Introduction to Distribution / distribution of drugs in the body / What is the distribuation / BPharm Notes / KCL pharmacy Notes / Solution Short notes

 Introduction to Distribution 

Distribution 

2.1.1. Introduction

 The processes which lower the plasma drug concentration are termed disposition. For the disposition of drugs, mainly two processes are involved: 

 1) Distribution:

 This process involves the reversible transfer of a drug between ompartments. Drug distribution is also defined as the reversible transfer of a drug between one compartment and another. 

2) Elimination:

 This process involves irreversible loss of drug from the body. Elimination is further divided into two processes, namely biotransformation (metabolism) and excretion. 

Distribution of drugs occurs through the circulatory system (by the circulation of blood). Therefore, blood or plasma si gnifies one of the compartments, while extravascular fluids and other body tissues signify the other compartments. In other words, distribution of drug is a reversible transfer of drug between the blood and the extravascular fluids and tissues. Distribution is a passive transport process and the driving fo rce for this process is obtained from the difference of concentration gradient between the blood and extravascular tissues. By the diffusion process, the drug concentration increases in tissues until it reaches equilibrium where the amount of drug entering the tissues becomes equal to the amount of drug draining out from the tissues. At equilibrium state, the drug concentration in the tissues depends on the rate at which the drug is distributed in the tissues and on the drug concentration in the plasma.

Plasma concentration  ⇌ Tissue concentration

Drug distribution does not occur uniformly throughout the body because different tissues get the drug from the plasma at different rates and in different concentrations. 

2.1.2. Tissue Permeability of Drugs 

If the blood flows rapidly and uniformly to the entire body tissues, differences in the degree of distribution between tissues will indicate the differences in the tissue penetrability of the drug. This process will be tissue permeability rate -limited. In distribution of drugs, following are the two main rate-determining steps: 

1) Rate of Tissue Permeability: 

Tissue permeability of a drug mainly depends on two factors, i.e., the physicochemical properties of the drug and the physiological barriers restricting diff usion of drug into tissues. Molecular size, degree of ionisation, and partition coefficient are t he main physicochemical properties influencing drug distribution. 

Most of the drugs having molecular weight less than 500 -600 Daltons can feasibly diffuse int o the extracellular interstitial fluids by crossing the capillary membrane . But, penetration of drugs from the extracellular fluid into the cells is determined by the molecular size, ionis ation constant, and drug lipophilicity. Only small, water -soluble molecules and ions of size less than 50 Daltons enter the cell via aqueous filled channels , while the larger - sized particles can be passed by a specialised transport system. The tissue permeability of a drug is mainly determined by its degree of ionisation. 

The ionisation and diffusion of drugs into cells decide the pH of blood and extravascular flu id. A drug which remains unionis ed at these pH values permeates the cells with a faster rate. The pH of blood and ECF generally remain constant at pH 7.4, therefore they do not affect dr ug diffusion unless conditions like systemic acidosis or alkalosis are static or remain unaltered.

Drugs are mostly weak acids or weak bases , and their degree of ionis ation at plasma or ECF pH depends on their pK a value. All polar and hydrophilic drugs get ionised at plasma pH, cannot penet rate the lipoidal cell membrane, and tissue permeability is the rate -limiting step in the ir distribution. Only lipophilic unionised drugs rapidly cross the cell membrane.

In case of polar drugs in which permeability is the rate -limiting step in the ir distribution, effective partition coefficient of drug is the driving force and it is calculated as follows: unioniseddrug K of at pH

Effective K o/w o/w = Fraction unionised at pH7.4 X   K of unioniseddrug

 The degree up to which effective partitio n coefficient influences rapid ity of drug distribution can be explained by the following example (table 2.1): 

The degree up to which effective partitio n coefficient influences rapid ity of drug distribution can be explained by the following example (table 2.1):

 

Permeability is the rate-limiting step in drug distribution: 

i) If the drug under consideration is ionic, polar, or water-soluble. 

ii) If the highly selective physiological barriers restrict such drugs to diffuse into the cell. On the other hand, perfusion is the rate-limiting step in drug distribution: 

 i) If the drug is highly lipophilic. 

ii) If the membrane across which the drug is to diffuse is highly permeable (such as those of the capillaries and muscles). Only highly lipophilic drugs (like thiopental) can cross the most selective barriers such as the blood -brain barrier (BBB), while highly permeable capillary wall allows almost all the drugs (except those bound to plasma proteins) to pass. In both the cases, the rate of blood flow or perfusion to the tissue is the rate -limiting step . Thus, greater the blood flow, faster the distribution. 

2) Rate of Blood Perfusion:

 Perfusion rate is the volume of blood that flows per unit time per unit volume of the tissue. Its unit is ml/min/ml of the tissue. If K t/b represents tissue/bloo d partition coefficient of drug, the first -order distribution rate constant (Kt) is expressed as:

                                             Kt =  PerfusionRate / K t/b

The tissue distribution half-life is given as:

The extent up to which a drug is distributed in a parti cular tissue or organ depends on the size of tissue (i.e., tissue volume) and the tissue/blood partition coefficient of the drug. This can be explained by taking the example of thiopental (a lipophilic drug) , which has a high tissue/blood partition coefficient towards the brain and higher for adipose tissue. Because brain (site of action) is a highly perfused organ, thiopental diffuses very rapidly into the brain and shows a rapid onset of action when given intravenously

Adipose tissue s are poorly perfused, therefore , distribution occurs very slowly with the same drug. If thiopental concentration in the adipose tissue shifts towards equilibrium, the drug rapidly diffuses out of the brain and localises in the adipose tissue whose volume is 5 times more than brain and has greater affinity for the drug. Such tissue redistribution results in rapid termination of action of thiopental.

2.1.3. Physiological Barriers 

Different types of barrier s are found in the body that restrict the distribution of various compounds that enter the blood to different tissues. These barriers are present in the body for protecting the sensitive tissues from the effect of various chemicals that enter the blood via different routes. The physiological barriers are discussed below: 

1) Blood Capillary Membrane :

 Drug passes the capillary membrane t hrough passive diffusion an d hydrostatic pressure. By passive diffusion , drug molecules travel across the region of high concentration to low concentration; it can be described by Fick’s law of diffusion.

The negative sign indicates drug movement from inside the blood capillary into the tissues. 

2) Simple Capillary Endothelial Barrier :

 Capillaries supply blood to most of the tissues. Capillary endothelium allows passage of drugs (ionised or unionised of molecular size ˂ 600 Daltons) int o the interstitial fluid. Only drugs bound to the blood components are restricted because of the large molecular size of the complex. 

3) Cell Membrane :

 Drug present in ECF is transported by passive diffusion into the cell. Factors influencing the penetration of drugs into cells are same as those observed in the gastrointestinal absorption of drugs. For the transport of drugs, cell membrane acts like a lipid barrier. Permeability of drugs through cell membrane chec ks the entry into the cell. The physicochemical properties that influence permeation of drugs across such a barrier are illustrated in figure 2.3. 

4) Blood-Brain Barrier (BBB):

 Permeability of capillaries present in the brain and spinal cord is different from that of the capillaries of rest of the body. Endothelial cells of capillaries are covered by a layer of glial cells that have tight intercellular junctions providing thicker lipid bar rier. This layer of glial cells reduces diffusion and penetration of water -soluble and polar drugs into the brain and spinal cord. Figure 2.4 represents this lipid barrier (BBB). 

Normally, only lipid-soluble drugs can penetrate the interstitial fluid of the brain and spinal cord, while water-soluble compounds need specific carriers to cross the endothelial lining. In diffusion process , many transport mechanisms are involved. Degree of ionisation in plasma and drug lipid solubility determines the penetration rate of a drug into the brain. Highly lipid-soluble drugs (e.g., thiopental) cross BBB immediately, and reach the brain from plasma. Polar drugs ( e.g., barbital) penetrate the CNS slowly. Weak organic acid s (e.g., penicillin G having pKa 2.6) are found in completely ionised form in plasma, but penetratethe brain at a low rate due to poor lipid solubility. 

Approaches to Promote Crossing the BBB 

i) Permeation enhancers ( e.g., Dimethyl Sulfoxide or DMSO) are used for increasing penetration.

ii) Mannitol infused in internal carotid artery result in osmotic disruption of BBB.

iii) Carriers (e.g., dihydropyridine redox system) are used to transport drug into brain. 

5) Blood-Cerebrospinal Fluid Barrier :

 Cerebrospinal fluid form s in choroid plexus, found in the roof of the fourth ventricle and projects between the cerebellum and pons on the lower bra in stem. At anterior brain stem in the roof of the diencephalon, two extensive folds of choroid plex us originate and extend through inter-ventricular foramina. Floors of the lateral ventricles are covered by folds of the choroid plexus. Drug diffuses easily through the blood -CSF barrier because the junctions between the endothelial cells of blood capilla ries are open; so the drug molecules easily reach the extracellular fluid (ECF) from the blood at the barrier. But at the region of choroid plexus , tight junctions are present between the cells that obstruct the penetration of polar drugs. So, only lipid - soluble drugs can diffuse through the lipoidal barrier (figure 2.5).  

As the CSF is almost devoid of protein, the CSF concentration of lipid - soluble drugs represents the free drug concentration in plasma. Concentration of drugs is greater i n brain tissues as compared to the CSF, e.g., in epileptic patients concentration of p henytoin is 6 times higher in the temporal lobe than in the CSF.

6) Placental Barrier: 

Maternal and the foetal blood vesse ls are separated by placental barrier, which is made up of endothelium and many layers of tissue of foetal trophoblast basement membrane. Figure 2.6 shows the blood flow in maternal and foetal blood vessels. Placental barrier is less effective than BBB because drugs having molecular weight less than 1000 Daltons and with moderate to high lipid solubility ( e.g., ethanol, sulphonamides, barbiturates, gaseous anaesthetics, steroids, narcotic analgesics, anticonvulsants , and antibiotics) can cross the placental barrier through simple diffusion. Immunoglobulins are transferred by endocytosis, whereas, nutrients essential for foetal growth are transported by carrier-mediated process.

Drugs may give rise to lethal effects on the following two critical stages during foetal development: 

 i) First Trimester: It is the duration when the foetal organs are developing. At this stage , most of the drugs produce teratogenic effects (congenital defects), e.g., thalidomide, phenytoin, isotretinoin, etc. 

ii) Latter Stages: In the l atter stages of pregnancy, drugs may affect the physiological functions of body, e.g., respiratory depression by morphine. Therefore, it is better to avoid using any drug during the pregnancy period due to the uncertainty of harmful effects. 

7) Blood-Testes Barrier:

 A layer is formed by the extensions of sustentacular cells (sertoli cells) that surround the seminiferous tubule beneath the spermatogonia. To maintain stable conditions, diffusion from interstitial fluid to the seminiferous tubule is prevented by the tight junctions present between the sustentacular cells. 

2.1.4. Factors Affecting Drug Distribution Drugs distribution is affected by the following factors: 

1) Age: Distribution varies with difference in: 

i) Total Body Content (Intracellular and Extracellular): It is maximum in infants. 

ii) Fat Content: It is greater in infants and in elderly people. 

iii) Skeletal Muscles: It is less in infants and elderly people. 

iv) Organic Composition: Poorly developed BBB, low myelin content, and high cerebral blood flow in infants cause greater drug penetration in the brain. 

v) Plasma Protein Content: Albumin content is low in infants and elderly people. 

 2) Pregnancy: 

Growth of uterus, placenta and foetus rais es volume for drug distribution in pregnancy. Drug may also distribute in foetus which acts as a separate compartment. Plasma and ECF volume also increases , but albumin content is reduced.

3) Obesity:

 High adipose ti ssue content results in low drug distribution and perfusion. High fatty acid content alters the binding property of acidic drugs. 

4) Diet:

 Fat-rich diet increases free fatty acid concentr ation in the blood that affects the binding of acidic drugs, e.g., NSAIDs, albumin, etc

. 

5) Disease States:

 Drug distribution is seve

rely affected in diseased conditions: 

i) Alteration in albumin and other drug-protein concentration, 

ii) Reduced or altered perfusion to organs and tissues, and 

iii) Alteration in tissue pH. In case of enceph alitis and meningitis, the BBB becomes more permeable, therefore, concentration of ionic antibiotics (e.g., penicillin G and ampicillin) increases in brain tissues.

 6) Drug Interaction: 

Two or more drugs administered together compete for the binding site, tend to replace each other, and the free drug may produce lethal effects, e.g., phenylbutazone and warfarin.

2.1.5. Volume of Distribution 

Varying concentrations of drug reaches different organs and tissues of the body. The process o f distribution is considered to be complete at distribution equilibrium. At this stage, different tissues and organs contain varying concentrations of drug that can be determined by the volume of tissues in which the drug is present. So, different body tis sues and organs have different concentrations of drug. The physiological meaning of volume of distribution is not clear. But, a constant relationship is seen between the amount of drug in body (X) and the concentration of drug in plasma 

(C): X  C Or, X  Vd 

Where, Vd = Apparent volume of distribution, which is a proportionality constant having the unit of volume.

Determination of Volume of Distribution 

1) The drug dose is administered by a rapid intravenous bolus injection , and then blood samples are taken at specific time intervals. 

2) A suitable assay method is used to calculate the plasma concentration of each drug sample. 

3) The obtained data is plotted on a graph paper so that the plasma profile of the drug can be obtained. 4) The drug level in plasma immediately after the administration of drug dose is calculated by back-extrapolating the plasma concentration versus time profile of the drug to time zero.

 

2.1.6. Apparent Volume of Distribution 

Apparent volume of distribution is the hypothetical volume of body fluid into which a drug is dissolved or distributed . It is named as apparent volume because each part of the body equilibrated with the drug does not have equal concentration. 

Thus, apparent volume of distribution can be represented as: 

Apparent Volumeof Distribution  = Amount of Drugin theBody / PlasmaDrugConcentration 

There is no direct relationship between the apparent volume of distribution and true volume of distribution; while the real volume of distribution has direct physiological meaning and is related to the body water. By using specific tracers or markers, the volume of each of these real physiologic al compartments can be determined. Hig h molecular weight substance s that can totally bind to plasma albumin (e.g., high molecular weight dyes such as Evans blue, indocyanine green and I -131 albumin) are used to determine the plasma protein. In case of intravascular route, these remain intact to the plasma. If the concentration of haematocrit is known, total blood volume can also be estimated. The ECF volume can also be estimated by substances that can easily penetrate the capillary membrane and rapidly distribute throughout the ECF but do not cross the cell membranes(e.g., the Na+ ,  Cl , Br, SCN and SO4 2 ions, insulin, mannitol, and raffinose).The volume of ECF is approximately 15 litres, excluding the plasma. Tracer elements either negligibly bound or do not bound to plasma or tissue proteins, thus their apparent volume of distribution remain same to their true volume of distribution. These conditions differ for most of drugs that bind to extravascular tissues or plasma proteins or to both. A general concept can be made in respect of apparent volume of distribution of these drugs: 

 1) Apparent Volume of Distribution Smaller than True Volume of Distribution: Drugs that selectively bind to plasma proteins or other blood components (i.e., those that are less bound to extravascular tissues, e.g., warfarin) have apparent volume of distribution smaller than their true volume of distribution. The V d of such drugs are found between blood volume and Total Body Water ( TBW) volume (i.e., between 6 -42 litres); for example, warfarin has a Vd of about 10 litres. 

2) Apparent Volume of Distribution Larger than True Volume of Distribution: Drugs that selectively bind to extravascular tissues, (i.e., those that are less bound to blood components, e.g., chloroquine) have apparent volume of distribution larger than their true volume of distribution. The Vd of such drugs is always greater than 42 litres or TBW volume. For example, chloroquine has a V d of approximately 15,000 litres. Such drugs leave the body slowly and are generally more toxic than the drugs that do not distribute deeply into body tissues.

2.1.7. Binding of Drugs 

In general, protein binding is defined as the binding of a drug to blood plasma proteins. This binding can be between the drug and tissue membranes, RBCs, and other blood components. The effectiveness of a drug on the body depends on the amount of drug bound to protein. The bound drug remains in the blood and the unbound drug metabolises into the active part of the drug. Therefore, if a drug is 95% bound to a binding protein and 5% is free, it indicates that 5% of the drug is active in the system and gives rise to pharmacological effects

Generally, protein binding is reversib le, and therefore a chemical equilibrium develops, in which the chemical reaction occurs in backward and forward direction without any net change in reactants and products. This indicatesthat while achieving equilibrium, a cell which is effective at extra cting the unbound drug may extract more drug as it disassociates. Reversible protein binding can be expressed as: 

Protein + Drug ⇌ Protein-Drug Complex

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