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Kiran’s Success Learning Forum ---------------

Distribution
Dr. Kiran Vakade

Introduction

 Distribution in pharmacology is a branch of pharmacokinetics which describes the reversible

transfer of drug from one location to another within the body.
 Once a drug enters into systemic circulation by absorption or direct administration, it gets
distributed in the body.
 Movements proceeds until equilibrium is established between unbound drug in the plasma and
the tissue fluids. Subsequently there is a parallel decline in both due to elimination
Factors affecting distribution:
 The extent and pattern of distribution of a drug depends on
1. Its lipid solubility,
2. Ionization at physiological pH,
3. Concentration gradient
4. Extent of binding to plasma proteins and tissue proteins,
5. Differences in the regional blood flow.
6. Presence of tissue specific transporters
7. Fat: lean body ratio which can vary with age, sex and obesity.
8. Diseases like CHF, uremia, cirrhosis.

Note: In a normal person of 70 kg approximate volume of different body water is as follows;

 Total body water = 42 L
 Intracellular = 28 L
 Extracellular = 14 L
A. Interstitial fluid = 10 L
B. Plasma volume = 4 L

Apparent Volume of Distribution (V) :

Drug administered i.v.

V= --------------------------------------------
Plasma concentration
 If body is considered as single homogenous compartment it is defined as the volume in which
drug appears to be distributed (apparent), if concentration throughout the body was same as in
plasma.

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 Volume of distribution does not represent a real volume but it is the apparent volume that
required for the distribution of a drug , if the concentration throughout the body considered same
as that present in plasma
 Chloroquine has aVd 1300 L, and this amount is not present in the body, it means drug is
concentrated in some tissues. Chloroquine is concentrated in spleen, liver, kidney. On prolonged
use it also accumulated in retina and cornea.
 If drug has high plasma concentration it will have low aVD.
 If drug has low plasma concentration, it will have higher aVd and drug may concentrate in
different tissues.
Significance of volume of distribution
1. A drug with high apparent volume of distribution is concentrated in some of the tissues and may
responsible for toxicity. e.g. Chloroquine in Retina – Bull’s eye retinopathy if used in
rheumatoid arthritis
2. If a drug has high aVd, it has to be given by loading dose in order to achieve the adequate
therapeutic concentration. e.g. Chloroquine in Malaria.
3. If a drug has high aVd, it is difficult to remove by hemodialysis. On the other hand if a drug has
low aVd is easily removed by hemodialysis but it should have low plasma protein binding as
plasma protein bound drug cannot be removed by hemodialysis.
Redistribution:
 Redistribution is the process of reversible movement of drug from site of tissue to systemic
circulation.
 This phenomenon is important for highly lipid soluble drugs.
 Highly lipid soluble drugs get initially distributed to organs with high blood flow (brain, heart,
and kidney). Later, less vascular but more bulky tissues (muscle, fat) take up the drug, plasma
concentration falls and the drug is withdrawn from highly perfused sites. If the site of action of
the drug was in one of the highly perfused organs, redistribution results in the termination of drug
action.
 Anaesthetic action of thiopentone sod. Injected i.v. is terminated in few minutes due to
redistribution.
 A relatively short hypnotic action (6-8 hours) of diazepam/ nitrazepam is due to redistribution
despite their elimination t1/2 of > 30 hours.
 However when same drug is given repeatedly or continuously over long periods, low perfusion
high capacity site is get progressively filled up and the drug becomes longer acting.
Distribution in CNS

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 Blood Brain Barrier (BBB): The capillary endothelial cells in brain have tight junction and lack
large paracellular spaces. Further, an investment of nural tissues covers the capillaries. Together
they form Blood Brain Barrier. This barrier is lipoidal.
 Efflux transporters like P-gp and organic anion transporters (OATP) present in the brain and
choroidal vessels extrude many drugs that enters the brain .
 Only unionized, lipid soluble drugs can cross the BBB and Blood CSF barrier by passive
diffusion. e.g. Propranolol, physostigmine, atropine sulphate, ether, halothane, thiopentone
sodium.
 Most of the lipid insoluble drugs and quaternary compounds cannot cross the BBB e.g.
Streptomycin, neostigmine, atropine methyl nitrate.
 It has been proposed that some drugs accumulated in the brain by utilizing the transporters for
endogenous substances. e.g. some water soluble drugs like Levodopa and methyldopa cross BBB
by utilizing transporters for aromatic amino acids.
 Enzymatic BBB: Monoamine Oxidase (MAO), cholinesterase, and some other enzymes are
present in the capillary walls or in the cells lining them. They do not allow catecholamines,5 HT,
acetylcholine, etc to enter brain in the active form
 Inflammation of meninges or brain increases the permeability of these barriers. Penicillins,
chloramphenicol or ampicillin which otherwise have poor permeability through BBB, exhibit
increased permeability in these diseased states. Cefotaxime and ceftriaxone crosses the BBB even
when meninges are not inflamed and thus these are preferred agents now a day for treatment of
meningitis.
 The BBB is deficient at five sites
1. Pituitary gland
2. Pineal gland
3. Area Prostrema near the floor of IV ventricle (CTZ located there):
 Even lipid insoluble drugs are emetics
 This property is utilized to prevent the side effects of antiemetic drugs. e.g administration
domperidone does not produce extrapyramidal side effects like metochlopramide when
used as antiemetic as it does not cross BBB so reaches CTZ but not in other brain areas.
4. Median eminence
5. Choroid plexus capillaries.
Drug Distribution across placental barrier
 The blood between foetus and mother is separated by a layer of trophoblastic cells in chorionic
villi.
 Like other biological membrane, placental membrane is lipoidal in nature and lipid soluble,
unionized drugs crosses placenta more easily by passive diffusion e.g. general anaesthetics,
sedative-hypnotics, opioids
 Ionized, polar, water soluble drugs and essential nutrients cross the placental barrier by carrier
mediated transport.
 Amino acids and glucose transported across placenta by active transport while immunoglobulin
by pinocytosis.
 Placenta is also a site for drug metabolism as well which may lower/ modify the exposure of the
foetus to the administered drug.

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 Efflux transporters such as P-gp, BCRP, MRP-3 are present on placenta- which also serve to limit
foetal exposure to maternally administered drugs.
 Placenta is considered as an incomplete barrier and almost any drug taken by mother can affect
the foetus.
Plasma Protein Binding:
Introduction
 After entry into systemic circulation, some drugs may bound to the plasma proteins.
 The bound form and free form of a drug are always in equilibrium when plasma concentration
falls drug is released from the binding site so plasma protein acts as temporary reservoir.
 Only the free drug is pharmacologically active and responsible for therapeutic effect.
 Also bound form of a drug is not available for distribution, metabolism and excretion.
 Acidic drugs bind to albumin while basic drugs bind with α1 acid glycoprotein. This binding is
usually reversible. Apart from this, there are certain hormone carrier proteins such as sex
hormones (estrogen, testosterone) bind to sex hormone binding globulin, steroids bind to
corticosteroid binding globulin (transcortin), thyroxin binds with thyroid binding globulin
(thyroglobulin), antigens bind with γ globulins.
Important proteins that contribute to drug binding:
1. Plasma Albumin:
 It is the most important plasma protein that binds with the drugs.
 Most of the acidic drugs bind to the albumin.
 There are two binding sites for acidic drugs on human serum albumin.
 Acidic drugs like aspirin (salicylate), indomethacin, naproxane, tolbutamide, glibenclamide,
warfarin bind to albumin
2. α1 acid glycoprotein:
 Most of the basic drugs bind to α1 acid glycoprotein. e.g. β bockers, prazocin, verapamil,
quinidine, lidocaine, bupivacaine etc.
 α1 acid glycoprotein is an acute phase reactant i.e. its plasma concentration increases in
physiological stress and pathological states (e.g. acute M.I, rheumatoid arthritis, Crohn’s
disease). Hence binding of basic drugs increases during such circumstances, so free fraction
may be reduced.
Clinical significance of Plasma protein binding:

1. The bound fraction is not available for action. However, it is in equilibrium with free drug and
as the concentration of drug falls; the drug is slowly released from the binding site and so
maintains the plasma concentration. Thus bound form acts as temporary storage site.
2. Highly plasma protein bound drugs are largely restricted to vascular compartment because
protein bound does not cross membrane (except through large paracellular spaces, such as in
capillaries). They tend have smaller volumes of distribution.
3. High degree of protein binding generally makes drug long acting, because bound fraction is
not available for metabolism and excretion unless it is actively extracted by liver or by kidney
tubules.

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4. Highly protein bound drugs are not removed by hemodialysis and need special techniques for
treatment of poisoning.
5. Degree of PPB should be taken into consideration while comparing results of in vivo and in vitro
studies.
6. Displacement Interactions:
 The drug bound with higher affinity will displace that bound with lower affinity.
 For displacement interactions binding site should be same.
 Acidic drugs do not displace basic drugs because binding proteins are different.
 The overall impact of many displacement interactions is minimal because displaced drug will
diffuse into the tissues as well as get metabolised or excreted. Clinical significant
displacement interactions are seen with drugs having high protein binding, low therapeutic
index and limited volume of distribution.
 Drug displacement interactions are not significant with basic drugs because many binding
sites are present on α1 acid glycoprotein to bind basic drugs and aVd of basic drugs is very
high.
 Some clinically important displacement interactions are:
 Aspirin displaces sulfonylureas.
 Indomethacin, Phenytoin displaces warfarin.
 Sulfonamides and vit. K displaces bilirubin (kernicterus in neonates).
 Aspirin displaces methotrexate.
7. Alteration in the level of plasma proteins:
 Reduced level of albumin i.e. hypoalbuminemia may seen in malnutrition, hepatic diseases,
pregnancy and renal diseases. So free concentration of acidic drugs is increased in
hypoalbuminemia.
 Increased level of α1 acid glycoprotein: It is an acute phase reactant protein. Its plasma
concentration increases in physiological stress and pathological states. (e.g. in pregnancy,
diseases like MI, Rheumatoid arthritis, Cron’s disease). Free form of drug may be reduced
and even that may lead to reduced or loss of therapeutic effect.
Tissue Storage:
Various drugs and toxic agents have affinity for certain tissues and based on that they are
responsible for the toxicity of the organ and this property can be utilized for therapeutic purpose,
moreover duration of action of drug is prolonged. e.g.
1. Chloroquine is concentrated in liver, kidney and retina. Chloroquine is used for hepatic
amoebiasis as it concentrates in liver. When chloroquine is used for long period as in
Rheumatoid arthritis, it may produce Bull’s eye retinopathy as it accumulated in
nucleoproteins of retina.
2. Digoxin and emetine bind to muscle proteins (skeletal muscle, myocardium)
3. Bisphosphonates binds tightly to hydroxyapatite crystals of bone matrix  Advantage in case
of osteoporosis (DOA longer).
4. Gentamicin may cause nephrotoxicity.
5. Tetracycline accumulated in teeth and bone  responsible for toxicity.