12/03/2017

Distribution of
drugs

Drug disposition

After entry into blood

The drug gets subjected to various processes known
as disposition

Distribution Elimination

Biotransformation Excretion
2

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• Drug disposition is defined as processes that

tend to lower the plasma concentration of drug.
• 2 major drug disposition processes are:
– Distribution: It is reversible transfer of a drug between
compartments
– Elimination: It is irreversible loss of drug from the
body it be either by biotransformation or excretion.

Drug Drug
distributed metabolised
in body

Drug (and
metabolites)
in plasma

Interrelationship
between different
processes of drug
disposition
Drug
excreted

2
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Distribution

• It is defined as the reversible transfer of a drug

between one compartment and another
• Since the process is carried out by the circulation
of blood, one of the compartment is always
blood or plasma and the other represents
extravascular fluids and other body tissues
• Thus distribution is the reversible transfer of a
drug between blood & extravascular fluids and
tissues

• It is a passive process
• The driving force is concentration gradient
between the blood and ev tissues
• Thus the process stops when equilibrium is
reached
• As pharmacological action of a drug depends on
its concentration at the site of action,
distribution plays a significant role in:
Onset of action
Intensity of action
Duration of action

3
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Steps in drug distribution

Permeation of free Permeation of drug in

Entry into interstitial
drug in the blood ECF through
or ECF
through capillary walls membrane

This is the rate

Enters into ICF Enters into tissues
limiting step

It depends upon:
• Rate of perfusion to
extracellular tissues
• Membrane permeability of
the drug 7

Factors affecting distribution of drugs

Tissue Organ/ tissue

Binding of Miscellaneous
permeability size and
drugs factors
of drug perfusion rate

Age
Physicochemical
Binding to blood
properties of Pregnancy
components
drugs
Obesity

Diet
Physiological Binding to
barriers to extravascular Disease states
diffusion tissue proteins
Drug interactions
8

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1] Tissue permeability of drugs

Distribution

Rate determining
step

Rate of blood
Tissue permeability
perfusion

Physiological barriers
that restrict diffusion Physicochemical
of drug into tissues properties of drugs

A. Physicochemical properties of drugs

• Less than 500 – 600 daltons cross membranes easily into ECF

Molecular size • Only small, water soluble molecules and ions below the size of 50
daltons enter the cell via aqueous channels
• Rest enter by specialised transport system

Degree of • pH of blood and tissues affect ionisation of drug

ionization • A drug which is neutral and unionised at this pH diffuses easily

Partition • Only unionised lipophilic drugs cross the barriers

coefficient • Eg. Phenobarbital and salicylic acid

Stereochemical • Can affect interaction with macromolecules like proteins

• Tissue localisation may happen because of stereochemical nature of
nature drug
10

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B. Physiological barriers to distribution of

drugs
• Simple capillary endothelial barrier
• Simple cell membrane barrier
• Blood brain barrier
• Blood CSF barrier
• Blood placental barrier
• Blood testis barrier

11

Simple capillary endothelial barrier

Practically not a barrier to most

drugs

All drugs, ionised or unionised

with size lesser than 600 daltons
can diffuse through capillary
endothelium into interstitial fluid

Only drugs bound to blood

components do not pass on
account of their size

12

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Simple cell membrane barrier

• Once the drug diffuses from capillary wall into ECF
• It has to enter the cells passing via their membranes
• This is limited by its permeability through the membrane

13

14

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Blood brain barrier

• Impedes and regulates the influx of most compounds
from blood to brain.
• Formed by brain microvascular endothelial cells (BMEC),
astrocyte foot process and pericytes.
• Essential for normal function of CNS.
• Regulates passage of molecules in and out of brain to
maintain neural environment.
• Responsible for metabolic activities such as the
metabolism of L-dopa to regulate its concentration in
the brain

15

16

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17

18

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• It is a continuous zipper like tight junctioned

endothelial cell layer
• The microvascular endothelium shares a common
basement membrane with astrocytes and pericytes
• Endothelial layer should be viewed as 2 separate
membranes:
– Inside of the vessel – luminal
– Outside of the vessel – abluminal
• Both separated by 300-500 nm thick layer of
cytoplasm
• Surface area of cerebral capillary endothelium is 100
cm2/g of brain tissue.

19

• Presence of astrocytes and pericytes form a solid

envelop around the brain capillaries
• As a result paracellular passage is blocked
• Thus for the drug to go into the brain it has to
pass by transcellular route
• However there are specific areas in the brain
where BBB does not exist
– The trigger area
– The median hypothalamic eminence

20

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• The drugs administered intranasally may diffuse

directly into the CNS because of the continuity
between the submucosal areas of the nose and
the subarachnoid space of the olfactory lobe

21

Characteristics of the blood-

brain barrier are indicated:
(1) tight junctions that seal
the pathway between the
capillary (endothelial) cells;
(2) the lipid nature of the
cell membranes of the
capillary wall which makes
it a barrier to water-soluble
molecules;
(3), (4), and (5) represent
some of the carriers and ion
channels;
(6) the 'enzymatic barrier
that removes molecules
from the blood;
(7) the efflux pumps which
extrude fat-soluble
molecules that have crossed
into the cells
22

11
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Functions of BBB

1. Protects the brain from “foreign substances”.

2. Protects the brain from hormones and
neurotransmitters in the rest of body.
3. Maintains a constant environment for the brain

23

Transport across BBB

Tight
junctions
exclude Transcellular
paracellular pathways
pathway also blocked

Absence of
pinocytosis

1. Large molecules do not pass

through the BBB easily.
2. Hydrophilic molecules do not
penetrate into the brain.
3. Whereas, small lipophilic
molecules penetrate rapidly 24

12
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• A solute may thus gain access to brain via only 1

of the 2 pathways:
– Passive diffusion through lipoidal barrier – small
molecules with high o/w partition coefficient
– Active transport of essential nutrients such as sugars
and amino acids. Thus structurally similar foreign
molecules can also penetrate the BBB by the same
mechanism

25

Endogenous ion

Membrane

Ionic drug

Membrane

Abluminal
Luminal side
PASSIVE DIFFUSION side
26

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Thiopental • 50 times more lipophilic than phenobarbital crosses

BBB rapidly

• Polar, water soluble and ionised at plasma pH does

not cross BBB in normal condition
Penicillin • In meningitis the barrier swells and gets disrupted.
• there is increased vascular permeability and
decreased efflux of penicillin from the brain

• Can’t be given directly as it doesn’t cross the BBB

Dopamine • Levodopa is given which is lipophilic, it penetrates
the CNS where it gets metabolised to dopamine

27

• Targeting of polar drugs to brain has always

been a problem.
• Possible approaches are:
– Use of penetration enhancers such as DMSO
– Osmotic disruption of the BBB by infusing internal
carotid artery with hypotonic solution of mannitol or
arabinose to initiate endothelial cell shrinkage
– Use of dihydropyridine redox system as drug carriers
to brain

28

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How Does DHP Deliver Drugs to

the Brain?
‘ DHP-drug’ fusion injected into blood

DHP receptor
Blood

Blood Brain Barrier

Brain

CNS oxidases

Polar pyridinium ion

which can’t cross
back 29

Blood cerebrospinal fluid barrier

• CSF is formed mainly by choroid plexus of the

lateral, third and fourth ventricles
• It is similar in composition to the brain ECF
• The capillary endothelium that lines the choroid
plexus has open junctions or gaps
• Drug can pass easily into the extracellular spaces
between the capillary wall and choroidal cells

30

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31

• However, the choroidal cells are joined to each

other by tight junctions forming the blood-CSF
barrier which has permeability characteristics
similar to that of BBB
• Just like BBB, only highly lipid soluble drugs can
cross the blood-CSF barrier with relative ease
• Moderately lipid soluble and partially ionised
drugs permeate slowly

32

16
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• A drug that enters the CSF slowly cannot achieve a

high concentration as the bulk flow of CSF
continuously removes the drug
• Thus for any given drug, its concentration in the brain
will always be higher than in the CSF
• Although the mechanism of diffusion of drugs into
CNS and CSF are similar, the degree of uptake may
vary significantly
– In some cases CSF drug conc is greater eg.
Sulphamethoxazole and trimethoprim
– In other cases cerebral drug conc is greater eg. Beta blockers

33

Blood placental barrier

• Maternal and foetal blood vessels are separated

by:
– A number of tissue layers made of trophoblast
basement membrane; and
– The endothelium
• Which together constitute the placental barrier

34

17
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35

• Thickness of placental barrier:

– 25 µm in early pregnancy
– 2 µm at full term
• But its effectiveness doesn’t change
• Not as effective as BBB
• Drugs with molecular weight less than 1000 daltons
and moderate to high lipid solubility cross the
barrier by diffusion quite rapidly
– Eg. Ethanol, sulphonamides, barbiturates, gaseous
anaesthetics, steroids, narcotic analgesics, anticonvulsants
and some antibiotics like chloramphenicol

36

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• Nutrients essential for foetal growth are

transported by carrier mediated processes
• Immunoglobulins are transported by
endocytosis

37

• Teratogenicity
• Teratogenicity is defined as foetal abnormalities
caused by administration of drug during
pregnancy
• An agents that causes toxic effects on foetus is
called as teratogen
• It is always better to restrict all drugs during
pregnancy because of uncertainty of their
hazardous effects.

38

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Period Significance Harmful effects

First 2 weeks Fertilization and Miscarraige
implantation stage
2 – 8 weeks Period of organogenesis Cleft palate, optic atrophy,
mental retardation, neural
tube defects etc
8 weeks onwards Growth and development Development and
functional abnormalities

39

Blood testis barrier

• This barrier is located not at the capillary

endothelium level but at sertoli-sertoli cell
junction
• It is a tight junction between the neighboring
sertoli cells
• It restricts the passage of drugs to
spermatocytes and spermatids

40

20
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41

2] Organ/ tissue size and perfusion rate

Distribution is
Distribution is
permeability
perfusion rate
rate-limited
limited when:
when:

When the The membrane

highly selective across which
When the drug
physiological the drug is
under
barriers restrict The drug is supposed to
consideration is
the diffusion of highly lipophilic diffuse is highly
ionic, polar or
such drugs to permeable eg
water soluble
the inside of capillaries,
cell muscles etc
42

21
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• Perfusion rate: it is the volume of blood that

flows per unit per time per unit volume of the
tissue
• Units: ml/min/ml

43

Organ/ tissue Perfusion rate (ml/min/ml)

Highly perfused
Lungs 10.2
Kidneys 4.5
Liver 0.8
Heart 0.6
Brain 0.5
Moderately perfused
Muscles 0.034
Skin 0.033
Poorly perfused
Adipose tissue 0.03
Bone 0.02

44

22
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• If Kt/b is the tissue/blood partition coefficient of

drug then the first order distribution rate
constant, Kt is given by:
𝑃𝑒𝑟𝑓𝑢𝑠𝑖𝑜𝑛 𝑟𝑎𝑡𝑒
• 𝐾𝑡 =
𝐾𝑡/𝑏
• The tissue distribution half life is given by:
0.693 0.693𝐾𝑡/𝑏
• 𝑡1(𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛) = =
2 𝐾𝑡 𝑃𝑒𝑟𝑓𝑢𝑠𝑖𝑜𝑛 𝑟𝑎𝑡𝑒

45

3] Binding of drug to tissue components

• Would be covered later

46

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4] Miscellaneous factors affecting drug

distribution
A] Age: Differences in distribution pattern of a drug
in different age groups are mainly due to
differences in:
Total body water • Greater in infants

Fat content • Higher in infants and elderly

Skeletal muscles • Lesser in infants and elderly

Organ penetration • BBB poorly developed in infants

Plasma protein binding • Low albumin content in infants and elderly

47

B] Pregnancy
During pregnancy, the growth of uterus, placenta and foetus increases
the volume available for distribution
Plasma and ECF levels also increase

Albumin levels fall

48

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C] Obesity
High adipose tissue content:
 Takes up large fraction of lipophilic drug
 Blood flow is lower
 High fatty acid levels alter the binding
characteristics of acidic drugs

49

D] Diet

Increases free fatty Affects biding of

High fat diet acid levels in acid drugs to
circulation albumin eg NSAIDs

50

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E] Disease States:
Number of mechanisms maybe involved in the
alteration of drug distribution characteristics in
disease states:
– Altered albumin and other drug-binding proteins
– Altered or reduced perfusion to organs or tissues
– Altered tissue pH

51

F] Drug Interactions: 3 types

1. Competition between drugs for binding sites

2. Competition between drugs and normal body
constituents
3. Allosteric changes in protein molecule

52

26
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Competition between drugs for binding

sites (displacement interactions)

Even a
metabolite
may cause
displacement
interaction

Displacer
Displaced
drug

53

• Clinically significant interactions will result when:

1] The displaced drug:
i. Is more than 95% bound
ii. Has a small Vd (< 0.15 L/Kg)
iii. Shows a rapid onset of therapeutic or adverse
effects
iv. Has a narrow therapeutic index

54

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2] The displacer drug:

i. Has a high degree of affinity as the drug to be
displaced
ii. Competes for the same binding site
iii. The drug/protein conc ratio is high (above 0.1)
iv. Shows a rapid and large increase in plasma conc

55

Competition between drugs and normal

body constituents

Free fatty acids

Binds to
Increased in:
albumin
Pathological – Pharmacological
Physiological Influences
diabetes, MI, – heparin and
condition - binding of BZD
alcohol caffeine
fasting and propranolol
abstinence administration

56

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Can be impaired by many

Bilirubin Binds to HSA
acidic drugs

Drugs like sodium

In neonates; BBB is weak
salicylate, sodium
Free bilirubin crosses and bilirubin
benzoate,
BBB metabolising ability is
sulphonamides displace
less
bilirubin

Degeneration of brain
Causes kernicterus
and mental retardation

57

Allosteric changes in protein molecule

Aspirin acetylates Binding of

Structure of
lysine fraction of NSAIDs to
albumin changes
albumin albumin changes

Molecule which Flufenamic acid – Phenylbutazone

brings about shows decreased – shows
affinity increased affinity
change –
allosteric
effector
58

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VOLUME OF DISTRIBUTION

59

Vd can’t have a
Different tissues
Drug in circulation true physiological
have different conc
meaning

Can be determined
Distributes to
by volume of
various organs and Hence apparent Vd
tissues in which the
tissues
drug is present

In reality, different
Distribution is over organs and tissues
at equilibrium have different drug
conc

60

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• There exists a direct linear relationship between

the conc of drug in plasma, C, and the amount of
drug in body, X
• 𝑋 ∝ 𝐶 OR 𝑋 = 𝑉𝑑 𝐶
• Where Vd is the proportionality constant having
the units of volume and known as apparent
volume of distribution

61

• Definition of Vd: It is the hypothetical volume of

body fluids into which a drug is dissolved or
distributed
• It bears no correlation with the real volume of
distribution

62

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Real volume of distribution

• Real Vd has direct physiological meaning and is

related to the body water.
Sr. no Body fluid Volume (L) % of body % of TBW
weight
1 Vascular fluid/ blood 6 9 15
(plasma)
2 ECF (excluding plasma) 12 17 28
3 ICF (excluding blood cells) 24 34 57
Total body water (TBW) 42 60 100

Fluid compartments of a 70 Kg adult

63

The volume of each of these real physiologic compartments

can be determined by the use of specific tracers or markers
Sr Compartme Details Example Approximate
no nt volume (L)
1a Plasma Substance should be: Evans blue, 3
1. Having high molecular weight indocyanine green
2. Totally bound to HAS and I131 , albumin
Cr51
1b Erythrocytes -- 2
2 ECF Substances should: Non-metabolisable 15
1. Penetrate the capillary saccharides like
membrane inulin, mannitol,
2. Rapidly distribute throughout raffinose and
ECF radioisotopes of
3. But not cross cell membrane Na+, Cl-, Br-, SO4-2
etc
3 TBW Substance should: Heavy water (D2O), 42
1. Distribute equally in all water tritiated water
compartments of the body (HTO)
4 ICF TBW – ECF volume -- 24
64
Markers used to measure the volume of real physiological compartments

32
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Not/Negligibly bound to
Tracers plasma or tissue
proteins

Situation is different
with drugs as they
either bind to plasma Apparent Vd = real Vd
protein or tissues or
both

65

Generalization regarding Vd of drugs

Drugs which selectively bind to plasma proteins other blood components

Eg. warfarin

Apparent Vd < true Vd

Vd of such drugs lies between blood volume and TBW

Between 6 – 42 liters Eg. Warfarin – Vd of 10 L

66

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Drugs which selectively bind to extravascular tissues

Eg. chloroquine

Apparent Vd > true Vd

Vd of such drugs > TBW

> 42 liters Eg. Chloroquine – Vd of 15,000 L

Such drugs leave the body slowly and are generally more toxic
67

Factors affecting Vd
1. Alteration in binding of drug to
blood components – increase in Vd
2. Alteration in binding of drugs to ev
components – decreases the Vd
3. Changes in tissue perfusion
4. Changes in tissue permeability
5. Changes in physicochemical
characteristics of the drugs – eg.
Ionisation
6. Changes in body weight
7. Age
8. Disease state

68

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Applications/ Significance of Vd
Values range from about 5% of body volume to as high as 40000 L.

The latter figure is much higher than anyone’s total volume, so Vd is an

artificial concept.
It will predict whether the drug will reside in the blood or in the tissue.

Water soluble drugs will reside in the blood, and fat soluble drugs will
reside in cell membranes, adipose tissue and other fat-rich areas.
Volume of Distribution also relates to whether a drug is Free/ protein
bound

69

Drugs that are charged tend to bind to serum proteins. Protein bound drugs form
macromolecular complexes that cannot cross biological membranes and remain
confined to the bloodstream.
Pathological states may also change Vd.

Because Vd mathematically relates blood concentration to dosage it may be employed

in interpretation of laboratory results.

Useful for providing an estimate of dosage, it follows that it can help estimate the
amount of antidote to be given.

Indicate whether there is any value in trying to enhance elimination as, for example, by
dialysis.

70

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PROTEIN BINDING OF DRUGS

71

Drug in
body

Can interact
with

Blood EV tissues

72

36
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• The phenomena of complex formation with

proteins is known as protein binding of drugs

Drug bound to Elicits

Intracellular
cell protein eg Primary receptor pharmacological
binding
receptor response
Protein binding
Drug binds to Does not elicit
Extracellular Secondary or
extracellular pharmacological
binding silent receptor
protein response

73

• Most important silent receptor – albumin

• Binding to proteins makes a drug:
– PK and PD inert
– Confined to a particular site
– Increases size thus can’t undergo membrane transport
– Half life is increased

74

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Mechanism of protein binding

• Binding of drug to proteins is reversible. Thus

only weak bonds are involved:
1. Hydrogen bonds
2. Hydrophobic interactions
3. Ionic bonds
4. van der Waal’s forces

75

• Irreversible drug binding – RARE – involves

covalent bonding
Can cause carcinogenicity or tissue toxicity
eg. Covalent binding of chloroform and paracetamol
metabolites result in hepatotoxicity

76

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BINDING OF DRUGS TO BLOOD

COMPONENTS

77

• Most common
• Drug encounter a variety of blood proteins first
• The order of binding of drugs to various plasma
proteins is:

Albumin

α1 acid
glycoprotein

Lipoproteins

Globulins

78

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Drug proteins to which drugs bind

Protein Molecular weight Conc (g%) Drugs that bind
Human serum 65,000 3.5 – 5.0 Large variety of all types
albumin of drugs
α1 acid glycoprotein 44,000 0.04 – 0.1 Basic drugs eg.
Imipramine, lidocain,
quinidine
Lipoproteins 2,00,000 – 34, 00, Variable Basic lipophilic drug eg
000 chlorpromazine
α1 globulin 59,000 0.003 – 0.007 Steroids like
corticosteroids, thyroxine,
cyanocoalamine

α2 globulin 1,34,000 0.015 – 0.06 Vitamins A, D, E and K,

cupric ions
Haemoglobin 64,500 11 – 16 Phenytoin, phenobarbital,
phenothiazines
79

Human serum albumin

• Most abundant plasma protein
• 59% of total plasma and 3.5 – 5.0g%
• Molecular weight of 65,000
• Large drug binding capacity
• Can bind with several compounds with
varied structures
• Binds to both:
– Endogenous compounds like bilirubin, fatty
acids, tryptophan etc
– Large variety of drugs from acidic to
neutral to basic drugs

80

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• 4 sites on HAS have been

identified for binding
• Site 1: Warfarin or
azapropazone binding
site
• Site 2: Diazepam binding
site
– Most drugs bind to sites 1
and 2
• Site 3: Digitoxin binding
site
• Site 4: Tamoxifen binding
site

81

• Main binding site

Primary
• Eg. Dicoumarol – primary
site site – site 1

• Little binding of the drug

Secondary
• Eg. Dicoumarol –
site secondary site – site 2

82

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Binding of drugs to α1 acid glycoproteins

(AAG)
• Synonym – orosomucoid
• Molecular weight – 44,000
• Plasma conc range – 0.04 – 0.1 g%
• Binds to basic drugs
• Eg. Imipramine, amitriptiline, lidocaine,
propranolol, quinidine etc

83

Binding of drugs to lipoproteins

• Binding to HAS and AAG requires the formation

of hydrophilic bonds and hydrophobic bonds
• Lipoproteins are also able to form hydrophobic
bonds with lipophilic drugs
• Drug dissolves in the lipid core and thus binds
• However its plasma conc is less than HAS and
AAG

84

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• Molecular weight – 2 lakhs to 34 lakhs

• Core – hydrophobic – made up of triglycerides
and cholesteryl esters [more in VLDL]
• Surface – hydrophilic – apoproteins (free
cholesterol and proteins) [more in HDL]

85

Lipoproteins

Based on
density

Chylomicrons VLDL LDL HDL

Least dense and Predominant in Most dense and

largest in size humans smallest in size

86

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• Binding to lipoproteins – non-competitive

• Binding site – nonspecific
• Not dependent on conc gradient
• Depends on partitioning of drug in hydrophobic
core of lipoprotein molecule
• Significant binding if:
– Drug predominantly binds to it
– Levels of HSA and AAG in plasma have decreased

87

Binding of drugs to globulins

Sr. no Name Synonym Binds to

1 α1 globulin Transcortin or corticosteroid Steroid drugslike cortisone,

binding globulin (CBG) prednisole etc
Also thyroxine and
cyanocolbalamine

2 α2 globulin Ceruloplasmin Vitamins A, D, E, K and cupric ions

3 β1 globulin Transferrin Ferrous ions

4 β2 globulin -- Carotinoids

5 γ globulin -- Antigens 88

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Binding of drugs to blood cells

RBC has a size 500

times greater than Blood
albumin

40% cells 60% plasma

5% other cells
95% RBC like WBC,
platelets etc 89

RBC comprises of 3 components which

can bind to drugs
Sr no Component of RBC Details Drugs that bind
1 Haemoglobin Molecular weight – 64,500 Phenytoin,
Conc – 7 to 8 times that of phenobarbital,
HAS phenothiazines etc
2 Carbonic anhydrase -- Acetazolamide,
chlorthalidone
3 Cell membrane -- Imipramine,
chlorpromazine

Hydrophilic drugs do not enter RBC

eg. Ampicillin
Lipophilic drugs enter the RBC freely
eg. phenytoin
90

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TISSUE BINDING OF DRUGS

(TISSUE LOCALISATION)

91

Hence tissue
Comprises of Which is 100
Body tissues binding is
40% of body times that of
(except HSA) also very
weight HSA
important

92

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Important because:

• It is the ratio of amount of drug in the

Apparent body to free drug in plasma
Vd • As free drug in plasma would be less,
apparent Vd would be INCREASED

Localisation • Majority of drugs bind irreversibly to

tissue proteins
of drugs • Increase in biological half life

93

Factors affecting localisation of drugs in

tissues:
1. Lipophilicity
2. Structural features of drugs
3. Perfusion rate
4. pH differences
• Excessive tissue binding – the
tissue acts as storage for
drug
• Drugs binding to both
plasma proteins and tissues –
competition in binding sites

94

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Order of tissue binding

Liver

Kidney

Lungs

Muscles

95

Liver Lungs Kidneys

• Epoxides of • Basic drugs • Metallothionin

halogentade • Eg. Imipramine, present in
hydrocarbons chlorpromazine, kidney binds to
(CHCl3) and antihistaminics Pb, Hg, Cd etc
paracetamol • Renal
• Hepatotoxicity accumulation
and toxicity

96

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Skin Eyes Hair

• Interaction with • Interaction with • Chloroquine,

melanin melanin phenothiazines,
• Chloroquine • Chloroquine, arsenic
and phenothiazines
phenothiazines • Retinopathy

97

Bones Fats Nucleic acid

• Tetracycline – • Lipophilic • Chloroquine,

binds to bones drugs quinacrine
and teeth • Eg. Thiopental, binds to DNA
leading to pesticides • Distortion of
odontogenesis its double
[permanent helical
yellowing of structure
teeth in infants
and children]
• Lead –
replaces Ca
from bones
and makes
them brittle
98

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Criteria Plasma protein – Tissue – drug

drug binding binding

Bonds involved Weak Strong

Type of binding Reversible Irreversible

Apparent Vd Low High

Half life of drug Short Long

Toxicity Uncommon Frequent

Displacement Possible Rare

interactions
Nature of binding Competitive Non-competitive
99

Factors affecting protein drug binding

Protein drug
binding

Protein/
Drug related Drug Patient
tissue related
factors interactions related factors
factors

100

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Drug related
factors

Physicochemical
Conc of drug in Drug – protein/
characteristics
body tissue affinity
of drugs

101

Physicochemical characteristics of the

drug

Lipophilicity pKa Stereoselectivity

• Increases drug • Acidic drugs – • Acidic drugs eg.

binding penicillins, Etodolac – R and
• Eg. Cloxacillin is sulphonamides S both bind to
more bound than bind to HAS site 1. S form
ampicillin • Basic drugs – binds strongly to
• Thiopental imipramine, site 2
localises in atenolol bind to • Basic drugs eg.
tissues AAG Chloroquine – S
• Neutral drugs – form (66%) more
bind to plasma protein
lipoproteins bound than R
form (42.7%)
102

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Concentration of drug in body

HSA Other components

• Not of concern for • AAG –

drugs binding to therapeutics conc
HSA as of lidocaine
therapeutics conc saturate AAG
of any drug
CANNOT saturate
HSA

103

Drug – protein/ tissue affinity

Lidocaine • AAG > HSA

• Cardiac muscles > skeletal muscles or

Digoxin plasma

Iophenoxic • Radio-opaque contrast media

• Very high affinity to plasma proteins (half
acid life of 2.5 years)

104

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Protein/ tissue
related factors

Physicochemical
Conc of protein/
properties of Number of binding
binding
protein/ binding sites on proteins
component
component

105

Physicochemical properties of protein/

binding component

• Lipoproteins and adipose tissue

Lipophilicity binds to drugs by dissolving
them in their lipid core

• Physiological pH determines the

pKa active anionic and cationic
groups of albumin

106

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Conc of protein/ binding component

107

Number of binding sites on proteins

• 4 binding sites
• More drugs bind
Albumin • Sometimes same drugs bind to more
than 1 binding site on albumin

• 1 binding site
• Low plasma conc and low molecular
AAG weight
• Thus less drugs bind to AAG

108

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Drug Interactions

Competition Competition
Allosteric changes
between drugs/ between drugs
in protein
metabolites for and normal body
molecule
binding sites constituents

109

Competition between drugs for binding

sites (displacement interactions)

Even a
metabolite
may cause
displacement
interaction

Displacer
Displaced
drug

110

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• Clinically significant interactions will result when:

1] The displaced drug:
i. Is more than 95% bound
ii. Has a small Vd (< 0.15 L/Kg)
iii. Shows a rapid onset of therapeutic or adverse
effects
iv. Has a narrow therapeutic index

111

2] The displacer drug:

i. Has a high degree of affinity as the drug to be
displaced
ii. Competes for the same binding site
iii. The drug/protein conc ratio is high (above 0.1)
iv. Shows a rapid and large increase in plasma conc

112

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Patient
related factors

Inter-subject
Age Disease states
variations

113

Age

Neonates • Albumin content low

• Increased conc of free drug eg phenytoin, diazepam etc

• Digoxin – 4 – 6 times adult dose is given to children

Children • Drug binds greater in infants

• Abnormally large renal clearance of digoxin is seen in
children

• Albumin content lower. Thus more free drug

• Increased levels of AAG
Elderly • Especially complicated when drugs bind to both eg
lidocaine, propranolol etc
114

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Inter-subject variation

• Mostly because of genetic and environmental

factors
• Not very significant

115

Disease states
Disease Influence on plasma Influence on drug –
protein plasma protein binding

Renal failure Decreased albumin Acidic drugs – decreased

content binding
Basic and neutral drug –
unaffected

Hepatic failure Decreased albumin Acidic drugs – decreased

synthesis binding
Basic and neutral drug –
unaffected

Inflammation (burns, Increased AAG levels Basic drugs – increased

trauma, surgery, binding
infections) Acidic and neutral drugs
- unaffected
116

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Significance of protein/ tissue binding of

drugs
Systemic
Absorption solubility of Distribution
drugs

Tissue binding, Displacement

apparent Vd and Elimination interactions and
drug storage toxicity

Therapy and
Diagnosis
drug targeting

117

Absorption
Free drug at
Sink condition Conc gradient
site of
maintained re-established
administration

Transferred
Disturbs Driving force
into systemic
equilibrium restarts
circulation

Driving force – Bound drug

conc gradient become free

Equilibrium
Process stops
achieved
118

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Systemic solubility of drug

Lipoproteins acts as a Water insoluble drugs
vehicle for following
Neutral endogenous
types of compounds macromolecules eg heparin
and dissolves them
Steroids
which allows them to
circulate throughout Oil soluble vitamins
the body

119

Distribution

Plasma protein – It acts as a buffer by

drug binding maintaining
Protein bound drug
promotes equal equilibrium between
distribution of drug free and bound drug

Bound drug doesn’t

Cannot cross Prevents subsequent cross the BBB,
capillary adverse reactions placenta and
glomerulus

Thus does not enter

into tissues for Prevent
which it has very accumulation
high affinity

120

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Tissue binding, apparent Vd and drug

storage

Drug extensively bound Remains confined to

Small Vd
to blood components blood

Drug extensively bound Leave blood

Large Vd
to tissue components compartment

121

Blood or tissue
component to which Known as depot or Eg. RBC is a depot for
the drug has storage site tetrahydrocannabinol
maximum affinity

122

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Elimination
Exception –
Only free drug is penicillin Short half life – 2
eliminated extensively bound reasons
to plasma proteins

Eg. Tetracycline 65% Rapid equilibration

Drug – protein
bound – half life 8.5 between free and
complex is large
h bound state

Eg. Doxycycline 93% Free drug rapidly

Cannot be filtered
bound – half life excreted by active
by glomerulus
15.1 h secretion

Drug > 95% binding Slowly eliminated

123

Displacement interactions and toxicity

• More of concern with potent drugs having a low

Vd
• Eg. Warfarin and phenylbutazone
• Kernicterus due to NSAIDs and sulphonamides

124

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Diagnosis

Melanomas • Cl in chloroquine is replaced with I131

• Chloroquine localises in eye due to
of eye interaction with melanin

Disorders of • High affinity for iodine

thyroid • Hence use radioisotope of I for
tagging a compound
gland

125

Therapy and drug targeting

• Tumor cells have high affinity for LDL

Cancer • Thus bind an antineoplastic agent to it

Adrenal glands • HDL transports more to these organs

and testes

• Estradiol has high affinity for prostrate

Prostrate • Attaching nitrogen mustards with estradiol
helps in treating tumors of prostrate glands

126

63