    Total body water (both ICF and ECF): This is much greater in infants.

    Fat content: This is higher in infants and the elderly.

    Skeletal muscles: They are lesser in infants and the elderly.

    Organ composition: The BBB is poorly formed in infants, the myelin content is low, and cerebral blood flow is high, hence

    greater penetration of drugs into the brain.

    Plasma protein content: Albumin content is less in both infants and the elderly.


    b) Pregnancy

    The volume for distribution of drugs increases during the pregnancy for the growth of the uterus, placenta, and fetus.

    The fetus represents a separate compartment for the distribution of the drug as the plasma and ECF volume increases.


    c) Obesity

    In obese patients, the high-level adipose tissue can take up a large fraction of lipophilic drugs, and the perfusion through it is low.

    The high fatty acids levels may alter the binding characteristics of acidic drugs.


    d) Diet

    A diet with high fats will increase the free fatty acid levels in circulation and thereby affect the binding of acidic drugs like NSAIDs to albumin.


    e) Diseased State

    The mechanism involved in the alteration of drug distribution in disease states are:

    Altered albumin & other drug-binding protein concentration.

    Alteration or reduced perfusion to organ or tissue.

    Altered tissue pH.

    Alteration of permeability of physiological barrier (BBB).

    E.g., BBB (in meningitis & encephalitis) becomes more permeable to polar antibiotics ampicillin, penicillin G. 

    In patients with CCF, the perfusion rate decreases to the entire body by affecting the distribution of all drugs.


    f) Drug Interactions

    When two drugs having similar binding site affinity are administered, the displacement interactions may occur. 

    Ex. Warfarin (Displaced Drug) & Phenylbutazone (Displacer) for HSA.


    Apparent Volume Of Distribution

    It is a proportionality constant relating the plasma concentration (C) to the total amount of the drug in the body(X).


    `X = Vd\times C`


    `Vd = \frac{X}{C}`


    Where, 

    Vd = Apparent volume of distribution.

    X = The amount of the drug in the body.

    C = Plasma drug concentration.

    The apparent volume of distribution is dependent on the concentration of a drug in plasma.

    Drugs with high apparent volume are: 

    More concentrated in the extravascular tissues, and less in the intravascular tissues.


    Reference

    1. Drug distribution - SlideShare.

    2. Factors affecting distribution of drugs.

    3. DRUG DISPOSITION.

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